MIT News - Microbes MIT News is dedicated to communicating to the media and the public the news and achievements of the students, faculty, staff and the greater MIT community. en Wed, 03 Jul 2019 11:40:02 -0400 Featured video: Saving iguanas with science and engineering Professor Otto Cordero and colleagues ask: Can microbiome engineering make the Galapagos marine iguana more resilient to climate change? Wed, 03 Jul 2019 11:40:02 -0400 MIT News Office <div class="cms-placeholder-content-video"></div> <p>All ecosystems around the globe are impacted by the interplay between herbivores and their gut microbes. Strict herbivores such as grazers are dependent on the enzymes produced by their gut microbes to digest the complex plant fibers that constitute their diet. These animals form a symbiotic relationship with their microbes, one that affects ecosystems around the globe because it allows for energy to be transferred from plants to animals.</p> <p>One of the most remarkable examples of this symbiotic relationship is found in the Galapagos islands, where marine iguanas have evolved to graze exclusively on fast-growing algae found on the shores of the archipelago’s island. Unfortunately, specialization comes at a cost: Due to their strict dependency on just one type of algae, these iguanas are highly susceptible to environmental fluctuations that change the type of algae available on the islands. In the past, El Niño events — whose intensity and frequency is exacerbated by climate change — have led to a shift in the algal species, causing up to a 90 percent loss of the iguana population.</p> <p>Associate Professor Otto Cordero of the Department of Civil and Environmental Engineering recently teamed up with researchers from the Universidad San Francisco de Quito and with Professor Itzhak Mizrahi from Ben Gurion University of the Negev. The group hypothesized that the susceptibility of the marine iguanas is caused by a loss of functional diversity in their microbiomes — in other words, that generations of a specialized diet has led to a shift in the iguana gut microbiome, favoring microorganisms that can only digest one type of algae.</p> <p>To test this idea, the team visited the islands and collected samples from various iguana colonies around the archipelago. The group plans to identify the enzymes and the microbes responsible for the algal breakdown, and to study potential microbiome interventions that could expand the iguana diet and enable them to consume other forms of algae. If successful, this would represent a novel strategy for conservation based on microbiome engineering.</p> <p><em>Submitted by: MIT Department of Civil and Environmental Engineering</em> | <em>Video by: Wild Hope Collective </em>|<em> 5 min, 33 sec</em></p> MIT Professor Otto Cordero is researching whether microbiome engineering could make the threatened Galapagos marine iguana more resilient to climate change.Featured video, Ecology, Evolution, Microbes, Animals, Climate change, Microbiology, Civil and environmental engineering, School of Engineering How a declining environment affects populations Study finds that competition between bacterial species can be upended when conditions deteriorate. Mon, 13 May 2019 23:59:59 -0400 Anne Trafton | MIT News Office <p>Stable ecosystems occasionally experience events that cause widespread death — for example, bacteria in the human gut may be wiped out by antibiotics, or ocean life may be depleted by overfishing. A new study from MIT physicists reveals how these events affect dynamics between different species within a community.</p> <p>In their studies, performed in bacteria, the researchers found that a species with a small population size under normal conditions can increase in abundance as conditions deteriorate. These findings are consistent with a theoretical model that had been previously developed but has been difficult to test in larger organisms.</p> <p>“For a single species within a complex community, an increase in mortality doesn’t necessarily mean that the net effect is that you’re going to be harmed. It could be that although the mortality itself is not good for you, the fact that your competitor species are also experiencing an increase in mortality, and they may be more sensitive to it than you are, means that you could do better,” says Jeff Gore, an MIT associate professor of physics and the senior author of the study.</p> <p>The findings in bacteria may also be applicable to larger organisms in real-world populations, which are much more difficult to study because it is usually impossible to control the conditions of the experiment the way researchers can with bacteria growing in a test tube.</p> <p>“We think that this may be happening in complex communities in natural environments, but it’s hard to do the experiments that are necessary to really nail it down. Whereas in the context of the lab, we can make very clear measurements where you see this effect in a very obvious way,” Gore says.</p> <p>Clare Abreu, an MIT graduate student, is the lead author of the study, which appeared in <em>Nature Communications </em>on May 9. Vilhelm Andersen Woltz, an MIT undergraduate, and Jonathan Friedman, a former MIT postdoc, are also authors of the paper.</p> <p><strong>Competition for resources</strong></p> <p>Microbial communities, such as those found in soil, oceans, or the human gut, usually contain thousands of different species. Gore’s lab is interested in studying the factors that determine which species are present in a given environment, and how the composition of those populations affect their functions, whether that’s cycling carbon in the ocean or helping each other resist antibiotic treatment in the gut.</p> <p>By performing controlled experiments in the lab, Gore hopes to learn how different species interact with each other, and to test hypotheses that predict how populations respond to their environment. In 2013, he discovered early signs that warn of <a href="">population collapse</a>, in yeast, and he has also studied how different species of bacteria can <a href="">protect each other</a> against antibiotics.</p> <p>“We’re using experimentally tractable, simple communities to try to determine the principles that determine which species can coexist, and how that changes in different environments,” Gore says.</p> <p>To explore whether these experimental results might be applicable to larger communities, last year Gore and his colleagues published a paper in which they showed that interactions between pairs of species that compete for resources can be used to predict, with about 90 percent accuracy, the outcome when three of the species compete with each other.</p> <p>In the new study, Gore and Abreu decided to see if they could use pairwise interactions to predict how trios of competing species would respond as environmental conditions deteriorate. To simulate this in the lab, the researchers used the process of dilution — that is, discarding a large percentage (ranging from 90 percent to 99.999999 percent) of the population at the end of each day and transferring the remainder to fresh resources. This could be analogous to real-world conditions such as overfishing or loss of habitat.</p> <p>“We’re trying to get at the general question of how an increase in mortality might change the composition of a community,” Gore says.</p> <p>The researchers studied combinations of five species of soil bacteria. In their experiments, in which they tested pairs of species at a time, they found a specific pattern that fit the predictions made by a classical model of species interactions, known as the Lotka-Volterra model.</p> <p>According to this model, declining environmental conditions should favor faster growers. The researchers found that this was the case: Even in conditions where a slower grower originally dominated the population, as the dilution rate was increased, the populations shifted until eventually the faster grower either became the larger fraction of the population or took over completely. The final outcome depends on how strong each competitor is, as well as their relative abundance in the starting population.</p> <p>The researchers also found that the results of the pairwise competitions could accurately predict what would happen when three species grew together in an environment with deteriorating conditions.</p> <p>“This is an exciting advance in our understanding of microbial ecology,” says Sean Gibbons, an assistant professor at the Institute for Systems Biology, who was not involved in the research. “The observation that nonspecific mortality rates can alter competitive outcomes is surprising, although more work needs to be done to understand whether or not dilution is having a more nuanced effect on environmental conditions.”</p> <p><strong>Population models</strong></p> <p>The Lotka-Volterra model analyzed in this study was originally developed for interactions between larger organisms. Such models are easier to test in microbial populations because it is much easier to control experimental conditions for bacteria than for, say, deer living in a forest.</p> <p>“There’s no particular reason to believe that the models are more applicable to microbes than they are to macroorganisms. It’s just that with microbes, we can study hundreds of these communities at a time, and turn the experimental knobs and make clear measurements,” Gore says. “With microorganisms, we can arrive at a clear understanding of when is it that these models are working and when is it that they’re not.”</p> <p>Gore and his students are now studying how specific environmental changes, including changes in temperature and resources, can alter the composition of microbial communities. They are also working on experimentally manipulating populations that include more than two bacterial species.</p> <p>The research was funded, in part, by the National Institutes of Health.</p> MIT researchers have shown that in microbial communities, bacterial species with a small population size under normal conditions can increase in abundance as environmental conditions deteriorate.Research, Physics, Microbes, Bacteria, Ecology, Evolution, School of Science Painting a fuller picture of how antibiotics act Machine learning reveals metabolic pathways disrupted by the drugs, offering new targets to combat resistance. Thu, 09 May 2019 10:59:59 -0400 Anne Trafton | MIT News Office <p>Most antibiotics work by interfering with critical functions such as DNA replication or construction of the bacterial cell wall. However, these mechanisms represent only part of the full picture of how antibiotics act.</p> <p>In a new study of antibiotic action, MIT researchers developed a new machine-learning approach to discover an additional mechanism that helps some antibiotics kill bacteria. This secondary mechanism involves activating the bacterial metabolism of nucleotides that the cells need to replicate their DNA.&nbsp;</p> <p>“There are dramatic energy demands placed on the cell as a result of the drug stress. These energy demands require a metabolic response, and some of the metabolic byproducts are toxic and help contribute to killing the cells,” says James Collins, the Termeer Professor of Medical Engineering and Science in MIT’s Institute for Medical Engineering and Science (IMES) and Department of Biological Engineering, and the senior author of the study. Collins is also the faculty co-lead of the Abdul Latif Jameel Clinic for Machine Learning in Health.</p> <p>Exploiting this mechanism could help researchers to discover new drugs that could be used along with antibiotics to enhance their killing ability, the researchers say.</p> <p>Jason Yang, an IMES research scientist, is the lead author of the paper, which appears in the May 9 issue of <em>Cell</em>. Other authors include Sarah Wright, a recent MIT MEng recipient; Meagan Hamblin, a former Broad Institute research technician; Miguel Alcantar, an MIT graduate student; Allison Lopatkin, an IMES postdoc; Douglas McCloskey and Lars Schrubbers of the Novo Nordisk Foundation Center for Biosustainability; Sangeeta Satish and Amir Nili, both recent graduates of Boston University; Bernhard Palsson, a professor of bioengineering at the University of California at San Diego; and Graham Walker, an MIT professor of biology.</p> <p><strong>“White-box” machine-learning</strong></p> <p>Collins and Walker have studied the mechanisms of antibiotic action for many years, and their work has shown that antibiotic treatment tends to create a great deal of cellular stress that makes huge energy demands on bacterial cells. In the new study, Collins and Yang decided to take a machine-learning approach to investigate how this happens and what the consequences are.</p> <p>Before they began their computer modeling, the researchers performed hundreds of experiments in <em>E. coli</em>. They treated the bacteria with one of three antibiotics — ampicillin, ciprofloxacin, or gentamicin, and in each experiment, they also added one of about 200 different metabolites, including an array of amino acids, carbohydrates, and nucleotides (the building blocks of DNA). For each combination of antibiotics and metabolites, they measured the effects on cell survival.</p> <p>“We used a diverse set of metabolic perturbations so that we could see the effects of perturbing nucleotide metabolism, amino acid metabolism, and other kinds of metabolic subnetworks,” Yang says. “We wanted to fundamentally understand which previously undescribed metabolic pathways might be important for us to understand how antibiotics kill.”</p> <p>Many other researchers have used machine-learning models to analyze data from biological experiments, by training an algorithm to generate predictions based on experimental data. However, these models are typically “black-box,” meaning that they don’t reveal the mechanisms that underlie their predictions.</p> <p>To get around that problem, the MIT team took a novel approach that they call “white-box” machine-learning. Instead of feeding their data directly into a machine-learning algorithm, they first ran it through a genome-scale computer model of <em>E. coli</em> metabolism that had been characterized by Palsson’s lab. This allowed them to generate an array of “metabolic states” described by the data. Then, they fed these states into a machine-learning algorithm, which was able to identify links between the different states and the outcomes of antibiotic treatment.</p> <p>Because the researchers already knew the experimental conditions that produced each state, they were able to determine which metabolic pathways were responsible for higher levels of cell death.</p> <p>“What we demonstrate here is that by having the network simulations first interpret the data and then having the machine-learning algorithm build a predictive model for our antibiotic lethality phenotypes, the items that get selected by that predictive model themselves directly map onto pathways that we’ve been able to experimentally validate, which is very exciting,” Yang says.</p> <p>Markus Covert, an associate professor of bioengineering at Stanford University, says the study is an important step toward showing that machine learning can be used to uncover the biological mechanisms that link inputs and outputs.</p> <p>“Biology, especially for medical applications, is all about mechanism,” says Covert, who was not involved in the research. “You want to find something that is druggable. For the typical biologist, it hasn’t been meaningful to find these kinds of links without knowing why the inputs and outputs are linked.”</p> <p><strong>Metabolic stress</strong></p> <p>This model yielded the novel discovery that nucleotide metabolism, especially metabolism of purines such as adenine, plays a key role in antibiotics’ ability to kill bacterial cells. Antibiotic treatment leads to cellular stress, which causes cells to run low on purine nucleotides. The cells’ efforts to ramp up production of these nucleotides, which are necessary for copying DNA, boost the cells’ overall metabolism and leads to a buildup of harmful metabolic byproducts that can kill the cells.</p> <p>“We now believe what’s going on is that in response to this very severe purine depletion, cells turn on purine metabolism to try to deal with that, but purine metabolism itself is very energetically expensive and so this amplifies the energic imbalance that the cells are already facing,” Yang says.</p> <p>The findings suggest that it may be possible to enhance the effects of some antibiotics by delivering them along with other drugs that stimulate metabolic activity. “If we can move the cells to a more energetically stressful state, and induce the cell to turn on more metabolic activity, this might be a way to potentiate antibiotics,” Yang says.</p> <p>The “white-box” modeling approach used in this study could also be useful for studying how different types of drugs affect diseases such as cancer, diabetes, or neurodegenerative diseases, the researchers say. They are now using a similar approach to study how tuberculosis survives antibiotic treatment and becomes drug-resistant.</p> <p>The research was funded by the Defense Threat Reduction Agency, the National Institutes of Health, the Novo Nordisk Foundation, the Paul G. Allen Frontiers Group, the Broad Institute of MIT and Harvard, and the Wyss Institute for Biologically Inspired Engineering.</p> MIT biological engineers used a novel machine-learning approach to discover a mechanism that helps certain antibiotics kill bacteria.Image: Chelsea Turner, MITResearch, Microbes, Bacteria, Machine learning, Biological engineering, Drug resistance, Artificial intelligence, Institute of Medical Engineering and Science (IMES), School of Engineering, Medicine, National Institutes of Health (NIH), J-Clinic Designing ocean ecological systems in the lab Associate Professor Otto Cordero and colleagues discover simple assembly rules for marine microbiomes. Thu, 25 Apr 2019 11:00:00 -0400 Taylor De Leon | Civil and Environmental Engineering <p>Researchers from MIT have discovered simple rules of assembly of ocean microbiomes that degrade complex polysaccharides in coastal environments. Microbiomes, or microbial communities, are composed of hundreds or thousands of diverse species, making it a challenge to identify the principles that govern their structure and function.</p> <p>The findings indicate that marine microbiomes can be simplified by grouping species into two types of functional modules. The first type contain polysaccharide specialists that produce the enzymes required to break down the complex sugars. The second type contains species that consume simple metabolic byproducts released by the specialist degraders and are therefore independent of the polysaccharide. This partitioning reveals a simple design for the microbiome: a trophic network in which energy is funneled from degraders to consumers.</p> <p>“Our work reveals fundamental principles of microbial community assembly that can help us make sense of the vast diversity of microbes in the environment,” states Otto X. Cordero, principal investigator on the research and associate professor in the Department of Civil and Environmental Engineering (CEE).&nbsp;</p> <p>Cordero’s co-authors on the <a href="" target="_blank">paper</a>, which was published in <em>Current Biology,</em> include CEE research affiliates Tim Enke and Manoshi S. Datta, CEE postdoc Julia Schwartzman, and Computational and Systems Biology Program research affiliate Nathan Cermak, as well as researchers from science and technology university ETH Zurich in Switzerland.</p> <p>The simple trophic organization revealed by this study allowed Cordero and colleagues to predict microbiome species composition based on the profile of energy resources available to the community.&nbsp;</p> <p>“The significance of these discoveries is that we have identified simple rules of assembly, which allows us to predict community composition and rationally design ecological systems in the lab,” emphasizes Cordero.&nbsp;</p> <p>In order to investigate the modular organization of the microbial communities, the researchers conducted fieldwork with synthetic marine particles made of polysaccharides that are abundant in marine environments, such as chitin, alginate, agarose and carrageenan, as well as combinations of these substrates.</p> <p>The team immersed the microscopic particles in natural samples of seawater and studied the colonization dynamics of bacteria using genome sequencing. This analysis allowed the researchers to disentangle the effect of polysaccharide composition on microbiome assembly.</p> <p>“A promising application of this work is to apply these principles in order to design synthetic communities that degrade complex biological materials, such as those found in agricultural waste and animal feed,” says Cordero.&nbsp;</p> Microscopic particles were immersed in natural seawater and examined underneath the microscope in order to observe the colonization dynamics of bacteria using genome sequencing.Image: Julia SchwartzmanCivil and environmental engineering, School of Engineering, Microbes, Research, Oceanography and ocean engineering, Bacteria The complex world of carbohydrate chemistry Drawn to MIT by its “amazing women who were doing science,” Professor Laura Kiessling explores sugar-protein interactions that influence cell behavior. Wed, 24 Apr 2019 23:59:59 -0400 Anne Trafton | MIT News Office <p>Every living cell is coated with a layer of carbohydrates. The composition of these molecules essentially serves as an identification card for a cell, says <a href="">Laura Kiessling</a>, the Novartis Professor of Chemistry at MIT.</p> <p>While researchers have learned much about how these coats vary from cell to cell, Kiessling is now investigating “how proteins check those IDs, and what cells do when they are let into the party,” as she puts it. Her lab is working on identifying some of the key carbohydrates expressed by human and bacterial cells, and exploring how they interact with proteins and other molecules. Such knowledge could be exploited to develop new treatments and diagnostics for a variety of diseases.</p> <p>Kiessling, who joined MIT’s faculty in 2017 after 26 years at the University of Wisconsin at Madison, is developing vaccines that interact with cell surface carbohydrates, and she is also exploring ways to disrupt microbes’ ability to assemble the carbohydrates they need to build their cell walls.</p> <p>“Bacteria have cell walls made of building blocks that we don’t use and that can be unique to different species,” she says. “That opens opportunities for new kinds of antibiotics that are narrow-spectrum. They don’t target all bacteria, but they target pathways that pathogenic bacteria need to build critical cell surface carbohydrates.”</p> <p><strong>Drawn to MIT</strong></p> <p>Growing up in rural Wisconsin, Kiessling spent a lot of time doing outdoor activities, such as camping and observing the wildlife in the pond in her parents’ backyard. With one of her brothers, she performed “shocking” experiments with a kids’ electronics kit and tried to convert the family lawnmower into a go-cart. When it was time to choose a college, she decided on the University of Wisconsin at Madison. At the time, top students in Wisconsin high schools could be admitted automatically to the state university, so she didn’t apply anywhere else.</p> <p>Her closest friend at the university had a sister who was a student at MIT, so for spring break their first year, Kiessling and her friend decided to head to Cambridge for a visit. After a 20-hour train ride from Chicago, Kiessling spent the next several days attending classes and hanging out with her friend’s sister in her dorm, McCormick Hall, <a href="">MIT’s first women’s dorm</a> and today the only women-only residence hall.</p> <p>“I met all these amazing women who were doing science, and I thought, oh my gosh, I should transfer here,” Kiessling recalls. She met someone who worked in the admissions office and convinced them to give her an interview, then formally applied as soon as she got back to Wisconsin. In August, she found out that she had been accepted, and transferred at the beginning of her sophomore year.</p> <p>At MIT, she majored in chemistry, where her lab partner and close friend was Cady Coleman ’83, who later became an astronaut. She also rowed on MIT’s crew team, along with Elizabeth Bradley, a future Olympian. After graduating, Kiessling decided to go to Yale University for graduate school, where she focused on organic chemistry.</p> <p>At Yale, she worked in the lab of Stuart Schreiber, who is now a member of the Broad Institute of MIT and Harvard. At the time, they were working on synthesizing a naturally occurring antitumor agent that cleaves DNA. “That got me really interested in using chemistry to study biological processes,” Kiessling says.</p> <p>After finishing her PhD, Kiessling did a postdoc at Caltech, working with Peter Dervan, a professor of chemistry, on a strategy for modifying DNA. Their idea was to use chemical compounds to recognize DNA sequences so that they could be selectively cut out, similar to the way that the CRISPR genome-editing system works now.</p> <p><strong>Carbo-loading</strong></p> <p>When Kiessling joined the faculty at the University of Wisconsin in 1991, she was inspired to study carbohydrates by an argument she had had with some of her labmates at Yale over how carbohydrates interact with DNA. She thought that the carbohydrates must be involved in recognizing DNA, while others believed their role was more limited.</p> <p>“The basis for that argument made me start thinking about carbohydrates, and I realized we don’t know very much about their biological roles,” she says. “So when I went to start my own lab, I thought this would be an exciting field to get involved in.”</p> <p>Carbohydrates on cell surfaces often interact with proteins, including a class of proteins called lectins. Kiessling has previously shown that many of these lectin-carbohydrate interactions are multivalent, meaning they involve multiple receptors binding to multiple binding partners, and she has designed polymers, similar to carbohydrates, that can mimic these interactions.</p> <p>She also recently discovered that some human lectins, found in the gut and lung, only bind to carbohydrates found on the surface of bacteria. This interaction appears to help human cells grab onto and retain bacterial cells that may be potentially useful.</p> <p>“A lot of these lectins are at mucosal barriers, and they’ve evolved to presumably help us keep microbes in the right spot,” Kiessling says.</p> <p>She is also studying how cells synthesize carbohydrates, in hopes of developing drugs that could specifically block the production of carbohydrates expressed by pathogens such as the mycobacteria that cause tuberculosis.</p> <p>In another project, she is developing cancer vaccines that could target carbohydrate-binding proteins located on the surfaces of immune cells. She is also working on a vaccine that targets a protein produced by chickens when they contract bacterial infections. This protein limits chicken growth, which is partly why chickens raised for food are treated with antibiotics. Blocking that protein, Kiessling hopes, could help to eliminate the need for antibiotic treatment.</p> <p>Many of these projects involve collaborations with other MIT faculty members, including a large number of female professors. The possibility of such collaborations is one of the reasons that Kiessling decided to join the faculty here.</p> <p>“MIT and the area surrounding MIT is the mecca of science,” she says. “The original reason I was drawn to MIT as a student is I could find other women who loved science as much as I do. And as a faculty member here, there are also so many women faculty who love science as much as I do.”</p> Chemistry professor Laura Kiessling is developing vaccines that interact with cell surface carbohydrates, and exploring ways to disrupt microbes’ ability to assemble the carbohydrates they need to build their cell walls.Image: M. Scott BrauerFaculty, Chemistry, Microbes, Bacteria, Antibiotics, Profile, Women, Biology, Alumni/ae, Women in STEM, School of Science New technique pinpoints milestones in the evolution of bacteria Results show bacterial genomes provide “shadow history” of animal evolution. Thu, 07 Feb 2019 23:59:59 -0500 Jennifer Chu | MIT News Office <p>Bacteria have evolved all manner of adaptations to live in every habitat on Earth. But unlike plants and animals, which can be preserved as fossils, bacteria have left behind little physical evidence of their evolution, making it difficult for scientists to determine exactly when different groups of bacteria evolved.</p> <p>Now MIT scientists have devised a reliable way to determine when certain groups of bacteria appeared in the evolutionary record. The technique could be used to identify when significant changes occurred in the evolution of bacteria, and to reveal details about the primitive environments that drove such changes in the first place.</p> <p>In a paper published online Jan. 28 in the journal <em>BMC Evolutionary Biology</em>, the researchers report using the technique to determine that, around 450 to 350 million years ago, during the Paleozoic Era, several major groups of soil bacteria acquired a specific gene from fungi that allowed them to break down chitin — a fibrous material found in the cell walls of fungi and in the exoskeletons of arthropods — and use its products to grow.</p> <p>This evolutionary adaptation in bacteria may have been driven by a significant shift in the environment. Around the same time, arthropods such as early spiders, insects, and centipedes, were moving from the oceans onto land. As these terrestrial arthropods spread and diversified, they left behind chitin, creating richer soil environments and a new opportunity for bacteria — particularly those that acquired the chitinase gene — to thrive.</p> <p>“Before this period, you would have had soils, but it might have looked like the dry valleys of Antarctica,” says Gregory Fournier, the Cecil and Ida Green Assistant Professor of Geobiology in MIT’s Department of Earth, Atmospheric, and Planetary Sciences. “With animals living in soils for the first time, that provided new opportunities for microbes to take advantage and diversify.”</p> <p>Fournier says that, by tracing certain genes such as chitinase in bacteria, scientists can gain new insight into the early history of animals and the environments in which they lived.</p> <p>“Microbes contain in their genomes a shadow history of animal life that we can use to fill gaps in our understanding of not only microbes, but also of the early history of animals,” Fournier says.</p> <p>The paper’s authors include lead author Danielle Gruen PhD ’18, now a postdoc at the National Institutes of Health, and former postdoc Joanna Wolfe, now a research scientist at Harvard University.</p> <p><strong>Missing fossils</strong></p> <p>Without a fossil record, scientists have used other techniques to lay out bacteria’s “tree of life” — a map of genetic relationships, showing many branches and splits as bacteria have evolved into hundreds of thousands of species through time. Scientists have established such maps by analyzing and comparing the gene sequences of existing bacteria.</p> <p>Using a “molecular clock” approach, they can estimate the rates at which certain genetic mutations may have occurred, and calculate the time at which two species may have diverged.</p> <p><strong>“</strong>But that can only tell you relative time, and there’s a huge uncertainty associated with these estimates,” Fournier says. “We have to anchor this tree somehow to the geological record, to absolute time.”</p> <p>The team found they could use fossils from an entirely different organism to anchor the time at which certain groups of bacteria evolved. While in the vast majority of cases, genes are passed down through generations, from parent to offspring, every so often, a gene can hop from one organism to another, via a virus or through the environment, in a process known as horizontal gene transfer. The same genetic sequence, therefore, can appear in two organisms that otherwise would have entirely different genetic histories.</p> <p>Fournier and his colleagues reasoned that if they could identify a common gene between bacteria and an entirely different organism — one with a clear fossil record — they might be able to pin bacteria’s evolution to the point at which this gene was transferred from the fossil-dated organism, to bacteria.</p> <p><strong>Splitting trees</strong></p> <p>They looked through the genome sequences of thousands of organisms and identified a single gene, chitinase, that appeared in several major bacterial groups, as well as in most species of fungi, which have a well-established fossil record.</p> <p>They then used algorithms to produce a tree of all the different species with the chitinase genes, showing the relationships between species based on mutations in their genomes. Next, they employed a molecular clock approach to determine the relative times at which each species of bacteria containing chitinase branched from its respective ancestor. They repeated this same process for fungi.</p> <p>The researchers traced chitinase in fungi to the point at which it most resembled the gene when it first appeared in bacteria, and reasoned that that must have been when fungi transferred the gene to bacteria. They then used fungi’s fossil record to pinpoint the time at which transfer likely occurred.</p> <p>They found that, following the subsequent transfer of this gene across several groups of bacteria, three major groups of soil bacteria containing the chitinase gene all diversified around 450 to 350 million years ago. This rapid burst of microbe diversity was likely in response to a similar diversification of land animals, and specifically, chitin-producing arthropods, which occurred around this same period, as the fossil record shows.</p> <p>“This result supports [the idea] that microbial groups tend to acquire genes for using resources as soon as they are available in the environment,” Fournier notes. “In principle, this approach can therefore be used to date many more groups of microbes, using the transfer of other genes that use other resources.”</p> <p>Fournier is now developing an automated pipeline for detecting useful gene transfers between bacteria and other organisms, from huge amounts of gene data. For instance, he is looking at microbial genes responsible for breaking down collagen, a compound that is produced only in animals, and is found in soft body tissues.</p> <p>“If we have a shadow history in the microbes of genes that eat soft body tissue, we could maybe reconstruct the early history of soft body tissues, which don’t preserve well in the fossil record,” Fournier says.</p> <p>This research was supported, in part, by the National Science Foundation and the Simons Foundation.</p> An exoskeleton-consuming gene found in bacteria sheds light on the first arthropods to walk the Earth.Image: MIT NewsBacteria, Biology, Evolution, EAPS, Earth and atmospheric sciences, Environment, Genetics, Microbes, Research, School of Science, National Science Foundation (NSF) Study: Much of the surface ocean will shift in color by end of 21st century Climate-driven changes in phytoplankton communities will intensify the blue and green regions of the world’s oceans. Mon, 04 Feb 2019 04:59:59 -0500 Jennifer Chu | MIT News Office <p>Climate change is causing significant changes to phytoplankton in the world’s oceans, and a new MIT study finds that over the coming decades these changes will affect the ocean’s color, intensifying its blue regions and its green ones. Satellites should detect these changes in hue, providing early warning of wide-scale changes to marine ecosystems.</p> <p>Writing in <em>Nature Communications</em>, researchers report that they have developed a global model that simulates the growth and interaction of different species of phytoplankton, or algae, and how the mix of species in various locations will change as temperatures rise around the world. The researchers also simulated the way phytoplankton absorb and reflect light, and how the ocean’s color changes as global warming affects the makeup of phytoplankton communities.</p> <p>The researchers ran the model through the end of the 21st century and found that, by the year 2100, more than 50 percent of the world’s oceans will shift in color, due to climate change.</p> <p>The study suggests that blue regions, such as the subtropics, will become even more blue, reflecting even less phytoplankton — and life in general — in those waters, compared with today. Some regions that are greener today, such as near the poles, may turn even deeper green, as warmer temperatures brew up larger blooms of more diverse phytoplankton.</p> <p>“The model suggests the changes won’t appear huge to the naked eye, and the ocean will still look like it has blue regions in the subtropics and greener regions near the equator and poles,” says lead author Stephanie Dutkiewicz, a principal research scientist at MIT’s Department of Earth, Atmospheric, and Planetary Sciences and the Joint Program on the Science and Policy of Global Change. “That basic pattern will still be there. But it’ll be enough different that it will affect the rest of the food web that phytoplankton supports.”</p> <p>Dutkiewicz’s co-authors include Oliver Jahn of MIT, Anna Hickman of the University of Southhampton, Stephanie Henson of the National Oceanography Centre Southampton, Claudie Beaulieu of the University of California at Santa Cruz,&nbsp;and Erwan Monier, former principal research scientist at the MIT Center for Global Change Science, and currently assistant professor at the University of California at Davis, in the Department of Land, Air and Water Resources.</p> <p><strong>Chlorophyll count</strong></p> <p>The ocean’s color depends on how sunlight interacts with whatever is in the water. Water molecules alone absorb almost all sunlight except for the blue part of the spectrum, which is reflected back out. Hence, relatively barren open-ocean regions appear as deep blue from space. If there are any organisms in the ocean, they can absorb and reflect different wavelengths of light, depending on their individual properties.</p> <p>Phytoplankton, for instance, contain chlorophyll, a pigment which absorbs mostly in the blue portions of sunlight to produce carbon for photosynthesis, and less in the green portions. As a result, more green light is reflected back out of the ocean, giving algae-rich regions a greenish hue.</p> <p>Since the late 1990s, satellites have taken continuous measurements of the ocean’s color. Scientists have used these measurements to derive the amount of chlorophyll, and by extension, phytoplankton, in a given ocean region. But Dutkiewicz says chlorophyll doesn’t necessarily reflect the sensitive signal of climate change. Any significant swings in chlorophyll could very well be due to global warming, but they could also be due to “natural variability” — normal, periodic upticks in chlorophyll due to natural, weather-related phenomena.</p> <p>“An El Niño or La Niña event will throw up a very large change in chlorophyll because it’s changing the amount of nutrients that are coming into the system,” Dutkiewicz says. “Because of these big, natural changes that happen every few years, it’s hard to see if things are changing due to climate change, if you’re just looking at chlorophyll.”</p> <p><strong>Modeling ocean light</strong></p> <p>Instead of looking to derived estimates of chlorophyll, the team wondered whether they could see a clear signal of climate change’s effect on phytoplankton by looking at satellite measurements of reflected light alone.</p> <p>The group tweaked a computer model that it has used in the past to predict phytoplankton changes with rising temperatures and ocean acidification. This model takes information about phytoplankton, such as what they consume and how they grow, and incorporates this information into a physical model that simulates the ocean’s currents and mixing.&nbsp;</p> <p>This time around, the researchers added a new element to the model, that has not been included in other ocean modeling techniques: the ability to estimate the specific wavelengths of light that are absorbed and reflected by the ocean, depending on the amount and type of organisms in a given region.</p> <p>“Sunlight will come into the ocean, and anything that’s in the ocean will absorb it, like chlorophyll,” Dutkiewicz says. “Other things will absorb or scatter it, like something with a hard shell. So it’s a complicated process, how light is reflected back out of the ocean to give it its color.”</p> <p>When the group compared results of their model to actual measurements of reflected light that satellites had taken in the past, they found the two agreed well enough that the model could be used to predict the ocean’s color as environmental conditions change in the future.</p> <p>“The nice thing about this model is, we can use it as a laboratory, a place where we can experiment, to see how our planet is going to change,” Dutkiewicz says.</p> <p><strong>A signal in blues and greens</strong></p> <p>As the researchers cranked up global temperatures in the model, by up to 3 degrees Celsius by 2100 — what most scientists predict will occur under a business-as-usual scenario of relatively no action to reduce greenhouse gases — they found that wavelengths of light in the blue/green waveband responded the fastest.</p> <p>What’s more, Dutkiewicz observed that this blue/green waveband showed a very clear signal, or shift, due specifically to climate change, taking place much earlier than what scientists have previously found when they looked to chlorophyll, which they projected would exhibit a climate-driven change by 2055.</p> <p>“Chlorophyll is changing, but you can’t really see it because of its incredible natural variability,” Dutkiewicz says. “But you can see a significant, climate-related shift in some of these wavebands, in the signal being sent out to the satellites. So that’s where we should be looking in satellite measurements, for a real signal of change.”</p> <p>According to their model, climate change is already changing the makeup of phytoplankton, and by extension, the color of the oceans. By the end of the century, our blue planet may look visibly altered.</p> <p>“There will be a noticeable difference in the color of 50 percent of the ocean by the end of the 21st century,” Dutkiewicz says. “It could be potentially quite serious. Different types of phytoplankton absorb light differently, and if climate change shifts one community of phytoplankton to another, that will also change the types of food webs they can support. “</p> <p>This research was supported, in part, by NASA and the Department of Energy.</p> A new MIT study finds that over the coming decades climate change will affect the ocean’s color, intensifying its blue regions and its green ones.Image: NASA Earth ObservatoryClimate change, Computer modeling, EAPS, Earth and atmospheric sciences, Environment, Global Warming, Greenhouse gases, Microbes, Oceanography and ocean engineering, Satellites, Research, School of Science, Water, NASA, Department of Energy (DoE), Joint Program on the Science and Policy of Global Change Sallie “Penny” Chisholm awarded the 2019 Crafoord Prize Institute Professor honored for discovering &lt;i&gt;Prochlorococcus,&lt;/i&gt; the most abundant photosynthesizing organism on Earth. Tue, 22 Jan 2019 12:14:38 -0500 Allison Dougherty | Department of Civil and Environmental Engineering <p>MIT Institute Professor Sallie “Penny” Chisholm of the departments of Civil and Environmental Engineering and Biology is the recipient of the 2019 <a href="" target="_blank">Crafoord Prize</a>.</p> <p><a href="">Announced on Jan. 17</a>, Chisholm was awarded the prize “for the discovery and pioneering studies of the most abundant photosynthesizing organism on Earth,&nbsp;<em>Prochlorococcus</em>.”</p> <p><em>Prochlorococcus </em>is a type of phytoplankton found in the ocean that is able to photosynthesize like plants on land.&nbsp; The process of photosynthesis is responsible for the oxygen humans breathe, which makes it critical to life on Earth. <em>Prochlorococcus</em> accounts for approximately 10 percent of all ocean photosynthesis, which draws carbon dioxide out of the atmosphere, provides it with oxygen, and forms the base of the food chain.</p> <p>While the organism is the most abundant photosynthesizer on the planet (the total amount of <em>Prochlorococcus</em> on Earth has been estimated to be 3*10<sup>27</sup>, or 3,000,000,000,000,000,000,000,000,000), it wasn’t until the mid-1980’s that<em> Prochlorococcus </em>was discovered by Chisholm and colleagues at the Woods Hole Oceanographic Institution. The reason the organism remained unknown for so long can be attributed to its small size. The tiny bacteria is half of a micrometer in size, 1/100 the width of a human hair, making it the smallest photosynthesizing organism.</p> <p>Since its discovery, Chisholm and her team have found that although each cell has only 2,000 genes, the species as a whole has more than 80,000 different genes in its gene pool, which is four times more than the genetic makeup of humans. This vast diversity of genes distributed among the global population contributes to why <em>Prochlorococcus </em>is able to exist prominently in various environments containing different levels of light, heat, and nutrients.</p> <p>Chisholm, who has been at MIT since 1976, now studies how <em>Prochlorococcus </em>interacts with various components of seawater and other microorganisms found in the ocean; its role in shaping the ocean ecosystem over evolutionary time; and how its populations may shift in response to climate change.</p> <p>In April, Chisholm delivered a <a href="" target="_blank">TED Talk</a> that dove deeper into the properties of <em>Prochlorococcus</em>, comparing the organism’s genetic diversity to iPhone apps, and expanded on the the beauty of this microorganism as the smallest living thing that can convert solar energy and carbon dioxide into fuel through photosynthesis. Understanding its simple design could aid in efforts to engineer artificial photosynthesis machines — reducing our dependency on fossil fuels. &nbsp;</p> <p><em>Prochlorococcus</em> has even inspired Chisholm to educate future generations of scientists through a series of children’s books called the “<a href="">Sunlight Series</a>,” with co-author and illustrator Molly Bang. The series describes the Earth’s natural processes in layman’s terms and through imagery. While none of Chisholm’s books mention <em>Prochlorococcus</em> by name, Chisholm says the simplicity of <em>Prochlorococcus </em>compelled her to create the series.</p> <p>Chisholm will present her prize lecture in Sweden at Lund University on May 13, and will receive her prize at the Royal Swedish Academy of Sciences prize award ceremony on May 15, in the presence of H. M. King Carl XVI Gustaf and H. M. Queen Silvia of Sweden.</p> <p>The Crafoord Prize&nbsp;is awarded in partnership between the Royal Swedish Academy of Sciences and the Crafoord Foundation, with the academy responsible for selecting the Crafoord Laureates. Awards are presented in one of four disciplines each year: mathematics and astronomy, geosciences, biosciences, or polyarthritis (such as rheumatoid arthritis).</p> MIT Institute Professor Penny Chisholm Photo: Alan SilfenAwards, honors and fellowships, Faculty, Biology, Civil and environmental engineering, Bacteria, Microbes, School of Engineering, School of Science, Ocean science, Oceanography and ocean engineering Technique identifies electricity-producing bacteria Microbes screened with a new microfluidic process might be used in power generation or environmental cleanup. Fri, 11 Jan 2019 14:00:00 -0500 Jennifer Chu | MIT News Office <p>Living in extreme conditions requires creative adaptations. For certain species of bacteria that exist in oxygen-deprived environments, this means finding a way to breathe that doesn’t involve oxygen. These hardy microbes, which can be found deep within mines, at the bottom of lakes, and even in the human gut, have evolved a unique form of breathing that involves excreting and pumping out electrons. In other words, these microbes can actually produce electricity.</p> <p>Scientists and engineers are exploring ways to harness these microbial power plants to run fuel cells and purify sewage water, among other uses. But pinning down a microbe’s electrical properties has been a challenge: The cells are much smaller than mammalian cells and extremely difficult to grow in laboratory conditions.</p> <p>Now MIT engineers have developed a microfluidic technique that can quickly process small samples of bacteria and gauge a specific property that’s highly correlated with bacteria’s ability to produce electricity. They say that this property, known as polarizability, can be used to assess a bacteria’s electrochemical activity in a safer, more efficient manner compared to current techniques.</p> <p>“The vision is to pick out those strongest candidates to do the desirable tasks that humans want the cells to do,” says Qianru Wang, a postdoc in MIT’s Department of Mechanical Engineering.</p> <p>“There is recent work suggesting there might be a much broader range of bacteria that have [electricity-producing] properties,” adds Cullen Buie, associate professor of mechanical engineering at MIT. “Thus, a tool that allows you to probe those organisms could be much more important than we thought. It’s not just a small handful of microbes that can do this.”</p> <p>Buie and Wang have published their results today in <em>Science Advances</em>.</p> <p><strong>Just between frogs</strong></p> <p>Bacteria that produce electricity do so by generating electrons within their cells, then transferring those electrons across their cell membranes via tiny channels formed by surface proteins, in a process known as extracellular electron transfer, or EET.</p> <p>Existing techniques for probing bacteria’s electrochemical activity involve growing large batches of cells and measuring the activity of EET proteins — a meticulous, time-consuming process. Other techniques require rupturing a cell in order to purify and probe the proteins. Buie looked for a faster, less destructive method to assess bacteria’s electrical function.</p> <p>For the past 10 years, his group has been building microfluidic chips etched with small channels, through which they flow microliter-samples of bacteria. Each channel is pinched in the middle to form an hourglass configuration. When a voltage is applied across a channel, the pinched section — about 100 times smaller than the rest of the channel — puts a squeeze on the electric field, making it 100 times stronger than the surrounding field. The gradient of the electric field creates a phenomenon known as dielectrophoresis, or a force that pushes the cell against its motion induced by the electric field. As a result, dielectrophoresis can repel a particle or stop it in its tracks at different applied voltages, depending on that particle’s surface properties.</p> <p>Researchers including Buie have used dielectrophoresis to quickly sort bacteria according to general properties, such as size and species. This time around, Buie wondered whether the technique could suss out bacteria’s electrochemical activity — a far more subtle property.</p> <p>“Basically, people were using dielectrophoresis to separate bacteria that were as different as, say, a frog from a bird, whereas we’re trying to distinguish between frog siblings — tinier differences,” Wang says.</p> <p><strong>An electric correlation</strong></p> <p>In their new study, the researchers used their microfluidic setup to compare various strains of bacteria, each with a different, known electrochemical activity. The strains included&nbsp; a “wild-type” or natural strain of bacteria that actively produces electricity in microbial fuel cells, and several strains that the researchers had genetically engineered. In general, the team aimed to see whether there was a correlation between a bacteria’s electrical ability and how it behaves in a microfluidic device under a dielectrophoretic force.</p> <p>The team flowed very small, microliter samples of each bacterial strain through the hourglass-shaped microfluidic channel and slowly amped up the voltage across the channel, one volt per second, from 0 to 80 volts. Through an imaging technique known as particle image velocimetry, they observed that the resulting electric field propelled bacterial cells through the channel until they approached the pinched section, where the much stronger field acted to push back on the bacteria via dielectrophoresis and trap them in place.</p> <p>Some bacteria were trapped at lower applied voltages, and others at higher voltages. Wang took note of the “trapping voltage” for each bacterial cell, measured their cell sizes,&nbsp; and then used a computer simulation to calculate a cell’s polarizability — how easy it is for a cell to form electric dipoles in response to an external electric field. &nbsp;</p> <p>From her calculations, Wang discovered that bacteria that were more electrochemically active tended to have a higher polarizability. She observed this correlation across all species of bacteria that the group tested.</p> <p>“We have the necessary evidence to see that there’s a strong correlation between polarizability and electrochemical activity,” Wang says. “In fact, polarizability might be something we could use as a proxy to select microorganisms with high electrochemical activity.”</p> <p>Wang says that, at least for the strains they measured, researchers can gauge their electricity production by measuring their polarizability — something that the group can easily, efficiently, and nondestructively track using their microfluidic technique.</p> <p>Collaborators on the team are currently using the method to test new strains of bacteria that have recently been identified as potential electricity producers.</p> <p>“If the same trend of correlation stands for those newer strains, then this technique can have a broader application, in clean energy generation, bioremediation, and biofuels production,” Wang says.&nbsp;</p> <p>This research was supported in part by the National Science Foundation, and the Institute for Collaborative Biotechnologies, through a grant from the U.S. Army.</p> A microfluidic technique quickly sorts bacteria based on their capability to generate electricity.Image: Qianru WangBacteria, Energy, Mechanical engineering, Microbes, Microfluidics, Research, School of Engineering, National Science Foundation (NSF) Engineering &quot;capture compounds&quot; to probe cell growth Researchers develop a method to investigate how bacteria respond to starvation and to identify which proteins bind to the “magic spot” — ppGpp. Mon, 17 Dec 2018 15:00:00 -0500 Raleigh McElvery | Department of Biology <p>In 1969, scientist Michael Cashel was analyzing the compounds produced by starved bacteria when he noticed two spots appearing on his chromatogram&nbsp;as if by magic. Today, we know one of these&nbsp;“magic spots,” as researchers call them, as guanosine tetraphosphate, or ppGpp for short. We also understand that it is&nbsp;a signaling molecule present in virtually all bacteria, helping tune cell growth and size based on nutrient availability.</p> <p>And yet, despite decades of study, precisely how ppGpp regulates bacterial growth has remained rather mysterious. Delving further&nbsp;requires a more comprehensive list of the molecules that ppGpp binds to exert its effects.</p> <p>Now, collaborators from MIT’s departments of Biology and Chemistry have developed a method to do just that, and used their new approach to pinpoint over 50 ppGpp targets in <em>Escherichia coli</em> — roughly half which had not been identified previously. Many of these targets are enzymes required to produce nucleotides, the building blocks of DNA and RNA. During times when the bacteria do not have enough nutrients to grow and divide normally, the researchers propose that ppGpp prevents these enzymes from creating new nucleotides from scratch, helping cells enter a dormant state.</p> <p>&nbsp;“With small molecules or metabolites like ppGpp, it’s been difficult historically to determine which proteins they bind,” says Michael Laub, a professor of biology, a Howard Hughes Medical Institute investigator, and the senior author of the study. “This has been an intractable problem that’s held the field back for some time, but our new approach allows you to nail down the likely targets in a matter of weeks.”</p> <p>Postdoc Boyuan Wang is the first author of the study, which appeares in <em>Nature Chemical Biology</em> on Dec. 17.</p> <p><strong>The magic spot</strong></p> <p>Since ppGpp was discovered nearly 50 years ago, it has been shown to suppress DNA replication, transcription, translation, and various metabolic pathways. It puts the brakes on cell growth and allows bacteria to persist in the face of starvation, stress, and antibiotics. Its influence over numerous regulatory processes has remained somewhat of a mystery, however — after all, it doesn’t just modulate a single pathway but coordinates multiple operations simultaneously to orchestrate a mass shutdown of the cell.</p> <p>In order to discern which proteins ppGpp binds to effect such widespread change, the researchers built what they call “capture compounds” that contain ppGpp, allowing them to fish out its targets from bacterial extracts. These compounds included a photoreactive crosslinker that latched tightly onto the proteins of interest in the presence of light, and a biotin handle that helped the scientists pull out the proteins to identify them. Most importantly, they were joined to ppGpp in such a way that they wouldn’t interfere with its ability to bind to its targets. This method is more efficient and accurate compared to more traditional means of distinguishing ppGpp targets, which are far more arduous and lack sensitivity.</p> <p>“Our approach solves these problems because you’re no longer required to do such labor-intensive protocols in order to identify ppGpp targets — and it works even in bacteria beyond <em>E. coli</em>,” says Wang. “Although ppGpp is common among many bacterial species, it seems to exert its effects through different mechanisms, which complicates things. Our capture compounds provide a way to unravel this diversity, and in short order.”</p> <p><strong>Putting the brakes on nucleotide production</strong></p> <p>Although the 56 ppGpp targets Wang identified in his screen control a myriad of cellular processes, he homed in on the enzyme PurF — which initiates the biosynthesis of purine nucleotides bearing adenine and guanine bases, also known as A and G.</p> <p>When bacteria are stressed or starved, they enter a dormant state to survive. But simply curbing translation and transcription is not enough; nucleotides are still being generated and will build up if their synthesis is not put on pause. Cells can build nucleotides in one of two ways: either by salvaging existing materials or starting completely from scratch. PurF kicks off the first step in the latter process leading to the A and G nucleotides. However, when ppGpp binds to PurF, it causes the enzyme to change its shape, which prevents it from doing its job, thus reducing nucleotide production in the cell.</p> <p>“This is the first time that an enzyme involved in that specific pathway or function has been identified as a ppGpp target,” Wang says. “If you limit the consumption of nucleotides but not their production, the nucleotide pool is going to explode, which isn’t good for the cell. So we’ve shown that ppGpp actually addresses this problem as well.”</p> <p>In addition to PurF and other enzymes required for nucleotide production, the researchers noticed that ppGpp also binds to many GTPase enzymes involved in translation. This could indicate a failsafe&nbsp;mechanism&nbsp;slowing down translation by striking multiple, similar enzymes in an almost redundant manner in the face of starvation.</p> <p>As Wang continues to refine his method, he aims to increase its specificity and ensure his capture compounds bind to the exact same proteins they would inside a live cell. He also hopes to screen for ppGpp binding proteins in other bacteria, including pathogens that rely on ppGpp to survive within their hosts and propagate conditions like tuberculosis.</p> <p>“This is an exciting chemical approach to better&nbsp;understand the function of a long-studied conserved signaling molecule in bacteria,” says Jue Wang, professor of bacteriology at the University of Wisconsin at Madison, who was not involved with the study. “Their findings and techniques are highly relevant to many other bacteria, and will greatly improve knowledge of how bacteria use this critical signaling molecule to mediate everything from surviving in the human gut to causing disease.”</p> <p>Adds Laub: “We are still discovering new nucleotide-based signaling molecules in bacteria even today, and every single one of them could eventually be derivatized in a similar way to identify their binding partners.”</p> <p>This research was supported by a fellowship from the Jane Coffin Childs Memorial Fund for Medical Research and a grant from the National Institutes of Health.</p> An MIT team has discovered that the small molecule ppGpp (red) binds to the PurF enzyme (subunits shown in green and purple).Image courtesy of the researchersSchool of Science, Biology, Chemistry, Bacteria, DNA, Microbes, Research Surviving one of Earth’s most extreme environments New research finds a unique component of cell membranes in an archaea species conveys protection against acidic surroundings. Fri, 14 Dec 2018 15:35:02 -0500 Fatima Husain | EAPS <p>Even in Earth’s most inhospitable environments, life has taken hold.</p> <p>Extremophiles are the&nbsp;organisms most well-known for withstanding extreme temperatures, pHs, salinity, and even nutrient-starvation. They have evolved special mechanisms that enable them to survive in their environments, but getting to the bottom of that resilience requires targeted and methodical interrogation.</p> <p>At Yellowstone National Park and similar sites, extremophiles reside in environments such as acid hot springs or thermal acid soils. Here&nbsp;they are exposed, often intermittently, to some of the lowest naturally-occurring pHs on Earth, and temperatures nearing the boiling point of water. To survive in these rapidly fluctuating conditions, organisms protect themselves with complex membranes, composed of interlocked lipids linked to their backbones with strong ether bonds, rather than the ester bonds most commonly found in eukaryotes and bacteria.</p> <p>In&nbsp;<em>Sulfolobus acidocaldarius,</em> an archaeon that lives in high-acid, high-temperature environments that are common in Yellowstone, cellular membrane lipids called glycerol dialkyl glycerol tetraether&nbsp;(GDGTs) are linked to an uncommon sugar-like molecule called calditol. A group of scientists recently <a href="" target="_blank">published&nbsp;findings</a> in the&nbsp;<em>Proceedings of the National Academy of Sciences</em>&nbsp;(PNAS), identifying how calditol is made in the cell and how, specifically, it is responsible for acid-tolerance in these organisms. The work is helping&nbsp;scientists get closer to understanding how life evolved to survive in extreme environments.</p> <p><a href="">Roger Summons</a>, the Schlumberger Professor of Geobiology in MIT’s Department of Earth, Atmospheric and Planetary Sciences (EAPS) and one of the authors of the study, credits advances in molecular biology, bioinformatics, and targeted gene deletion strategies for enabling this discovery.</p> <p>“The era of genomics has brought a range of new tools to advance lipid biomarker research,” Summons says.&nbsp;<a href="">Paula Welander</a>, a former EAPS postdoc in the&nbsp;<a href="">Summons Lab</a>&nbsp;and now assistant professor in the Department of Earth System Science at Stanford University, directed the study that was also conducted by Zhirui Zeng and Jeremy H. Wei at Stanford, and Xiao-lei Liu, an assistant professor of organic geochemistry at the University of Oklahoma.</p> <p>“This study is an excellent example of how an interdisciplinary approach, including microbial physiologists and organic geochemists, can address outstanding questions regarding lipid biomarkers,” Welander says.</p> <p>To identify calditol’s role in the&nbsp;<em>Sulfolobus acidocaldarius</em>&nbsp;membranes, the researchers used tools in comparative genomics, gene deletion, and lipid analysis to zero in on a particular protein within the class of radical S-andenosylmethionine (SAM) enzymes that is required to synthesize calditol. When they searched for what coded that protein in calditol-producing archaeal genomes, they found just a few candidate genes.</p> <p>To test the protein’s importance for acid tolerance, the researchers created mutants — with the membrane-related genes deleted — and analyzed their lipids. By subjecting the calditol-free mutant to highly acidic conditions, the researchers were able to confirm the true function of the calditol component of the membrane. Only the naturally-occurring, calditol-producing&nbsp;Sulfolobus&nbsp;and the mutant strain with the radical-SAM gene restored, were able to grow after a significant drop in pH.</p> <p>“While Welander and colleagues have demonstrated the presence of radical-SAM lipid biosynthesis genes in bacteria, this is the first time one has been unambiguously identified in archaea,” Summons says. “Calditol-linked to membrane lipids in these organisms confer significant protective effects.”</p> <p>Adds Welander: “Researchers have hypothesized for many years that producing calditol would provide this type of protective effect, but this has not been demonstrated directly. Here we finally show this link directly.”</p> <p>Even further, the fact that a radical SAM protein is involved in linking calditol to the membranes might help scientists better understand the chemistry and evolution of membrane lipids from a wide variety of environments across the planet.</p> <p>Summons says the&nbsp;result speaks to “the possible presence of a variety of other radical chemistries to modify membrane lipids once they’ve been synthesized.”&nbsp;</p> <p>“In turn, this could help us better understand the biosynthesis of other archaea-specific lipids and help us write the evolutionary history of these strikingly distinctive membranes,” he says.</p> <p>The study was supported by&nbsp;the Simons Foundation Collaboration on the Origins of Life.</p> Extremophiles are capable of living in some of the harshest locations on Earth, such as the Grand Prismatic Spring at Yellowstone National Park.Photo: Jim Peaco/National Park ServiceSchool of Science, Bacteria, Biology, Earth and atmospheric sciences, Evolution, Genetics, Geology, Microbes, Research, EAPS, Climate, Climate change Tracking the footprints of protein synthesis Researchers refine a method to quantify protein production, show that the precision with which bacteria and eukaryotes tune their gene expression is remarkably similar. Fri, 14 Dec 2018 15:15:00 -0500 Raleigh McElvery | Department of Biology <p>To trace which proteins are produced and when, researchers say, just follow the ribosome “footprints.”</p> <p>Researchers are tracking these large molecular machines, following their trails of protein synthesis to determine how precisely cells produce their protein components. Building too few might upset growth, metabolism, and maintenance, while too many might be wasteful and potentially toxic. Whether eukaryotic cells tune their gene expression to produce just enough&nbsp;of each protein remains a longstanding question.</p> <p>Bacteria appear to generate the exact levels needed to function — no more, no less. However, more complex organisms have different metabolic needs, means to control gene expression, and ways to eliminate unwanted proteins, perhaps engendering a different strategy to ensure correct protein levels. Using a combination of their own experiments and open access databases, a duo of scientists from the MIT Department of Biology aimed to establish how precisely cells from organisms like budding yeast, zebrafish, mice, and humans tune their protein production. Do these eukaryotic cells generate precise amounts of protein, or do they make roughly the correct amount and rely on processes like degradation to trim the excess?</p> <p>To answer this question, the researchers refined an existing technique, known as ribosome profiling, to quantify the protein synthesis rates by tracking the ribosome footprints. They were intrigued to find that, for the proteins they studied, eukaryotes precisely tuned their protein production just like bacteria. Despite the fundamental differences between these organisms, they shared a basic strategy.</p> <p>“We tend to think of gene expression as a production line, transforming genetic information into well-defined protein machines,” says Gene-Wei Li, an assistant professor of biology and senior author of the study. “But in actuality, it’s not yet clear whether all organisms or all cells operate under the same principles of protein production. The impetus of this study was to understand if proteins are made as precisely in eukaryotes as they are in bacteria, while also resolving ambiguities in existing methods for measuring protein synthesis rates.”</p> <p>Graduate student James Taggart was the first author of this <a href="" target="_blank">study</a>, which appears in the journal&nbsp;<em>Cell Systems</em> on Dec. 12.</p> <p><strong>A clear case of proportional synthesis</strong></p> <p>In 2014, when Li was still a postdoc at the University of California at San Francisco, he and his colleagues set out to <a href="">measure protein synthesis rates</a> in bacteria. They examined the subunits of multi-protein complexes in <em>Escherichia coli</em>, and showed that the bacteria operated under laws of proportional synthesis&nbsp;— meaning they were generating proteins in the exact ratio needed for cellular function. If bacteria produce too much for some reason, a degradation pathway is activated to break down those subunits, but this process constitutes more of a failsafe than the primary means to regulate protein abundance.</p> <p>In the present study, Li and Taggart aimed to make similar measurements in eukaryotes, starting with budding yeast. They used the same technique as Li in 2014 — ribosome profiling — but with a few modifications.</p> <p>Developed in 2009, ribosome profiling permits researchers to capture a snapshot of which mRNAs are being translated at a single moment in time. By using drugs that literally stop ribosomes in their tracks, scientists can freeze these molecular machines in place and destroy any un-protected mRNA that is not occupied (and thus shielded) by a stagnant ribosome. The fragments of mRNA — the ribosome footprints — can be sequenced to provide a barcode identifying which proteins were being made. The density of such footprints reveals the synthesis rates of each protein relative to the others.</p> <p>Although ribosome profiling revolutionized our ability to gauge protein synthesis across&nbsp;the entire genome, it is sometimes difficult to map each mRNA fragment back to its original location within the genome and the protein product to which it corresponds. A portion of one gene may have a sequence that’s identical to another gene that encodes an entirely separate protein.</p> <p>Here’s where Taggart tweaked the approach slightly: he excluded these ambiguous mRNA fragments in his analysis, and only counted the unique ribosome footprints that he could trace back to specific proteins. He then divided the number of ribosome footprints by the length of the gene, minus the ambiguous sequences and non-coding intron regions. While more common analytic approaches fail to accurately account for these ambiguous footprints, Taggart only considered&nbsp;what he calls “meaningful” footprints that he could map to specific regions on the genome. As a result, his modifications generated more precise synthesis rates.</p> <p>He ultimately curated a comprehensive list of roughly 500 proteins in yeast, comprising about 100 different protein complexes. As he monitored the yeast’s protein output, it appeared they produced just the right amount of subunits to complete the complex — no more, no less. It was a clear case of proportional synthesis.</p> <p><strong>Protein overload</strong></p> <p>Once they fine-tuned their method of quantifying protein production, the researchers wondered what would happen if they upset the cell’s careful synthesis balance. Do eukaryotes have a widespread mechanism to regulate the amount of protein they produce?</p> <p>Although yeast normally only have 16 chromosomes, with the help of <a href="">Angelika Amon’s lab</a>, the researchers duplicated each of them, one at a time, so the cell would have the capacity to build twice as many proteins using the genetic information from that extra chromosome. In humans, this kind of imbalance, known as aneuploidy, can lead to disorders like Down syndrome.</p> <p>Rather than sensing the excess protein and subsequently reducing production, the yeast did not initiate any internal communication to shut down operations at the level of transcription or translation. This runs counter to what is observed in some bacteria.</p> <p>“It was interesting to see that bacteria and yeast both make the exact amount of protein they need,” Taggart says, “although the ways they ensure precise synthesis are different. Many bacterial genes possess the negative feedback loops that yeast appear to lack.”</p> <p>Using data from open access databases, the researchers also identified proportional synthesis in higher eukaryotes, including zebrafish, mice, and humans for the subunits they examined from three large, highly conserved protein complexes. Despite the clear physiological and genetic difference between organisms, the complexes were produced in just the right ratios. The only exception was during zebrafish embryonic development, when the researchers concluded that protein production may not be proportional. This signified that the requirements for proportional synthesis might vary over the course of an organism’s lifetime, depending on age, nutrient availability, and stress.</p> <p>“Perhaps this precision is something we can learn from biology,” Li says. Once researchers fully understand how cells fine-tune their protein production, he explains, they can apply that knowledge to designing their own molecules and pathways.</p> <p>Eduardo Torres,&nbsp;an assistant professor of molecular, cell and cancer biology at the University of Massachusetts Medical School, says these requirements are conserved from bacteria to humans, “suggesting that the evolutionary pressure to produce protein amounts efficiently is a fundamental aspect of cell biology."</p> <p>“The next step would be to understand the mechanisms behind the balanced synthesis of protein complexes,” says Torres, who was&nbsp;not involved in the study.&nbsp;“Future studies integrating knowledge of several aspects of the regulation of gene expression will be necessary to understand how cells fine-tune the expression of each subunit of a particular complex.”</p> <p>Taggart also finds their findings compelling from an evolutionary perspective. “It appears eukaryotes have also evolved under pressure to achieve this proportional synthesis even though they're different from bacteria in so many other ways,” he says. “In all domains of life, protein synthesis is both an engine for proliferation and a hub for&nbsp;regulation.”</p> <p>The research was supported by a National Institutes of Health (NIH) grant, the Pew Biomedical Scholars Program, Sloan Research Fellowship, Searle Scholars Program, Smith Family Award for Excellence in Biomedical Research, National Science Foundation Graduate Research Fellowship, and an NIH Pre-Doctoral Training Grant.</p> Cells have evolved to produce the components of their multi-protein complexes in precise ratios.Image courtesy of the researchersSchool of Science, Biology, Bacteria, DNA, Genetics, Health, Microbes, Research, National Science Foundation (NSF), National Institutes of Health (NIH), RNA 3Q: Eric Alm on the mysteries of the microbiome “A diet or treatment of the microbiome may lead to increased diversity, but that does not mean it&#039;s better or healthier for you,” says the engineering professor. Fri, 07 Dec 2018 14:45:00 -0500 Meg Murphy | School of Engineering <p><em>Eric Alm is a professor of civil and environmental engineering and biological engineering at MIT and</em><em>&nbsp;co-director of the Center for Microbiome Informatics and Therapeutics. He&nbsp;also serves on the board of directors for the non-profit stool bank, OpenBiome, and clinical-stage biopharmaceutical company Finch Therapeutics.&nbsp;</em><em>His work focuses on understanding and engineering the human microbiome, which he defines as the microbes — bacteria, fungi, protozoa, and viruses — that live on and inside the human body. The microbiome plays a key role in human health and disease, and Alm and his colleagues strive to translate basic science discoveries rapidly into clinical settings, where they can contribute to better outcomes for patients. </em></p> <p><strong>Q.</strong> People are increasingly curious about the state of their microbiome. Could you tell us what a healthy microbiome looks like? Does the number of different types of bacteria species in the microbiome matter for health?</p> <p><strong>A.</strong> We don’t really know if diversity matters. If you’re very unhealthy, diversity in the microbiome can be very low as a result of an infection — where one particular bacterium takes over the gut and diversity goes down because you’ve been colonized by an infectious agent. But more might not necessarily be better if you’re within the range of diversity that is common among healthy people. So a diet or treatment of the microbiome may lead to increased diversity, but that does not mean it’s better or healthier for you. Diversity is not synonymous with healthy, but we don't have anything else that is synonymous with healthy either. Eating plenty of fiber and maintaining a varied diet is probably the best we can do for now until we have better science and knowledge about what healthy means.</p> <p><strong>Q.</strong> You cofounded the Global Microbiome Conservancy (GMbC) to identify and preserve gut bacteria from different peoples around the world. Could you tell us more about what you’re doing and why?</p> <p><strong>A. </strong>The microbiome is very homogenous in populations from industrialized nations that have access to antibiotics, processed foods, and modern sanitation. We have an extensive collection of over 7,000 different microbes that you’d find in folks from North America. But when we looked at the microbial species in people living in less developed nations, we discovered we hadn’t even scratched the surface in terms of microbial diversity, especially among people living "traditional," non-industrialized lifestyles. Those populations have a much greater microbial diversity than we see in North Americans, as well as very different organisms that might have totally different effects on host metabolism. This could be really important for health — not only in developing countries but maybe also for ourselves.</p> <p>GMbC’s biobank now houses about 4,000 strains from non-industrialized communities in seven countries, and we’re actively sampling in many other locations. We’ve built a global network of about 70 scientists, anthropologists, and collaborators working with indigenous and other non-industrialized communities in about 35 countries. We get samples and bring them back to MIT where we isolate the bacteria and preserve it for future generations so this biodiversity is not lost. Right now the 7,000 strains that we derived from urban North American individuals includes only five previously unknown genera — but the 4,000 strains from the non-industrialized parts of Africa and the Arctic where we’ve sampled have already yielded 55 unknown genera.</p> <p><strong>Q. </strong>You’ve also helped people gain access to a procedure that involves transplanting stool from a healthy donor into the colon of a patient. Could you tell us more about the use of fecal transplants?</p> <p><strong>A.</strong> <em>Clostridium difficile finection</em> is the most common hospital acquired gut infection, and our interest in the disease came after reading a scientific paper that showed fecal transplants work were effective even in cases where standard antibiotic therapy had failed. Patients, however, could not get access to treatment at that time, because doctors didn’t have access to the material for fecal transplants. We knew how to do it in the lab, and in 2013, my graduate student Mark Smith started a non-profit stool bank called OpenBiome, and we treated our first patient later that year. We’ve treated about 40,000 people so far. We’re partnering with over 1,000 hospital networks across the U.S. to make sure everyone has safe access to this medical procedure.</p> <p>The FDA does not currently allow large-scale treatment for indications other than <em>C. diff.</em> but clinical studies into other applications in various diseases exist. At the Center for Microbiome Informatics and Therapeutics at MIT, for instance, we’re involved in clinical studies that involve fecal transplants for patients with inflammatory bowel disease, or IBD. We look at various strains of bacteria and the immune response and even the metabolites in the blood to see how that changes in response to a fecal transplant. We’re also studying the effects of diet on the microbiome. For example, we know that microbes can metabolize fiber to short chain fatty acids like butyrate, which seems important in IBD. One of the interesting things we’ve found is that depending on the microbiome, different people require different fibers to make butyrate. Some individuals will take inulin and convert it into butyrate but not pectin and vice versa. We are working toward things like personalized fiber supplements for people with IBD.</p> MIT professor Eric Alm cofounded the Global Microbiome Conservancy, which identifies and preserves gut bacteria from different peoples around the world.Photo: Gretchen ErtlSchool of Engineering, Biological engineering, Civil and environmental engineering, 3 Questions, Center for Microbiome Informatics and Therapeutics, microbiome, Microbes, Research, Health, Health sciences and technology MIT engineers repurpose wasp venom as an antibiotic drug Altered peptides from a South American wasp’s venom can kill bacteria but are nontoxic to human cells. Fri, 07 Dec 2018 04:59:59 -0500 Anne Trafton | MIT News Office <p>The venom of insects such as wasps and bees is full of compounds that can kill bacteria. Unfortunately, many of these compounds are also toxic for humans, making it impossible to use them as antibiotic drugs.</p> <p>After performing a systematic study of the antimicrobial properties of a toxin normally found in a South American wasp, researchers at MIT have now created variants of the peptide that are potent against bacteria but nontoxic to human cells.</p> <p>In a study of mice, the researchers found that their strongest peptide could completely eliminate <em>Pseudomonas aeruginosa</em>, a strain of bacteria that causes respiratory and other infections and is resistant to most antibiotics.</p> <p>“We’ve repurposed a toxic molecule into one that is a viable molecule to treat infections,” says Cesar de la Fuente-Nunez, an MIT postdoc. “By systematically analyzing the structure and function of these peptides, we’ve been able to tune their properties and activity.”</p> <p>De la Fuente-Nunez is one of the senior authors of the paper, which appears in the Dec. 7 issue of the journal <em>Nature Communications Biology</em>. Timothy Lu, an MIT associate professor of electrical engineering and computer science and of biological engineering, and Vani Oliveira, an associate professor at the Federal University of ABC in Brazil, are also senior authors. The paper’s lead author is Marcelo Der Torossian Torres, a former visiting student at MIT.</p> <p><strong>Venomous variants</strong></p> <p>As part of their immune defenses, many organisms, including humans, produce peptides that can kill bacteria. To help fight the emergence of antibiotic-resistant bacteria, many scientists have been trying to adapt these peptides as potential new drugs.</p> <p>The peptide that de la Fuente-Nunez and his colleagues focused on in this study was isolated from a wasp known as <em>Polybia paulista</em>. This peptide is small enough — only 12 amino acids — that the researchers believed it would be feasible to create some variants of the peptide and test them to see if they might become more potent against microbes and less harmful to humans.</p> <p>“It’s a small enough peptide that you can try to mutate as many amino acid residues as possible to try to figure out how each building block is contributing to antimicrobial activity and toxicity,” de la Fuente-Nunez says.</p> <p>Like many other antimicrobial peptides, this venom-derived peptide is believed to kill microbes by disrupting bacterial cell membranes. The peptide has an alpha helical structure, which is known to interact strongly with cell membranes.</p> <p>In the first phase of their study, the researchers created a few dozen variants of the original peptide and then measured how those changes affected the peptides’ helical structure and their hydrophobicity, which also helps to determine how well the peptides interact with membranes. They then tested these peptides against seven strains of bacteria and two of fungus, making it possible to correlate their structure and physicochemical properties with their antimicrobial potency.</p> <p>Based on the structure-function relationships they identified, the researchers then designed another few dozen peptides for further testing. They were able to identify optimal percentages of hydrophobic amino acids and positively charged amino acids, and they also identified a cluster of amino acids where any changes would impair the overall function of the molecule.</p> <p><strong>Fighting infection</strong></p> <p>To measure the peptides’ toxicity, the researchers exposed them to human embryonic kidney cells grown in a lab dish. They selected the most promising compounds to test in mice infected with <em>Pseudomonas aeruginosa</em>, a common source of respiratory and urinary tract infections, and found that several of the peptides could reduce the infection. One of them, given at a high dose, could eliminate it completely.</p> <p>“After four days, that compound can completely clear the infection, and that was quite surprising and exciting because we don’t typically see that with other experimental antimicrobials or other antibiotics that we’ve tested in the past with this particular mouse model,” de la Fuente-Nunez says.</p> <p>“This represents a beautiful model of how work of this type should be done,” says Michael Zasloff, a professor of surgery and pediatrics scientific director at the MedStar Georgetown Transplant Institute, who was not involved in the research. “It’s a very comprehensive approach to redesigning a naturally occurring antimicrobial peptide.”</p> <p>The researchers have begun creating additional variants that they hope will be able to clear infections at lower doses. De la Fuente-Nunez also plans to apply this approach to other types of naturally occurring antimicrobial peptides when he joins the faculty of the University of Pennsylvania next year.&nbsp;</p> <p>“I do think some of the principles that we’ve learned here can be applicable to other similar peptides that are derived from nature,” he says. “Things like helicity and hydrophobicity are very important for a lot of these molecules, and some of the rules that we’ve learned here can definitely be extrapolated.”</p> <p>The research was funded, in part, by the Ramon Areces Foundation and the Defense Threat Reduction Agency.</p> MIT engineers have developed new antimicrobial peptides based on a naturally occurring peptide produced by a South American wasp.Image: Wikimedia, Charles J. SharpResearch, Microbes, Biological engineering, Electrical Engineering & Computer Science (eecs), School of Engineering, Medicine, Bacteria, Genetics, Antibiotics, Drug development Bursting bubbles launch bacteria from water to air Study illuminates new mode of bacteria dispersal. Thu, 15 Nov 2018 00:00:00 -0500 Jennifer Chu | MIT News Office <p>Wherever there’s water, there’s bound to be bubbles floating at the surface. From standing puddles, lakes, and streams, to swimming pools, hot tubs, public fountains, and toilets, bubbles are ubiquitous, indoors and out.</p> <p>A new MIT study shows how bubbles contaminated with bacteria can act as tiny microbial grenades, bursting and launching microorganisms, including potential pathogens, out of the water and into the air.</p> <p>In <a href="" target="_blank">the study</a>, published today in the journal <em>Physical Review Letters</em>, the researchers found that bacteria can affect a bubble’s longevity: A bacteria-covered bubble floating at the water’s surface can last more than 10 times longer than an uncontaminated one can, persisting for minutes instead of seconds. During this time, the cap of the contaminated bubble thins. The thinner the bubble, the higher the number of droplets it can launch into the air when the bubble inevitably bursts. A single droplet, the researchers estimate, can carry up to thousands of microorganisms, and each bubble can emit hundreds of droplets. &nbsp;</p> <p>“We discovered bacteria&nbsp;can manipulate interfaces in a manner that can enhance their own&nbsp;water-to-air dispersal,” says Lydia Bourouiba, assistant professor of civil and environmental engineering and director of the Fluid Dynamics of Disease Transmission Laboratory.</p> <p>Bourouiba’s co-author on the paper is graduate student Stephane Poulain.</p> <p><img alt="" src="/sites/" style="width: 595px; height: 208px;" /></p> <p><em><span style="font-size:10px;">When an old bubble bursts at the water surface, its cap fragments into numerous small droplets.</span></em></p> <p><strong>Something in the water</strong></p> <p>Bourouiba has spent the past several years meticulously generating, imaging, and characterizing clean, uncontaminated bubbles, with the goal of establishing a baseline of normal bubble behavior.</p> <p>“We first had to understand the physics of clean bubbles before we could add organisms like bacteria to see what effect they have on the system,” Bourouiba says.</p> <p>As it happens, the researchers first noticed bacteria’s effect somewhat by accident. The team was in the midst of moving to a new lab space, and in the shuffle, a beaker of water had been left out in the open. When the researcher used it in subsequent experiments, the results were not what the team expected.</p> <p>“The bubbles produced from this water lived much longer and had a peculiar thinning evolution compared to that of typical clean water bubbles,” Poulain says.</p> <p>Bourouiba suspected the water had been contaminated, and the team soon confirmed her hypothesis. They analyzed the water and found evidence of bacteria that are naturally present indoors.</p> <p><strong>The juice effect</strong></p> <p>To directly study bacteria’s effect on bubbles, the team set up an experiment in which they filled a column with a solution of water and various bacteria species, including <em>E. coli</em>. The researchers developed a system to generate bubbles with an air pump, one at a time, inside the column, in order to control the volume and size of each bubble. When a bubble rose to the surface, the team used high-speed imaging coupled with a range of optical techniques to capture its behavior, at the surface and as it burst.</p> <p>The researchers observed that, once a bubble contaminated with <em>E. coli</em> made it to the water’s surface, its own surface, or cap, immediately started to thin, mostly by draining back into the water, like a melting shell of chocolate. This behavior was similar to that of uncontaminated bubbles.</p> <p>But the contaminated bubbles remained on the surface more than 10 times longer than uncontaminated bubbles. And after a critical period of time, the bacteria-laden bubbles started thinning much faster. Bourouiba suspected that it might not be the bacteria themselves, but what they secrete, that holds the bubble in place for longer.</p> <p>“Bacteria are alive, and like anything alive, they make waste, and that waste typically is something that potentially could interact with the bubble’s interface,” Bourouiba says. “So we separated the organisms from their ‘juice.’”</p> <p>The researchers washed bacteria away from their secretions, then repeated their experiments, using the bacteria’s secretions. Just as Bourouiba suspected, the bubbles containing the secretions alone lasted much longer than clean bubbles. The secretions, the group concluded, must be the key ingredient in extending a bubble’s lifetime. But how?</p> <p>Again, Bourouiba had a hypothesis: Bacterial secretions may be acting to reduce a bubble’s surface tension, making it more elastic, more resistant to perturbations, and in the end, more likely to live longer on a water’s surface. This behavior, she noted, was similar to surface-active compounds, or surfactants, such as the compounds in detergents that make soap bubbles.</p> <p>To test this idea, the researchers repeated the experiments, this time by swapping out bacteria for common synthetic surfactants, and found that they too produced longer-lasting bubbles that also thinned dramatically after a certain time period. This experiment confirmed that bacteria’s secretions act as surfactants extending the lifetime of contaminated bubbles.</p> <p>The researchers then looked for an explanation for the drastic change in a contaminated bubble’s rate of thinning. In clean bubbles, the thinning of the cap was mostly the result of drainage, as water in the cap mostly drains back into the fluid from which the bubble rose. Such bubbles live on the order of seconds, and their drainage speed continuously slows down as the bubble thins.</p> <p>But if a bubble lasts past a critical time, evaporation starts playing a more dominant role than drainage, essentially shaving off water molecules from the bubble’s cap. The researchers concluded that, if a bubble contains bacteria, the bacteria and their secretions, make a bubble last longer on a water’s surface — long enough that evaporation becomes more important than drainage in thining the bubble’s cap.</p> <p>As a bubble’s cap gets thinner, the droplets it will spray out when it inevitably bursts become smaller, faster, and more numerous. The team found that a single bacteria-laden bubble can create 10 times more droplets, which are 10 times smaller and ejected 10 times faster than what a clean bubble can produce. This amounts to hundreds of droplets that measure only a few dozens of microns and that are emitted at speeds of the order of 10 meters per second.</p> <p><img alt="" src="/sites/" /></p> <p><em><span style="font-size:10px;">Droplets from bursting bubbles are expelled in the atmosphere, where they can be transported for a long time.</span></em></p> <p>“The mechanism [Bourouiba] identified is also at work when foam&nbsp;bubbles burst at the surface of the ocean,” says Andrea Prosperetti, a professor of mechanical engineering at the University of Houston, who was not involved in the research. “The size of these tiny film&nbsp;droplets determines how well they can be picked up and carried&nbsp;by the wind. This process has significant implications for climate and weather.&nbsp;The same basic process affects the health hazards of oil spills in the ocean: The tiny film drops carry hazardous chemicals from the oil, which can be inhaled by people and animals in the coastal regions. So, these humble, tiny drops have outsized consequences in many processes crucial to life.”</p> MIT researchers have found that bacteria can affect a bubble’s longevity.Image: Poulain and Bourouiba, MIT/ Bacteria, Fluid dynamics, Civil and environmental engineering, Disease, Environment, Institute for Medical Engineering and Science (IMES), Mechanical engineering, Microbes, Research, School of Engineering Studying the hotbed of horizontal gene transfers Global Microbiome Conservancy research reveals surprising new insights into human gut microbiomes. Mon, 22 Oct 2018 13:00:00 -0400 Fatima Husain | EAPS <p>For over 200,000 years, humans and their gut microbiomes have coevolved into some of the most complex collections of living organisms on the planet. But as human lifestyles vary from the urban to rural, so do the bacterial diversities of gut microbiomes.</p> <p>That's why a&nbsp;nonprofit global collaboration of more than&nbsp;70 scientists has been working for the past two years to interrogate and preserve that diversity of gut microbiomes from populations around the world, racing against the proliferation of antibiotic overuse and Western-style diets, which are known to contribute to a decrease in gut bacterial diversity. The Global Microbiome Conservancy, <a href="">launched in 2016</a>, already has some surprising insights that further shed light on the black box of gut bacterial diversity and human digestion.</p> <p>The MIT-based scientists who founded the conservancy come from a disparate set of disciplines: biological engineering, evolutionary biology, organic geochemistry, and biomedical research. Such collaborations may allow for interdisciplinary innovation that stands to improve the understanding of the science within our guts, says&nbsp;Mathilde Poyet, a postdoc in the Department of Biological Engineering’s <a href="">Alm Lab</a>. Poyet&nbsp;believes the interdisciplinary nature of the collaboration promotes the conservancy’s goals, which she says are to “preserve the full biodiversity of the human gut microbiome before it is lost, and to advance our understanding of the origins and functions of the human gut microbiomes,” within a “robust research ecosystem.”</p> <p>Poyet and fellow MIT-based postdocs Mathieu Groussin, who also works in the Alm Lab, and Ainara Sistiaga, a Marie Curie Postdoctoral Fellow in the <a href="">Summons Lab</a> within the Department of Earth, Atmospheric and Planetary Sciences (EAPS),&nbsp;presented the preliminary results of their work at the first MIT Microbiome Club meeting of the 2018-19 academic year. At the meeting, Poyet, Groussin, and Sistiaga spoke about their research progress as well as what’s surprised them most so far.</p> <p>In addition to biobanking and characterizing bacterial isolates collected from fecal samples from around the world, Poyet focuses on the horizontal exchange of genetic materials between living organisms, known as horizontal gene transfer (HGT). Unlike vertical transfers, horizontal gene transfers are acquisitions of genetic material from non-parental lineages.</p> <p>“Transfers of genes are known to be crucial for bacterial evolution and the human gut microbiome is an important hotbed for horizontal gene transfers,” Poyet says. “But all previous studies fell short at characterizing the timescale of these HGT events.” &nbsp;</p> <p>With the collection of bacterial isolates and genomes she built, Poyet is now able to identify evidence of very recent horizontal gene transfers, supporting the notion that these transfers frequently occur during the human lifetime. The effects of highly active horizontal gene transfers mean that gut bacteria could experience a sort of turnover of genetic material over time, which the conservancy hopes to study further as they collect more data.</p> <p>From additional preliminary analysis, Poyet and Groussin have found that in industrialized populations, which tend to have less gut bacterial diversity, meaning the rate of gene exchange through horizontal gene transfer is greater. “As HGT is a mechanism frequently used by bacteria to rapidly adapt to changing environments, this result suggests that an industrialized lifestyle imposes a stronger selective pressure on the gut microbiome of individual people, possibly as a result of the high consumption of antibiotics,” Poyet says.</p> <p>Ainara Sistiaga has been zeroing in on a dietary element that could also have implications for gastrointestinal bacteria and human health: lipids. Lipids, the hydrophobic biomolecules often referred to as fats, are unexplored in the gut microbiome. Sistiaga aims to change that.</p> <p>With fecal samples collected through the conservancy, Sistiaga performs lipid analysis — a series of chemistry-rooted procedures that help researchers characterize which lipids are present as well as their abundances.</p> <p>One lipid of particular interest is cholesterol, a molecule widely implicated in heart disease and stroke. As meat-heavy diets increase in popularity around the world, global cholesterol intake is set to rise as well. Theoretically, in most humans, some of the cholesterol that reaches the gut should undergo a bacterial conversion into a byproduct that the body cannot reabsorb and would be excreted. But Sistiaga finds that all gut microbiomes execute metabolic functions differently. “What we have observed is that most of the participants in rural populations are performing this conversion much more efficiently than Western donors,” Sistiaga says. So, in order to describe and understand how such processes work within the gut, Sistiaga hopes to use methods informed from organic geochemistry to characterize the fate of cholesterol in humans from around the world.</p> <p>After the presentation, the MIT researchers fielded questions from the audience. “People were interested in all aspects of the presentation — traveling, how to get involved, the science, the preliminary results, the potential outcomes of this project,” Sistiaga says. “Even after the Q&amp;A, a lot of people approached us for more specific questions.”</p> <p>As part of its&nbsp;efforts, the Global Microbiome Conservancy&nbsp;establishes long-term collaborations with local populations and researchers for sampling and analysis — and the participants themselves maintain ownership of their samples.&nbsp;Within the next two years, the conservancy&nbsp;is set to increase its global coverage. The current microbiome studies conducted focus on samples collected from 19 distinct populations sampled worldwide from Arctic regions, sub-Saharan countries and North America, but they’ll soon be complemented with samples from Malaysia and Peru. Poyet adds, “We anticipate [samples from Asia and South America] will yield novel and unique microbial communities that must be preserved.”</p> <p>“It’s been exciting to unveil the microbiome of these underrepresented communities, and I think we are just seeing the tip of the iceberg,” Sistiaga says. “Everything we’ve observed so far confirms how important and truly urgent this work is.”</p> A woman in Ghana carries a basket of fish. Local diets and lifestyles have created a remarkable diversity in the human microbiome worldwide.Photo: Mathieu GroussinSchool of Science, School of Engineering, Biological engineering, Earth and atmospheric sciences, Bacteria, Health, Health sciences and technology, Research, Collaboration, Genetics, Microbes, Biology Probiotics and antibiotics create a killer combination Delivered together, the two join forces to eradicate drug-resistant bacteria. Wed, 17 Oct 2018 10:22:34 -0400 Anne Trafton | MIT News Office <p>In the fight against drug-resistant bacteria, MIT researchers have enlisted the help of beneficial bacteria known as probiotics.</p> <p>In <a href="" target="_blank">a new study</a>, the researchers showed that by delivering a combination of antibiotic drugs and probiotics, they could eradicate two strains of drug-resistant bacteria that often infect wounds. To achieve this, they encapsulated the probiotic bacteria in a protective shell of alginate, a biocompatible material that prevents the probiotics from being killed by the antibiotic.</p> <p>“There are so many bacteria now that are resistant to antibiotics, which is a serious problem for human health. We think one way to treat them is by encapsulating a live probiotic and letting it do its job,” says Ana Jaklenec, a research scientist at MIT’s Koch Institute for Integrative Cancer Research and one of the senior authors of the study.</p> <p>If shown to be successful in future tests in animals and humans, the probiotic/antibiotic combination could be incorporated into dressings for wounds, where it could help heal infected chronic wounds, the researchers say.</p> <p>Robert Langer, the David H. Koch Institute Professor and a member of the Koch Institute, is also a senior author of the paper, which appears in the journal <em>Advanced Materials</em> on Oct. 17. Zhihao Li, a former MIT visiting scientist, is the study’s lead author.</p> <p><strong>Bacteria wars</strong></p> <p>The human body contains trillions of bacterial cells, many of which are beneficial. In some cases, these bacteria help fend off infection by secreting antimicrobial peptides and other compounds that kill pathogenic strains of bacteria. Others outcompete harmful strains by taking up nutrients and other critical resources.</p> <p>Scientists have previously tested the idea of applying probiotics to chronic wounds, and they’ve had some success in studies of patients with burns, Li says. However, the probiotic strains usually can’t combat all of the bacteria that would be found in an infected wound. Combining these strains with traditional antibiotics would help to kill more of the pathogenic bacteria, but the antibiotic would likely also kill off the probiotic bacteria.</p> <p>The MIT team devised a way to get around this problem by encapsulating the probiotic bacteria so that they would not be affected by the antibiotic. They chose alginate in part because it is already used in dressings for chronic wounds, where it helps to absorb secretions and keep the wound dry. Additionally, the researchers also found that alginate is a component of the biofilms that clusters of bacteria form to protect themselves from antibiotics.</p> <p>“We looked into the molecular components of biofilms and we found that for <em>Pseudomonas</em> infection, alginate is very important for its resistance against antibiotics,” Li says. “However, so far no one has used this ability to protect good bacteria from antibiotics.”</p> <p>For this study, the researchers chose to encapsulate a type of commercially available probiotic known as Bio-K+, which consists of three strains of <em>Lactobacillus</em> bacteria. These strains are known to kill methicillin-resistant <em>Staphylococcus aureus </em>(MRSA). The exact mechanism by which they do this is not known, but one possibility is that the pathogens are susceptible to lactic acid produced by the probiotics. Another possibility is that the probiotics secrete antimicrobial peptides or other proteins that kill the pathogens or disrupt their ability to form biofilms.</p> <p>The researchers delivered the encapsulated probiotics along with an antibiotic called tobramycin, which they chose among other tested antibiotics because it effectively kills <em>Pseudomonas aeruginosa</em>, another strain commonly found in wound infections. When MRSA and <em>Pseudomonas aeruginosa</em> growing in a lab dish were exposed to the combination of encapsulated Bio-K+ and tobramycin, all of the pathogenic bacteria were wiped out.</p> <p>“It was quite a drastic effect,” Jaklenec says. “It completely eradicated the bacteria.”</p> <p>When they tried the same experiment with nonencapsulated probiotics, the probiotics were killed by the antibiotics, allowing the MRSA bacteria to survive.</p> <p>“When we just used one component, either antibiotics or probiotics, they couldn’t eradicate all the pathogens. That’s something which can be very important in clinical settings where you have wounds with different bacteria, and antibiotics are not enough to kill all the bacteria,” Li says.</p> <p><strong>Better wound healing</strong></p> <p>The researchers envision that this approach could be used to develop new types of bandages or other wound dressings embedded with antibiotics and alginate-encapsulated probiotics. Before that can happen, they plan to further test the approach in animals and possibly in humans.</p> <p>“The good thing about alginate is it’s FDA-approved, and the probiotic we use is approved as well,” Li says. “I think probiotics can be something that may revolutionize wound treatment in the future. With our work, we have expanded the application possibilities of probiotics.”</p> <p>In a study published in 2016, the researchers demonstrated that coating probiotics with layers of alginate and another polysaccharide called chitosan could protect them from being broken down in the gastrointestinal tract. This could help researchers develop ways to treat disease or improve digestion with orally delivered probiotics. Another potential application is using these probiotics to replenish the gut microbiome after treatment with antibiotics, which can wipe out beneficial bacteria at the same time that they clear up an infection.</p> <p>Li’s work on this project was funded by the Swiss Janggen-Poehn Foundation and by Beatrice Beck-Schimmer and Hans-Ruedi Gonzenbach.</p> MIT chemical engineers have devised a way to encapsulate probiotics so that they can be delivered along with antibiotics to kill multiple strains of bacteria.Image: Ryan AllenResearch, Chemical engineering, Microbes, Antibiotics, Koch Institute, School of Engineering Detangling DNA replication Researchers identify an essential protein that helps enzymes relax overtwisted DNA so each strand can be copied during cell division. Mon, 17 Sep 2018 12:30:00 -0400 Raleigh McElvery | Department of Biology <p>DNA is a lengthy molecule — approximately 1,000-fold longer than the cell in which it resides — so&nbsp;it can’t be jammed in haphazardly. Rather, it must be neatly organized so proteins involved in critical processes can access the information contained in its nucleotide bases. Think of the double helix like a pair of shoe laces twisted together, coiled upon themselves again and again to make the molecule even more compact.</p> <p>However, when it comes time for cell division, this <a href="">supercoiled</a>&nbsp;nature makes it difficult for proteins involved in DNA replication to access the strands, separate them, and copy them so one DNA molecule can become two.</p> <p>Replication begins at specific regions of the chromosome where specialized proteins separate the two strands, pulling apart the double helix as you would the two shoe laces. However, this local separation actually tangles the rest of the molecule further, and without intervention creates a buildup of tension, stalling replication. Enter the enzymes known as topoisomerases, which travel ahead of the strands as they are being peeled apart, snipping them, untwisting them, and then rejoining them to relieve the tension that arises from supercoiling.</p> <p>These topoisomerases are generally thought to be sufficient to allow replication to proceed. However, a team of researchers from MIT and the Duke University School of Medicine suggests the enzymes may require guidance from additional proteins, which recognize the shape characteristic of overtwisted DNA.</p> <p>“We’ve known for a long time that topoisomerases are necessary for replication, but it’s never been clear if they were sufficient on their own,” says Michael Laub, an MIT professor of biology, Howard Hughes Medical Institute Investigator, and senior author of the study. “This is the first paper to identify a protein in bacteria, or eukaryotes, that is required to localize topoisomerases ahead of replication forks and to help them do what they need to do there.”</p> <p>Postdoc Monica Guo ’07 and former graduate student Diane Haakonsen PhD ’16 are co-first authors of the study, which appeared online in the journal&nbsp;<em>Cell </em>on Sept.&nbsp;13.</p> <p><strong>Necessary but not sufficient</strong></p> <p>Although it’s well established that topoisomerases are crucial to DNA replication, it is now becoming clear that we know relatively little about the mechanisms regulating their activity, including where and when they act to relieve supercoiling.</p> <p>These enzymes fall into two groups, type I and type II, depending on how many strands of DNA they cut. The researchers focused on type II topoisomerases found in a common species of freshwater bacteria, <em>Caulobacter crescentus</em>. Type II topoisomerases in bacteria are of particular interest because a number of antibiotics target them in order to prevent DNA replication, treating a wide variety of microbial infections, including tuberculosis. Without topoisomerases, the bacteria can’t grow. Since these bacterial enzymes are unique, poisons directed at them won’t harm human topoisomerases.</p> <p>For a long time, type II topoisomerases were generally assumed adequate on their own to manage the overtwisted supercoils that arise during replication. Although researchers working in <em>E. coli</em> and other, higher organisms have pinpointed additional proteins that can activate or repress these enzymes, none of these proteins were required for replication.</p> <p>Such findings hinted that there might be similar interactions taking place in other organisms. In order to understand the protein factors involved in compacting <em>Caulobacter</em> DNA — regulating topoisomerase activity specifically — the researchers screened their bacteria for proteins that bound tightly to supercoiled DNA. From there, they honed in on one protein, GapR, which they observed was essential for DNA replication. In bacteria missing GapR, the DNA became overtwisted, replication slowed, and the bacteria eventually died.</p> <p>Surprisingly, the researchers found that GapR recognized the structure of overtwisted DNA rather than specific nucleotide sequences.</p> <p>“The vast majority of DNA-binding proteins localize to specific locations of the genome by recognizing a specific set of bases,” Laub says. “But GapR basically pays no attention to the actual underlying sequence — just the shape of overtwisted DNA, which uniquely arises in front of replication forks and transcription machinery.”</p> <p>The crystal structure of the protein bound to DNA, solved by Duke’s Maria Schumacher, revealed that GapR recognizes the backbone of DNA (rather than the bases), forming a snug clamp that encircles the overtwisted DNA. However, when the DNA is relaxed in its standard form, it no longer fits inside the clamp. This might signify that GapR sits on DNA only at positions where topoisomerase is needed.</p> <p><strong>An exciting milestone</strong></p> <p>Although GapR appears to be required for DNA replication, it’s still not clear precisely how this protein promotes topoisomerase function to relieve supercoiling.</p> <p>“In the absence of any other proteins, GapR is able to help type II topoisomerases remove positive supercoils faster, but we still don’t quite know how,” Guo says. “One idea is that GapR interacts with topoisomerases, recognizing the overtwisted DNA and recruiting the topoisomerases. Another possibility is that GapR is essentially grabbing onto the DNA and limiting the movement of the positive supercoils, so topoisomerases can target and eliminate them more quickly.”</p> <p>Anthony Maxwell, a professor of biological chemistry at the John Innes Centre who was not involved with the study, says the buildup of DNA supercoils is a key problem in both bacterial replication and transcription.</p> <p>“Identifying GapR and its potential role in controlling supercoiling <em>in vivo</em> is an exciting milestone in understanding the control of DNA topology in bacteria,” he says.&nbsp;“Further work will be required to show how exactly these proteins cooperate to maintain bacterial genomic integrity.”</p> <p>According to Guo, the&nbsp;study provides insight into a fundamental process — DNA replication — and the ways topoisomerases are regulated, which could extend to eukaryotes.</p> <p>“This was the first demonstration that a topoisomerase activator is required for DNA replication,” she says. “Although there’s no GapR homolog in higher organisms, there could be similar proteins that recognize the shape of the DNA and aid or position topoisomerases.”</p> <p>This could open up a new field of drug research, she says, targeting activators like GapR to increase the efficacy of existing topoisomerase poisons to treat conditions like respiratory and urinary tract infections. After all, many topoisomerase inhibitors have become less effective due to antibiotic resistance. But only time will tell; there is still much to learn in order to untangle the complex process of DNA replication, along with its many twists and turns.</p> <p>The research was funded by NIH grants, the HHMI International Predoctoral Fellowship, and the Jane Coffin Childs Memorial Fellowship.</p> Four GapR subunits assemble as a dimer-of-dimer complex, forming a clamp around overtwisted DNA, which arises during DNA replication and transcription.Image courtesy of the researchers.School of Science, Biology, Bacteria, DNA, Genetics, Microbes, Research, National Institutes of Health (NIH) How phytoplankton survive in ocean gyres with low nutrient supplies Model of nutrient recycling may explain longstanding mystery. Fri, 14 Sep 2018 16:23:30 -0400 Helen Knight | MIT News correspondent <p>Subtropical gyres are huge, sustained currents spanning thousands of kilometers across the Pacific and Atlantic oceans, where very little grows.</p> <p>With nutrients in short supply, phytoplankton, the microscopic plants that form the basis of the marine food chain, struggle to thrive.</p> <p>However, some phytoplankton do live within the hostile environment of these gyres, and exactly how they obtain their nutrients has long been a mystery.</p> <p>Now research by Edward Doddridge, a postdoc in the Department of Earth, Atmospheric and Planetary Sciences at MIT, has found that phytoplankton growth in subtropical gyres is affected by a layer of water well below the ocean surface, which allows nutrients to be recycled back to the surface.</p> <p>Working with David Marshall at Oxford University, Doddridge has developed a model to investigate the mechanism behind phytoplankton growth within the gyres, which appears in the <em>Journal of Geophysical Research: Oceans</em>.</p> <p>According to the textbooks, winds push surface waters into the center of the gyres and then downward, taking nutrients away from the sunlit zone and therefore preventing phytoplankton from thriving.</p> <p>But previous research by Doddridge has suggested that this view is too simplistic, and that the motion of eddies — the ocean equivalent of weather systems — within the gyres acts against this movement, preventing the water from being pushed far downward.</p> <p>To investigate this further, the researchers developed a simple computer model, in which they split the ocean into two layers: the sunlit layer and a layer of homogenous water below it, called mode water. Beneath this layer of mode water is the abyss, which was not included in the model.</p> <p>Within the model, the researchers included both the wind-led process of water convergence from the sides of the gyre and then downward, and the way that eddies should act against this movement.</p> <p>When they ran the model, its results broadly mirrored observations of the gyres themselves, with higher nutrient concentration and phytoplankton productivity at the edges of the gyres, and lower productivity in the center.</p> <p>They then began varying the different parameters of the model, to investigate what effect this would have on nutrient levels and phytoplankton productivity.</p> <p>They first varied a mechanism proposed previously by researchers and known as eddy pumping, in which the swirling motion of circular currents draws colder, nutrient-rich water up from below.</p> <p>“We changed how much fluid this mechanism could swap between the sunlit layer and the homogenous layer below, and we found that as we increased the eddy pumping, the nutrient concentration went up, as suggested by previous research,” says Doddridge.</p> <p>However, the effect of this eddy pumping began to plateau at higher levels. The more the researchers increased the eddy pumping mechanism, the smaller the increase in nutrient concentration became.</p> <p>They then varied the process of horizontal water convergence and downward pumping within the gyres, known as residual Ekman transport. They found this process had a considerable impact on nutrient concentration.</p> <p>Finally, the researchers varied the thickness of the layer of homogenous water below the sunlit layer, which they also found to have a significant impact on nutrient concentration.</p> <p>Previous research had suggested that as this layer of mode water gets thicker, it blocks nutrients coming up from below, resulting in lower productivity levels in the sunlit zone. However, the results of the model suggest the opposite is the case, with a thicker mode layer leading to greater nutrient concentration. This was particularly the case when the level of Ekman transport was low, Doddridge says.</p> <p>“When phytoplankton and other things living in the sunlit layer die, or get eaten and excreted, they start falling down through the ocean, and their nutrients are absorbed back into the water,” Doddridge says.</p> <p>“So the thicker that homogenous layer is, the longer it takes these particles to fall through it, and the more of their nutrients are absorbed into the fluid, to be recycled as food.”</p> <p>While the nutrients remain in the homogenous layer, it does not take much energy for them to be mixed back up to the surface, Doddridge says. But if they quickly drop below it into the abyss — because the homogenous layer is thin, for example — the nutrients are essentially cut off from the surface water above, he says.</p> <p>When the researchers tested the results of the model using data from satellites, autonomous robots, and ships, they found that it supported their findings, suggesting that thicker mode water does indeed enhance phytoplankton growth within subtropical gyres.</p> <p>In the future, Doddridge would like to carry out further experiments using more complex models, to gain further insights into the way in which nutrients are fed into and recycled within subtropical gyres.</p> <p>The nutrient-poor upper ocean waters of the subtropical gyre play globally important roles in ocean carbon uptake, with biological processes mediating a large fraction of this carbon uptake, but the processes supplying nutrients required to support net biological production in these ecosystems remains unclear, according to Matthew Church at the University of Montana, who was not involved in the research.</p> <p>“The paper highlights the key role of physical processes (specifically eddies) in regulating both the upward supply of nutrients, and the downward flux of sinking organic matter,” Church says. “The authors conclude that this latter term, specifically the depth over which organic particles are remineralized, sets constraints on productivity of the overlying waters. This model-derived conclusion presents a field-testable hypothesis.”</p> Edward Doddridge, a postdoc in the Department of Earth, Atmospheric and Planetary Sciences at MIT, co-developed a model to investigate the mechanism behind phytoplankton growth within subtropical gyres.Research, EAPS, Ocean science, Microbes, Earth and atmospheric sciences, School of Science Biological engineers discover new antibiotic candidates Screen of human proteins reveals some with antimicrobial power. Mon, 20 Aug 2018 00:00:00 -0400 Anne Trafton | MIT News Office <p>The human body produces many antimicrobial peptides that help the immune system fend off infection. Scientists hoping to harness these peptides as potential antibiotics have now discovered that other peptides in the human body can also have potent antimicrobial effects, expanding the pool of new antibiotic candidates.&nbsp;</p> <p>In the new study, researchers from MIT and the University of Naples Federico II found that fragments of the protein pepsinogen, an enzyme used to digest food in the stomach, can kill bacteria such as <em>Salmonella</em> and <em>E. coli.</em></p> <p>The researchers believe that by modifying these peptides to enhance their antimicrobial activity, they may be able to develop synthetic peptides that could be used as antibiotics against drug-resistant bacteria.</p> <p>“These peptides really constitute a great template for engineering. The idea now is to use synthetic biology to modify them further and make them more potent,” says Cesar de la Fuente-Nunez, an MIT postdoc and Areces Foundation Fellow, and one of the senior authors of the paper.</p> <p>Other MIT authors of the paper, which appears in the Aug. 20 issue of the journal <em>ACS Synthetic Biology</em>, are Timothy Lu, an associate professor of electrical engineering and computer science and of biological engineering, and Marcelo Der Torossian Torres, a former visiting student.</p> <p><strong>Discovering new functions</strong></p> <p>Antimicrobial peptides, which are found in nearly all living organisms, can kill many microbes, but they are typically not powerful enough to act as antibiotic drugs on their own. Many scientists, including de la Fuente-Nunez and Lu, have been exploring ways to create <a href="">more potent versions</a> of these peptides, in hopes of finding new weapons to combat the growing problem posed by antibiotic-resistant bacteria.</p> <p>In this study, the researchers wanted to explore whether other proteins found in the human body, outside of the previously known antimicrobial peptides, might also be able to kill bacteria. To that end, they developed a search algorithm that analyzes databases of human protein sequences in search of similarities to known antimicrobial peptides.</p> <p>“It’s a data-mining approach to very easily find peptides that were previously unexplored,” de la Fuente-Nunez says. “We have patterns that we know are associated with classical antimicrobial peptides, and the search engine goes through the database and finds patterns that look similar to what we know makes up a peptide that kills bacteria.”</p> <p>In a screen of nearly 2,000 human proteins, the algorithm identified about 800 with possible antimicrobial activity. In the <em>ACS Synthetic Biology</em> paper, the research team focused on the peptide pepsinogen, whose role is to break down proteins in food. After pepsinogen is secreted by cells that line the stomach, hydrochloric acid in the stomach mixes with pepsinogen, converting it into pepsin A, which digests proteins, and into several other small fragments.</p> <p>Those fragments, which previously had no known functions, showed up as candidates in the antimicrobial screen.</p> <p>Once the researchers identified those candidates, they tested them against bacteria grown in lab dishes and found that they could kill a variety of microbes, including foodborne pathogens, such as <em>Salmonella</em> and <em>E. coli</em>, as well as others, including <em>Pseudomonas aeruginosa</em>, which often infects the lungs of cystic fibrosis patients. This effect was seen at both acidic pH, similar to that of the stomach, and neutral pH.</p> <p>“The human stomach is attacked by many pathogenic bacteria, so it makes sense that we would have a host defense mechanism to defend ourselves from such attacks,” de la Fuente-Nunez says.</p> <p><strong>More potent drugs</strong></p> <p>The researchers also tested the three pepsinogen fragments against a <em>Pseudomonas aeruginosa</em> skin infection in mice, and found that the peptides significantly reduced the infections. The exact mechanism by which the peptides kill bacteria is unknown, but the researchers’ hypothesis is that their positive charges allow the peptides to bind to the negatively charged bacterial membranes and poke holes in them, a mechanism similar to that of other antimicrobial peptides.</p> <p>As bacteria become increasingly resistant to conventional antibiotics, there is an urgent need for innovation in drug development, says Dianne Newman, a professor of biology and geobiology at Caltech who was not involved in the research. “Disappointingly, major pharmaceutical companies have recently left this space, thus the creative approach taken in this study is timely and may hold promise on an applied level,” she says.</p> <p>The researchers now hope to modify these peptides to make them more effective, so that they could be potentially used as antibiotics. They are also seeking new peptides from organisms other than humans, and they plan to further investigate some of the other human peptides identified by the algorithm.</p> <p>“We have an atlas of all these molecules, and the next step is to demonstrate whether each of them actually has antimicrobial properties and whether each of them could be developed as a new antimicrobial,” de la Fuente-Nunez says.</p> MIT researchers have discovered that peptides normally secreted by cells that line the stomach have previously unknown antimicrobial activity.Image: Ella Maru StudioResearch, Biological engineering, Microbes, School of Engineering A single-injection vaccine for the polio virus Nanoparticles could offer a new way to help eradicate the disease worldwide. Mon, 21 May 2018 14:59:59 -0400 Anne Trafton | MIT News Office <p>A new nanoparticle vaccine developed by MIT researchers could assist efforts to eradicate polio worldwide. The vaccine, which delivers multiple doses in just one injection, could make it easier to immunize children in remote regions of Pakistan and other countries where the disease is still found.&nbsp;</p> <p>While the number of reported cases of polio dropped by 99 percent worldwide between 1988 and 2013, according to the Centers for Disease Control, the disease has not been completely eradicated, in part because of the difficulty in reaching children in remote areas to give them the two to four polio vaccine injections required to build up immunity.</p> <p>“Having a one-shot vaccine that can elicit full protection could be very valuable in being able to achieve eradication,” says Ana Jaklenec, a research scientist at MIT’s Koch Institute for Integrative Cancer Research and one of the senior authors of the paper. &nbsp;</p> <p>Robert Langer, the David H. Koch Institute Professor at MIT, is also a senior author of the study, which appears in the <em>Proceedings of the National Academy of Sciences</em> the week of May 21. Stephany Tzeng, a former MIT postdoc who is now a research associate at Johns Hopkins University School of Medicine, is the paper’s lead author.</p> <p>“We are very excited about the approaches and results in this paper, which I hope will someday lead to better vaccines for patients around the world,”&nbsp;Langer says.</p> <p><strong>Global eradication</strong></p> <p>There are no drugs against poliovirus, and in about 1 percent of cases, it enters the nervous system, where it can cause paralysis. The first polio vaccine, also called the Salk vaccine, was developed in the 1950s. This vaccine consists of an inactivated version of the virus, which is usually given as a series of two to four injections, beginning at 2 months of age. In 1961, an oral vaccine was developed, which offers some protection with only one dose but is more effective with two to three doses.</p> <p>The oral vaccine, which consists of a virus that has reduced virulence but is still viable, has been phased out in most countries because in very rare cases, it can mutate to a virulent form and cause infection. It is still used in some developing countries, however, because it is easier to administer the drops than to reach children for multiple injections of the Salk vaccine.</p> <p>For polio eradication efforts to succeed, the oral vaccine must be completely phased out, to eliminate the chance of the virus reactivating in an immunized person. Several years ago, Langer’s lab received funding from the Bill and Melinda Gates Foundation to try to develop an injectable vaccine that could be given just once but carry multiple doses.</p> <p>“The goal is to ensure that everyone globally is immunized,” Jaklenec says. “Children in some of these hard-to-reach developing world locations tend to not get the full series of shots necessary for protection.”</p> <p>To create a single-injection vaccine, the MIT team encapsulated the inactivated polio vaccine in a biodegradable polymer known as PLGA. This polymer can be designed to degrade after a certain period of time, allowing the researchers to control when the vaccine is released.</p> <p>“There’s always a little bit of vaccine that’s left on the surface or very close to the surface of the particle, and as soon as we put it in the body, whatever is at the surface can just diffuse away. That’s the initial burst,” Tzeng says. “Then the particles sit at the injection site and over time, as the polymer degrades, they release the vaccine in bursts at defined time points, based on the degradation rate of the polymer.”</p> <p>The researchers had to overcome one major obstacle that has stymied previous efforts to use PLGA for polio vaccine delivery: The polymer breaks down into byproducts called glycolic acid and lactic acid, and these acids can harm the virus so that it no longer provokes the right kind of antibody response.</p> <p>To prevent this from happening, the MIT team added positively charged polymers to their particles. These polymers act as “proton sponges,” sopping up extra protons and making the environment less acidic, allowing the virus to remain stable in the body.</p> <p>“I think the beauty of&nbsp;the paper is that the traditional microparticle formulation design principles for antigen stabilization are applicable to the delivery of a very complex antigen system. Single dose vaccination for developing world applications is a Holy Grail, and they are getting close,” says David Putnam, a professor of biomedical engineering and chemical and biomolecular engineering at Cornell University who was not involved in the research.</p> <p><strong>Successful immunization</strong></p> <p>In the <em>PNAS</em> study, the researchers designed particles that would deliver an initial burst at the time of injection, followed by a second release about 25 days later. They injected the particles into rats, then sent blood samples from the immunized rats to the Centers for Disease Control for testing. Those studies revealed that the blood samples from rats immunized with the single-injection particle vaccine had an antibody response against poliovirus just as strong as, or stronger than, antibodies from rats that received two injections of Salk polio vaccine.</p> <p>To deliver more than two doses, the researchers say they could design particles that release vaccine at injection and one month later, and mix them with particles that release at injection and two months later, resulting in three overall doses, each a month apart. The polymers that the researchers used in the vaccines are already FDA-approved for use in humans, so they hope to soon be able to test the vaccines in clinical trials.</p> <p>The researchers are also working on applying this approach to create stable, single-injection vaccines for other viruses such as Ebola and HIV.</p> <p>The research was funded by the Bill and Melinda Gates Foundation.</p> MIT researchers developed these polymer microspheres containing polio vaccine that can be released in two separate bursts.Courtesy of the researchersResearch, Chemical engineering, Nanoscience and nanotechnology, Koch Institute, School of Engineering, Drug delivery, Drug development, Developing countries, Medicine, Disease, Vaccines, Microbes Jeff Gore: A physicist exploring population dynamics of microbes MIT professor sees many “big, deep questions in biology” that benefit from study by both physicists and life scientists. Mon, 14 May 2018 23:59:59 -0400 Anne Trafton | MIT News Office <p>It’s a pretty good bet that among MIT’s physics faculty, Jeff Gore is the only one with test tubes of yeast growing in his lab.</p> <p>Gore, a biophysicist who studies population dynamics, uses yeast and other microbes to explore the fundamental rules that govern phenomena such as population collapse. His microbial communities offer a window into principles that also influence larger-scale populations that are much more difficult to study.</p> <p>“Microbes are a wonderful experimentally tractable model system to try to ask the kinds of questions we’re interested in, regarding all these phenomena that are also at play in fisheries, or in zebra populations, which are very difficult to approach experimentally,” says Gore, who recently earned tenure in MIT’s Department of Physics.</p> <p>Since joining MIT’s faculty in 2010, Gore has explored the roles of “cheaters” and “cooperators” in microbial communities, as well as perturbations that can nudge a stable population toward a tipping point that leads to collapse. The rapid timescale of microbial growth allows Gore and his students to conduct an experiment in just a few days, test their predictions, revise their models based on the experimental results, and then launch new experiments.</p> <p>“Going back and forth between experiment and modeling is a key part of how I like to do science, and it’s really only feasible, given the timescales, in these experimentally tractable organisms with short generation times,” he says.</p> <p><strong>A physical approach to biology</strong></p> <p>Gore, who grew up on a Christmas tree farm in Corvallis, Oregon, first visited MIT as a high school senior and immediately felt at home.</p> <p>“I was staying with an older graduate from my high school at one of the fraternities across the river,” he recalls. “I played ping pong with different members of the fraternity for hours, and chatted with each of them about what they were doing, what they were excited about. It definitely felt like a place that I was going to appreciate.”</p> <p>Gore began his undergraduate career as a physics major but gradually added more majors until he ended up with four concentrations, in physics, mathematics, economics, and electrical engineering.</p> <p>After graduating from MIT, Gore went to the University of California at Berkeley, where he began studying electron transport in carbon nanotubes. However, his PhD advisor left Berkeley soon after that, so he switched to a biophysics lab, where he worked on building new kinds of microscopes to look at and manipulate individual biological molecules, such as DNA.&nbsp;&nbsp;</p> <p>He found that he enjoyed applying tools and strategies from physics to try to discover patterns that underlie biological phenomena.</p> <p>“I think many physicists, probably myself included, when we first learn biology there are a lot of things to memorize, and we tend not to be very good at memorizing things, so we decide we don’t like it,” Gore says. “But over time I realized that there are a bunch of big, deep questions in biology where the approach of a physicist is complementary to the approach taken by a molecular or cell biologist.”</p> <p>He says that another appealing aspect of biophysics is that it offers the opportunity to run experiments that can be contained on a lab bench, as opposed to the huge particle colliders that are required to answer many of the fundamental questions remaining in traditional physics.</p> <p>“I like experiments, and I wanted to do experiments that could be put on a bench, where you could really have the lead in your own project,” he says. “You may not be able to find out the origin of dark matter, but you have real control over your own experiment.”</p> <p><strong>Population predictions</strong></p> <p>After finishing his PhD, Gore returned to MIT as a Pappalardo Fellow in the Department of Physics, where he began studying population dynamics of microbes. Using game theory, a mathematical approach traditionally used by economists to predict individuals’ behavior in certain situations, he set out to explore cooperative behavior, which benefits other members of a species at a cost to the individual.</p> <p>Working with yeast populations in which some members cooperate, by producing an excess of food, and others cheat, by gorging themselves on the food produced by others, Gore found that if an individual benefits even slightly by cooperating, it can survive even when surrounded by individuals that don’t cooperate. This helps to explain the perpetuation of cooperative behavior, which had puzzled biologists because if only the fittest individuals survive, genes for a behavior that benefits other members of the population more than the cooperating individual should die out.</p> <p>As a faculty member, Gore has expanded his research to include analysis of the conditions that can lead to population collapse. In 2012, he showed that he could measure a population’s risk of collapse by monitoring how quickly it recovers from small disturbances such as food shortages or overcrowding. Later, he found that monitoring variations in population density in neighboring regions — a measure that is easier to obtain — can also be used to predict risk of collapse.</p> <p>Since Gore joined MIT’s faculty, the physics department has increased its focus on the field of biophysics, hiring three more specialists in that area. That core group, along with several other biophysicists in the department, launched the Physics of Living Systems group about three years ago.</p> <p>“We’re working to develop a critical mass of faculty who are taking this physics approach to understanding biology, which is different and hopefully complementary to the approach taken by other departments,” Gore says. “There really are a distinct set of approaches to biology in different departments, which is great because the different approaches give different insights.”</p> Jeff GoreImage: Jared CharneyFaculty, Physics, School of Science, Profile, Biology, Evolution, Microbes, Alumni/ae Artificial antimicrobial peptides could help overcome drug-resistant bacteria With aid of computer algorithm, researchers develop peptides more powerful than those found in nature. Mon, 16 Apr 2018 04:59:59 -0400 Anne Trafton | MIT News Office <p>During the past several years, many strains of bacteria have become resistant to existing antibiotics, and very few new drugs have been added to the antibiotic arsenal.</p> <p>To help combat this growing public health problem, some scientists are exploring antimicrobial peptides — naturally occurring peptides found in most organisms. Most of these are not powerful enough to fight off infections in humans, so researchers are trying to come up with new, more potent versions.</p> <p>Researchers at MIT and the Catholic University of Brasilia have now developed a streamlined approach to developing such drugs. Their new strategy, which relies on a computer algorithm that mimics the natural process of evolution, has already yielded one potential drug candidate that successfully killed bacteria in mice.</p> <p>“We can use computers to do a lot of the work for us, as a discovery tool of new antimicrobial peptide sequences,” says Cesar de la Fuente-Nunez, an MIT postdoc and Areces Foundation Fellow. “This computational approach is much more cost-effective and much more time-effective.”</p> <p>De la Fuente-Nunez and Octavio Franco of the Catholic University of Brasilia and the Dom Bosco Catholic University are the corresponding authors of the paper, which appears in the April 16 issue of <em>Nature Communications</em>. Timothy Lu, an MIT associate professor of electrical engineering and computer science, and of biological engineering, is also an author.</p> <p><strong>Artificial peptides</strong></p> <p>Antimicrobial peptides kill microbes in many different ways. They enter microbial cells by damaging their membranes, and once inside, they can disrupt cellular targets such as DNA, RNA, and proteins.</p> <p>In their search for more powerful, artificial antimicrobial peptides, scientists typically synthesize hundreds of new variants, which is a laborious and time-consuming process, and then test them against different types of bacteria.</p> <p>De la Fuente-Nunez and his colleagues wanted to find a way to make computers do most of the design work. To achieve that, the researchers created a computer algorithm that incorporates the same principles as Darwin’s theory of natural selection. The algorithm can start with any peptide sequence, generate thousands of variants, and test them for the desired traits that the researchers have specified.</p> <p>“By using this approach, we were able to explore many, many more peptides than if we had done this manually. Then we only had to screen a tiny fraction of the entirety of the sequences that the computer was able to browse through,” de la Fuente-Nunez says.</p> <p>In this study, the researchers began with an antimicrobial peptide found in the seeds of the guava plant. This peptide, known as Pg-AMP1, has only weak antimicrobial activity. The researchers told the algorithm to come up with peptide sequences with two features that help peptides to penetrate bacterial membranes: a tendency to form alpha helices and a certain level of hydrophobicity.</p> <p>After the algorithm generated and evaluated tens of thousands of peptide sequences, the researchers synthesized the most promising 100 candidates to test against bacteria grown in lab dishes. The top performer, known as guavanin 2, contains 20 amino acids. Unlike the original Pg-AMP1 peptide, which is rich in the amino acid glycine, guavanin is rich in arginine but has only one glycine molecule.</p> <p><strong>More powerful</strong></p> <p>These differences make guavanin 2 much more potent, especially against a type of bacteria known as Gram-negative. Gram-negative bacteria include many species responsible for the most common hospital-acquired infections, including pneumonia and urinary tract infections.</p> <p>The researchers tested guavanin 2 in mice with a skin infection caused by a type of Gram-negative bacteria known as <em>Pseudomonas aeruginosa</em>, and found that it cleared the infections much more effectively than the original Pg-AMP1 peptide.</p> <p>“This work is important because new types of antibiotics are needed to overcome the growing problem of antibiotic resistance,” says Mikhail Shapiro, an assistant professor of chemical engineering at Caltech, who was not involved in the study. “The authors take an innovative approach to this problem by computationally designing antimicrobial peptides using an&nbsp;‘in silico’&nbsp;evolutionary algorithm, which scores new peptides based on a set of properties known to be correlated with effectiveness. They also include an impressive array of experiments to show that the resulting peptides indeed have the properties needed to serve as antibiotics, and that they work in at least one mouse model of infections.”</p> <p>De la Fuente-Nunez and his colleagues now plan to further develop guavanin 2 for potential human use, and they also plan to use their algorithm to seek other potent antimicrobial peptides. There are currently no artificial antimicrobial peptides approved for use in human patients.</p> <p>“A <a href="">report</a> commissioned by the British government estimates that antibiotic-resistant bacteria will kill 10 million people per year by the year 2050, so coming up with new methods to generate antimicrobials is of huge interest, both from a scientific perspective and also from a global health perspective,” de la Fuente-Nunez says.</p> <p>The research was funded by the Ramón Areces Foundation and the Defense Threat Reduction Agency (DTRA).</p> Image: Ella MarushchenkoResearch, Electrical Engineering & Computer Science (eecs), Biological engineering, School of Engineering, Synthetic biology, Bacteria, Microbes, Antibiotics, Medicine With The Herman Project, home bakers become citizen scientists Network tracks the evolution of microbial communities in sourdough starter mixtures shared around the world. Thu, 12 Apr 2018 00:00:00 -0400 Carolyn Schmitt | Department of Civil and Environmental Engineering <p>Researchers from MIT are taking their microbial research out of the lab and into the kitchen.</p> <p>Their new <a href="">Herman Project</a> modernizes a longstanding tradition, with a digital network that tracks the evolution of sourdough starters as they are shared by home bakers around the world. By crowdsourcing information from the project’s participants, the researchers, based in the Department of Civil and Environmental Engineering (CEE), are investigating how the starters’ microbial communities change in different conditions and environments.</p> <p>Sourdough starters — a mixture of flour and water that, through the growth of bacteria, is responsible for the unique taste of sourdough bread — have traditionally been shared among friends and families. The starters, known affectionately as “Herman,” are typically shared with paper instructions for “feeding” the sourdough starter, and an accompanying letter to track the sourdough starter’s path as it is passed from person to person.</p> <p>Gabriel Leventhal, a postdoc in CEE and creator of The Herman Project, grew up participating in starter networks. Now, working with CEE Assistant Professor Otto X. Cordero and undergraduate students Sarah Weidman and Lindsey McAllister, Leventhal launched The Herman Project to create a more modern, online way to track the spread of the sourdough starters and to leverage the resulting data for science.</p> <p>“The Herman Project isn’t just doing citizen science and asking people to help us gather data. We’re giving people the opportunity to participate in the scientific process,” Leventhal says. “We plan to have feedback with the data that’s generated from the [sourdough] samples, where we can share the data and the genetic makeup of a starter, so participants can see how the starter changes over time, and potentially also do little experiments at home with their starters.”</p> <p>To help kick-start the project, Cordero and Leventhal hosted two first-year students, Weidman and McAllister, in their lab over MIT’s Independent Activities Period as part of CEE’s mini-Undergraduate Research Opportunities Program (UROP). Weidman and McAllister fine-tuned the instructions for participants, designed an accessible online platform, tested The Herman Project in its beta phase, and conducted online research for The Herman Project website.</p> <p>“My primary part was working on the instructions, and we wanted to make it more visual and look as easy as possible,” McAllister says. “We tried to make it very simple and easy to follow. I learned graphic design tools and made a big wheel that we later ended up animating to make it more interactive and highlight where in the wheel you were. Then at the end, it gave you a way to find out what our next steps would be.”</p> <p>Meanwhile, Weidman translated the complex, scientific details of sourdough into more understandable blurbs for the website. “I really liked how we were able to take what we were learning and present it to the community,” she says.</p> <p>The Herman Project works by giving each sample of “Herman,” the sourdough starter, an identification number, and using an online platform to instruct users for how to feed Herman. Herman needs to be fed with additional flour and water over four days to acclimatize to its new kitchen environment and to let the mixture ferment. Herman is then ready to be mixed with baking ingredients and cooked. Not all of the starter is used, however, and participants save some of Herman to use for future baking.</p> <p>As Herman is passed between friends, the new participants also log information on The Herman Project website, noting their location and type of flour used while growing their new starter. Each user thus adds data for the researchers to study and expand the network. In addition to participants logging their approximate location and environmental conditions of Herman as it is fed, they are also asked to share a sample of Herman with Cordero’s lab. The researchers, assisted by Weidman and McAllister, will isolate the microbes and study how the microbial communities differ across time and environments. The project's network is currently centralized in the greater Boston area, as members of Cordero’s lab begin to share Herman with their peers.</p> <p>“The Herman Project allows us to study microbial evolution in the context of communities, where multiple species coexist and interact,” Cordero explains. “This is one of the frontiers in our field. I found it really elegant and exciting that we can take advantage of the social dynamics around sourdough to ‘crowdsource’ an evolution experiment through the Herman Project.”</p> <p>The utilization of microbes such as bacteria and yeast is essential for the creation of sourdough and other fermented foods like wine and beer. For sourdough, microbes break down complex carbohydrates in the flour and water mixture and ferment the dough over a series of days. This creates carbon dioxide and produces air bubbles to help the dough rise. The process also produces lactic acid, which gives the dough its sour flavor.&nbsp;</p> <p>For The Herman Project, combining the networked information about the spread of different sourdough starters with the microbial data from the dough samples allows the researchers to analyze how microbial communities change as they transfer between different environmental conditions.</p> <p>A lot is known about how individual microbes evolve, but Leventhal and Cordero are seeking to use The Herman Project to ask questions about if and how being part of a microbial community impacts the way microbes evolve in different conditions.&nbsp;</p> <p>“I think The Herman Project could help us address many important questions,” Cordero says. “For instance, what is the impact of strain-level (within-species) diversity with respect to stability and function, are there alternative trajectories for evolution, and if so, what controls them? These are important questions to address if we want to learn how to control and design microbial consortia.”</p> <p>“Microbial communities have been used as biotechnology by human societies for millennia.&nbsp;A key difference between using microbes as engineering tools and inert components, however, is that “microbes are 'alive' — they grow, they get mutations, and they evolve. We need to understand how this influences their function as a community if we want to use them sustainably,” Leventhal says.</p> <p>Under Leventhal’s guidance, Weidman and McAllister are planning to conduct analyses of the bacteria and yeast genomes to get a complete understanding of the microbial community of each sample as part of their UROP.</p> <p>“The Herman Project is a really cool way to take something that a lot of people know about, and to investigate what’s actually happening,” McAllister says.</p> Gabriel Leventhal (right), a postdoc in the Department of Civil and Environmental Engineering, works with UROP students Sarah Weidman (left) and Lindsey McAllister (center) to analyze samples from The Herman Project, a citizen-science sourdough project. Photo: Allison Dougherty/Department of Civil and Environmental EngineeringCivil and environmental engineering, School of Engineering, Undergraduate Research Opportunities Program (UROP), Bacteria, Evolution, Microbes, Crowdsourcing Understanding microbial competition for nitrogen Interactions among microorganisms account for nitrite accumulation just below the sunlit zone, with implications for oceanic carbon and nitrogen cycling. Tue, 10 Apr 2018 14:30:01 -0400 Lauren Hinkel | Oceans at MIT <p>Nitrogen is a hot commodity in the surface ocean. Primary producers including phytoplankton and other microorganisms consume and transform it into organic molecules to build biomass, while others transform inorganic forms to access their chemical store of energy. All of these steps are part of the complex nitrogen cycle of the upper water column.</p> <p>About 200 meters down, just below the ocean’s sunlit zone, resides a layer of nitrite, an intermediate compound in the nitrogen cycle. Scientists have found this robust feature, called the primary nitrite maximum, throughout the world’s oxygenated oceans. While several individual hypotheses have been put forward, none have convincingly explained this marine signature until now.</p> <p>A recent <em>Nature Communications</em>&nbsp;<a href="" target="_blank">study</a> led by researchers in the Program in Atmospheres, Oceans and Climate (<a href="" target="_blank">PAOC</a>) within MIT’s Department of Earth, Atmospheric and Planetary Sciences (<a href="" target="_blank">EAPS</a>) uses theory, modeling, and observational data to investigate the ecological mechanisms producing the observed nitrite accumulation and dictating its location in the water column. Lead author <a href="" target="_blank">Emily Zakem</a> — a former EAPS graduate student who is now a postdoc at the University of Southern California — along with EAPS Principal Research Scientist&nbsp;<a href="" target="_blank">Stephanie Dutkiewicz</a>&nbsp;and Professor&nbsp;<a href="" target="_blank">Mick Follows&nbsp;</a>show that physiological constraints and resource competition between phytoplankton and nitrifying microorganisms in the sunlit layer can yield this ocean trait.&nbsp;</p> <p><strong>Regulating the biological pump</strong></p> <p>Despite its low oceanic concentration, nitrite (NO<sub>2</sub><sup>-</sup>) plays a key role in global carbon and nitrogen cycles. Most of the nitrogen in the ocean resides in the inorganic form of nitrate (NO<sub>3</sub><sup>-</sup>), which primary producers and microorganisms chemically reduce it to build organic molecules. Remineralization occurs when the reverse process takes place: Phytoplankton and other heterotrophic bacteria break down these organic compounds into ammonium (NH<sub>4</sub><sup>+</sup>), a form of inorganic nitrogen. Ammonium then can be consumed again by primary producers, which get their energy from light. Other microorganisms called chemoautotrophs also use the ammonium both to make new biomass and as a source of energy. To do this, they extract oxygen from seawater and transform it, a process called nitrification, which occurs in two steps. First, the microbes convert ammonium into nitrite and then to nitrate.</p> <p>Somewhere along the line, nitrite has been accumulating at the base of the sunlit zone, which has implications for ocean biogeochemistry. “Broadly, we’re trying to understand what controls the remineralization of organic matter in the ocean. It’s that remineralization that is responsible for forming the biological pump, which is the extra storage of carbon in the ocean due to biological activity,” says Zakem. It’s this strong influence that nitrogen has on the global carbon cycle that captures Follows’ interest. “Growth of phytoplankton on nitrate is called ‘new production’ and that balances the amount that’s sinking out of the surface and controls how much carbon is stored in the ocean. Growth of phytoplankton on ammonium is called recycled production, which does not increase ocean carbon storage,” Follows says. “So we wish to understand what controls the rates of supply and relative consumption of these different nitrogen species.”</p> <p><strong>Battle for nitrogen</strong>&nbsp;</p> <p>The primary nitrite maximum resides between two groups of microorganisms in most of the world’s oceans. Above it in the sunlit zone are the phytoplankton, and in the primary nitrite maximum and slightly below that rest an abundance of nitrifying microbes in an area with high rates of nitrification. Researchers classify these microbes into two groups based on their preferred nitrogen source: the ammonium oxidizing organisms (AOO) and nitrite oxidizing organisms (NOO). In high latitudes like the Earth’s subpolar regions, nitrite accumulates in the surface sunlit zone as well as deeper.</p> <p>Scientists have postulated that there might be two not mutually exclusive reasons for the build-up of nitrite: Nitrification by chemoautotrophic microbes, and when stressed, phytoplankton can reduce nitrate to nitrite. Since isotopic evidence does not support the latter, the group looked into the former.&nbsp;</p> <p>“The long-standing hypothesis was that the locations of nitrification were controlled by the inhibition of light of these [nitrifying] microorganisms, so the microorganisms that carry out this process were restricted from the surface,” Zakem says, implying that these nitrifying chemoautotrophs got sunburned. But instead of assuming that was true, the group examined the ecological interactions among these and other organisms in the surface ocean, letting the dynamics fall out naturally. To do this they collected microbial samples from the subtropical North Pacific and evaluated them for metabolism rates, efficiencies and abundances, and assessed the physiological needs and constraints of the different nitrifying microbes by reducing the biological complexity of their metabolisms down to its underlying chemistry and thus hypothesizing some of the more fundamental constrains. They used this information to inform the dynamics of the nitrifying microbes in both a one-dimensional and three-dimensional biogeochemical model.</p> <p>The group found that by employing this framework, they could resolve the interactions between these nitrifying chemoautotrophs and phytoplankton and therefore simulate the accumulation of nitrite at the primary nitrite maximum in the appropriate locations. In the surface ocean when inorganic nitrogen is a limiting factor, phytoplankton and ammonium oxidizing microbes have similar abilities to acquire ammonium, but because phytoplankton need less nitrogen to grow and have a faster growth rate, they are able to outcompete the nitrifiers, excluding them from the sunlit zone. In this way, they were able to provide an ecological explanation for where nitrification happens without having to rely on light inhibition dictating the location.</p> <p>Comparing the fundamental physiologies of the nitrifiers revealed that differences in metabolisms and cell size could account for the nitrite build-up. The researchers found that the second step of the nitrification process that’s carried out by the nitrite oxidizers requires more nitrogen for the same amount of biomass being created by these organisms, meaning that the ammonia oxidizers can do more with less, and that there are fewer nitrite oxidizers than the ammonia oxidizers. The nitrite oxidizing microbes also have a higher surface to volume constraint than the smaller and ubiquitous ammonium oxidizing microbes, making nitrogen uptake more difficult. “This is an alternative explanation for why nitrite should accumulate,” Zakem says. “We have two reasons that point in the same direction. We can’t distinguish which one it is, but all of the observations are consistent with either of these two or some combination of both being the control.”</p> <p>The researchers were also able use a global climate model to reproduce an accumulation of nitrite in the sunlit zone of places like subpolar regions, where phytoplankton are limited by another resource other than nitrogen like light or iron. Here, nitrifiers can co-exist with phytoplankton since there’s more nitrogen available to them. Additionally, the deep mixed layer in the water can draw resources away from the phytoplankton, giving the nitrifiers a better chance at survival in the surface.</p> <p>“There’s this long standing hypothesis that the nitrifiers were inhibited by light and that’s why they only exist at the subsurface,” Zakem says. “We’re saying that maybe we have a more fundamental explanation: that this light inhibition does exist because we’ve observed it, but that’s a consequence of long-term exclusion from the surface.”</p> <p><strong>Thinking bigger</strong></p> <p>“This study pulled together theory, numerical simulations, and observations to tease apart and provide a simple quantitative and mechanistic description for some phenomena that were mysterious in the ocean,” Follows says. “That helps us tease apart the nitrogen cycle, which has an impact on the carbon cycle. It's also opened up the box for using these kind of tools to address other questions in the microbial oceanography.” He notes that the fact that these microbes are shunting ammonium into nitrate near the sunlit zone complicates the story of carbon storage in the ocean.</p> <p>Two researchers who were not involved with the study, Karen Casciotti, associate professor in the Stanford University Department of Earth System Science, and Angela Landolfi, a scientist in the&nbsp;marine biogeochemical modeling department at the GEOMAR Helmholtz Centre for Ocean&nbsp;Research Kiel, agree. “This study is of great significance as it provides evidence of how organisms’ individual traits affect competitive interactions among microbial populations and provide a direct control on nutrients' distribution in the ocean,” says Landolfi. “In essence Zakem et al., provide a better understanding of the link between different levels of complexity from individual- to community up to environmental level, providing a mechanistic framework to predict changes in community composition and their biogeochemical impact under climatic changes,” says Landolfi.</p> <p>This research was funded by the Simons Foundation’s Simons Collaboration on Ocean Processes and Ecology, the Gordon and Betty Moore Foundation, and the National Science Foundation.</p> New MIT research describes how marine microorganisms contribute to a layer of nitrite just below the ocean's sunlit zone.Research, Microbiology, Chemistry, Biology, Oceanography and ocean engineering, Ocean science, Microbes, Carbon, Ecology, EAPS, School of Science Determining the timing of methanogen evolution Scientists conclude methane-producing microbes date back 3.5 billion years, supporting the hypothesis that they could have contributed to early global warming. Wed, 04 Apr 2018 13:15:00 -0400 Helen Hill | EAPS <p>Early forms of life very likely had metabolisms that transformed the primordial Earth, such as initiating the carbon cycle and producing most of the planet’s oxygen through photosynthesis. About 3.5 billion years ago, the Earth seems to have already been covered in liquid oceans, but the sun at that time was not bright or warm enough to melt ice. To explain how the oceans remained unfrozen, it has been suggested that greenhouse gases such as methane produced warming in the early atmosphere, just as they do in global warming today.</p> <p>Naturally occurring methane is mainly produced by a group of microbes, methanogenic archaea, through a metabolism called methanogenesis. While there is some evidence from carbon isotope data that sources of methane as ancient&nbsp;as 3.5 billion years old may have been biological in origin, until now there has been no solid evidence that methane-producing microbes existed early enough in Earth’s history to be responsible for keeping the early Earth warmed up.</p> <p>Now, in a <a href="" target="_blank">paper</a> published in the journal&nbsp;<em>Nature Ecology and Evolution</em>, Jo Wolfe, a postdoc in the Department of Earth, Atmospheric and Planetary Sciences (EAPS) at MIT, and Gregory Fournier, an assistant professor in EAPS, report new work combining horizontal gene transfer data with the microbial fossil record that allowed them to estimate absolute ages for methane-producing microbes on the geological timeline.</p> <p><strong>Paleontology meets genetics</strong></p> <p>Wolfe is a paleontologist specializing in how fossil and living animal species are related in the tree of life. Fournier specializes in exploring how genomes from living organisms can be used to study the early evolution of microbes. Cracking this puzzle required both areas of expertise.</p> <p>"Trace chemical evidence hints that methane and the microbes that produced it could have been present, but we didn't know whether methogenic archaea were actually present at that time," Wolfe says.</p> <p>To bridge between fossil and genomic data, Wolfe and Fournier used genomes from living microbes that preserve a record of their early history. These DNA sequences can be accessed through phylogenetic analysis and compared to one another, the researchers&nbsp;explain, in order to find the best branching “tree” that describes their evolution. As one works back along this tree, the branches represent increasingly ancient lineages of microbes that existed in Earth’s deep history. Changes along these branches can be measured, producing a molecular clock&nbsp;that&nbsp;calculates the rate of evolution along each branch, and, from that, a probabilistic estimate of the relative and absolute timing of common ancestors within the tree. A&nbsp;molecular clock requires fossils, however, which methanogens lack.&nbsp;</p> <p><strong>Calibrating the tree of life</strong></p> <p>In order to solve this difficulty, Wolfe and Fournier harnessed horizontal gene transfers, or swaps of genetic material between the ancestors of different groups of organisms. Unlike vertical transmission of DNA from parent to offspring — which is how most human genes are inherited — horizontal transfers can pass genes between distantly related microorganisms. They found that genes were donated from a group within the methanogenic archaea to the ancestor of all oxygen-producing photosynthetic cyanobacteria, which do have some fossils. Using the gene transfers and the cyanobacterial fossils together, they were able to constrain and guide the molecular clock of methane producers, and found that the methane-producing microbes were indeed over 3.5 billion years old, supporting the hypothesis that these microbes could have contributed to early global warming.</p> <p>"This is the first study to combine gene transfers and fossils to estimate absolute ages for microbes on the geological timeline," Fournier says. "Knowing the ages of microbial groups allows us to expand this powerful approach to study other events in early planetary and environmental evolution, and eventually, to build a timescale for the tree of all life."</p> <p>The&nbsp;research&nbsp;was funded by the Simons Foundation Collaboration and the National Science Foundation.</p> Artist’s view of the young Earth as it is believed to have looked 3.5 billion years agoImage: NASA GSFCSchool of Science, Earth and atmospheric sciences, Research, Climate change, EAPS, Global Warming, Greenhouse gases, Microbes, National Science Foundation (NSF), Evolution Scientists find different cell types contain the same enzyme ratios New discovery suggests that all life may share a common design principle. Thu, 29 Mar 2018 12:00:00 -0400 Justin Chen | Department of Biology <p>By studying bacteria and yeast, researchers at MIT have discovered that vastly different types of cells still share fundamental similarities, conserved across species and refined over time. More specifically, these cells contain the same proportion of specialized proteins, known as enzymes, which coordinate chemical reactions within the cell.</p> <p>To grow and divide, cells rely on a unique mixture of enzymes that perform millions of chemical reactions per second. Many enzymes, working in relay, perform a linked series of chemical reactions called a “pathway,” where the products of one chemical reaction are the starting materials for the next. By making many incremental changes to molecules, enzymes in a pathway perform vital functions such as turning nutrients into energy or duplicating DNA.</p> <p>For decades, scientists wondered whether the relative amounts of enzymes in a pathway were tightly controlled in order to better coordinate their chemical reactions. Now, researchers have demonstrated that cells not only produce precise amounts of enzymes, but that evolutionary pressure selects for a preferred ratio of enzymes. In this way, enzymes behave like ingredients of a cake that must be combined in the correct proportions and all life may share the same enzyme recipe.</p> <p>“We still don’t know why this combination of enzymes is ideal,” says Gene-Wei Li, assistant professor of biology at MIT, “but this question opens up an entirely new field of biology that we’re calling systems level optimization of pathways. In this discipline, researchers would study how different enzymes and pathways behave within the complex environment of the cell.”</p> <p>Li is the senior author of the study, which appears online in the journal <em>Cell</em> on March 29, and in print on April 19. The paper’s lead author, Jean-Benoît Lalanne, is a graduate student in the MIT Department of Physics.</p> <p><strong>An unexpected observation</strong></p> <p>For more than 100 years, biologists have studied enzymes by watching them catalyze chemical reactions in test tubes, and — more recently — using X-rays to observe their molecular structure.</p> <p>And yet, despite years of work describing individual proteins in great detail, scientists still don’t understand many of the basic properties of enzymes within the cell. For example, it is not yet possible to predict the optimal amount of enzyme a cell should make to maximize its chance of survival.</p> <p>The calculation is tricky because the answer depends not only on the specific function of the enzyme, but also how its actions may have a ripple effect on other chemical reactions and enzymes within the cell.</p> <p>“Even if we know exactly what an enzyme does,” Li says, “we still don’t have a sense for how much of that protein the cell will make. Thinking about biochemical pathways is even more complicated. If we gave biochemists three enzymes in a pathway that, for example, break down sugar into energy, they would probably not know how to mix the proteins at the proper ratios to optimize the reaction.”</p> <p>The study of the relative amounts of substances — including proteins — is known as “stoichiometry.” To investigate the stoichiometry of enzymes in different types of cells, Li and his colleagues analyzed three different species of bacteria — <em>Escherichia</em> <em>coli,</em> <em>Bacillus</em><em> subtilis,</em> and <em>Vibrio</em> <em>natriegens — </em>as well as the budding yeast <em>Saccharomyces</em><em> cerevisiae.</em> Among these cells, scientists compared the amount of enzymes in 21 pathways responsible for a variety of tasks including repairing DNA, constructing fatty acids, and converting sugar to energy. Because these species of yeast and bacteria have evolved to live in different environments and have different cellular structures, such as the presence or lack of a nucleus, researchers were surprised to find that all four cells types had nearly identical enzyme stoichiometry in all pathways examined.</p> <p>Li’s team followed up their unexpected results by detailing how bacteria achieve a consistent enzyme stoichiometry. Cells control enzyme production by regulating two processes. The first, transcription, converts the information contained in a strand of DNA into many copies of messenger RNA (mRNA). The second, translation, occurs as ribosomes decode the mRNAs to construct proteins. By analyzing transcription across all three bacterial species, Li’s team discovered that the different bacteria produced varying amounts of mRNA encoding for enzymes in a pathway.</p> <p>Different amounts of mRNA theoretically lead to differences in protein production, but the researchers found instead that the cells adjusted their rates of translation to compensate for changes in transcription. Cells that produced more mRNA slowed their rates of protein synthesis, while cells that produced less mRNA increased the speed of protein synthesis. Thanks to this compensation, the stoichiometry of enzymes remained constant across the different bacteria.</p> <p>“It is remarkable that <em>E. coli</em> and <em>B. subtilis </em>need the same relative amount of the corresponding proteins, as seen by the compensatory variations in transcription and translation efficiencies,” says Johan Elf, professor of physical biology at Uppsala University in Sweden. “These results raise interesting questions about how enzyme production in different cells have evolved."</p> <p>“Examining bacterial gene clusters was really striking,” lead author Lalanne says. “Over a long evolutionary history, these genes have shifted positions, mutated into different sequences, and been bombarded by mobile pieces of DNA that randomly insert themselves into the genome. Despite all this, the bacteria have compensated for these changes by adjusting translation to maintain the stoichiometry of their enzymes. This suggests that evolutionary forces, which we don’t yet understand, have shaped cells to have the same enzyme stoichiometry.”<br /> <br /> <strong>Searching for the stoichiometry regulating human health</strong></p> <p>In the future, Li and his colleagues will test whether their findings in bacteria and yeast extend to humans. Because unicellular and multicellular organisms manage energy and nutrients differently, and experience different selection pressures, researchers are not sure what they will discover.</p> <p>“Perhaps there will be enzymes whose stoichiometry varies, and a smaller subset of enzymes whose levels are more conserved,” Li says. “This would indicate that the human body is sensitive to changes in specific enzymes that could make good drug targets. But we won’t know until we look.”</p> <p>Beyond the human body, Li and his team believe that it is possible to find simplicity underlying the complex bustle of molecules within all cells. Like other mathematical patterns in nature, such as the the spiral of seashells or the branching pattern of trees, the stoichiometry of enzymes may be a widespread design principle of life.</p> <p>The research was funded by the National Institutes of Health, Pew Biomedical Scholars Program, Sloan Research Fellowship, Searle Scholars Program, National Sciences and Engineering Research Council of Canada, Howard Hughes Medical Institute, National Science Foundation, Helen Hay Whitney Foundation, Jane Coffin Childs Memorial Fund, and the Smith Family Foundation.</p> MIT researchers have discovered that enzymes performing the same function in yeast and bacteria may have different structures, but are present in the same relative amounts within each type of cell.Image: Haynathart/Wikimedia CommonsResearch, Bacteria, Biology, Evolution, Genetics, Microbes, Physics, DNA, RNA, School of Science Timothy Lu seeks to combat disease by reprogramming biological systems Synthetic biologist hopes to develop treatments for cancer and other diseases. Sun, 04 Mar 2018 23:59:59 -0500 Anne Trafton | MIT News Office <p>In high school and college, Timothy Lu spent a lot of time programming computers. But as his college graduation approached, he turned his attention toward programming biological systems. The field of synthetic biology was just beginning to emerge, and he wanted to be part of it.</p> <p>Since that time, Lu has devoted his career to coming up with novel ways to engineer cells, both bacterial and human, to perform new functions. Using this approach, he hopes to develop new therapies for a range of diseases, from cancer to drug-resistant infections.</p> <p>Achieving this goal requires overcoming many more challenges than programming computer chips does, he says, because living cells behave in more unpredictable ways and the underlying programming language is not deeply understood.</p> <p>“The advantage of the semiconductor industry is they were able to build individual units and put them together and scale them very efficiently. They weren’t putting things into an existing system that was already messy and where you didn’t know the wiring diagram,” says Lu, who recently earned tenure in MIT’s Department of Electrical Engineering and Computer Science. “In contrast, we’re simultaneously trying to figure out how to assemble genetic circuits together and also stick it into this giant mish-mash of what the cell normally does. That’s the key challenge.”</p> <p><strong>Fundamental challenges</strong></p> <p>Lu’s early interest in computer programming was inspired by his father, who worked as an electrical engineer at IBM.</p> <p>“My dad brought home some of the early PCs that they were building at IBM, and I spent a lot of time programming computers and making them do very simple things,” Lu recalls.</p> <p>When Lu was 10 years old, his family moved from upstate New York to Taiwan, where his parents had grown up. He returned to the United States to attend MIT, where he majored in electrical engineering and computer science. When he graduated in 2003, Lu realized that he enjoyed programming but wanted to apply this interest to nascent technologies with fundamental challenges that had yet to be solved.</p> <p>He soon became intrigued by the idea of programming biological systems. Many Boston-area researchers were beginning to work in this field, known as synthetic biology. Lu decided to apply to the Harvard-MIT Program in Health Sciences and Technology (HST), and he arranged to do his PhD research in a lab at Boston University headed by synthetic biology pioneer James Collins (who is now a faculty member at MIT).</p> <p>As part of his HST coursework, Lu saw many patients with antibiotic-resistant infections and became interested in trying to develop new treatments for such infections. In Collins’ lab, Lu worked on engineering viruses that infect bacteria, also known as bacteriophages. He engineered these bacteriophages to produce enzymes that help to chew up biofilms (layers of bacteria that stick to surfaces), and in 2008, he <a href="">won the Lemelson-MIT Student Prize</a> for this work. In a related project, he engineered bacteria to express factors that make them more susceptible to existing antibiotics.</p> <p>After finishing his PhD, and an MD as well, Lu pondered a few career paths, including practicing medicine or working at a startup based on his research, but he ended up applying for a faculty position in MIT’s Department of Electrical Engineering and Computer Science, which was looking for someone interested in programming biological circuits. MIT had recently hired a couple of prominent synthetic biologists to launch the Institute’s new Synthetic Biology Center, and Lu was eager to get involved.</p> <p>“At the time, MIT was trying to build up its synthetic biology team. I knew if I joined I would be the most junior member but would be part of something that was going to quickly grow, so it was exciting for me,” says Lu, who later received a joint appointment in MIT’s Department of Biological Engineering.</p> <p><strong>Disease-fighting circuits</strong></p> <p>Much of Lu’s research focuses on designing genetic circuits that can perform computations in living cells, such as counting events or tracking whether a specific event has occurred and then provoking the appropriate response.</p> <p>“My deepest personal interest is in the clinical applications of synthetic biology,” Lu says. “Can you program cells or viruses to sense and respond to their environment, so that you can try to detect the presence of disease and treat it effectively and safely?”</p> <p>In a recent study, Lu and his colleagues <a href="">developed a synthetic gene circuit</a> that triggers the body’s immune system to attack cancers when it detects signs of the disease. They are also working on designing more control elements to help them turn such circuits on and off, and developing ways to help circuits change their output in response to different disease biomarkers.</p> <p>Lu’s lab also continues to pursue novel antimicrobial treatments, including engineered bacteriophages as well as <a href="">new types of antimicrobial peptides</a>. By modifying these naturally occurring proteins, Lu hopes to make them more efficient at killing microbes, and potentially to develop them for use against infection in humans.</p> <p>Such research has become increasingly important, Lu says, as more strains of bacteria become resistant to existing drugs.</p> <p>“When we first started, in the early 2000s, people didn’t care about antibiotic resistance that much. Most antibiotics were still working and people didn’t think it was a big deal,” he says. “But over time, resistance has continued to grow, and the antibiotic pipeline has become drier and drier. So we still firmly believe that we need new strategies. The days when you would just go and dig in the dirt and easily find new antibiotics with broad-spectrum activity are over.”</p> Timothy Lu's early interest in computer programming was inspired by his father, who worked as an electrical engineer at IBM.Image: M. Scott BrauerResearch, Faculty, Electrical Engineering & Computer Science (eecs), Biological engineering, School of Engineering, DNA, Microbes, Synthetic biology, Medicine, Health sciences and technology, Profile, Cancer A microbial approach to agriculture A new special subject, Agricultural Microbial Ecology, takes students to Israel. Wed, 14 Feb 2018 13:00:00 -0500 Carolyn Schmitt | Department of Civil and Environmental Engineering <p>The ability of animals to digest plant material is facilitated by tiny microbes in the gut that can break down complex carbohydrates. This dependency on microbes is most extreme in herbivores such as cows, which have developed a symbiotic relationship with their gut microbes. Cow microbiomes — the assemblage of microbes that inhabit their digestive system —&nbsp;have tremendous importance for agriculture, as they mediate the conversion of solar energy, stored in plant tissues, into animal protein consumed by humans across the globe.</p> <p>Engineering these microbial communities to increase the efficiency of the plant-to-biomass conversion pipeline is thus a major challenge for microbiologists and engineers, and one that puts to test the still-limited understanding of how to control complex ecological systems such as gut-associated microbiomes.</p> <p>A new special subject, 1.S992 (Agricultural Microbial Ecology) from the Department of Civil and Environmental Engineering (CEE), took a group of undergraduate students to Israel over MIT’s Independent Activities Period to learn the cutting-edge techniques and methods used to study these microbial communities, and to explore the frontier of microbiome engineering alongside graduate students from Ben-Gurion University of the Negev (BGU).</p> <p>“Professor Itzhak Mizrahi [of BGU] studies the cow rumen [one chamber of a cow stomach], and at MIT we study the ocean, but we are fundamentally studying processes that are very similar. We both study microbes degrading complex materials; in the ocean it’s algal cell walls, and in the rumen it’s plant fibers,” explains CEE assistant professor Otto X. Cordero, a microbiologist who studies micro-scale ecology and who led the special subject with Mizrahi. “The goal of the class is to learn how to explore the problem of how to rationally design a microbial consortium. What this means is we are trying to understand, for different species and organisms, what compounds are produced when they degrade one resource and how other organisms can utilize those compounds. We want to learn how to predict the functioning of an interconnected metabolic system.”</p> <p>To help with their research, Cordero and Mizrahi enlisted the help of students from their respective universities. For two weeks, MIT students worked with students from BGU to reverse-engineer microbial communities that inhabit the cow rumen. It is in the rumen that microbial communities have the special ability to break down recalcitrant plant materials and turn them into energy. The students thus designed different microbial ecosystems that could potentially be transplanted into an animal to make it degrade plant material more efficiently — a feature with considerable agricultural benefits.</p> <p>“By seeking to understand the collective functions of the microbial system and interactions within communities, we are trying to determine the factors that control the function and efficiency of the cow rumen,” Cordero explains. “For example, we could determine how much of the excreted product goes to biomass, the animal’s weight, versus going to gases such as methane, a potent greenhouse gas.”</p> <p>Agricultural Microbial Ecology was designed to be a hands-on, lab-based program to give students a more complete understanding of the technology and methods used to analyze the microbiomes and to expose students to a new way of thinking about microbial communities.</p> <p>“We specifically aimed to provide the students with conceptual and technical understanding of how microbes, which are the building blocks of the microbiome, could be isolated from their environments, studied for their characteristics, and reassembled again in a desired manner,” Mizrahi explains. &nbsp;&nbsp;&nbsp;</p> <p>In the lab, the students analyzed the preferred resources and excretion products of more than 30 different relevant species from the rumen and human gut. Using this information, the students designed communities that could consume certain resources and convert them into desired compounds, while minimizing the production of others.</p> <p>“We got to learn how to assemble a microbial community from the bottom up, and while it's certainly fast-paced, it was really cool to be able to experience every step of the process and have ownership over almost every aspect of our microbial communities at the end,” says Mikayla Murphy, a CEE senior who participated in the class.</p> <p>At BGU, the students used cutting-edge tools and techniques, including advanced microscopy that allowed the students to take images of the microbes, gas chromatrography-mass spectrometry to identify the metabolites produced by rumen microbes, as well as genomics to predict the presence of various metabolic pathways.</p> <p>These efforts provide insight into how these microbial communities can be manipulated. Biotechnology companies are trying to do similar work, but many are essentially mixing communities at random, Cordero explains. “The challenge is to understand the logic behind these processes,” he says.</p> <p>After two weeks in Israel, the students bonded inside and outside of the lab. “It was amazing to see how science can make students from different backgrounds and cultures engaged towards a specific goal,” Mizrahi says.</p> <p>In addition to experiencing Israeli culture and college life, the groups from MIT and BGU also took advantage of local attractions and historical sites. During the weekends, the students embarked on adventures like visiting and swimming (and floating) in the Dead Sea, hiking in the desert in the Negev region of&nbsp;Southern Israel, and spending time in Jerusalem.</p> <p>“My biggest takeaway [from the subject] is that knowledge of microbial ecology can be a really powerful tool, and thus it will probably be an important field of study for many years to come,” Murphy says. “Although microbes are small, they have a large impact on a lot of our biggest problems, such as climate change and food production.”</p> <p>The subject was made possible in part by MIT International Science and Technology Initiatives, the National Science Foundation, the United States-Israel Binational Science Foundation, and the United States–Israel Binational Science Foundation.</p> A new special subject, 1.S992 (Agricultural Microbial Ecology) from the Department of Civil and Environmental Engineering, took a group of undergraduate students to Israel over MIT’s Independent Activities Period to learn cutting-edge techniques used to study microbial communities.Photo: Otto X. CorderoSchool of Engineering, Civil and environmental engineering, Biology, Classes and programs, Independent Activities Period, Students, Agriculture, National Science Foundation (NSF), Bacteria, Microbes New type of virus found in the ocean The unusual characteristics of these abundant, bacteria-killing viruses could lead to evolutionary insights. Wed, 24 Jan 2018 13:00:00 -0500 David L. Chandler | MIT News Office <p>A type of virus that dominates water samples taken from the world’s oceans has long escaped analysis because it has characteristics that standard tests can’t detect. However, researchers at MIT and the Albert Einstein College of Medicine have now managed to isolate and study representatives of these elusive viruses, which provide a key missing link in virus evolution and play an important role in regulating bacterial populations, as a new study reports.</p> <p>Viruses are the main predators of bacteria, and the findings suggest that the current view of bacterial virus diversity has a major blind spot. These conclusions have emerged through detailed analysis of marine samples led by MIT postdoc Kathryn Kauffman, professor of civil and environmental engineering Martin Polz, professor Libusha Kelly of Albert Einstein College of Medicine, and nine others. The results are being reported this week in the journal <em>Nature</em>.</p> <p>The newly identified viruses lack the “tail” found on most catalogued and sequenced bacterial viruses, and have several other unusual properties that have led to their being missed by previous studies. To honor that fact, the researchers named this new group the <em>Autolykiviridae</em> — after a character from Greek mythology who was storied for being difficult to catch. And, unlike typical viruses that prey on just one or two types of bacteria, these tailless varieties can infect dozens of different types, often of different species, underscoring their ecological relevance.</p> <p>This research “opens new avenues for furthering our understanding of the roles of viruses in the ocean,” says Jed Fuhrman, the McCulloch-Crosby Chair of Marine Biology at the University of Southern California, who was not involved in this work. “In a practical sense, it also shows how we need to alter some commonly used methods in order to capture these kinds of viruses for various studies,” he says. “I’d say it is an important advance in the field.”</p> <p>Current environmental models of virus-bacteria interactions are based on the well-studied tailed viruses, Kauffman explains, so they may be missing important aspects of the interactions taking place in nature.</p> <p>“We already knew that viruses are very important there,” Kauffman says, referring to the surface ocean, where the researchers’ samples were drawn, and where about 10 million viruses are found in every milliliter of water. Polz says that while “most of the viruses studied in labs have tails, most of those in the ocean don’t.” So the team decided to study one subset of tailless viruses, which infects a group of bacteria called <em>Vibrio</em>. After extensive tests, they found “that some of these were infecting unusually large numbers of hosts,” he says.</p> <p>After sequencing representatives of the <em>Autolykiviridae</em>, the researchers found “their genomes were quite different from other viruses,” Polz says. For one thing, their genomes are very short: about 10,000 bases, compared to the typical 40,000-50,000 for tailed viruses. “When we found that, we were surprised,” he says.</p> <p>With the new sequence information, the researchers were able to comb through databases and found that such viruses exist in many places. The research also showed that these viruses tend to be underrepresented in databases because of the ways samples are typically handled in labs. The methods the team developed to obtain these viruses from environmental samples could help researchers avoid such losses of information in the future. In addition, Kauffman says, typically the way researchers test for viral activity is by infecting bacteria with the viral sample and then checking the samples a day later to look for signs that patches of the bacteria have been killed off. But these particular nontailed viruses often act more slowly, and the killed-off regions don’t show up until several days have passed — so their presence was never noticed in most studies.</p> <p>The new group of viruses may especially be widespread. “We don’t think it’s ocean-specific at all,” Polz says. For example, the viruses may even be prevalent in the human biome, and they may play roles in major biogeochemical cycles, he says, such as the cycling of carbon.</p> <p>Another important aspect of theses findings is that the <em>Autolykiviridae</em> were shown to be &nbsp;members of an ancient viral lineage that is defined by specific types of capsids, the protein shell encasing the viral DNA. Though this lineage is known to be very diverse in animals and protists — and includes viruses such as the adenoviruses that infect humans, and the giant viruses that infect algae — very few viruses of this kind have been found to infect bacteria.</p> <p>“This work substantially changes the existing ideas on the composition of the ocean virome by showing that the content of small, tailless viruses … is comparable to that of the tailed viruses … that are currently thought to dominate the virosphere,” says Eugene V. Koonin, a senior investigator at the National Institutes of Health, who was not involved in this research. “This work is important also for understanding the evolution of the virus world because it shows that viruses related to the most common viruses of eukaryotes (such as adenoviruses, poxviruses, and others), at least in terms of the capsid structure, are much wider-spread in prokaryotes than previously suspected.”</p> <p>Koonin adds, “I further wonder whether the viruses reported here might only represent the tip of the proverbial iceberg, because capsid proteins can be highly diverged in sequence so that many are missed even in sensitive database searches. The findings are also of practical importance because the tailless viruses appear to play a major ecological role in the ocean, being responsible for a substantial fraction of bacteria-killing.”</p> <p>The work was supported by the National Science Foundation and the Woods Hole Oceanographic Institution’s Ocean Ventures Fund.</p> Electron microscope images of marine bacteria infected with the non-tailed viruses studied in this research. The bacterial cell walls are seen as long double lines, and the viruses are the small round objects with dark centers. Courtesy of researchers Research, Civil and environmental engineering, Biology, Biological engineering, Microbes, Bacteria, Viruses, Evolution, Ocean science, School of Engineering, School of Science, National Science Foundation (NSF) Microbial communities demonstrate high turnover New research provides insight into the behavior of microbial communities in the ocean. Thu, 18 Jan 2018 19:05:01 -0500 Carolyn Schmitt | Department of Civil and Environmental Engineering <p>When Mark Twain famously said “If you don’t like the weather in New England, just wait a few minutes,” he probably didn’t anticipate MIT researchers would apply his remark to their microbial research. But a new study does just that.</p> <p>A team from MIT, using water samples from the New England coast, found that microbial communities are able to form despite rapidly varying conditions in the coastal environment. Biological communities are typically defined as the set of organisms living and interacting in a certain area, carrying out important ecological functions, such as all the organisms in a forest. In the ocean, however, water is constantly moving, making it more difficult to answer the question of what constitutes a community.</p> <p>Using novel analytical techniques, the MIT researchers show that communities of interacting microbes form but are short-lived. They reach their peak abundance after only a few days and are subsequently replaced by another community. Following the forest analogy, imagine returning after a week and finding entirely different species of plants and animals populating the same area.</p> <p>This rapid turnover struck the researchers as similar to Twain’s quote: “The good news may be that if you don’t like the microbial community, just wait for a few days,” they quip at the conclusion of their paper, published in <em>Nature Communications</em>.&nbsp;</p> <p>“We know relatively little about how microbial communities — the assemblage of microbes in the ocean — change over time and space,” says Martin Polz, professor of civil and environmental engineering (CEE) at MIT and corresponding author on the paper. “People have gone out and taken samples in distinct locations, so we are getting to know more about the global diversity, but when you go to a particular location and ask, ‘How is it changing over time?’ we actually know relatively little.”&nbsp;</p> <p>To fill this void, Polz and the research team collected daily ocean water samples from Canoe Cove in Nahant, Massachusetts, over a three-month period.</p> <p>Together, the researchers, including graduate student Brian Cleary of the Broad Institute and MIT's computational and systems biology program; former CEE postdoc Antonio Martin-Platero; CEE postdoc Kathryn Kauffman; former CEE postdoc Sarah Preheim; Eric Alm, professor of civil and environmental engineering and biological engineering; Polz; and Dennis McGillicuddy of the Woods Hole Oceanographic Institution analyzed the samples.</p> <p>In their analysis the researchers took into account temporal and spatial aspects of water movement, such as from ocean currents. The research was conducted between the summer and fall seasons, and, contrary to what may be expected, the team found that the community formation doesn’t necessarily change as a result of seasonal transitions, but rather follows the every-few-days routine. This is not to say that seasonal changes don’t influence the formation of communities, though.</p> <p>“Temperature alone is a huge factor in structuring communities, but it’s not enough to go and sample once per season to have an idea of what’s going on in the season,” says Polz. “The community turnover is much faster than that, and this indicates that the ecological conditions are shifting on equally fast time scales since the organisms respond to physical and chemical changes.”</p> <p>That the abundance of specific microbes in the community drops sharply after only a few days signals that they may be competing with other microbes for resources to survive. This suggests that while chemistry and physics govern overall community turnover, within communities biological interactions cause even more rapid fluctuations in species abundances.</p> <p>“We think the [rapid community changes] are basically set by the ocean physics. We analyzed chemical and physical data and for some of these events we could identify a characteristic period of upwelling, when nutrient rich deep water is transported to the surface and stimulate a certain set of microbes,” says Polz. “We also looked at satellite data, which measures temperature and chlorophyll, and we saw that features developing in the ocean are corresponding with these communities. The physics really sets the chemical and temperature regimes that trigger the blooms of these communities but physical changes probably also terminate them. Because the water is constantly moving, different water bodies mix, and other local features form.”</p> <p>In collaboration with Alm and his lab, the researchers also created a new algorithm to analyze the samples and sequence the genes to get a more complete understanding of the patterns and behavior of the microbial communities. Using the algorithm, Cleary explains, the researchers looked for relationships between microbes based on how they are fluctuating throughout the time series.</p> <p>“There are microbes fluctuating around in an environment, but we obviously are not directly observing either the cooperative or competitive interactions between pairs [of microbes], and we aren’t directly observing the low-frequency changes that might correspond to a nutrient regime,” says Cleary. “With our algorithm, we can infer the entire community structure from these fluctuations at different frequency levels.”</p> <p>The researchers’ findings also provide insight into the conditions that more permanent organisms in the region face as the microbial plankton turnover. A comprehensive understanding of microbial behavior in the ocean can inform human health, fisheries, and aquaculture, specifically through monitoring water quality.&nbsp;</p> <p>“This paper represents a significant advance in our knowledge of the forces that mediate community assembly in fluid environments, and provides a wealth of new information to support new hypothesis-driven research into the specific mechanisms that underpin this complex association,” says Jack Gilbert, faculty director of the Microbiome Center at the University of Chicago, who was not involved in this work.&nbsp;</p> <p>The research was funded in part by the National Science Foundation and the United States Department of Energy.</p> Postdoc Kathryn Kauffman and former guest researcher Aidong Ruan process ocean water samples at Canoe Cove in Nahant, Massachusetts. The researchers were observing how microbial communities change over time in a particular location. Photo: Gitta SzaboSchool of Engineering, Civil and environmental engineering, Woods Hole, Computational biology, Systems biology, Microbiology, Broad Institute, Department of Energy (DoE), National Science Foundation (NSF), Microbes, Environment, Biological engineering Celebrating a decade of interdisciplinary microbiology The Microbiology Graduate PhD Program spans 50 labs across 10 departments and divisions, offering a broad approach to microbial science and engineering. Tue, 12 Dec 2017 17:00:00 -0500 Raleigh McElvery | Department of Biology <p>Ten years ago, MIT launched the <a href="">Microbiology Graduate PhD Program</a>. Today, it boasts 28 alumni and 33 current students, and offers a broad, interdisciplinary approach to microbial science and engineering. Between five and eight trainees enroll each year and can choose among more than 50 labs spanning 10 departments and divisions — from biology and biological engineering to chemical engineering and physics.</p> <p>Many diverse disciplines are rooted in microbiology. Basic scientists use microorganisms as model systems to understand fundamental biological processes. Engineers leverage microorganisms to create new manufacturing processes and energy sources. Even ecologists, biomedical researchers, and earth scientists dedicate their careers to investigating the role of microbes in our ecosystems, on our bodies, and on our planet. In sum, the study of microbiology permeates so many research areas that no single department at MIT could house them all.&nbsp;</p> <p>The idea for an interdisciplinary microbiology program first came to Alan Grossman, head of the Department of Biology, while he was <a href="">recovering from a heart transplant</a> back in 2006.</p> <p>“There were people scattered all over MIT who were doing microbial science and engineering, but there was no mechanism to connect them or give students outside those departments easy access to the labs,” Grossman says. “I began by talking to a few faculty members in order to gauge general interest, before pitching it to a handful of department heads and forming a committee. Everyone was very excited about it, and it really grew from the ground up.”</p> <p>The Committee on Graduate Programs approved his proposal in May 2007, and the first cohort of eight students began in the fall of 2008. <a href="">Martin Polz</a>, co-director since 2015 and professor of civil and environmental engineering, sat on Grossman’s initial committee.</p> <p>“MIT’s program is unique from most other microbiology programs because it’s so interdisciplinary,” Polz says. “Many microbiology programs across the country are associated with medical schools and focused primarily on pathogenesis. The students who apply here really appreciate the breadth of our program, and it has become a fixture at MIT over the years.”</p> <p><a href="">Kristala Prather</a>, co-director since 2013 and professor of chemical engineering, said the program also provides an opportunity to bring life scientists and engineers together to tackle research questions.</p> <p>“I find there is a difference in the way engineers and scientists approach research problems,” Prather says. “Each approach has rigor, but having both perspectives breeds a richer set of discussions than just hearing from one discipline alone.”</p> <p>During the past 10 years, Prather has watched a thriving and diverse community unite, spurred by a common interest in the microbial world.</p> <p><a href="">Nathaniel Chu</a>, who matriculated in 2014, said the program allows him to sample different disciplines while still maintaining a close affiliation with his advisor’s home department, Biological Engineering. As part of Eric Alm’s lab, Chu studies the interaction between the gut microbiome and immune system, and how imbalances in that delicate relationship can trigger conditions such as Type 2 diabetes, obesity, and inflammatory bowel disease.</p> <p>“The program provides flexibility to explore your research interests, and my advisor has given me a lot of space to conceive and manage my own projects,” Chu says. “I’ve been able to interact with a diverse set of individuals within the microbiology circle, including clinical partners, immunologists, geneticists, bioinformaticians, and computational biologists.”</p> <p><a href="">Jacquin Niles</a>, incoming co-director, was a junior faculty member in Department of Biological Engineering when Grossman first proposed the idea. He says the students — past and present — are the heart of the program.</p> <p>&nbsp;“A lot has changed over the 10 years the program has been in existence, but the caliber of students has remained consistent,” Niles&nbsp;says. “If I had to emphasize any particular aspect of the program, the students would be numbers one, two, and three. Each generation has been exceptional, and they are all very much on top of their research game.”</p> <p><a href="">Michael Laub</a>, co-director from 2012 to 2015 and professor of biology, adds that the early students deserve much credit for the program’s success. “They took a chance on a brand-new initiative, and as a result we ended up attracting ambitious, risk-taking, and creative folks who really paved the way for current students,” he says.</p> <p>Alumni pursue a variety of careers, ranging from academia to industry. Some join existing institutions or companies. Others start their own.</p> <p>Mark Smith PhD ’14 was a member of the second graduating class. Like Chu, he was one of Alm’s advisees, studying networks of gene exchange within the human microbiome, and building statistical models to determine the role of environment in various gut-related diseases. Smith went on to co-found a nonprofit organization known as OpenBiome, harnessing the microbiome to cure recurrent <em>Clostridium difficile</em> infections. In 2016, he co-founded another company, Finch Therapeutics Group, focused on scaling and commercializing clinical treatments for diseases rooted in the microbiome. In 2017, he was <a href="">named</a> to the <em>Forbes </em>30 Under 30 list for science.</p> <p>“OpenBiome and Finch Therapeutics were really a translation of the initial work that was done through the microbiology program, and a step toward developing those tools to improve human health,” Smith says. “The program taught me the foundational work I’ve come to rely on in almost every aspect of my job today.”</p> <p>Like Smith, Jacob Rubens PhD ’16 aims to apply his training at MIT to help develop new products. After working in Timothy Lu’s lab — straddling the realms of biological engineering and electrical engineering — Rubens joined Flagship Pioneering, a company that starts, funds, and runs breakthrough biotechnology startups in Cambridge, Massachusetts. Rubens was also <a href="">named</a> to the <em>Forbes</em> 30 Under 30 list for science in 2017.</p> <p>During the six years that Rubens was at MIT, he watched the microbiology cohort grow from roughly 20 to a force permeating more labs across campus than he could count.</p> <p>&nbsp;“It’s heartwarming to see people bringing a microbiological perspective into all these different spaces, and influencing cutting-edge research across the Institute,” he says. “As a microbiology student, you become an integrator and synthesizer of many different viewpoints, and a node to foster cross-talk between disciplines.”</p> <p>As Niles prepares to assume the role of co-director in July 2018 and usher in the program’s second decade, he intends to maintain its integrity and structure.</p> <p>“The program has matured into what it is today thanks to a lot of previous, careful thought,” he says. “The students have indicated that there is a lot of value in the structure that we’ve refined over the years, and so my goal is to continue that positive momentum.”</p> Microbiology Graduate PhD Program participants celebrate their 10-year anniversary at their fall 2017 retreat.Photo: Susan KahnSchool of Science, Biology, Microbiology, Chemical engineering, Civil and environmental engineering, Biological engineering, Graduate, postdoctoral, Classes and programs, Microbes, School of Engineering Boosting the antibiotic arsenal New strategy could enable existing drugs to kill bacteria that cause chronic infections. Thu, 07 Dec 2017 12:00:00 -0500 Anne Trafton | MIT News Office <p>MIT researchers have discovered a way to make bacteria more vulnerable to a class of antibiotics known as quinolones, which include ciprofloxacin and are often used to treat infections such as <em>Escherichia coli</em> and <em>Staphylococcus aureus</em>.</p> <p>The new strategy overcomes a key limitation of these drugs, which is that they often fail against infections that feature a very high density of bacteria. These include many chronic, difficult-to-treat infections, such as <em>Pseudomonas aeruginosa</em>, often found in the lungs of cystic fibrosis patients, and methicillin-resistant <em>Staphylococcus aureus</em> (MRSA).</p> <p>“Given that the number of new antibiotics being developed is diminishing, we face challenges in treating these infections. So efforts such as this could enable us to expand the efficacy of existing antibiotics,” says James Collins, the Termeer Professor of Medical Engineering and Science in MIT’s Institute for Medical Engineering and Science (IMES) and Department of Biological Engineering and the senior author of the study.</p> <p>Arnaud Gutierrez, a former MIT postdoc, and Saloni Jain, a recent Boston University PhD recipient, are the lead authors of the study, which appears in the Dec. 7 online edition of <em>Molecular Cell</em>.</p> <p><strong>Overcoming bacterial defenses</strong></p> <p>Bacteria that have become tolerant to a drug enter a physiological state that allows them to evade the drug’s action. (This is different from bacterial resistance, which occurs when microbes acquire genetic mutations that protect them from antibiotics.) “Tolerance is not well-understood, and we don’t have the means to circumvent it or overcome it,” Collins says.</p> <p>In a study published in 2011, Collins and his colleagues found that they could increase the ability of antibiotics known as aminoglycosides to kill drug-tolerant bacteria by delivering a type of sugar along with the drug. The sugar helps to boost the metabolism of the bacteria, making it more likely that the microbes will undergo cell death in response to the DNA damage caused by the antibiotic.</p> <p>However, aminoglycosides can have serious side effects, so they are not widely used. In their new study, Collins and his colleagues decided to explore whether they could use a similar approach to boost the effectiveness of quinolones, a class of antibiotics used more often than aminoglycosides. Quinolones work by interfering with bacterial enzymes called topoisomerases, which help with DNA replication and repair.</p> <p>With quinolones, the researchers found that it wasn’t enough to add just sugar; they also had to add a type of molecule known as a terminal electron acceptor. Electron acceptors play an essential role in cellular respiration, the process that bacteria use to extract energy from sugar. In cells, the electron acceptor is usually oxygen, but other molecules, including fumarate, an acidic organic compound that is used as a food additive, can also be used.</p> <p>In tests in high-density bacterial colonies grown in a lab dish, the researchers found that delivering quinolones along with glucose and fumarate could eliminate several types of bacteria, including <em>Pseudomonas aeruginosa</em>, <em>Staphylococcus aureus, </em>and<em> Mycobacterium smegmatis, </em>a close relative of the bacterium that causes tuberculosis.</p> <p>“If you simply add a carbon source like glucose, that’s not enough to enable the quinolone to kill. If you simply add oxygen, or another terminal electron acceptor, that by itself is not enough to cause killing either. But if you combine the two, you can eradicate the tolerant infection,” Collins says.</p> <p><strong>Metabolic state</strong></p> <p>The findings suggest that high-density bacterial infections rapidly consume nutrients and oxygen from their environment, which then provokes them to enter a starvation state that helps them to survive. In this state, they greatly reduce their metabolic activity, which allows them to avoid the cell death pathway that is normally triggered when DNA is damaged by antibiotics.</p> <p>“This finding highlights that the metabolic state of the bug significantly influences how the antibiotic will impact the bug. And, for the antibiotic to be effective as a killing agent, it requires downstream cellular respiration as part of the process,” Collins says.</p> <p>The researchers now hope to test this approach in bacterial infections in animals, and they are also exploring how to best deliver the drug combination for different types of infections. A topical treatment could work well for <em>Staphylococcus aureus</em> infections, while an inhaled version could be used to treat <em>Pseudomonas aeruginosa</em> infections of the lungs, Collins says.</p> <p>Collins also hopes to test this approach with other types of antibiotics, including the class that includes penicillin and ampicillin.</p> <p>“This study encourages work to find new ways to stimulate bacterial respiration and thereby enhance the production of reactive oxygen (or even non-oxygen) species during antibiotic treatment, for better eradication of bacterial pathogens, particularly those having low metabolic activity that may render them tolerant to antimicrobials,” says Karl Drlica, a professor at the Public Health Research Institute at Rutgers New Jersey Medical School, who was not involved in the research.</p> <p>The research was funded by the Defense Threat Reduction Agency, the Broad Institute of MIT and Harvard, and a gift from Anita and Josh Bekenstein.</p> MIT researchers have discovered a way to make bacteria more vulnerable to a class of antibiotics known as quinolones, which include ciprofloxacin and are often used to treat infections such as Escherichia coli and Staphylococcus aureus. Image: Chelsea Turner/MITResearch, Biological engineering, Institute for Medical Engineering and Science (IMES), Bacteria, Microbes, Medicine, Drug development Engineers 3-D print a “living tattoo” New technique 3-D prints programmed cells into living devices for first time. Tue, 05 Dec 2017 11:00:00 -0500 Jennifer Chu | MIT News Office <p>MIT engineers have devised a 3-D printing technique that uses a new kind of ink made from genetically programmed living cells.</p> <p>The cells are engineered to light up in response to a variety of stimuli. When mixed with a slurry of hydrogel and nutrients, the cells can be printed, layer by layer, to form three-dimensional, interactive structures and devices.</p> <p>The team has then demonstrated its technique by printing a “living tattoo” — a thin, transparent patch patterned with live bacteria cells in the shape of a tree. Each branch of the tree is lined with cells sensitive to a different chemical or molecular compound. When the patch is adhered to skin that has been exposed to the same compounds, corresponding regions of the tree light up in response.</p> <p>The researchers, led by Xuanhe Zhao, the Noyce Career Development Professor in MIT’s Department of Mechanical Engineering, and Timothy Lu, associate professor of biological engineering and of electrical engineering and computer science, say that their technique can be used to fabricate “active” materials for wearable sensors and interactive displays. Such materials can be patterned with live cells engineered to sense environmental chemicals and pollutants as well as changes in pH and temperature.</p> <p>What’s more, the team developed a model to predict the interactions between cells within a given 3-D-printed structure, under a variety of conditions. The team says researchers can use the model as a guide in designing responsive living materials.</p> <p>Zhao, Lu, and their colleagues have published their results today in the journal <em>Advanced Materials</em>. The paper’s co-authors are graduate students Xinyue Liu, Hyunwoo Yuk, Shaoting Lin, German Alberto Parada, Tzu-Chieh Tang, Eléonore Tham, and postdoc Cesar de la Fuente-Nunez.</p> <div class="cms-placeholder-content-video"></div> <p><strong>A hardy alternative</strong></p> <p>In recent years, scientists have explored a variety of responsive materials as the basis for 3D-printed inks. For instance, scientists have used inks made from temperature-sensitive polymers to print <a href="">heat-responsive shape-shifting objects</a>. Others have printed photoactivated structures from polymers that shrink and stretch in response to light. &nbsp;</p> <p>Zhao’s team, working with bioengineers in Lu’s lab, realized that live cells might also serve as responsive materials for 3D-printed inks, particularly as they can be genetically engineered to respond to a variety of stimuli. The researchers are not the first to consider 3-D printing genetically engineered cells; others have attempted to do so using live mammalian cells, but with little success.</p> <p>“It turns out those cells were dying during the printing process, because mammalian cells are basically lipid bilayer balloons,” Yuk says. “They are too weak, and they easily rupture.”</p> <p>Instead, the team identified a hardier cell type in bacteria. Bacterial cells have tough cell walls that are able to survive relatively harsh conditions, such as the forces applied to ink as it is pushed through a printer’s nozzle. Furthermore, bacteria, unlike mammalian cells, are compatible with most hydrogels — gel-like materials that are made from a mix of mostly water and a bit of polymer. The group found that hydrogels can provide an aqueous environment that can support living bacteria.</p> <p>The researchers carried out a screening test to identify the type of hydrogel that would best host bacterial cells. After an extensive search, a hydrogel with pluronic acid was found to be the most compatible material. The hydrogel also exhibited an ideal consistency for 3-D printing.</p> <p>“This hydrogel has ideal flow characteristics for printing through a nozzle,” Zhao says. “It’s like squeezing out toothpaste. You need [the ink] to flow out of a nozzle like toothpaste, and it can maintain its shape after it’s printed.”</p> <p><strong>From tattoos to living computers</strong></p> <p>Lu provided the team with bacterial cells engineered to light up in response to a variety of chemical stimuli. The researchers then came up with a recipe for their 3-D ink, using a combination of bacteria, hydrogel, and nutrients to sustain the cells and maintain their functionality.</p> <p>“We found this new ink formula works very well and can print at a high resolution of about 30 micrometers per feature,” Zhao says. “That means each line we print contains only a few cells. We can also print relatively large-scale structures, measuring several centimeters.”</p> <p>They printed the ink using a custom 3-D printer that they built using standard elements combined with fixtures they machined themselves. To demonstrate the technique, the team printed a pattern of hydrogel with cells in the shape of a tree on an elastomer layer. After printing, they solidified, or cured, the patch by exposing it to ultraviolet radiation. They then adhere the transparent elastomer layer with the living patterns on it, to skin.</p> <p>To test the patch, the researchers smeared several chemical compounds onto the back of a test subject’s hand, then pressed the hydrogel patch over the exposed skin. Over several hours, branches of the patch’s tree lit up when bacteria sensed their corresponding chemical stimuli.</p> <p>The researchers also engineered bacteria to communicate with each other; for instance they programmed some cells to light up only when they receive a certain signal from another cell. To test this type of communication in a 3-D structure, they printed a thin sheet of hydrogel filaments with “input,” or signal-producing bacteria and chemicals, overlaid with another layer of filaments of an “output,” or signal-receiving bacteria. They found the output filaments lit up only when they overlapped and received input signals from corresponding bacteria .</p> <p>Yuk says in the future, researchers may use the team’s technique to print “living computers” — structures with multiple types of cells that communicate with each other, passing signals back and forth, much like transistors on a microchip.</p> <p>“This is very future work, but we expect to be able to print living computational platforms that could be wearable,” Yuk says.</p> <p>For more near-term applications, the researchers are aiming to fabricate customized sensors, in the form of flexible patches and stickers that could be engineered to detect a variety of chemical and molecular compounds. They also envision their technique may be used to manufacture drug capsules and surgical implants, containing cells engineered produce compounds such as glucose, to be released therapeutically over time.</p> <p>“We can use bacterial cells like workers in a 3-D factory,” Liu says. “They can be engineered to produce drugs within a 3-D scaffold, and applications should not be confined to epidermal devices. As long as the fabrication method and approach are viable, applications such as implants and ingestibles should be possible.”</p> <p>This research was supported, in part, by the Office of Naval Research, National Science Foundation, National Institutes of Health, and MIT Institute for Soldier Nanotechnologies.</p> MIT engineers have devised a 3-D printing technique that uses a new kind of ink made from genetically programmed living cells. Courtesy of the researchers3-D printing, Biological engineering, Drug delivery, Materials Science and Engineering, Mechanical engineering, Electrical Engineering & Computer Science (eecs), Microbes, Research, School of Engineering, Synthetic biology, National Science Foundation (NSF), National Institutes of Health (NIH) Gut microbes can protect against high blood pressure Strain of intestinal bacteria can stop a high-salt diet from inducing inflammatory response linked to hypertension. Wed, 15 Nov 2017 13:00:00 -0500 Anne Trafton | MIT News Office <p>Microbes living in your gut may help protect against the effects of a high-salt diet, according to a new study from MIT.</p> <p>The MIT team, working with researchers in Germany, found that in both mice and humans, a high-salt diet shrinks the population of a certain type of beneficial bacteria. As a result, pro-inflammatory immune cells called Th-17 cells grow in number. These immune cells have been linked with high blood pressure, although the exact mechanism of how they contribute to hypertension is not yet known.</p> <p>The researchers further showed that treatment with a probiotic could reverse these effects, but they caution that people should not interpret the findings as license to eat as much salt as they want, as long as they take a probiotic.</p> <p>“I think certainly there’s some promise in developing probiotics that could be targeted to possibly fixing some of the effects of a high-salt diet, but people shouldn’t think they can eat fast food and then pop a probiotic, and it will be canceled out,” says Eric Alm, director of MIT’s Center for Microbiome Informatics and Therapeutics and a professor of biological engineering and civil and environmental engineering at MIT.</p> <p>Alm, Dominik Muller of the Max-Delbruck Center for Molecular Medicine in Berlin, and Ralf Linker of Friedrich-Alexander University in Erlangen, Germany, are the senior authors of the study, which is published today in <em>Nature</em>. The paper’s lead author is Nicola Wilck of the Max-Delbruck Center for Molecular Medicine. Authors from MIT include graduate students Mariana Matus and Sean Kearney, and recent PhD recipient Scott Olesen.</p> <p><strong>Too much salt</strong></p> <p>Scientists have long known that a high-salt diet can lead to cardiovascular disease. As sodium accumulates in the bloodstream, the body retains more fluid to dilute the sodium, and the heart and blood vessels have to work harder to pump the extra volume of water. This can stiffen the blood vessels, potentially leading to high blood pressure, heart attack, and stroke.</p> <p>Recent evidence has also implicated the body’s immune system in some of the effects of a high-salt diet. Muller’s lab has previously shown that salt increases the population of Th-17 immune cells, which stimulate inflammation and can lead to hypertension. Muller and his colleagues have also found that excess salt can drive the development of an autoimmune disease that is similar to multiple sclerosis, in mice.</p> <p>Meanwhile, Alm’s lab has studied interactions of human gut microbes with populations of different types of immune cells. He has shown that the balance between pro-inflammatory cells such as Th-17 and anti-inflammatory cells is influenced by the composition of the gut microbiome. The researchers have also found that probiotics can tip this balance in favor of anti-inflammatory cells.</p> <p>In the new study, the researchers teamed up to determine how a high-salt diet would affect the microbiome, and whether those changes might be linked to the detrimental health effects of such a diet.</p> <p>For two weeks, the researchers fed mice a diet in which sodium chloride (table salt) made up 4 percent of what the animals were eating, compared to 0.5 percent for mice on a normal diet. They found that this diet led to a drop in the population of a type of bacteria called <em>Lactobacillus murinus</em>. These mice also had greater populations of inflammatory Th-17 cells, and their blood pressure went up.</p> <p>When mice experiencing high blood pressure were given a probiotic containing <em>Lactobacillus murinus, </em>Th-17 populations went down and hypertension was reduced.</p> <p>In a study of 12 human subjects, the researchers found that adding 6,000 milligrams of sodium chloride per day to the subjects’ diet, for a duration of two weeks, also changed the composition of bacteria in the gut. Populations of <em>lactobacillus</em> bacteria went down, and the subjects’ blood pressure went up along with their counts of Th-17 cells.</p> <p>When subjects were given a commercially available probiotic for a week before going on a high-salt diet, their gut <em>lactobacillus</em> levels and blood pressure remained normal.</p> <p><strong>A smoking gun</strong></p> <p>It is still unclear exactly how Th-17 cells contribute to the development of high blood pressure and other ill effects of a high-salt diet.</p> <p>“We’re learning that the immune system exerts a lot of control on the body, above and beyond what we generally think of as immunity,” Alm says. “The mechanisms by which it exerts that control are still being unraveled.”</p> <p>The researchers hope that their findings, along with future studies, will help to shed more light on the mechanism by which a high-salt diet influences disease. “If you can find that smoking gun and uncover the complete molecular details of what’s going on, you may make it more likely that people adhere to a healthy diet,” Alm says.</p> <p>Alm and others at the Center for Microbiome Informatics and Therapeutics are also studying how other dietary factors such as fiber, fat, and protein affect the microbiome. They have collected thousands of different strains of bacteria representing the most abundant species in the human gut, and they hope to learn more about the relationships between these bacteria, diet, and diseases such as inflammatory bowel disease.</p> <p>The research was funded by the German Center for Cardiovascular Research, the MIT Center for Microbiome Informatics and Therapeutics, and the MetaCardis consortium.</p> “I think certainly there’s some promise in developing probiotics that could be targeted to possibly fixing some of the effects of a high-salt diet, but people shouldn’t think they can eat fast food and then pop a probiotic, and it will be canceled out,” says MIT Professor Eric Alm. Image: Chelsea Turner/MITResearch, Biological engineering, Civil and environmental engineering, Food, Microbes, School of Engineering, Health, Medicine New test rapidly diagnoses Zika Paper-based diagnostic avoids false positives from Dengue fever and other related viruses. Wed, 27 Sep 2017 14:00:00 -0400 Anne Trafton | MIT News Office <p>MIT researchers have developed a paper-based test that can diagnose Zika infection within 20 minutes. Unlike existing tests, the new diagnostic does not cross-react with Dengue virus, a close relative of the Zika virus that can produce false positives on many Zika tests.</p> <p>This test could offer an easy-to-use, cheap, and portable diagnostic in countries where Zika and Dengue are both prevalent and the gold-standard test that measures viral RNA in the bloodstream is not available.</p> <p>“It’s important to have a single test that can differentiate between the four serotypes of Dengue and Zika, because they co-circulate. They’re spread by the same mosquito,” says Kimberly Hamad-Schifferli, an associate professor of engineering at the University of Massachusetts at Boston, a visiting scientist in MIT’s Department of Mechanical Engineering, and a co-senior author of the paper.</p> <p>The researchers worked with scientists around the world to test the new device on patient samples and confirmed that it can accurately distinguish Zika virus from related viruses.</p> <p>Lee Gehrke, the Hermann L.F. von Helmholtz Professor in MIT’s Institute for Medical Engineering and Science (IMES), is also a senior author of the study, which appears in the Sept. 27 issue of <em>Science Translational Medicine</em>. The paper’s first authors are IMES research scientist Irene Bosch and Department of Mechanical Engineering postdoc Helena de Puig.</p> <p><strong>No more false positives</strong></p> <p>One of the biggest challenges in diagnosing Zika is that many of the tests are based on antibodies that interact with a viral protein called NS1, which is found in the bloodstream of infected patients. Unfortunately, many other viruses from the same family, known as flaviviruses, have similar versions of NS1 and can produce a false positive. Flaviviruses include West Nile virus and the virus that causes yellow fever, as well as Dengue virus.</p> <p>In an effort to create a more precise diagnostic, the MIT team set out to find antibodies that would interact exclusively with NS1 protein produced by the Zika virus, as well as antibodies specific to NS1 from each of the four different strains of the Dengue virus.</p> <p>To achieve this, the researchers exposed mice to Zika and Dengue viruses and then screened the resulting antibodies, in pairs, against every flavivirus’ version of the NS1 protein. This allowed them to identify pairs of antibodies that react only with one version of NS1 and not any of the others.</p> <p>“We knew by informatics analysis that if we looked enough, and we teased out the repertoire of the B cells of these animals, we would eventually find those antibodies,” Bosch says. “We were able to tease out the very few antibodies within the repertoire that would give you uniqueness in the detection.”</p> <p>The researchers used these pairs to create five separate tests, one for each virus. They coated strips of paper with one antibody from each pair, while the second antibody was attached to gold nanoparticles. After adding the patient’s blood sample to a solution of these nanoparticles, the paper strip is dipped into the solution. If the target NS1 protein is present, it attaches to the antibodies on the paper strip as well as the nanoparticle-bound antibodies, and a colored spot appears on the strip within 20 minutes.</p> <p>This approach requires five test strips per sample to test for each virus, but the researchers are now working on a version that would test for all five with one strip.</p> <p>Most countries where Zika and Dengue are prevalent do not allow patient samples to be shipped out of the country, so the researchers traveled to several countries, including Mexico, Colombia, India, and Brazil, to test their devices with patient samples.</p> <p>They found that their results were comparable to those obtained by polymerase chain reaction (PCR) tests, which detect viral RNA in the bloodstream. PCR tests are not widely used in areas where Zika virus is found because they require trained personnel and lab equipment that are not available everywhere.</p> <p>“Since conventional methods require a great deal of time for sample collection and diagnostics, this inexpensive, paper-based, rapid diagnostic will be very useful for the diagnosis of many infectious diseases,” says Luke Lee, an associate president of the National University of Singapore and director of the Biomedical Institute for Global Health Research and Technology in Singapore.</p> <p><strong>Emerging viruses</strong></p> <p>Dengue infects hundreds of millions of people annually, mostly in tropical regions. It is usually not fatal, but in areas where there is more than one serotype circulating, it is more likely to produce a severe, potentially life-threatening illness. A diagnostic that can distinguish between all four serotypes of Dengue fever could give doctors a way to discover early on when a new serotype has entered their region.</p> <p>“When we have traveled to the places where these viruses are problems, the people there unanimously say that they need more surveillance. They need to know which viruses are circulating in their environments,” Gehrke says.</p> <p>The researchers believe that their approach should also enable them to quickly develop diagnostic tests for other related viruses that might emerge in the future.</p> <p>“By already screening this group of antibodies that we have against all these antigens we have, like West Nile, we already know how well they react. So that’s information we could use in the future to develop additional tests that can be used to detect other emerging viruses,” Gehrke says.</p> <p>They are now working on a diagnostic for the emerging Powassan virus, which is carried by the same tick that spreads Lyme disease. Powassan, found mainly in the northeastern United States and the Great Lakes region, causes a severe form of encephalitis.</p> <p>The research was funded by the U.S. Public Health Service, the Science, Technology and Innovation Fund of Colombia, and a Tata Center for Technology and Design fellowship.</p> “It’s important to have a single test that can differentiate between the four serotypes of Dengue and Zika, because they co-circulate. They’re spread by the same mosquito,” says Kimberly Hamad-Schifferli, an associate professor of engineering at the University of Massachusetts at Boston and a visiting scientist in MIT’s Department of Mechanical Engineering. Courtesy of the researchersResearch, Disease, Microbes, Institute for Medical Engineering and Science (IMES), Health sciences and technology, Health care, Mechanical engineering, School of Engineering Biochemists discover mechanism that helps flu viruses evolve Influenza viruses can hijack host cellular machinery to help mutated viral proteins fold and function. Tue, 26 Sep 2017 07:59:59 -0400 Anne Trafton | MIT News Office <p>Influenza viruses mutate rapidly, which is why flu vaccines have to be redesigned every year. A new study from MIT sheds light on just how these viruses evolve so quickly, and offers a potential way to slow them down.</p> <p>The MIT team found that flu viruses’ rapid evolution relies in part on their ability to hijack some of the cellular machinery of the infected host cell — specifically, a group of proteins called chaperones, which help other proteins fold into the correct shape. When the viruses were unable to get help from these chaperones, they did not evolve as rapidly as when they could obtain extensive help from host chaperones. Moreover, the specific evolutionary trajectories followed by individual flu proteins depend on host chaperone activities.</p> <p>The findings suggest that interfering with host cell chaperones could help prevent flu viruses from becoming resistant to existing drugs and vaccines, says Matthew Shoulders, the Whitehead Career Development Associate Professor of Chemistry at MIT.</p> <p>“It’s relatively easy to make a drug that kills a virus, or an antibody that stops a virus from propagating, but it’s very hard to make one that the virus doesn’t promptly escape from once you start using it,” Shoulders says. “Our data suggest that, at some point in the future, targeting host chaperones might restrict the ability of a virus to evolve and allow us to kill viruses before they become drug resistant.”</p> <p>Shoulders is the senior author of the study, which is a collaborative effort with Leonid Mirny, a professor of physics at MIT; and Yu-Shan Lin, a professor at Tufts University. Angela Phillips, an MIT graduate student and National Science Foundation graduate fellow, is the lead author of the paper, which appears in the journal <em>eLife</em> on Sept. 26.</p> <p><strong>A little help</strong></p> <p>Flu viruses carry eight genome segments, all encoded by RNA. Of particular interest to flu researchers is the gene for the hemagglutinin protein, which is displayed on the surface of the viral envelope and interacts with cells of the infected host. Most flu vaccines target this protein, but these vaccines have to be updated every year to keep up with the protein’s ability to evolve quickly.</p> <p>However, this rapid evolution also poses a challenge for the viruses themselves. When proteins mutate, they may become unable to fold into the shape they need to assume to perform their function. Previous research, such as the pioneering work of the late Susan Lindquist, a biology professor at MIT, has shown that in many organisms, evolution of endogenous proteins depends on the ability of that organism’s chaperones to help mutated proteins fold.</p> <p>In this study, the MIT team investigated whether viruses can take advantage of their host’s chaperone proteins to help with their own evolution.</p> <p>“Viral proteins are known to interact with host chaperones, so we suspected that this interplay could have a major impact on what evolutionary pathways are available to the virus,” Shoulders says.</p> <p>To test their hypothesis, the researchers generated one set of cells with low protein-folding activity by inhibiting a key chaperone protein called heat shock protein 90 (Hsp90). In another set of cells, they used chemical genetic methods previously developed by Shoulders to enhance the levels of numerous chaperone proteins, creating a cellular environment with high protein-folding activity.</p> <p>The researchers infected both sets of cells, plus a group of cells with normal chaperone levels, with a strain of flu and then allowed the virus to evolve for nearly 200 generations. They found that the virus did indeed evolve faster in the cells with higher chaperone levels than in the cells with inhibited chaperone proteins.</p> <p>“This finding suggests that influenza will acquire new traits that might be beneficial for it faster when you have the heat shock response activated, and slower when you have key chaperones inhibited,” Shoulders says.</p> <p><strong>Blocking escape routes</strong></p> <p>The researchers also identified specific proteins that tend to become more mutated in cells with more chaperones. One of these is the hemagglutinin protein, and another is an enzyme called PA, which is a type of RNA polymerase that helps the virus copy its genes. The team also identified specific amino acids within these proteins that are more likely to become mutated in different protein-folding environments.</p> <p>“The authors develop very nice chemical genetic tools for precisely manipulating proteostasis in human cells, and the application of their methods led to a number of interesting findings,” says Jesse Bloom, a viral evolution expert and associate member of the Fred Hutchinson Cancer Research Center, who was not involved in the research. “Perhaps the most compelling is the identification of a specific mutation in influenza (H452Q in PA) that has different effects depending on whether the heat shock response is activated versus whether Hsp90 is inhibited. Identification of this mutation is proof of principle that a virus' ability to tolerate specific mutations can be affected by chaperones, providing the first link between host proteostasis and viral evolution.”</p> <p>Targeting this phenomenon could offer a way to delay viral evolution and decelerate escape from existing drugs and vaccines, the researchers say. Many chaperone inhibitors already exist, and some are now being tested in clinical trials to treat cancer and some viral infections. The new data imply that treating patients with a chaperone-inhibiting drug along with another antiviral therapy, such as a drug or vaccine, could help ensure that the virus does not evolve resistance to the therapeutic.</p> <p>The researchers believe this phenomenon is likely also found in other viruses, and they are now studying HIV, another virus that mutates rapidly. They also plan to study how a host cell’s protein-folding capacity may affect the evolution of antiviral drug or antibody resistance, using therapeutics that circulating viruses are already resistant to.</p> <p>“We can recapitulate environmental pressures like antiviral drugs in the lab, in the context of different host protein-folding environments, and see whether there’s a big impact. Our data suggest that there’s going to be, but we have to actually test it out,” Shoulders says.</p> <p>The research was funded by the Smith Family Foundation Award for Excellence in Biomedical Research and an NSF CAREER Award.</p> Virion hikers with varying levels of fitness, illustrated here as preparedness, attempt to climb Folded Peak  While some virions are too unfit to hit the trail (red), some are sufficiently fit to reach the summit without help from the park chaperones (blue). Other virions (yellow) are able to reach the summit by hijacking the park chaperones, which are also assisting certain host proteins, and some virions are unable to receive help from the park chaperones (gray). Image: Mary O’Reilly/O’Reilly Science ArtResearch, Chemistry, Microbes, School of Science, Influenza, Evolution, Health, Medicine, National Science Foundation (NSF) Mucus’ influence on bacterial behavior Summer Scholar Gaetana Michelet explores the role mucus plays in protecting people from getting sick. Fri, 08 Sep 2017 17:30:01 -0400 Denis Paiste | Materials Processing Center <p>Many bacteria that could potentially make us sick normally live in us without doing so, in part because of the protective role that mucus plays in our bodies. This summer, MPC-CMSE Summer Scholar Gaetana Michelet studied&nbsp;how complex materials such as mucus influence bacterial behavior, while working in the Biogel Lab of&nbsp;<a dir="ltr" href="" rel="noopener noreferrer" style="font-family: 'Helvetica Neue', Helvetica, Arial, sans-serif;" target="_blank">Katharina Ribbeck</a>, the Eugene Bell Career Development Professor of Tissue Engineering, at MIT.</p> <p>Michelet, a mechanical engineering student at the University of Puerto Rico, worked&nbsp;with MIT Postdoctoral Associate Gerardo Cárcamo. “We are curious to understand how certain problematic pathogens can live on our body without causing infections. We try to understand the role of mucus in this process,” Cárcamo says. His own research focuses on bacterial interactions such as cell-to-cell communication and bacterial competition in a mucus environment.</p> <p>During a visit to the lab, Michelet explains that she was working with microbes for her summer internship and learning different techniques used in microbiology, such as growing bacteria in different media, seeing how they interact with materials like mucus, and how they grow in different ways. “For this project, I have integrated my materials science knowledge with the microbiology I've learned here,” she says.</p> <div class="cms-placeholder-content-video"></div> <p>“For me, it has been a real pleasure to work with Gaetana.” Cárcamo adds. “She's a really motivated student willing to learn many new things, and it has been a real good experience.”</p> <p>Michelet notes that “Although I am a mechanical engineer, I am interested in pursuing a new career in bioengineering, so this summer has been very exciting because I had the opportunity to experience this area, and I think it's a big milestone for my career.”</p> <p>Michelet’s internship is supported in part by NSF’s Materials Research Science and Engineering Centers program [grant DMR-14-19807]. Participants in the Research Experience for Undergraduates, co-sponsored by the Materials Processing Center and the Center for Materials Science and Engineering, presented their results at a poster session during the last week of the program. The program ran from June 15, 2017, to August 5, 2017, on the MIT campus in Cambridge, Massachusetts.</p> 2017 MPC-CMSE Summer Scholar Gaetana Michelet holds a pipette in the Biogel Lab of Katharina Ribbeck, the Eugene Bell Career Development Professor of Tissue Engineering at MIT. Ribbeck studies how complex materials such as mucus influence bacterial behavior. Photo: Denis Paiste Materials Processing CenterResearch, Biological engineering, School of Engineering, Materials Processing Center, Bacteria, Microbes, Health Study suggests simple way to predict preterm births Test of cervical mucus may reveal pregnant women’s risk of going into labor too early. Mon, 04 Sep 2017 04:59:59 -0400 Anne Trafton | MIT News Office <p>Up to 18 percent of babies born worldwide arrive before they are full-term, defined as 37 weeks of gestation. About 1 million of those babies do not survive, and those who do can face developmental problems such as impaired vision or hearing, defects in the heart or lungs, or cognitive impairments.</p> <p>Currently there is no reliable way to predict whether a woman with a normal pregnancy will go into labor before 37 weeks. However, a study from MIT offers a new approach to evaluating this risk, by analyzing the properties of cervical mucus. The researchers found that cervical mucus from women who delivered their babies before 37 weeks was very different from that of women who delivered later.</p> <p>This type of analysis could offer an easy way to calculate the risk of early labor, potentially allowing doctors to try to intervene earlier to prevent preterm births.</p> <p>“Our prediction is that we might be able to identify risk for preterm birth ahead of time, before labor sets in,” says Katharina Ribbeck, an associate professor of biological engineering at MIT and the senior author of the study. “Diagnostic tools for this are missing.”</p> <p>Ribbeck worked on the study with Michael House, an associate professor at Tufts University School of Medicine. MIT postdoc Kathryn Smith-Dupont is the first author of the paper, which appears in the Sept. 4 issue of <em>Scientific Reports</em>.</p> <p><strong>Barrier to infection</strong></p> <p>Ribbeck’s lab at MIT investigates the distinctive chemical and mechanical properties of mucus, and how those properties help it to perform many critical roles as part of the body’s first line of defense against infection.</p> <p>Several years ago, Ribbeck began exploring whether changes in cervical mucus might play a role in preterm births. Between 25 and 40 percent of early births are believed to be caused by infections that occur when microbes reach the uterus through the cervical plug, which is made of mucus and normally blocks access to the uterus.</p> <p>In a study published in 2013, Ribbeck found that cervical mucus from pregnant women at high risk of early labor was mechanically weaker and more elastic than that of low-risk pregnant women.</p> <p>For the new study, she and her colleagues decided to investigate the mucus’s permeability to small particles. Mucus is formed from polymers known as mucins, and the composition and arrangement of these mucins determine how porous the gel is.</p> <p>The researchers collected samples from two groups of patients. The low-risk group included pregnant women who came in to their doctors’ offices for routine visits around 30 weeks and ended up giving birth after 37 weeks. The high-risk group included women who went into labor early, between 24 and 34 weeks. Doctors were able to halt labor in these women, and the samples were taken after they were stabilized. They all ended up giving birth before 37 weeks.</p> <p>The researchers tested the ability of negatively charged spheres about 1 micron in diameter to travel through the mucus, and found a small but statistically insignificant difference in porosity between the high- and low-risk samples. They then decided to do the same test with charged peptide probes, which are small enough to avoid getting stuck in the mucus network but are sensitive to the biochemical modifications of the mucus. With these peptide probes, the researchers found a significant differences in mucus permeability and adhesiveness: The peptides were able to pass through samples from high-risk women much more easily.</p> <p>This suggests that cervical mucus from women at high risk for early labor, for reasons not yet known, may be more susceptible to invasion by potentially harmful bacteria and microbes, making it more likely that those women will experience an infection that leads to preterm birth, Ribbeck says. In addition, the altered mucus may be less able to retain helpful immune system components such as antibodies or antimicrobial peptides, which would normally help to combat infection.</p> <p>“Mucins display all sorts of immunologically active factors that you may also lose when the adhesive properties change,” Ribbeck says.</p> <p>She suspects that this loss of adhesion might be caused by changes in molecular structure of the mucins, in particular, changes in the number and types of sugar molecules that comprise part of their structure.</p> <p><strong>Risk analysis</strong></p> <p>Currently, the most common way to try to predict the risk of preterm birth is to measure the length of the cervix, but although a shortened cervix is correlated with higher risk, there are also many cases where a shortened cervix does not lead to preterm birth. Another test involves measuring levels of fetal fibronectin, a material that essentially “glues” the fetal membranes to the uterine wall, in vaginal secretions. However, this is not a completely reliable predictor, and furthermore, women can deliver preterm when both cervical length and fetal fibronectin are normal.</p> <p>“There’s no currently well-accepted universal test,” says Smith-Dupont. “The pathophysiology and mechanisms of preterm birth are extremely complex, and what works to assess one patient may not work for another.”</p> <p>Ribbeck anticipates that cervical mucus testing could be done early in pregnancy, as part of a routine screen that would reveal whether a woman was at high risk of preterm birth. (This test would determine risk from infection, but not from other potential causes of early labor.)</p> <p>Errol Norwitz, chairman of the Department of Obstetrics and Gynecology at Tufts Medical Center, who was not involved in the research, says the new study is an innovative approach to combating a problem that has so far proven intractable. Identifying women at high risk, and potentially giving their babies the chance to remain in utero for even a few extra days, could make a big difference, he says.</p> <p>“Preterm birth is one of the biggest issues we face in child and baby health care around the world. It’s an enormous burden to individuals and families,” Norwitz says. “We sorely need a way to identify risk because all of the tools that we have now don’t work very well.”</p> <p>Through studies of the chemical composition of the altered mucus, Ribbeck also hopes to develop new ways to restore the normal function of the mucus. “If the mucus is thinner or less adhesive than it naturally is, then we can begin to think about factors to add so that we improve its barrier properties,” she says.</p> <p>The research was funded, in part, by the Burroughs Wellcome Fund Preterm Birth Initiative, the National Institutes of Health, and the National Institute of Environmental Health Sciences.</p> “Our prediction is that we might be able to identify risk for preterm birth ahead of time, before labor sets in,” says Katharina Ribbeck, an associate professor of biological engineering at MIT and the senior author of the study. “Diagnostic tools for this are missing.” Photo: Bryce VickmarkResearch, Biological engineering, Health, Medicine, Microbes, School of Engineering, National Institutes of Health (NIH) New way to test antibiotics could lead to better drugs Study finds bacterial response to drugs varies in different environments. Thu, 31 Aug 2017 12:00:00 -0400 Anne Trafton | MIT News Office <p>MIT and Harvard University researchers have engineered <em>E. coli</em> cells that can be used to study how bacteria at an infection site respond to antibiotic treatment, allowing scientists to learn more about how existing antibiotics work and potentially help them to develop new drugs.</p> <p>In the new study, which appears in the Aug. 31 issue of <em>Cell Host and Microbe</em>, the researchers found evidence that some existing hypotheses about how bacteria respond to antibiotics are not correct.</p> <p>“Our study shows that using engineered organisms can give you a window into infection sites and expand our understanding of what antibiotics are actually doing. This work indicates that some of our assumptions may be wrong,” says James Collins, the Termeer Professor of Medical Engineering and Science in MIT’s Institute for Medical Engineering and Science (IMES) and Department of Biological Engineering and the senior author of the study.</p> <p>The paper’s lead author is Laura Certain, a clinical fellow at Harvard’s Wyss Institute for Biologically Inspired Engineering.</p> <p><strong>Engineering bacteria</strong></p> <p>Much of the research in Collins’ lab focuses on trying to understand how antibiotics work, in hopes of designing more effective drugs. For the new study, Collins wanted to apply synthetic biology — the construction of novel genetic circuits in living cells — to design bacteria that could be used to study antibiotics and infection.</p> <p>Most studies of how antibiotics work are done with bacterial cells grown in a lab dish. However, Collins and Certain suspected that these drugs’ effects could be different in living animals because that environment, including available nutrients and other conditions, is very different from a lab dish.</p> <p>To allow them to study antibiotics under more realistic conditions, the researchers engineered a strain of <em>E. coli</em> bacteria that expresses a genetic “toggle switch” that flips only under certain conditions. Such switches can be incorporated into bacteria to allow them to record events such as exposure to a chemical.</p> <p>In this case, the researchers designed the bacteria to reveal whether they were dividing or not, allowing them to explore how antibiotics affect cells in either state. Previous studies done in bacteria grown in a lab dish have found that most antibiotics work better on cells that are dividing, while non-replicating cells are much harder to kill.</p> <p>The researchers delivered the bacteria to mice along with a small orthopedic implant, to mimic the infections that often occur at the sites of medical implants. The mice were then treated with the antibiotic levofloxacin. Before and after treatment, the cells were removed and treated with ATC, a molecule that turns on the toggle switch, but only in cells that are replicating.</p> <p>Scientists have hypothesized from previous studies that chronic infections usually consist largely of non-dividing bacteria. However, in this study, the researchers found that before antibiotic treatment, about half of the bacteria were still actively dividing.</p> <p>They also found that levofloxacin appeared to be highly and perhaps even more effective against non-dividing cells, contrary to what has been seen in cells grown in a dish. The researchers noted that the percentage of replicating cells increased after treatment, suggesting that levofloxacin did not kill all of the replicating cells.</p> <p>Another surprising finding contradicted scientists’ hypothesis that chronic persistent infections consisting of non-dividing bacteria are highly tolerant to antibiotics: They found the infections were still susceptible to antibiotics, when given at large enough doses.</p> <p><strong>More to learn</strong></p> <p>Collins says this study demonstrates that there is much more for scientists to learn about how antibiotics work, and suggests that engineered organisms could be useful for further investigating their effects.</p> <p>“This is going to challenge people to rethink what antibiotics are doing at an infection site,” Collins says. “I think that eventually these synthetic biology tools could also be quite useful in antibiotic development, to see whether the antibiotics are getting to the pathogens of interest, how effective they are, and what they are actually doing at the site.”</p> <p>He adds that the genetic toggle switch could be easily transferred to other types of bacteria, and could also be designed to test for other features such as how bacteria interact with immune cells at an infection site. This approach could also be used to study biofilms — sticky sheets of bacterial cells that can be very difficult to remove — and other pathogens such as fungi.</p> <p>The research was funded by the Paul G. Allen Frontiers Group, the Defense Threat Reduction Agency, and the Wyss Institute.</p> A new method allows scientists to learn more about how existing antibiotics work and potentially help them to develop new drugs. Image: MIT NewsResearch, Drug development, Biological engineering, Synthetic biology, Microbes, Disease, Institute for Medical Engineering and Science (IMES), School of Engineering Phytoplankton and chips Simons Foundation supports enhanced computer infrastructure for MIT&#039;s Darwin Project, which focuses on marine microbes and microbial communities. Fri, 04 Aug 2017 18:10:01 -0400 Helen Hill | EAPS <p>Microbes mediate the global marine cycles of elements, modulating atmospheric carbon dioxide and helping to maintain the oxygen we all breathe, yet there is much about them scientists still don’t understand. Now, an award from the Simons Foundation will give researchers from MIT's <a href="" target="_blank">Darwin Project</a> access to bigger, better computing resources to model these communities and probe how they work.</p> <p>The simulations of plankton populations made by Darwin Project researchers have become increasingly computationally demanding. MIT Professor Michael "<a href="" target="_blank">Mick" Follows</a>&nbsp;and Principal Research Engineer <a href="">Christopher Hill</a>, both affiliates of the Darwin Project, were therefore delighted to learn of their recent Simons Foundation award, providing them with enhanced compute infrastructure to help execute the simulations of ocean circulation, biogeochemical cycles, and microbial population dynamics that are the bread and butter of their research.</p> <p>The Darwin Project,&nbsp;an alliance between oceanographers and microbiologists in the MIT Department of Earth, Atmospheric and Planetary Sciences (EAPS) and the&nbsp;<a href="" target="_blank">Parsons Lab</a> in the MIT Department of Civil and Environmental Engineering, was conceived as an initiative to “advance the development and application of novel models of marine microbes and microbial communities, identifying the relationships of individuals and communities to their environment, connecting cellular-scale processes to global microbial community structure"&nbsp;with the goal of coupling “state of the art physical models of global ocean circulation with biogeochemistry and genome-informed models of microbial processes."</p> <p>In response to increases in model complexity and resolution over the course of past decade since the project’s inception in 2007, computational demands have ballooned. Increased fidelity and algorithmic sophistication in both biological and fluid dynamical component models and forays into new statistical analysis approaches, leveraging big-data innovations to analyze the simulations and field data, have grown inexorably.</p> <p>"The award allows us to grow our in-house computational and data infrastructure to accelerate and facilitate these new modeling capabilities," says Hill, who specializes in Earth and planetary computational science.</p> <p>The boost in computational infrastructure the award provides for will advance several linked areas of research, including the capacity to model marine microbial systems in more detail, enhanced fidelity of the modeled fluid dynamical environment, support for state of the art data analytics including machine learning techniques, and accelerating and extending genomic data processing capabilities.</p> <p>High diversity is a ubiquitous aspect of marine microbial communities that is not fully understood and, to date, is rarely resolved in simulations. Darwin Project researchers have broken new ground and continue to push the envelope in modeling in this area: In addition to resolving a much larger number of phenotypes and interactions than has typically been attempted by other investigators, the Darwin Project team has also been increasing the fidelity of the underlying physiological sub-models which define traits and trade-offs.</p> <p>"One thing we are doing is implementing simplified metabolic models which resolve additional constraints [electron and energy conservation] and higher fidelity [dynamic representations of macro-molecular and elemental composition]," says Fellows. "These advances require more state variables per phenotype. We have also an explicit radiative transfer model that allows us to better exploit satellite remote sensing data but both come at a greater computational expense.” Darwin researchers are also expanding their models to resolve not only phototrophic and grazer communities in the surface ocean, but to include heterotrophic&nbsp;and chemo-autotrophic populations throughout the water column.</p> <p>Follows and Hill believe these advances will provide better fidelity to real world observations, a more dynamic and fundamental description of marine microbial communities and biogeochemical cycles, and the potential to examine the underlying drivers and significance of diversity in the system.</p> <p>"Much of the biological action in the surface ocean occurs at scales currently unresolved in most biogeochemical simulations,” Follows explains. “Numerical models and recent observations show that the sub-mesoscale motions in the ocean have a profound impact on the supply of resources to the surface and the dispersal and communication between different populations. The integral impact of this, and how to properly parameterize it, is not yet clear, but one approach, that is within reach, is to resolve these scales of motion nested within global simulations,"</p> <p>Hill and Follows hope such advances will allow them to examine both local and regionally integrated effects of fine-scale physical drivers. "We have already completed a full annual cycle numerical simulation that resolves physical processes down to kilometer scales globally," says Hill. “Such simulations provide a basis for driving targeted modeling of, for example, the role of fronts that may involve fully non-hydrostatic dynamics and that could help explain in-situ measurements that suggest enhanced growth rates under such conditions.” Such work is strongly complementary to another Simons Foundation sponsored project, the Simons Collaboration on Ocean Processes and Ecology (SCOPE). As an initiative to&nbsp;advance our understanding of the biology, ecology, and biogeochemistry of microbial processes that dominate Earth’s largest biome — the global ocean — SCOPE seeks to measure, model, and conduct experiments at a model ecosystem site located 100 km north of the Hawaiian island of Oahu that is representative of a large portion of the North Pacific Ocean.</p> <p>The team has also already implemented algorithms to enable explicit modeling of the relevant fluid dynamics, but here too, the approaches are computationally demanding. "The improved facilities this award provides will enable these extremely demanding experiments to proceed," says Follows.</p> <p>Enhanced computer resources will also allow Darwin Project researchers to more effectively utilize data analytics. "We are adopting multiple statistical approaches for classifying fluid dynamical and ecosystem features in observations and in simulations which we plan to apply to biogeochemical problems," says Hill.&nbsp;“One current direction, which employs random forest classification to identify features corresponding to training sets, is showing particular promise for objectively quantifying links between biogeochemical event occurrence and physical environment phenomena.”</p> <p>Not only will&nbsp;these methods provide useful analysis tools for their simulations, the pair also see them bridging to real world interpretations of, for example, metagenomics surveys in the ocean. Follows and Hill see this direction as a route by which to bring simulations and observations closer in new and meaningful ways. The growth in computational infrastructure the Simons award allows for, creates the potential for making much larger queries across more realistic datasets.</p> <p>The Darwin Project is part of a long and fruitful collaboration with Institute Professor <a href="" target="_blank">Sallie "Penny" Chisholm</a> of MIT’s Department of Civil and Environmental Engineering. Steady growth in available large-scale metagenomic and single-cell genomic data resulting from genetics data activities in the Chisholm Lab are also driving additional computational processing resource needs.</p> <p>With the new Simons-supported enhancements in computational infrastructure, Darwin Project collaborators in the Chisholm Lab will be able to tackle assembly from larger metagenomic libraries and single-cell genome phylogenies using maximum likelihood and/or Bayesian algorithms. Currently, some large metagenomics assembly activities require compute resources with more memory than this team has readily had available. "Single-cell genome phylogeny activities are computationally demanding and require dedicating compute resources for weeks or months at a time, Hill explains. “This creates a bottleneck for other work. To accelerate work in these areas additional compute resources, some with larger memory than current resources and some with GPU accelerators are going to be hugely beneficial. The new systems will permit larger metagenomics library assembly than is currently possible."</p> Image: EAPSGrants, Industry, Oceanography and ocean engineering, Ocean science, Microbes, Computer science and technology, Analytics, Computer modeling, Climate, EAPS, Earth and atmospheric sciences, Environment, Civil and environmental engineering, School of Science, School of Engineering A rose by any other name would smell as yeast Emily Havens Greenhagen ’05 leads a team of scientists brewing perfume from yeast. Fri, 14 Jul 2017 15:00:01 -0400 Justin Chen | Department of Biology <p>From afar, the multistory fermenters — towering metal cylinders encompassed by scaffolding, ladders, and pipes — look like rockets on a launch pad. Climbing to the top of the fermenter, visitors to the Mexico City manufacturing plant can peer down at a set of paddles churning 50,000 liters of frothy, golden broth. Within the mixture, genetically engineered yeast are synthesizing lactones — a family of molecules responsible for the aromas of fruits and flowers. MIT Department of Biology alumna Emily Havens Greenhagen ’05 has visited the plant over several weeks to monitor her company’s most promising project: a plan to make perfume from yeast cells.</p> <p>Greenhagen is director of fermentation engineering at <a href="" target="_blank">Ginkgo Bioworks</a>, a Boston-based synthetic biology company seeking to turn microbes into customizable factories to produce products ranging from pesticides to perfumes. Scientists such as Greenhagen know that microbes can manufacture organic products more efficiently than any machine or production line. Instead of workers at an assembly line, yeast cells use enzymes — proteins that perform a specific task such as removing or adding a group of atoms to a molecule. Working together, teams of enzymes incrementally transform basic nutrients like sugar into other compounds such as alcohol and carbon dioxide. “By inserting DNA encoding for enzymes from different plants or animals into yeast cells,” Greenhagen says, “we can tailor microbes to produce different materials.”</p> <p>Manipulating yeast cells is an old idea. For hundreds of years, people have been brewing beer through fermentation, a natural process where yeast consume sugar to create alcohol and different flavorings. In the 1930s, scientists began using microbes to create antibiotics and biofuels. “What makes Ginkgo cutting edge is the automation and scale,” Greenhagen explains of the company co-founded in 2008 by synthetic biologist Tom Knight ’69, SM ’79, PhD ’83. “Using robots, we can genetically modify hundreds of yeast strains and test how they perform in just one week.”</p> <p>Ginkgo Bioworks’ automation played a critical role in creating the yeast strain that Greenhagen observed in the Mexico City manufacturing plant. These microbes, containing a set of enzymes needed to turn fatty acids into lactones, were engineered through thousands of trial-and-error experiments performed by robots. For each enzyme encoded in the final strain, a team of scientists and machines led by Greenhagen had tested hundreds of versions originating from diverse plant species and strategically mutated in different ways to work more efficiently in yeast cells.</p> <p>During the testing process, researchers grew thousands of yeast strains, each genetically engineered for a single enzyme, in small tabletop fermenters before combining the most effective genetic modifications into a single cell to produce lactones. Ten years ago, when Greenhagen first started in industry, fermenting was a labor-intensive process done by hand, requiring a single researcher to manage four reactors at a time. In contrast, members of Greenhagen’s team — using robots to mix different concentrations of nutrients, add yeast extract, and monitor the output of desired molecules — routinely managed 24 experiments simultaneously. As a result of automation, the development process took six months instead of a year and half. After a purification process, the developed scent could then be delivered to Robertet, a French fragrance and flavor manufacturer and Ginkgo’s first commercial customer. “The robots don’t just speed up projects,” Greenhagen says, “they take care of the monotonous tasks so that we have more time to think about results and design new experiments — the fun stuff that scientists really want to do.”</p> <p>Like Ginkgo Bioworks, Greenhagen embodies the convergence of biology and engineering. As a freshman at MIT, Greenhagen had decided to pursue chemical engineering but changed her plans when she learned about synthetic biology. “I couldn’t stop reading my textbook,” she recalls. “I was so excited by the idea that there are living organisms that we can modify to use as tools. That’s when I decided to become a scientist.”</p> <p>Greenhagen credits one particular microbiology course, taught by Professor Graham Walker, for shaping her thinking as a biologist. While lecturing on organelles, Walker encouraged students to imagine the room as a cell and to point out where the nucleus or mitochondria might be located. “His teaching style inspired me to really visualize what’s going on in the fermentation vessel,” Greenhagen says. “Whereas fermentation engineers worry more about physical variables like oxygen transfer and think of organisms as black boxes, my training at MIT gave me an empathy for microbes. It’s an approach that a lot of chemical engineers don’t necessarily think about and has been key to my success.”</p> <p>By harnessing biology and engineering, Greenhagen and others in the field of synthetic biology are beginning to transform manufacturing. Many consumer goods, from food to clothes to perfume, are produced using traditional ingredients and industrial processes that are increasingly unsustainable as planetary resources dwindle. By using microbes, companies can generate many of the raw resources they require with less energy and waste than factories.</p> <p>In the case of flavors and fragrances, companies like Robertet had been extracting the majority of their starting compounds from plants and flowers, whose growth may vary dramatically from year to year. In contrast, Ginkgo Bioworks’s yeast feed on basic crops like corn and sugar cane, which are more economical to raise, and release their products in highly reliable reactions. Encouraged by its success with perfumes, Ginkgo Bioworks is using similar approaches to make organic pesticides, industrial enzymes, and products for human health.</p> <p>For Greenhagen, scented yeast represent not only the potential of synthetic biology but also the culmination of years of work and education. Before joining Ginkgo Bioworks, Greenhagen had spent six years at another startup without seeing any of her projects commercialized. “When we were bought out by a larger company and taken off the commercialization path, I was told to sit back and relax but that’s not what I do,” she says.</p> <p>Greenhagen traces her driving mentality back to MIT lab courses and an Undergraduate Research Opportunities Program (UROP) project in Professor Leona Samson’s laboratory. There, Greenhagen says, students were expected to read papers, design their own experiments, and place their findings in the context of published results. “This critical thinking and problem solving combined with real-life experience inspired me to think of my education as a gift that I should put to use,” she says. Years later, having traveled thousands of miles to see her first commercialized product, Greenhagen says she is still moved by MIT. “When I walk through campus, I get goosebumps from all the memories. It is such an amazing place.”</p> “My training at MIT gave me an empathy for microbes,” says Emily Greenhagen. “It’s an approach that a lot of chemical engineers don’t necessarily think about and has been key to my success.”Photo: Justin KnightAlumni/ae, Biology, Biological engineering, Chemical engineering, Bioengineering and biotechnology, Synthetic biology, Research, Bacteria, Microbes, School of Science Microbe generates extraordinarily diverse array of peptides In marine bacteria, evolution of new specialized molecules follows a previously unknown path. Thu, 22 Jun 2017 23:59:59 -0400 David L. Chandler | MIT News Office <p>It’s one of the tiniest organisms on Earth, but also one of the most abundant. And now, the microscopic marine bacteria called <em>Prochlorococcus</em> can add one more superlative to its list of attributes: It evolves new kinds of metabolites called lanthipeptides, more abundantly and rapidly than any other known organism.</p> <p>While most bacteria contain genes to pump out one or two versions of this peptide, <em>Prochlorococcus</em> varieties can each produce more than two dozen different peptides (molecules that are similar to proteins, but smaller). And though all of Earth’s <em>Prochlorococcus</em> varieties belong to just a single species, some of their localized varieties in different regions of the world’s oceans each produce a unique collection of thousands of these peptides, unlike those generated by terrestrial bacteria.</p> <p>The startling findings, <a href="" target="_blank">published this week</a> in the journal <em>Proceedings of the National Academy of Science</em>, were discovered by former MIT graduate student Andres Cubillos-Ruiz, Institute Professor Sallie “Penny” Chisholm, University of Illinois chemistry professor Wilfred van der Donk, and two others.</p> <p>“This is incredibly significant work,” says Eric Schmidt, professor of medicinal chemistry at the University of Utah, who was not involved in the research. “The authors show how nature has evolved methods to create chemical diversity. What really sets it apart is that it examines how this evolution takes place in nature, instead of in the lab. They examine a huge habitat, the open ocean. This is amazing,” he says.</p> <p>“No one had seen the true extent of the diversity in these molecules” until this new study, Cubillos-Ruiz says. The first hints of this unexpected diversity surfaced in 2010, when Bo Li and Daniel Sher, members of van der Donk’s and Chisholm’s labs respectively, found that one variety of <em>Prochlorococcus</em> could produce as many as 29 different lanthipeptides. But the big surprise came when Cubillos-Ruiz looked at other populations and found that the same organisms, in a different location, produced similarly great numbers of the peptides, “and all of them were completely different,” he says.</p> <p>After considerable study examining the genomes of many <em>Prochlorococcus</em> cultures and pieces of DNA from the wild, the researchers determined that the way the extraordinary numbers of lanthipeptides evolve is, in itself, something that hasn’t been observed before. While most evolution takes place through tiny incremental changes, while preserving the vast majority of the genetic structure, the genes that enable <em>Prochlorococcus</em> to produce these lanthipeptides do just the opposite. They somehow undergo dramatic, wholesale changes all at once, resulting in the production of thousands of new varieties of these metabolites.</p> <p>Cubillos-Ruiz, who is now a postdoc at MIT’s Institute For Medical Engineering and Science, says the way these genes were changing “wasn’t following classic phylogenetic rules,” which dictate that changes should happen slowly and incrementally to avoid disruptive changes that impair function. But the story is a bit more complicated than that: The specific genes that encode for these lanthipeptides are composed of two parts, joined end to end. One part is actually very well-preserved across the lineages and different populations of the species. It’s the other end that goes through these major shakeups in structure. “The second half is amazingly variable,” he says. “The two halves of the gene have taken completely different evolutionary pathways, which is uncommon.”</p> <p>The actual functions of most of these thousands of peptides, which are known as prochlorosins, remain unknown, as they are very difficult to study under laboratory conditions. Similar compounds produced by terrestrial bacteria can serve as chemical signaling devices between the organisms, while others are known to have antimicrobial functions, and many others serve purposes that have yet to be determined. Because of the known antimicrobial functions, though, the team thinks it will be useful to screen these compounds to see if they might be candidates for new antibiotics or other useful biologic products.</p> <p>This evolutionary mechanism in <em>Prochlorococcus</em> represents “an intriguing mode of evolution for this kind of specialized metabolite,” Cubillos-Ruiz says. While evolution usually favors preservation of most of the genetic structure from the ancestor to the descendants, “in this organism, selection seems to favor cells that are able to produce many and very different lanthipeptides. So this built-in collective diversity appears to be part of its function, but we don’t yet know its purpose. We can speculate, but given their variability it’s hard to demonstrate.” Maybe it has to do with providing protection against attack by viruses, he says, or maybe it involves communicating with other bacteria.</p> <p>“<em>Prochlorococcus</em> is trying to tell us something, but we don’t yet know what that is,” says Chisholm, who has joint appointments in MIT’s departments of Civil and Environmental Engineering and Biology. “What [Cubillos-Ruiz] uncovered through this molecule is an evolutionary mechanism for diversity.” And that diversity clearly must have very important survival value, she says: “It’s such a small organism, with such a small genome, devoting so much of its genetic potential toward producing these molecules must mean they are playing an important role. The big question is: What is that role?”</p> <p>In fact, this kind of process may not be unique — it may be just that <em>Prochlorococcus</em>, an organism that Chisholm and her colleagues initially discovered in 1986 and have been studying ever since, has provided the wealth of data needed for such an analysis. “This might be happening in other kinds of bacteria,” Cubillos-Ruiz says, “so maybe if people start looking into other environments for that kind of diversity,” it may turn out not to be unique. “There are some hints it happens in other [biological] systems too,” he says.</p> <p>Christopher Walsh, emeritus professor of biological chemistry and molecular pharmacology at Harvard University, who was not involved in this work, says “The dramatic diversity of prochlorosins assembled by a single enzyme … raises surprising questions about how evolution of thousands of cyclic peptide structures can be &nbsp;accomplished by alterations that favor large changes rather than incremental ones.”</p> <p>According to Schmidt, “There are many possible practical applications. The first is fairly clear: By using this natural variation, the same process can be used to design and build chemicals that might be drugs or other materials. More fundamentally, by understanding the natural process of generating chemical diversity, this will help to create methods to synthesize desired applications in cells.”</p> <p>The research team also included former graduate student Jessie Berta-Thompson and postdoc Jamie Becker at MIT. The work was supported by the Gordon and Betty Moore Foundation, the National Science Foundation, and the Simons Foundation.&nbsp;</p> Researchers have discovered that Prochlorococcus varieties can each produce more than two dozen different peptides (molecules that are similar to proteins, but smaller).Image: Christine Daniloff/MIT Research, School of Engineering, School of Science, Civil and environmental engineering, Biology, Bacteria, Microbes A genomic take on geobiology Researchers in Greg Fournier’s geobiology lab are seeking to calibrate the ancient history of life on Earth using genomic analysis. Mon, 05 Jun 2017 16:30:02 -0400 Helen Hill | EAPS <p>Scientists know that atmospheric oxygen irreversibly accumulated on Earth around 2.3 billion years ago, at a time known as the&nbsp;<a href="" target="_blank">Great Oxidation Event</a>, or GOE. Prior to that time all life was microbial, and most, if not all, environments were anoxic (that is, contained no oxygen). Oxygen was first produced some time before the GOE through the evolution of a group of photosynthetic bacteria known as <a href="" target="_blank">cyanobacteria</a>. Releasing oxygen as a by-product of splitting water in order to acquire electrons to be energized by light, this process led to dramatic changes in both the biological and geochemical processes on a planetary scale. Eventually, the continued accumulation of oxygen led to an oxidized surface, atmosphere, and ocean that persist to this day.</p> <p>Besides shedding light on a fundamental change in Earth’s climate, it is hoped that understanding the GOE will help scientists gain insight into the rise of eukaryotes — cellular organisms like us humans, in which genetic material is DNA in the form of chromosomes contained within a distinct nucleus. Eukaryotes require oxygen to produce sterols, an important part of their cell membranes. Furthermore, eukaryotes also contain mitochondria, organelles descended from ancient bacteria that use oxygen to generate energy using aerobic respiration.</p> <p>There are currently two schools of thought regarding how oxygen levels rose: The first proposes a small initial rise at the time of the GOE, with levels low but stable until increasing again around 600 million years ago, approaching modern levels. The second posits a more oscillatory rise with a greater increase immediately following the GOE, and then a subsequent crash, with levels only increasing again 600 million years ago.</p> <p>While geologists have been able to establish increasingly precise dates for the onset of the GOE through geochemical analyses, the ability to detect transient variations in oxygen levels following the GOE are less readily detected in the rock record. However, in the past couple of decades, it would be fair to say, science has experienced a "great genomics event" through which biologists, armed with the ability to sequence genes increasingly rapidly, now find themselves hard at work sequencing everything they can lay their hands on. And it turns out genomics may hold the answer to how oxygen continued to accumulate,</p> <p>Greg Fournier, an assistant professor of geobiology in the Department of Earth, Atmospheric and Planetary Sciences at MIT, is an expert in molecular phylogenetics, discovering the evolutionary histories of genes and genomes within microbial lineages across geological timescales.</p> <p>A particular current interest is the detection of events in the evolution of microbial metabolisms that likely align with global changes in Earth’s biogeochemical cycles, including oxygen.</p> <p>Molecular oxygen (O<sub>2</sub>) readily changes to an extremely reactive “free radical” form with an unpaired electron called superoxide, a chemical highly damaging to many biological systems. Many organisms are protected against superoxides by superoxide dismutase&nbsp;enzymes that convert superoxide to hydrogen peroxide, the first step in detoxifying this compound. It is present in most extant bacteria (i.e. ones that are alive today) but is assumed to have originally appeared in response to the increasingly oxygen rich environment of the GOE.</p> <p>Fournier is an expert in a process called <a href="" target="_blank">horizontal gene transfer</a>, or HGT. HGT is the exchange of genetic material between cellular organisms other than by regular “vertical” transmission of DNA from parent to offspring. He believes HGT evidence of oxygen-related genes like superoxide dismutase&nbsp;will enable him to distinguish between a steady and a fluctuating build-up.</p> <p>“If oxygen rose and remained steady we should see many such transfer events associated with superoxide dismutase,<em>”&nbsp;</em>Fournier explains. “If it rose and then fell back we would expect to see transfer events followed by the disappearance of the gene in different lineages, since the need to protect against oxygen would have ceased.”</p> <p>Because genetic data from old extinct lineages are not available, members of Fournier’s Lab use gene sequences sampled across modern organisms, building evolutionary trees known as phylogenies to explore how they relate to one another. By comparing these gene trees to the best guesses of how the microbial organisms are related, transfer events may be detected, and their relative timing inferred.</p> <p>Abigail Caron, a postdoc in the Fournier Group, uses a computer cluster housed at the&nbsp;<a href="">Massachusetts Green High Performance Computing Center</a> (MGHPCC) to run genetic analyses on different bacteria looking for instances of horizontal gene transfer, and mapping these events across many lineages.</p> <p>For only a small number of gene sequences, Caron can use a process called Ranger DTL (Rapid&nbsp;ANalysis of&nbsp;Gene Family&nbsp;Evolution using&nbsp;Reconciliation&nbsp;DTL) run on her laptop. But seeking to compare and integrate gene histories across upwards of 8,000 bacterial species, incorporating complex models of uncertainty within individual tree analyses, as she is attempting to do, is too intensive for any single computer. Having the MGHPCC cluster to work on allows her to run multiple analyses simultaneously across dozens of processors, making such high-resolution investigations into the history of these genes possible.</p> A bubble of oxygen emerges from a cyanobacterial mat growing in the lab.Photo: Tanja BosakResearch, Bacteria, Evolution, Genetics, EAPS, School of Science, Microbes In search of the fundamental laws of microecology A new MIT-led Simons Foundation collaboration aims to understand basic principles and laws of microbial ecosystems. Tue, 30 May 2017 09:00:00 -0400 Department of Civil and Environmental Engineering <p>Model microorganisms growing in pure cultures have been the basis of biological research for many decades — open a cell biology textbook and almost everything you will find has been discovered in yeast or <em>E</em>. <em>coli</em> lab cultures. While this speaks to the power of research on individual species, ecologists would be quick to remind us that pure cultures rarely exist in nature. Organisms live in an ecological context, and are often cogs&nbsp;in a well-oiled ecological machine with multiple species.</p> <p>Microbial communities are one prime example of ecological systems that are far from being pure cultures, and&nbsp;these communities play fundamental roles in earth’s ecosystems. Despite their critical contributions to our world, our understanding of these collective systems lags decades behind our knowledge of pure cultures. The rules that govern their dynamics and function also remain largely unknown.</p> <p>Now, a new Simons Foundation collaboration called Theory of Microbial Ecosystems (THE-ME, pronounced "theme") is attempting&nbsp;to fill this gap by discovering the principles of how microbial communities form and function.</p> <p>Simons Collaborations like THE-ME are large-scale projects that bring together funded investigators&nbsp;from difference disciplines&nbsp;to find solutions to major scientific problems, such as the origin of life or the coding of information in the brain.&nbsp;THE-ME is being launched by a&nbsp;multidisciplinary team of researchers from across the United States and Europe, coordinated by MIT Department of Civil and Environmental Engineering&nbsp;Assistant Professor Otto X. Cordero and Professor Roman Stocker of ETH Zurich. They hope the effort will result in the development of fundamental quantitative theories that can help us understand and predict the behavior of microbial ecosystems.</p> <p>“Some of the biggest open questions in biology remain at the level of collectives,” Cordero says. “Cells have evolved internal regulatory programs that allow them to sense their environment and adjust their behavior. By contrast, ecological communities lack any form of centralized control, they are distributed and decentralized systems. How such systems self-organize in a reproducible fashion in the absence of a central conductor&nbsp;is one of the most important questions in biology.”</p> <p>THE-ME seeks to answer three central questions about microbial communities: how microbes in communities organize and distribute roles, how communities utilize resources for energy and growth, and how they respond&nbsp;to environmental disturbances and changes.</p> <p>Cordero and Stocker, both environmental scientists, assembled a research team that will&nbsp;take a multidisciplinary approach to answering these questions. Their strategy is to develop model systems to study the interaction between cellular processes and community-level processes. The researchers hope to use these findings to discover quantitative laws that dictate the behavior of such microbial ecosystems.</p> <p>To develop these model systems, the team of researchers will draw inspiration from the ocean, where communities of bacteria self-organize at micrometer scales to degrade particles of organic matter. One of the major benefits of studying oceanic microbes is their ecological relevance —&nbsp;by recycling organic matter these organisms drive the cycling of carbon in the planet. Moreover, new technology now allows scientists to recreate their&nbsp;microenvironments at microscales in the laboratory, allowing researchers to study their dynamics and function in&nbsp;synthetic ecosystems.</p> <p>“Many of the major discoveries in microbial ecology took place in the context of marine microbes and, incidentally, in the Parsons Lab at MIT, which has a great tradition of pioneering microbial ecology research. We hope to continue and build from that tradition,” Cordero says.</p> <p>In addition to Cordero and Stocker, the THE-ME research team includes Jeff Gore, a biophysicist and associate professor of physics at MIT; Mick Follows, professor of earth, atmospheric and planetary sciences at MIT; Martin Ackermann, a professor of molecular microbial ecology at ETH Zurich; and Sebastian Bonhoeffer, a theoretical biologist and professor at ETH Zurich. Also working with&nbsp;the team are Victoria Orphan, a molecular microbial ecologist and professor at Caltech; Mary Ann Moran, a marine microbiology and professor at University of Georgia; Terence Hwa PhD ’90, a theoretical physicist and professor at University of California at San Diego; and Naomi Levine PhD ’10, an ocean modeling theoretical ecologist and assistant professor at University of Southern California.</p> <p>“Roman and I were looking for researchers that are at the top of their fields and had a strong quantitative background,”&nbsp;Cordero says.&nbsp;“Most importantly, we had to find people that could work well together. I think we have assembled an amazing team of scientists and we are looking forward to getting this project underway. I’m confident this cross-continental, cross-institutional project will prove extremely valuable.”&nbsp;</p> <p>“The Simons Foundation truly makes large-scale research possible,” he adds. “We are extremely grateful for&nbsp;the foundation for funding THE-ME. The projects and experiments we are planning are foundational to microbiology and we appreciate the support of the Simons Foundation for our research endeavors.”&nbsp;</p> Marine bacteria form a community on a nutrient particle in the Cordero Lab.Image: Julien Barrere/Cordero LabCivil and environmental engineering, Bacteria, Earth and atmospheric sciences, Microbes, Ocean science, Research, School of Engineering, Funding Bacteria with multicolor vision Red, green, and blue light can be used to control gene expression in engineered E. coli. Fri, 26 May 2017 10:30:00 -0400 Rob Matheson | MIT News Office <p>MIT researchers have engineered bacteria with “multicolor vision” — <em>E. coli</em> that recognize red, green, or blue (RGB) light and, in response to each color, express different genes that perform different biological functions.</p> <p>To showcase the technology, the researchers produced several colored images on culture plates — one of which spells out “MIT” — by using RGB lights to control the pigment produced by the bacteria. Outside of the lab, the technology could also prove useful for commercial, pharmaceutical, and other applications.</p> <p>The <em>E. coli</em> is programmed with a protein- and enzyme-based system, analogous to a computer chip, with several different modules to process the light input and produce a biological output. In computing terms, a “sensor array” first becomes activated in the presence of either red, green, or blue light, and a “circuit” processes the signal. Then, a “resource allocator” connects the processed information to “actuators” that implement the corresponding biological function.</p> <p>Think of the new <em>E. coli</em> as microbial marionettes, with colored light instead of puppet strings making the bacteria act in a certain way, says MIT professor of biological engineering Chris Voigt, co-author of a paper in <em>Nature </em>describing the technology. “Using different colors, we can control different genes that are being expressed,” he says.</p> <p>The paper’s co-authors are former postdocs Jesus Fernandez-Rodriguez, Felix Moser, and Miryoung Song.</p> <p><strong>Synthetic-biology innovation comes together</strong></p> <p>In 2005, Voigt, who co-directs the Synthetic Biology Center at MIT, and other researchers pioneered a “bacterial camera” by programming a light sensor into a strain of <em>E. coli</em>, along with a gene that produced black pigment. When light shone through a stencil onto a bacteria-coated plate, the microbes formed black-and-white images. At the time, this feat required only four genes and three promoters — regions of DNA that initiate gene transcription — to get the job done.</p> <p>New synthetic biology tools, such as the genome-editing system CRISPR, have cropped up since then, opening broader possibilities to researchers. In contrast to the 2005 system, the new RGB system — the first to use three colors — consists of 18 genes and 14 promoters, among other parts, as well as 46,000 base pairs of DNA.</p> <p>But with greater complexity come greater challenges. Because the researchers were dealing with a sensor array that could detect three separate colors, for instance, they had to include in the microbial program a protein that prevents gene transcription of the two unused sensors.</p> <p>In computing terms, this is called a “NOT gate,” a circuit that produces an output signal — in this case, gene repression — only when there is not a signal on its input. With bacteria under a red light, for instance, the NOT gate would unleash that gene-repressing protein on the green and blue sensors, turning them off.</p> <p>About five years ago, Voigt led a team that engineered microbes to respond to red and green light. Adding a third sensor was a major challenge of the new research. “Inside the cell, all the new protein sensors you add interfere with each other, because it’s all molecules bumping around the cell, and they all require keeping the cell alive and happy. With every additional sensor you add, that gets exponentially harder,” he says.</p> <p>In that regard, Voigt adds, the system’s resource allocator, a new feature, also acts as a circuit breaker, shutting down the sensors if all three turn on at once, overloading the cell.</p> <p>From a genetic engineering perspective, the four-subsystem configuration was “the biggest impact of this work,” Voigt says. Each subsystem — the sensor array, circuits, resource actuators, and actuators — was designed, built, and optimized in isolation before being assembled into a final structure. This simplified, modular process could pave the way for more complex biological programming in the future, according to the researchers.</p> <p>Generally speaking, Voigt sees the new system as a culmination of a decade of synthetic-biology innovations. “It’s a representation of where we are currently, and all the pieces that needed to come together over the last decade to create systems of this scale and complexity,” he says.</p> <p><strong>Making “disco bacteria”</strong></p> <p>To make the new color images, the researchers programmed bacteria to produce the same pigment as the red, green, or blue light shone upon them. In an incubator, the researchers coated a petri dish with bacteria that are genetically identical. “You can think of it like undeveloped film, where you have the petri dish with bacteria on it,” Voigt says, “and the camera is the incubator.”</p> <p>At the top of the incubator is a hole, where a stenciled image is projected onto the plate. Over time, the bacteria grow, producing an enzyme that produces a pigment corresponding to whichever RBG color they’re illuminated by. In addition to the MIT logo, the researchers produced images of various patterns, multicolored fruit, and the video game character Super Mario.</p> <p>The engineered bacteria could also be used to rapidly start and stop the chemical reactions of microbes in industrial fermentation processes, which are used to make pharmaceuticals and other products. Today, controlling such chemical reactions requires dumping different chemical additives into large fermenting vats, which is time-consuming and inefficient.</p> <p>In their paper, the researchers demonstrated this “chemicals on-demand” concept on a small scale. Using CRISPR gene-editing tools, they modified three genes that produce acetate —&nbsp;a sometimes-unwanted byproduct of various bioprocesses — to produce less of the chemical in response to RGB lights.</p> <p>“Individually, and in combination with one another, the different colors of light reduce acetate production without sacrificing biomass accumulation,” the researchers wrote in their paper.</p> <p>Voigt has coined an amusing name for these industrial microbes. “I refer to them as ‘disco bacteria,’” he says, “because different colored lights are flashing inside the fermenter and controlling the cells.”</p> <p>A future application, Voigt adds, could be in controlling cells to form various materials and structures. Researchers, <a href="">including some at MIT</a>, have started programming cells to assemble into living materials that one day could be used to design solar cells, self-healing materials, or diagnostic sensors.</p> <p>“It’s amazing when you look at the world and see all the different materials,” Voigt says. “Things like cellulose, silk proteins, metals, nanowires, and living materials like organs — all these different things in nature we get from cells growing into different patterns. You can imagine using different colors of light to tell the cells how they should be growing as part of building that material.”</p> <p>The research was funded by the National Science Foundation’s Synthetic Biology Engineering Research Center, the Office of Naval Research’s Multidisciplinary University Research Initiative, and the National Institutes of Health.</p> Researchers produced colored images on culture plates by using red, green, and blue lights to control the pigment produced by bacteria with “multicolor vision.” The image has been color-corrected in Photoshop to improve contrast. Image: Felix MoserResearch, School of Engineering, Biological engineering, Synthetic biology, Bacteria, CRISPR, Pharmaceuticals, Industry, Genetics, DNA, Microbes, National Science Foundation (NSF), National Institutes of Health (NIH) Researchers design moisture-responsive workout suit Ventilating flaps lined with live cells open and close in response to an athlete’s sweat. Fri, 19 May 2017 13:59:59 -0400 Jennifer Chu | MIT News Office <p>A team of MIT researchers has designed a breathable workout suit with ventilating flaps that open and close in response to an athlete’s body heat and sweat. These flaps, which range from thumbnail- to finger-sized, are lined with live microbial cells that shrink and expand in response to changes in humidity. The cells act as tiny sensors and actuators, driving the flaps to open when an athlete works up a sweat, and pulling them closed when the body has cooled off.</p> <p>The researchers have also fashioned a running shoe with an inner layer of similar cell-lined flaps to air out and wick away moisture. Details of both designs are published today in <em>Science Advances</em>.</p> <div class="cms-placeholder-content-video"></div> <p>Why use live cells in responsive fabrics? The researchers say that moisture-sensitive cells require no additional elements to sense and respond to humidity. The microbial cells they have used are also proven to be safe to touch and even consume. What’s more, with new genetic engineering tools available today, cells can be prepared quickly and in vast quantities, to express multiple functionalities in addition to moisture response.</p> <p>To demonstrate this last point, the researchers engineered moisture-sensitive cells to not only pull flaps open but also light up in response to humid conditions.</p> <p>“We can combine our cells with genetic tools to introduce other functionalities into these living cells,” says Wen Wang, the paper’s lead author and a former research scientist in MIT’s Media Lab and Department of Chemical Engineering. “We use fluorescence as an example, and this can let people know you are running in the dark. In the future we can combine odor-releasing functionalities through genetic engineering. So maybe after going to the gym, the shirt can release a nice-smelling odor.”</p> <p>Wang’s co-authors include 14 researchers from MIT, specializing in fields including mechanical engineering, chemical engineering, architecture, biological engineering, and fashion design, as well as researchers from New Balance Athletics. Wang co-led the project, dubbed <a href="">bioLogic</a>, with former graduate student Lining Yao as part of MIT’s Tangible Media group, led by Hiroshi Ishii, the Jerome B. Wiesner Professor of Media Arts and Sciences.</p> <p><strong>Shape-shifting cells</strong></p> <p>In nature, biologists have observed that living things and their components, from pine cone scales to microbial cells and even specific proteins, can change their structures or volumes when there is a change in humidity. The MIT team hypothesized that natural shape-shifters such as yeast, bacteria, and other microbial cells might be used as building blocks to construct moisture-responsive fabrics.</p> <p>“These cells are so strong that they can induce bending of the substrate they are coated on,” Wang says.</p> <p>The researchers first worked with the most common nonpathogenic strain of <em>E. coli</em>, which was found to swell and shrink in response to changing humidity. They further engineered the cells to express green fluorescent protein, enabling the cell to glow when it senses humid conditions.</p> <p>They then used a cell-printing method they had previously developed to print <em>E. coli</em> onto sheets of rough, natural latex.</p> <p>The team printed parallel lines of <em>E. coli </em>cells onto sheets of latex, creating two-layer structures, and exposed the fabric to changing moisture conditions. When the fabric was placed on a hot plate to dry, the cells began to shrink, causing the overlying latex layer to curl up. When the fabric was then exposed to steam, the cells began to glow and expand, causing the latex flatten out. After undergoing 100 such dry/wet cycles, Wang says the fabric experienced “no dramatic degradation” in either its cell layer or its overall performance.</p> <p><strong>No sweat</strong></p> <p>The researchers worked the biofabric into a wearable garment, designing a running suit with cell-lined latex flaps patterned across the suit’s back. They tailored the size of each flap, as well as the degree to which they open, based on previously published maps of where the body produces heat and sweat.</p> <p>“People may think heat and sweat are the same, but in fact, some areas like the lower spine produce lots of sweat but not much heat,” Yao says. “We redesigned the garment using a fusion of heat and sweat maps to, for example, make flaps bigger where the body generates more heat.”</p> <p>Support frames underneath each flap keep the fabric’s inner cell layer from directly touching the skin, while at the same time, the cells are able to sense and react to humidity changes in the air lying just over the skin. In trials to test the running suit, study participants donned the garment and worked out on exercise treadmills and bicycles while researchers monitored their temperature and humidity using small sensors positioned across their backs.</p> <p>After five minutes of exercise, the suit’s flaps started opening up, right around the time when participants reported feeling warm and sweaty. According to sensor readings, the flaps effectively removed sweat from the body and lowered skin temperature, more so than when participants wore a similar running suit with nonfunctional flaps.</p> <p>When Wang tried on the suit herself, she found that the flaps created a welcome sensation. After pedaling hard for a few minutes, Wang recalls that “it felt like I was wearing an air conditioner on my back.”</p> <p><strong>Ventilated running shoes</strong></p> <p>The team also integrated the moisture-responsive fabric into a rough prototype of a running shoe. Where the bottom of the foot touches the sole of the shoe, the researchers sewed multiple flaps, curved downward, with the cell-lined layer facing toward — though not touching — a runner’s foot. They again designed the size and position of the flaps based on heat and sweat maps of the foot.</p> <p>“In the beginning, we thought of making the flaps on top of the shoe, but we found people don’t normally sweat on top of their feet,” Wang says. “But they sweat a lot on the bottom of their feet, which can lead to diseases like warts. So we thought, is it possible to keep your feet dry and avoid those diseases?”</p> <p>As with the workout suit, the flaps on the running shoe opened and lit up when researchers increased the surrounding humidity; in dry conditions the flaps faded and closed.</p> <p>Going forward, the team is looking to collaborate with sportswear companies to commercialize their designs, and is also exploring other uses, including moisture-responsive curtains, lampshades, and bedsheets.</p> <p>“We are also interested in rethinking packaging,” Wang says. “The concept of a second skin would suggest a new genre for responsive packaging.”</p> <p>“This work is an example of harnessing the power of biology to design new materials and devices and achieve new functions,” says Xuanhe Zhao, the Robert N. Noyce Career Development Associate Professor in the Department of Mechanical Engineering and a co-author on the paper. “We believe this new field of ‘living’ materials and devices will find important applications at the interface between engineering and biological systems.”</p> <p>This research was supported, in part, by MIT Media Lab and the Singapore-MIT Alliance.</p> This breathable workout suit prototype has ventilating flaps that open and close in response to an athlete’s body heat and sweat. The left photo was taken before exercise when ventilation flaps are flat; after exercise, the ventilation flaps have curved. Image: Hannah CohenAthletics, Bacteria, Bioengineering and biotechnology, Chemical engineering, Design, Materials Science and Engineering, Mechanical engineering, Microbes, Wearables, Research, School of Architecture and Planning, School of Engineering New technology could offer cheaper, faster food testing Specialized droplets interact with bacteria and can be analyzed using a smartphone. Wed, 05 Apr 2017 00:00:00 -0400 Anne Trafton | MIT News Office <p>The foodborne pathogen <em>Escherichia coli</em> O157 causes an estimated 73,000 illnesses and 60 deaths every year in the United States. Better safety tests could help avoid some of the illnesses caused by this strain of <em>E. coli</em> and other harmful bacteria, according to MIT researchers who have come up with a possible new solution.</p> <p>The new MIT test is based on a novel type of liquid droplet that can bind to bacterial proteins. This interaction, which can be detected by either the naked eye or a smartphone, could offer a much faster and cheaper alternative to existing food safety tests.</p> <p>“It’s a brand new way to do sensing,” says Timothy Swager, the John D. MacArthur Professor of Chemistry at MIT and the senior author of the study. “What we have here is something that can be massively cheaper, with low entry costs.”</p> <p>Qifan Zhang, an MIT graduate student, is the lead author of the paper, which appears in the journal <em>ACS Central Science</em>. Other authors are Suchol Savagatrup, an MIT postdoc; Peter Seeberger, director of the Max Planck Institute of Colloids and Interfaces in Germany; and Paulina Kaplonek, a graduate student at the Max Planck Institute.</p> <p><strong>Detecting bacteria</strong></p> <p>Two years ago, Swager’s lab developed a way to easily make complex droplets including droplets called <a href="">Janus emulsions</a>. These Janus droplets consist of two equally sized hemispheres, one made of a fluorocarbon and one made of a hydrocarbon. Fluorocarbon is denser than hydrocarbon, so when the droplets sit on a surface, the fluorocarbon half is always at the bottom.</p> <p>The researchers decided to explore using these droplets as sensors because of their unique optical properties. In their natural state, the Janus droplets are transparent when viewed from above, but they appear opaque if viewed from the side, because of the way that light bends as it travels <a href="">through the droplets</a>.</p> <p>To turn the droplets into sensors, the researchers designed a surfactant molecule containing mannose sugar to self-assemble at the hydrocarbon–water interface, which makes up the top half of the droplet surface. These molecules can bind to a protein called lectin, which is found on the surface of some strains of <em>E. coli</em>. When<em> E. coli</em> is present, the droplets attach to the proteins and become clumped together. This knocks the particles off balance, so that light hitting them scatters in many directions, and the droplets become opaque when viewed from above.</p> <p>“We’re using the native molecular recognition that these pathogens use. They recognize each other with these weak carbohydrate-lectin binding schemes.” Swager says. “We took advantage of the droplets’ multivalency to increase the binding affinity, and this is something that is very different than what other sensors are using.”</p> <p>To demonstrate how these droplets could be used for sensing, the researchers placed them into a Petri dish atop a QR code that can be scanned with a smartphone. When <em>E. coli</em> are present, the droplets clump together and the QR code can’t be read.</p> <p>Chad Mirkin, a professor of chemistry at Northwestern University and director of the International Institute for Nanotechnology, described the particles as “a powerful new class of assays.”</p> <p>“They are elegantly simple but rely on clever new approaches to making and manipulating emulsions,” says Mirkin, who was not involved in the research. “This proof-of-concept demonstration in detecting foodborne pathogens is compelling, as they constitute a major class of analytes that defines an unmet need in the biosensor community.”</p> <p><strong>Faster and cheaper</strong></p> <p>Current food safety testing often involves placing food samples in a culture dish to see if harmful bacterial colonies form, but that process takes two to three days. More rapid techniques based on bacterial DNA amplification or antibody-bacteria interactions are expensive and require special instruments.</p> <p>The MIT team hopes to adapt its new technology into arrays of small wells, each containing droplets customized to detect a different pathogen and linked to a different QR code. This could enable rapid, inexpensive detection of contamination using only a smartphone.</p> <p>“The great advantage of our device is you don’t need specialized instruments and technical training in order to do this,” Zhang says. “That can enable people from the factory, before shipping the food, to scan and test it to make sure it’s safe.”</p> <p>The researchers are now working on optimizing the food sample preparation so they can be placed into the wells with the droplets. They also plan to create droplets customized with more complex sugars that would bind to different bacterial proteins. In this paper, the researchers used a sugar that binds to a nonpathogenic type of <em>E. coli</em>, but they expect that they could adapt the sensor to other strains of <em>E. coli</em> and other harmful bacteria.</p> <p>“You could imagine making really selective droplets to catch different bacteria, based on the sugar we put on them,” Savagatrup says.</p> <p>The researchers are also trying to improve the sensitivity of the sensor, which currently is similar to existing techniques but has the potential to be much greater, they believe. They hope to launch a company to commercialize the technology within the next year and a half.</p> <p>The research was funded by the Abdul Latif Jameel World Water and Food Security Lab (J-WAFS) at MIT, the U.S. Army Research Office through the MIT Institute for Soldier Nanotechnologies, the Legatum Center for Development and Entrepreneurship at MIT, the Alexander von Humboldt Foundation, the Max-Planck Society, and the German Research Foundation.</p> A new safety test for foodborne pathogens is based on a novel type of liquid droplet that can bind to bacterial proteins. This interaction, which can be detected by either the naked eye or a smartphone, could offer a much faster and cheaper alternative to existing food safety tests.Image: Jose-Luis Olivares/MIT (droplet images courtesy of Qifan Zhang)Research, Chemistry, Bacteria, Disease, Microbes, School of Science, Health, Medicine, Abdul Latif Jameel World Water and Food Security Lab (J-WAFS), J-WAFS Progress toward a Zika vaccine Researchers program RNA nanoparticles that could protect against the virus. Wed, 29 Mar 2017 00:00:00 -0400 Anne Trafton | MIT News Office <p>Using a new strategy that can rapidly generate customized RNA vaccines, MIT researchers have devised a new vaccine candidate for the Zika virus.</p> <p>The vaccine consists of strands of genetic material known as messenger RNA, which are packaged into a nanoparticle that delivers the RNA into cells. Once inside cells, the RNA is translated into proteins that provoke an immune response from the host, but the RNA does not integrate itself into the host genome, making it potentially safer than a DNA vaccine or vaccinating with the virus itself.</p> <p>“It functions almost like a synthetic virus, except it’s not pathogenic and it doesn’t spread,” says Omar Khan, a postdoc at MIT’s Koch Institute for Integrative Cancer Research and an author of the new study. “We can control how long it’s expressed, and it’s RNA so it will never integrate into the host genome.”</p> <p>This research also yielded a new benchmark for evaluating the effectiveness of other Zika vaccine candidates, which could help others who are working toward the same goal.</p> <p>Jasdave Chahal, a postdoc at MIT’s Whitehead Institute for Biomedical Research, is the first author of the paper, which appears in <em>Scientific Reports</em>. The paper’s senior author is Hidde Ploegh, a former MIT biology professor and Whitehead Institute member who is now a senior investigator in the Program in Cellular and Molecular Medicine at Boston Children’s Hospital.</p> <p>Other authors of the paper are Tao Fang and Andrew Woodham, both former Whitehead Institute postdocs in the Ploegh lab; Jingjing Ling, an MIT graduate student; and Daniel Anderson, an associate professor in MIT’s Department of Chemical Engineering and a member of the Koch Institute and MIT’s Institute for Medical Engineering and Science (IMES).</p> <p><strong>Programmable vaccines</strong></p> <p>The MIT team first reported its new approach to <a href="">programmable RNA vaccines</a> last year. RNA vaccines are appealing because they induce host cells to produce many copies of the proteins encoded by the RNA. This provokes a stronger immune reaction than if the proteins were administered on their own. However, finding a safe and effective way to deliver these vaccines has proven challenging.</p> <p>The researchers devised an approach in which they package RNA sequences into a nanoparticle made from a branched molecule that is based on fractal-patterned dendrimers. This modified-dendrimer-RNA structure can be induced to fold over itself many times, producing a spherical particle about 150 nanometers in diameter. This is similar in size to a typical virus, allowing the particles to enter cells through the same viral entry mechanisms. In their 2016 paper, the researchers used this nanoparticle approach to generate experimental vaccines for Ebola, H1N1 influenza, and the parasite <em>Toxoplasma gondii</em>.</p> <p>In the new study, the researchers tackled Zika virus, which emerged as an epidemic centered in Brazil in 2015 and has since spread around the world, causing serious birth defects in babies born to infected mothers. Since the MIT method does not require working with the virus itself, the researchers believe they might be able to explore potential vaccines more rapidly than scientists pursuing a more traditional approach.</p> <p>Instead of using viral proteins or weakened forms of the virus as vaccines, which are the most common strategies, the researchers simply programmed their RNA nanoparticles with the sequences that encode Zika virus proteins. Once injected into the body, these molecules replicate themselves inside cells and instruct cells to produce the viral proteins.</p> <p>The entire process of designing, producing, and testing the vaccine in mice took less time than it took for the researchers to obtain permission to work with samples of the Zika virus, which they eventually did get.</p> <p>“That’s the beauty of it,” Chahal says. “Once we decided to do it, in two weeks we were ready to vaccinate mice. Access to virus itself was not necessary.”</p> <p><strong>Measuring response</strong></p> <p>When developing a vaccine, researchers usually aim to generate a response from both arms of the immune system — the adaptive arm, mediated by T cells and antibodies, and the innate arm, which is necessary to amplify the adaptive response. To measure whether an experimental vaccine has generated a strong T cell response, researchers can remove T cells from the body and then measure how they respond to fragments of the viral protein.</p> <p>Until now, researchers working on Zika vaccines have had to buy libraries of different protein fragments and then test T cells on them, which is an expensive and time-consuming process. Because the MIT researchers could generate so many T cells from their vaccinated mice, they were able to rapidly screen them against this library. They identified a sequence of eight amino acids that the activated T cells in the mouse respond to. Now that this sequence, also called an epitope, is known, other researchers can use it to test their own experimental Zika vaccines in the appropriate mouse models.</p> <p>“We can synthetically make these vaccines that are almost like infecting someone with the actual virus, and then generate an immune response and use the data from that response to help other people predict if their vaccines would work, if they bind to the same epitopes,” Khan says. The researchers hope to eventually move their Zika vaccine into tests in humans.</p> <p>“The identification and characterization of CD8 T cell epitopes in mice immunized with a Zika RNA vaccine is a very useful reference for all those working in the field of Zika vaccine development,” says Katja Fink, a principal investigator at the A*STAR Singapore Immunology Network. “RNA vaccines have received much attention in the last few years, and while the big breakthrough in humans has not been achieved yet, the technology holds promise to become a flexible platform that could provide rapid solutions for emerging viruses.”</p> <p>Fink, who was not involved in the research, added that the “initial data are promising but the Zika RNA vaccine approach described needs further testing to prove efficacy.”</p> <p>Another major area of focus for the researchers is cancer vaccines. Many scientists are working on vaccines that could program a patient’s immune system to attack tumor cells, but in order to do that, they need to know what the vaccine should target. The new MIT strategy could allow scientists to quickly generate personalized RNA vaccines based on the genetic sequence of an individual patient’s tumor cells.</p> <p>The research was funded by the National Institutes of Health, a Fujifilm/MediVector grant, the Lustgarten Foundation, a Koch Institute and Dana-Farber/Harvard Center Center Bridge Project award, the Department of Defense Office of Congressionally Directed Medical Research’s Joint Warfighter Medical Research Program, and the Cancer Center Support Grant from the National Cancer Institute.</p> MIT researchers have devised a new vaccine candidate for the Zika virus. “It functions almost like a synthetic virus, except it’s not pathogenic and it doesn’t spread,” says postdoc Omar Khan. Image: Jose-Luis Olivares/MITResearch, Cancer, Disease, Microbes, Vaccines, Chemical engineering, Koch Institute, Drug development, RNA, Medicine, Whitehead Institute, School of Engineering Tiny bacterium provides window into whole ecosystems Ubiquitous marine organism has co-evolved with other microbes, promoting more complex ecosystems. Mon, 27 Mar 2017 15:00:00 -0400 David L. Chandler | MIT News Office <p>William Blake may have seen a world in a grain of sand, but for scientists at MIT the smallest of all photosynthetic bacteria holds clues to the evolution of entire ecosystems, and perhaps even the whole biosphere.</p> <p>The key is a tiny bacterium called <em>Prochlorococcus</em>, which is the most abundant photosynthetic life form in the oceans. New research shows that this diminutive creature’s metabolism has evolved in a way that may have helped trigger the rise of other organisms, to form a more complex marine ecosystem. Its evolution may even have helped to drive global changes that made possible the development of Earth’s more complex organisms.</p> <p>The research also suggests that the co-evolution of <em>Prochlorococcus</em> and its interdependent co-organisms can be seen as a microcosm of the metabolic processes that take place inside the cells of much more complex organisms.</p> <p>The new analysis is published this week in the journal <em>Proceedings of the National Academy of Sciences</em>, in a paper by postdoc Rogier Braakman, Professor Michael Follows, and Institute Professor Sallie (Penny) Chisholm, who was part of the team that discovered this tiny organism and its outsized influence.</p> <p>“We have all these different strains that have been isolated from all over the world’s oceans, that have different genomes and different genetic capacity, but they’re all one species by traditional measures,” Chisholm explains. “So there’s this extraordinary genetic diversity within this single species that allows it to dominate such vast swaths of the Earth’s oceans.”</p> <p>Because <em>Prochlorococcus</em> is both so abundant and so well-studied, Braakman says it was an ideal subject for trying to figure out “within all this diversity, how do the metabolic networks change? What drives that, and what are the consequences of that?”</p> <p>They found a great amount of variation in the bacteria’s “metabolic network,” which refers to the ways that materials and energy pass in and out of the organism, along its phylogeny. The fact that such significant changes have taken place over the course of <em>Prochlorococcus</em> evolution “tells you something quite dramatic,” he says, because these metabolic processes are so fundamental to the organism’s survival that “it’s like the engine of the system. So imagine trying to change the engine of your car while you’re driving. It’s not easily done, so if something is changing, it’s telling you something significant.”</p> <p>The variations form a kind of layered structure, with more ancestral variants living deeper in the water column and more recent variants living near the surface. The team found that as <em>Prochlorococcus</em> started out living in the top layers of the ocean, where light is abundant but food is relatively scarce, it developed a higher and higher rate of metabolism. It took in more solar energy and used that to power a stronger uptake of scarce nutrients from the water — in effect, creating a more powerful vacuum cleaner but in the process also generating more waste, Braakman says.</p> <p>As newer variants vacuumed up nutrients in the surface layers, more ancestral types had to move down to greater depths where nutrients levels remained higher, ultimately resulting in the layered structure seen today.</p> <p>The carbon compounds that make up <em>Prochlorococcus’</em> waste in turn provided nutrients that drove the evolution of another kind of bacteria, known as SAR11, whose own waste products were useful to <em>Prochlorococcus</em>, thus forming a cooperative system that benefited both organisms. The mutual recycling of waste reinforces the collective maximization of metabolic rate. “It looks like the system is in fact evolving to maximize the total throughput” of energy, not just that of individual organisms, Braakman says.</p> <p>“As they optimize their ability to acquire nutrients, cells produce more organic carbon and end up promoting greater levels of mutualism,” Follows adds.</p> <p>That interdependent, cooperative relationship is very similar to the relationship between mitochondria and chloroplasts, the two kinds of subunits that provide the energy inside the cells of all forms of plant life, Braakman says. Chloroplasts collect energy from sunlight and use it to form chemical compounds that transfer energy to mitochondria, which can in turn release and transfer carbon and energy back to chloroplasts and the rest of the cell — through pathways very similar to those used by <em>Prochlorococcus</em> and SAR11.</p> <p>Other features of the two systems are also very similar, including their photosynthetic pigments and how they deal with the detoxification of hydrogen peroxide. This suggests parallel evolutionary processes produced the same outcome in very different environments. “Plant cells really look like microscopic ocean microbial ecosystems,” he explains.</p> <p>Partly because of those parallels, Braakman says this dynamic could potentially describe the evolution of the biosphere more generally. He suggests that the mathematical descriptions of <em>Prochlorococcus</em> evolution, which he and Follows developed together, emerge from basic principles of kinetics and thermodynamics and so could provide some insights into other systems as well. “It could be a universal kind of dynamic,” he says.</p> <p>“This framework can also help us model the interactions of life, sunlight, and ocean chemistry at the ocean scale,” Follows says.</p> <p>The metabolic evolution of <em>Prochlorococcus</em> may have had one other important effect: Through a complex geochemical cycle involving the carbon compounds the microbe produced and their interactions with iron, the bacteria may have contributed to a significant rise in oxygen in Earth’s atmosphere around half a billion years ago, from very low levels up to near-modern levels. This major rise in oxygen is believed to have unleashed a rapid explosion of new species also known as the Cambrian explosion, which saw the birth of most major animal phyla.</p> <p>What this analysis suggests, he says, “is what looks like a directional evolutionary process, which is steadily marching toward a direction where it’s increasing the energy flux through the system. One of the consequences of that is that then oxygen ended up rising in the atmosphere, and the complexity of the ecosystem increased.”</p> <p>A lot of evolutionary theory emphasizes competition, Braakman says, where “there are limited resources and we’re all fighting for them. But what this evolutionary dynamic is saying is that it’s a way of increasing the resources for the whole system, so everyone is better off. It increases total system resources.”</p> <p>This work, Chisholm says, demonstrates that “you really have to think about evolution at all these scales, to understand it. It’s not just about a bunch of selfish genes jumping around. If you want to understand life in all its dimensions, you have to look at the genes, but also all the way up to the ecosystems. None of it will make sense if you don’t look at it at all those scales.”</p> <p>This team’s “innovative integration of phylogeny, physiology, and genomics opens up novel avenues for research on phytoplankton evolution, while stimulating new thinking about the long term coevolution of Earth and life,” says Andrew Knoll, professor of natural history at Harvard University, who was not connected with this research.</p> <p>The research was supported by the Simons Foundation, the Life Sciences Research Foundation, the Gordon and Betty Moore Foundation, and the National Science Foundation.</p> The many genetic variations of the tiny bacteria called Prochlorococcus are distributed in a layered structure, with each variant adapted to the particular mix of sunlight and nutrients found in that layer of seawater.Image: Rogier Braakman (reproduced with permission from Proceedings of the National Academy of Sciences)Research, School of Engineering, School of Science, Civil and environmental engineering, Biology, EAPS, Earth and atmospheric sciences, National Science Foundation (NSF), Bacteria, Microbes