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Editor's Note: Microbiologist Carl R. Woese, a recipient of the Crafoord Prize, Leeuwenhoek Medal, and a National Medal of Science, died December 30, 2012, at the age of 84. This story was originally published in the June 1981 issue of Scientific American.
Early natural philosophers held that life on the earth is fundamentally dichotomous: all living things are either animals or plants. When microorganisms were discovered, they were divided in the same way. The large and motile ones were considered to be animals and the ones that appeared not to move, including the bacteria, were considered to be plants. As understanding of the microscopic world advanced it became apparent that a simple twofold classification would not suffice, and so additional categories were introduced: fungi, protozoa and bacteria. Ultimately, however, a new simplification took hold. It seemed that life might be dichotomous after all, but at a deeper level, namely in the structure of the living cell. All cells appeared to belong to one or the other of two groups: the eukaryotes, which are cells with a well-formed nucleus, and the prokaryotes, which do not have such a nucleus. Multicellular plants and animals are eukaryotic and so are many unicellular organisms. The only prokaryotes are the bacteria (including the cyanobacteria, which were formerly called blue-green algae).
In the past few years my colleagues and I have been led to propose a fundamental revision of this picture. Among the bacteria we have found a group of organisms that do not seem to belong to either of the basic categories. The organisms we have been studying are prokaryotic in the sense that they do not have a nucleus, and indeed outwardly they look much like ordinary bacteria. In their biochemistry, however, and in the structure of certain large molecules, they are as different from other prokaryotes as they are from eukaryotes. Phylogenetically they are neither prokaryotes nor eukaryotes. They make up a new "primary kingdom," with a completely different status in the history and the natural order of life.
We have named these organisms archaebacteria. The name reflects an untested conjecture about their evolutionary status. The phylogenetic evidence suggests that the archaebacteria are at least as old as the other major groups. Moreover, some of the archaebacteria have a form of metabolism that seems particularly well suited to the conditions believed to have prevailed in the early history of life on the earth. Hence it seems possible that the newest group of organisms is actually the oldest.
The evolutionary record
The earth is four and a half billion years old, and on the basis of the macroscopic fossil record it would appear to have been inhabited for less than a seventh of that time: the entire evolutionary progression from the most ancient marine forms to man spans only 600 million years. The fossil imprints of unicellular organisms too small to be seen with the unaided eye tell a different story. Microfossils of bacteria in particular are plentiful in sediments of all ages; they have been found in the oldest intact sedimentary rocks known, 3.5-billion year-old deposits in Australia. Over an enormous expanse of time, during which no higher forms existed, the bacteria arose and radiated to form a wide variety of types inhabiting a great many ecological niches. This age of microorganisms is the most important period in evolutionary history not only because of its duration but also because of the nature of the evolutionary events that took place over those billions of years.
Until recently, however, almost nothing was known about the age of microorganisms. Bacterial microfossils are not very informative structures; little can be inferred from the imprint of a small sphere or rod. The main paleontological indications of the nature of the early bacteria have come not from the individual microfossils but from the macroscopic structures called stromatolites, which are thought to be fossilized bacterial mats: colonies of bacteria embedded with minerals. Today such structures are formed primarily by several kinds of photosynthetic bacteria, usually the cyanobacteria. Stromatolites fossilized recently resemble the ancient ones to such an extent that it seems entirely reasonable to think the ancient structures were also made by photosynthetic bacteria. Therefore at least some of the ancient bacteria must have been photosynthesizers. Apart from that one fact virtually nothing could be established with certainty about the earliest microorganisms. The entire evolutionary tree of the bacteria remained obscure, as did the base of the tree for the higher forms of life.
In reconstructing early evolutionary events, however, biologists are not limited to the geologic fossil record. The cell itself retains evidence of its past in the amino acid sequences of its proteins and in the nucleotide sequences of its nucleic acids: DNA and RNA. This living record is potentially far richer and more extensive than the fossil record, and it reaches back in time beyond the oldest fossils, to the period when the common ancestor of all life existed.
In order to read the biochemical record it was necessary to develop a technology for determining (at least in part) the sequence of a gene or of the RNA or protein product encoded by a gene. For proteins this has been possible for about 25 years, but the direct sequencing of DNA and RNA has been feasible for only the past five years or so. The new technology for sequencing nucleic acids should enable biologists to uncover in relatively short order far more about the history of life than had been thought possible. It was by applying techniques of sequencing to the century-old problem of the natural relations among bacteria that my colleagues and I recognized the archaebacteria as a third form of life.
Eukaryotes and prokaryotes
In order to appreciate the special status of the archaebacteria it is helpful to consider some of the defining characteristics of eukaryotes and prokaryotes. The eukaryotic cell is comparatively large: roughly 10 micrometers on a side. It is surrounded by a double membrane, within which a number of structures can be discerned that are themselves defined by membranes. The nucleus contains the bulk of the cell's genetic material. The rod-shaped mitochondria are the site of cellular respiration, which generates the cell's main energy currency, adenosine triphosphate (ATP). In plant cells the chloroplast, another rod shaped body, converts the energy of light into the chemical energy of ATP.
Other specialized structures such as the Golgi apparatus (for secretion) and cilia (for motility) are often present. Many eukaryotic cells are laced with a membrane system, the endoplasmic reticulum, that provides a surface on which important reactions such as the synthesis of proteins take place.
The prokaryotic cell is vastly different. It is typically far smaller than the eukaryotic cell: by a factor of 10 in linear measure and hence by a factor of 1,000 in volume. The prokaryotic cell too is circumscribed by a double membrane, and in addition it almost always has a rigid cell wall. On the other hand, none of the internal structures characteristic of the eukaryotic cell are present; there are no mitochondria or chloroplasts and of course there is no membrane-bounded nucleus. The genome—the total complement of genetic material—is limited to between 2,000 and 3,000 genes in a prokaryotic cell; the typical eukaryotic genome is larger by several orders of magnitude.
The distinction between eukaryotes and prokaryotes was initially defined in terms of subcellular structures visible with a microscope. At that level all cells appeared to be either large and complex, and so eukaryotic, or small and simple, and so prokaryotic. The distinction between the two cell types was ultimately carried to the most basic biological level, the level of molecules. Here eukaryotic and prokaryotic cells have many features in common. For instance, they translate genetic information into proteins according to the same genetic code. Even where the molecular processes are the same, however, the details in the two forms are different; they are either characteristically eukaryotic or characteristically prokaryotic. For ex ample, the amino acid sequences of various enzymes tend to be typically prokaryotic or eukaryotic. All these differences between groups and similarities within each group made it seem certain to most biologists that the tree of life had two main stems, one stem prokaryotic and the other eukaryotic.
That conclusion was drawn too hastily; the aesthetic appeal of a dichotomy was too great. Simply because there are two types of cell at the microscopic level it does not follow that there must be only two types at the molecular level.
The evolutionary relation of prokaryotes and eukaryotes is actually more complicated than the evidence cited above would indicate. Two eukaryotic organelles, the mitochondrion and the chloroplast, each have their own DNA. Moreover, the pigments in the chloroplast (the chlorophylls and the carotenoids) are similar to those found in the cyanobacteria. Both mitochondria and chloroplasts are the size of bacteria; their apparatus for translating genetic information into proteins differs from the eukaryotic cell's own apparatus and has a number of properties in common with that of prokaryotes.
These facts and others have led to the idea that mitochondria and chloroplasts are descended from prokaryotes that be came trapped in a larger cell and established an endosymbiotic relation with it. The mitochondrion is thought to have been a respiring bacterium and the chloroplast to have been a photosynthesizing relative of the cyanobacteria. This conjecture, which in its simplest form is more than a century old, was essentially proved in the case of the chloroplast by the demonstration that the nucleotide sequence of one of the kinds of RNA in the organelle, ribosomal RNA, is specifically related to ribosomal-RNA sequences in cyanobacteria. Similarly, the ribosomal RNA of the mitochondrion in plants appears to be of the bacterial type. Thus it seems that at least two lines of prokaryotic descent are represented in the eukaryotic cell.
The urkaryote
Logically the next question is: Where does the rest of the eukaryotic cell come from? What was the original host cell: the urkaryote? It is generally agreed that the bulk of the eukaryotic cell (the nucleus and the cytoplasmic structures) represents a separate line of descent. The exact nature of the ancestral cell is not clear. Most investigators have tended to believe the main eukaryotic line also arose from among the ordinary bacteria. The idea is that some anaerobic bacterium deriving its energy from the fermentation of nutrients (rather than from their oxidation) at some point happened to lose its tough cell wall. Organisms of this kind are known; they are the mycoplasmas. A strain of mycoplasma then evolved the capacity to engulf other organisms, an ability retained by many eukaryotes today. Among the many kinds of organisms such a mycoplasma might have ingested two appear to have established a stable endosymbiotic relation with their host and to have become the mitochondrion and the chloroplast. In this way the eukaryotic cell was born. (The origin of its defining characteristic, the membrane-bounded nucleus, is still far from clear.)
This view is satisfying in some respects, but it fails to explain the many differences between eukaryotes and prokaryotes. In particular it does not ac count for the different details of molecular processes or for the large differences in the amino acid sequences of function ally analogous proteins in the two kinds of cells. It is often taken for granted that the differences are merely a consequence of the many small changes in cellular design that would be necessary in passing from the simple prokaryotic condition to the more complex eukaryotic one. It is questionable that so many changes (changes in the composition of almost all enzymes, for example) can reasonably be accounted for in this way.
Essentially for this reason some biologists think the line of descent that gave rise to the putative urkaryotic species may have diverged from the prokaryotic line at some earlier point, before the ancestor of the bacteria had itself arisen. The urkaryote could then have evolved independently to a form comparable in complexity to that of the bacteria. Such an assumption would at least provide more time for differences to emerge between prokaryotes and the urkaryote. The urkaryote, then, would represent a line of descent distinct from that of the prokaryotes, in accordance with the basic phylogenetic dichotomy.
So it stood at the beginning of the 1970s. The phylogeny of the higher eukaryotes, spanning some 500 million years, was reasonably well understood except for the all-important joining of the main eukaryotic branches. There was a definite, widely accepted hypothesis concerning the way in which the eukaryotic cell had evolved. Tests of the hypothesis and answers to the remaining questions, however, lay in the unexplored recesses of bacterial phylogeny, in the age of microorganisms.
Genetic sequencing
Bacteria constitute a world of extraordinary variety, far more than the microscope reveals. The ecological niches which they are found far exceed in variety those occupied by the higher forms of life. For a century microbiologists have tried in vain to understand the natural relations among bacteria and to impose some order on the bewildering array of forms, physiologies and ecologies. Variety among bacteria is mostly variety within simplicity, and so it provides little information about phylogenetic relations. In higher organisms the eye, for example, has evolved a number of times, but the eye is complicated enough for the independently evolved examples to be readily distinguishable from one another. Such is generally not the case for the form and structure of bacteria; rods, spheres and spirals, which are the typical bacterial shapes, are easily arrived at and have evolved many times. The same principle applies to bacterial biochemistry. Although some bacterial characteristics are valid phylogenetic indicators, it is impossible to tell in advance which ones are and which are not.
The simplest way in which the cell is a record of its past is in terms of genetic sequences. Every gene that exists in a cell today is a copy of a gene that existed eons ago. It is not an exact copy because mutations have altered the original genetic sequence, but vestiges of the original state often persist. What makes a gene a superb record of the past is its simplicity (it is a linear array) and the fact that genetic-sequence "space" is enormous, so that over the entire span of evolution only a small fraction of the possible genetic sequences can ever be realized. Hence if two genes are similar over a stretch comprising a significant number of nucleotides, this can only mean they have an ancestor in common; such genetically related molecules are said to be homologous.
A genetic sequence yields three kinds of evolutionary information. The sequence can reveal genealogical relations, it can measure evolutionary time and it is a record of ancestral characteristics. To the extent that two genes for the same function in different organisms are related, the organisms are related. The extent to which two such sequences differ measures the time since the organisms diverged from a common ancestor. From an extensive set of related sequences one can construct a phylogenetic tree in which the branch points measure (approximately) the relative times of the bifurcations. Finally, comparisons sons among an extensive set of homologous sequences make it possible to reconstruct with some accuracy various ancestral versions of a gene.
Since the relation between a gene and its product (either a protein or one of several kinds of RNA molecule) is generally a colinear one, the sequence of the product is ordinarily as useful for phylogenetic studies as the sequence of the gene itself. Because until recently only proteins could be sequenced it was through comparisons of proteins that the first phylogenies based on molecular evolution were constructed. Comparisons of the respiratory protein cytochrome c prove to be particularly valuable for confirming and extending the phylogenetic tree of the higher organisms. On the other hand, molecules such as cytochrome c are not as effective in establishing relations among bacteria. Such proteins are not universally distributed; they are not strictly constant in function and so are not entirely comparable, and because of the greater antiquity of bacterial lineages differences in sequence can be far greater among bacteria than they are among eukaryotes. These factors make bacterial phylogenies deduced from protein evolution in complete and uncertain.
Ribosomal RNA
There are other gene products that can serve as indicators of bacterial relations. All self-replicating entities necessarily have systems for maintaining and propagating genetic information and for translating it into the chains of amino acids that constitute proteins. Most of the large molecules engaged in these processes must trace their origin back to the very early stages in the evolution of the cell; they certainly emerged before cells became complex enough to be called prokaryotes. Therefore one would expect these molecules to have the requisite properties of a phylogenetic marker.
The most reasonable first choices among such molecules are the RNA molecules that are complexed with proteins to form the ribosomes. It is on the ribosomes that genetic information is translated into proteins. The ribosomal RNA is easy to isolate in workable quantities because a typical bacterial cell has from 10,000 to 20,000 ribosomes. Moreover, ribosomal-RNA molecules seem to have remained constant in function over great evolutionary distances. This is important because functional changes in a molecule bring with them additional changes in sequence that make it difficult or even impossible to compare one molecular sequence with another and thereby deduce phylogenetic relations. Still another advantage of the ribosomal RNAs is that at least some portions of their sequences change slowly enough for the common ancestral sequence not to be totally obliterated. In other words, the sequences make it possible to detect the deepest phylogenetic relations.
There are three kinds of ribosomal RNA molecules. In bacteria the "large" ribosomal RNA is the 23S RNA (S stands for Svedberg unit, a measure of the rate of sedimentation in an ultracentrifuge and hence an indirect measure of molecular size); it is approximately 2,900 nucleotides long. The "small" one, designated 16S ribosomal RNA, is about 1,540 nucleotides long. A very small one (5S) has only 120 nucleotides. The sizes are similar in eukaryotic cells: 18S, 25-28S and 5S. One might think that ease of characterization would make the small 5S RNA the most suitable one for phylogenetic studies. Actually it is not as accurate an indicator of phylogenetic relations as the larger ribosomal RNAs, chiefly for statistical reasons. (The 5S RNA sometimes exhibits anomalous large differences in sequence from one species to another.) The 16S ribosomal RNA is the molecule of choice, because the 23S molecule is almost twice as large and more than twice as difficult to characterize.
RNA dictionaries
At the University of Illinois in 1969 I decided to explore bacterial relations by comparing the sequences of the 16S ribosomal RNAs in different species. It was not yet feasible (as it is now) to determine the nucleotide sequence of the entire molecule. The technology did exist, however, for sequencing short segments of the molecule. The enzymes called ribonucleases yield short fragments of RNA by cutting an RNA strand at specific sites. Each nucleotide of RNA is composed of a sugar called ribose, a phosphate group and one of four nitrogenous bases: adenine (A), uracil (U), guanine (G) or cytosine (C). The enzyme T-sub-1 ribonuclease cuts an RNA strand at a particular bond on one side of each nucleotide that incorporates a guanine base. The T-sub-1 enzyme therefore digests an RNA "text" into short "words," called oligonucleotides. Each oligonucleotide includes, and ends with, a single G as in AACUCG or UCCUAUCG.
The oligonucleotides made in this way were short enough to be sequenced by the available techniques. The smallest words are of little value because they recur many times in each molecule. By the time the word length reaches six nucleotides, however, a particular sequence is unlikely to appear more than once in a 16S RNA molecule. (Given the constant terminal G, there are 3^5, or 243, possible six-letter sequences of this kind, and a typical 16S RNA molecule has roughly 25 such words.) When 16S RNAs from different organisms include the same six-letter sequence, it almost always reflects a true homology. By confining attention to words six letters long or longer one can generate a "dictionary" characteristic of a given organism, which can readily be compared with other such dictionaries to determine genealogical relations.
A simple way to analyze the data is in terms of an association coefficient S-sub-AB, which is defined as twice the number of nucleotides in the words common to both of the dictionaries A and B divided by the number of nucleotides in all words in the two dictionaries. S-sub-AB ranges from 1 when dictionaries A and B are identical to less than .1 when they are unrelated. (The coefficient is usually greater than zero even for unrelated sequences because of chance correspondences.) By compiling the S-sub-AB values for a number of organisms in a matrix one can discern a pattern of relatedness or unrelatedness among organisms. More over, it is possible by straightforward statistical methods to construct from a set of SAB values for a group of organisms a dendrogram, or tree, showing the relations among members of the group.
To date the ribosomal RNAs of almost 200 species of bacteria and eukaryotes have been characterized. Most of the bacteria form a coherent but very large (which is to say ancient) group. They are the eubacteria, or true bacteria, and as would be expected they are quite distinct from the eukaryotes. The relations among the various genera (represented by the branchings of the tree) determined through ribosomal-RNA analysis are at variance with many of the established prejudices about bacterial relations. What is important at this point is that the eubacteria are divided into a number of major branches and hat several of the branches include photosynthetic bacteria. This finding suggests all eubacteria stem from a com mon photosynthetic ancestor.
The discovery of archaebacteria
As the screening of bacteria continued a surprise emerged. In collaboration with Ralph S. Wolfe I looked at the ribosomal RNA of the methanogenic bacteria. These unusual organisms live only in oxygen-free environments and generate methane (CH4) by the reduction of carbon dioxide (C02), We discovered that methanogens do not fall within the phylogenetic group defined by the other bacteria. Indeed, they appear to represent an evolutionary branching that far antedated the common ancestor of all true bacteria. Not only were the methanogens separate but also the group they formed seemed to be about as deep phylogenetically—as ancient—as the group defined by the eubacteria.
There can be no doubt that the methanogens and their relatives are bacteria. They are the size of bacteria, they have no nuclear membrane, they have a low DNA content and so on. Surely, then, one would have expected them to be related more closely to other bacteria than to eukaryotes. Our analysis showed they are not. Methanogens are related as closely to eukaryotes as to eubacteria.
How could this be? There were supposed to be only two primary lines of descent, the eukaryotic and the prokaryotic. Here was a new group of organ isms: the methanogens and their relatives, which together have come to be called archaebacteria. They were obviously like other bacteria in their superficial characteristics, and so they had been assumed to be in the prokaryotic line of descent. It is not striking differences in morphological characteristics, however, that distinguish the prokaryote phylogenetically from the eukaryotic cell; it is the subtler and more ancient differences in molecular sequences and in details of function at the molecular level that distinguish them. Hence there is no reason two prokaryotic lines of descent cannot be just as distinct from each other as either one is from the eukaryotic line.
This idea was too novel to be easily accepted, and initially some biologists rejected out of hand the notion of a "third form of life." How could some thing that looked like a bacterium not be a bacterium and indeed not be related to bacteria? In time the simplicity of our argument and the accumulation of evidence prevailed. Although a few biologists still dispute our interpretation, the idea that archaebacteria represent a separate grouping at the highest level is be coming generally accepted.
The supposed great antiquity of the archaebacteria remains an unproved prejudice, but it is a plausible one. The methanogenic phenotype seems to cover a phylogenetic span as great as or greater than the span covered by any other comparable bacterial phenotype. This implies that the methanogens are as old as or older than any other bacterial group. Moreover, methanogenic metabolism (the reduction of carbon dioxide to methane) is ideally suited to the kind of atmosphere thought to have existed on the primitive earth: one that was rich in carbon dioxide and included some hydrogen but virtually no oxygen. The name archaebacteria implies that these organisms were the dominant ones in the primeval biosphere. When conditions changed, the methanogens' need for an anaerobic environment confined them to a limited range of relatively in accessible niches.
The measurements that revealed the existence of the archaebacteria (differences in R N A sequences) were genetic ones and were purely quantitative. They revealed nothing about the quality of the differences—the phenotypic differences—between the archaebacteria and the true bacteria. If our interpretation of the archaebacteria as a primary kingdom separate from that of the true bacteria is correct, then on detailed inspection the archaebacteria should prove to be as different from true bacteria in their molecular phenotype as either group is from eukaryotic cells.
Archaebacterial forms
The archaebacteria are indeed unusual organisms. The group is now known to include three very different kinds of bacteria: methanogens, extreme halophiles and thermoacidophiles.
The dominant form (in the sense that it constitutes a deep phylogenetic grouping) is the methanogen. Bacteria that give off methane have been known for some time. Alessandro Volta discovered in 1776 that "combustible air" is generated in bogs, streams and lakes whose sediments are rich in decaying vegetation, but the fact that a microorganism is responsible for generating "marsh gas" became known only much later. Methanogens are widely distributed in nature, but they are not commonly en countered because they are killed by oxygen and do not exist in the open.
In ancient times methanogens could have existed almost anywhere. Today they live only where oxygen has been excluded and where hydrogen and car bon dioxide are available. This generally means living in close association with other bacteria, such as the clostridia, that metabolize decaying organic matter and give off hydrogen as a waste product. Methanogens are found in stagnant water and in sewage-treatment plants (in amounts that have made it commercially feasible to manufacture methane). They are also found in the rumen of cattle and other ruminants and in the intestinal tract of animals in general. Methanogens can be isolated from the ocean bottom and from hot springs. In spite of their intolerance of oxygen they are obviously globally distributed.
The extreme halophiles are bacteria that require high concentrations of salt in order to survive; some of them grow readily in saturated brine. They can give a red color to salt evaporation ponds and can discolor and spoil salted fish. The extreme halophiles grow in salty habitats along the ocean borders and in inland waters such as the Great Salt Lake and the Dead Sea. Although the extreme halophiles have been studied by microbiologists for a long time, they have recently become particularly interesting for two reasons. They maintain large gradients in the concentration of certain ions across their cell membrane and exploit the gradients to move a variety of substances into and out of the cell. In addition the extreme halophiles have a comparatively simple photosynthetic mechanism based not on chlorophyll but on a membrane-bound pigment, bacterial rhodopsin, that is remarkably like one of the visual pigments.
The thermoacidophiles
The third known type of archaebacterium is the thermoacidophile, and the members of this group too are nota ble for their habitat. Sulfolobus, one of the two genera of thermoacidophiles, is found in hot sulfur springs. Its various species generally grow at temperatures near 80 degrees Celsius (176 degrees Fahrenheit); growth at temperatures above 90 degrees has been observed for some varieties. Moreover, the springs in which Sulfolobus flourishes are extremely acidic; pH values lower than 2 are common (a pH of 7 is neutral). Thermoplasma, the other genus of thermoacidophile, has so far been found only in smoldering piles of coal tailings. It is a mycoplasma: it has no cell wall but merely the limiting cell membrane.
Although archaebacterial thermoacidophiles can grow only in an acidic environment, the internal milieu of the cell has a quite moderate pH, near neutrality; this requires that a sizable pH gradient be maintained across the cell membrane. As in the extreme halophiles the gradient may play a role in pumping other molecules into and out of the cell. It is interesting that when the temperature is reduced and as a consequence Sulfolobus stops metabolizing, the cell's internal pH can no longer be maintained near neutrality and the cell dies.
For some time it had been recognized that various organisms now classified as archaebacteria are individually somewhat peculiar. In each instance the idiosyncrasy has been seen as just that: an adaptation to some peculiar niche or biochemical quirk. The ribosomal-RNA phylogenetic measurement, however, showed at least some of the idiosyncrasies might instead be general characteristics of a new group of organisms. Thus informed, investigators in many countries have undertaken to find the general properties that link archaebacteria to one another and to see how those properties either distinguish the archaebacteria from the other two major forms or relate them specifically to one or the other of those forms.
One generalization about bacteria has been that they have a cell wall incorporating the sugar derivative muramic acid, which is the basis of a complex polymer called a peptidoglycan. One extreme halophile and the thermoacidophile been that they have a cell wall incorporating the sugar derivative muramic acid, which is the basis of a complex polymer called a peptidoglycan. One extreme halophile and the thermoacidophile Sulfolobus were known to be exceptions to this generalization; they were considered to have an idiosyncratic wall structure. Otto Kandler of the University of Munich, collaborating with Wolfe, made a systematic study of cell-wall structure in other known archaebacteria. All of them turned out to be atypical. The archaebacteria have a variety of wall types, but none of them is of the muramic-acid-based peptidogly can type.
Lipids and RNAs
It was also known that the cell membrane of the extreme halophiles and of the thermoacidophiles is composed of unusual lipids. The lipids of both eukaryotes and eubacteria consist in the main of two straight-chain fatty acids bound at one end to a glycerol molecule through an ester linkage (-CO-O-). The lipids of the extreme halophiles and the thermoacidophiles are also composed of a glycerol group linked to two long hydrocarbon chains, but the connection between the glycerol and the chains is an ether (-O-) link rather than an ester link. Moreover, the hydrocarbon chains are not straight but branched: every fourth carbon atom in the chain carries a methyl group (CHa). The basic archaebacterial lipid, in other words, is a diether composed of glycerol and two molecules of an alcohol, phytanol. When a number of methanogens were examined for lipid composition, our expectation was confirmed: their lipids turned out to be typically archaebacterial branched chain glycerol ethers.
In the course of the ribosomal-RNA studies another unexpected archaebacterial property emerged, one that was to provide the first clue to the significance of the differences between archaebacteria and true bacteria. Central to the process of translation is the transfer RNA molecule. It recognizes a three base "codon" in messenger RNA specifying a particular amino acid, and it delivers that amino acid to be incorporated into the protein chain. A number of the nucleotides in a transfer-RNA molecule are modified, that is, their structure is altered chemically after they have been incorporated into the molecule; most often a methyl group is added to the nucleotide at some position on either the base or the sugar. Biologists had come to believe one particular modification was characteristic of a certain position in almost all transfer-RNA molecules in almost all organisms: at that position the base uracil has been methylated to form thymine (which is normally present only in DNA, not in RNA). It turns out that all transfer RNA's of all archaebacteria lack this thymine unit; instead the uracil has been modified in one of two other ways to yield a pseudouridine or an as yet un identified nucleotide.
If one compares both ribosomal RNA and transfer RNA in eukaryotes, eubacteria and archaebacteria, one finds a general pattern, of which the replacement of thymine in archaebacterial transfer RNA's is only one example. The same regions in the RNA's tend to be modified in all three primary lines of descent, but the nature of the modification tends to vary from one kingdom to another. The differences are of two kinds. Either the modification of a given base is different in each of the kingdoms, or a given base is modified in one kingdom and in another kingdom the modification is made to an adjacent base. These modes of variation suggest that the modifications have evolved separately in each major line of descent.
Several other molecular distinctions between the archaebacteria and the other groups are known (for example, in the subunit structure of the enzyme RNA polymerase), but the list is not long. The reason is not that additional differences do not exist; it is rather that the world of archaebacteria remains virtually unexplored. The study of archaebacterial genetics is in a primitive state; few mutants have even been isolated for genetic study. Nothing whatever is known about the control of gene expression in archaebacteria. The basic molecular biology of archaebacteria is not under stood. And yet to the extent that the archaebacteria have been characterized they have been found to differ significantly from both of the other major groups.
A new perspective
The discovery of a new primary kingdom of organisms is a major finding in its own right (comparable to going into the backyard and seeing an organism that is neither a plant nor an animal), but the real importance of the discovery lies in what it may reveal about the early history of life. When there were only two known primary lines of descent, one could not readily interpret the differences between the two. The recognition of three lines of descent equidistant from one another gives a much better perspective for judging which properties are ancestral and which have evolved recently. With the discovery of the archaebacteria two central evolutionary problems therefore become approachable: the nature of the common ancestor of all life and the evolution of the eukaryotic cell.
At what stage in the evolution of the cell did the fundamental division into the primary kingdoms take place? What was the nature of the universal ancestor? The assumption has been that the universal ancestor was a prokaryote, the simplest of today's living forms. Long ago, however, there must have been still simpler forms of the cell. Although nothing is known about such forms, one can make an educated guess as to certain of their general properties.
Consider the following argument. The translation mechanism is complex, comprising on the order of 100 large molecular components. It is also highly accurate in its functioning. In making proteins of the size common today (chains of from 100 to 500 amino acids), obtaining a flawless product 90 percent of the time or more requires an error rate of no more than a few parts in 10,000. Moreover, this accuracy must be attained by a mechanism of molecular dimensions. For such a mechanism to have evolved in a single step is clearly impossible. The primitive version of the mechanism must have been far simpler, smaller and less accurate.
Imprecision in translation would have required the synthesis of proteins that were smaller, and therefore less specific in their action, than proteins are to day. (Otherwise the probability of error in making a protein strand would have been too great.) Among the smaller and less specific proteins would have been the enzymes required to process genetic information. If those enzymes were less precise than today's versions are, the cell's mutation rate must necessarily have been higher and the size of its genome correspondingly smaller. The translation process is the link between genotype and phenotype, between information and its expression; as the process evolved to become more precise, the cell itself necessarily passed through a corresponding series of evolutionary refinements. It evolved from an entity having simple properties, imprecise and general functions and a rather small complement of genes to an entity that functioned with many highly specific enzymes and a complex, precise genetic apparatus. To emphasize the primitive genetic and translational mechanisms of the earlier, simpler cells, I call them progenotes.
The progenote as ancestor
The discovery of the archaebacteria provides the perspective needed to approach the question of whether the universal ancestor was a prokaryote or a progenote. Although the question is far from settled, the initial indications are that the universal ancestor was indeed a progenote. First of all consider that true bacteria and archaebacteria have probably existed for at least 3. 5 billion years. The time needed for the evolution of the first true bacteria or archaebacteria, then, had to be less than a billion years, and perhaps much less. Still, the kinds of evolutionary changes that have arisen within each of the bacterial kingdoms over the later interval of three billion years or more are minor compared with the differences that separate archaebacteria from true bacteria, such as the differences in lipids, in transfer-RNA and ribosomal-RNA sequences and modification patterns and in enzyme-subunit structure.
It would seem that the nature of evolution some four billion years ago was very different from what it was later. This implies that the organisms under going the evolution were also very different. The possibility that the universal ancestor was in the process of developing the cell wall is suggested by the fact that archaebacterial cell walls are as unlike true bacterial walls as eukaryotic walls are. Perhaps the universal ancestor was still developing or refining biochemical pathways as well; lipids are synthesized differently in the two bacterial kingdoms, and many coenzymes are different. If archaebacteria should be found to differ from true bacteria in their mechanisms for controlling gene expression (a possibility that has yet to be investigated), the implication would be that their common ancestor may have had only rudimentary mechanisms of genetic control.
The key question is whether the universal ancestor was still developing the genotype-phenotype link when it gave rise to its descendant lines. Two observations suggest it may have been. RNA polymerase is the enzyme that transcribes the gene into its messenger-RNA complement (which is then translated into protein). The subunit structure of the RNA polymerase is quite constant among the true bacteria, whereas the archaebacterial polymerase structure is different. Could this mean the RNA polymerase function was still being re fined at the time the two bacterial lines separated?
The second observation concerns the modified nucleotides in transfer and ribosomal RNAs. As I mentioned above, the patterns of modification are almost invariant within any primary kingdom, but they tend to differ between kingdoms. Although the function of modified nucleotides in transfer and ribosomal RNAs is not understood, it is reasonable to assume most of them serve to "fine tune" translation: to make it more precise. If that is so, it would appear that many of the modifications have evolved independently in each of the primary kingdoms. The independence of these modifications implies in turn that the universal ancestor did not have today's highly specialized transfer-RNA and ribosomal-RNA molecules but made do with more rudimentary translation machinery. At this stage one can say only that the facts are consistent with, and in deed suggestive of, the universal ancestor's having had rudimentary transcription and translation mechanisms, and so having been a progenote.
The origin of the urkaryote
In terms of their ribosomal-RNA catalogues the archaebacteria, eubacteria and eukaryotes appear to be equidistant from one another genealogically; no specific relation between any two of the three has been detected. Nevertheless, in terms of the amino acid sequence of one protein, the ribosomal A protein, the archaebacteria clearly seem to be relatives of the eukaryotes. Therefore it may be that archaebacteria as well as true bacteria participated in forming the eukaryotic cell. Perhaps it is to the archaebacteria one should look for the origin of the unexplained stage of the eukaryotic cell: the urkaryote that played host to the endosymbiont ancestors of the mitochondrion and the chloroplast. (Rather than searching for the hypothetical host, however, one should instead question whether there was such an entity. This is not a time to shape new discoveries in accordance with old prejudices.)
As I have indicated, the differences between the eukaryotic cell and the other major cell types at the molecular level are more extensive and pervasive than any of the differences visible with a microscope. The eukaryotic nucleus appears to contain at least three kinds of genes: those of eubacterial origin (presumed to have been appropriated from the genomes of the eukaryote's organelles), those of archaebacterial origin (for example the gene for the ribosomal A protein), and those of an unidentified third origin (exemplified by the cytoplasmic ribosomal RNA). To what extent is the eukaryotic nucleus genetically a chimera: an entity composed of parts assembled from disparate sources? At what stage (or stages) of evolution did the presumed assembly take place? And what was the nature of the organisms that supplied the various genes and structures?
Biologists have tended to look at the eukaryotic cell as having been formed by the association of fully evolved prokaryotic cells; their association is assumed to have created a "higher" type of cell, the eukaryotic. (The term prokaryote—"before the nucleus"—carries just this implication).) The question that an profitably be asked now is whether the evolutionary agents that gave the eukaryotic cell its basic molecular character really were of this nature. The eukaryotic cell appears to be a chimera at a very basic level. Even the eukaryotic ribosome seems to be chimeric, its component RNAs having come from a source other than that of at least one of its proteins. If this is a correct interpretation of the data (and future investigations must settle the point), the eukaryotic cell may be a different kind of entity than it is now taken to be. It may have been chimeric even before it reached a stage of complexity comparable to that of today's prokaryotes; it may have been chimeric as it emerged from the progenote condition. Rather than being an advanced, "higher" form, the eukaryotic cell may represent a throwback to the evolutionary dynamics of its long-gone ancestor, the progenote.
Perhaps the most exciting thing about the recent discoveries in molecular phylogeny is that they show how much information about the very early stages of evolution is locked into the cell itself. It is no longer necessary to rely solely on speculation to account for the origins of life. It has become customary to think of the last decades of this century as a time in biology when "genetic engineering" will make possible exciting developments in medicine and industry. It must also be recognized that biology is now on the threshold of a quieter revolution, one in which man will come to under stand the roots of all life and thereby gain a deeper understanding of the evolutionary process.


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Wednesday, May 30, 2012
Free Vintage Images - Postal Ephemera
34 comments:
Thanks for the freebie!ReplyDeleteReplies
You're welcome! xoDelete
-pamela ;)
Fabulous! Thank you so much!ReplyDeleteReplies
You're welcome Victoria! xoDelete
-pamela :)
Thanks, that is a fantastic page, I'll make a lot of use of it. Hugs linReplyDeleteReplies
Thanks Lin! Lots of fab images indeed! xoDelete
-pamela :)
Great freebie Thanks.xxxReplyDeleteReplies
You're welcome Wendy! I love sharing freebies! xoDelete
-pamela ;)
TY sooooo VVVVVVVVVVVV M!! This will work great for a men's card! It is so very difficult getting images that suit men, especially young men, these days.ReplyDelete
They're not babies, not boys - but young MEN. They don't seem to fit anywhere. Sigh.
TY again.
D :)Replies
Diane - you're right! These would be great for men-themed cards! I would love to see what you create with these...I'll pin them on Pinterest! xoDelete
-pamela :)
Thank you! hugsReplyDeleteReplies
You're welcome Sandra! Have a nice day! xoDelete
-pamela ;)
hallo pamela, fantastic postcards i love them thankyou very much, heidi xReplyDeleteReplies
Greetings Heidi!!! Glad you are loving these images! xoDelete
-pamela ;)
LOVE this one, Pamela! Thanks very much! :o)ReplyDeleteReplies
Hello Nancy! Glad you love this collage sheet! Reminds me that I need to catch up on blog hopping soon... xoDelete
-pamela ;)
wow I so need these, thank you. xReplyDeleteReplies
Hi Netty - glad you like these vintage images! They will be fun to create with... xoDelete
-pamela ;)
(I'm heading to the airport in an hour...spending 2-days in Vegas! Staying at the Paris, of course!)
LOOK at ALL those FUN IMAGES on this collage!!!!!!! Makes you want to enlarge it all & read it!!!!!!! And I LOVE the red, white & blue air mail stripes!!!!!!! ALWAYS HAVE!!!!!!!!! :) Thanks Pamela!!!!! :)ReplyDelete
love love love love love this :D THank you sooo much for posting these!!!ReplyDelete
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Gracias, Pamela, como la anterior me viene genial.ReplyDelete
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These will be great for travel pages...thanks so much!ReplyDelete
Love these ephemera!! Thanks for your orininality.ReplyDelete
Another GREAT collage.. it has my stamp of approval!!!!!! Thank you.ReplyDelete
Thanks for the great freebie. Just perfect for a friend who collects postcards. :)ReplyDelete
Thank you :)ReplyDelete
Thank you for this fabulous collage image!!! You bring us such variety of things!ReplyDelete
That you so much for this collage, I just love it:)ReplyDelete
- AnonymousJuly 30, 2012 at 8:08 AM
thank you!!!ReplyDelete
Loving this! Thank you :0)ReplyDelete
muchisimas gracias por tan bellas imagenesReplyDelete


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Show starts at 1pm EST (5pm GMT).
Archive of the show is here (right click to 'Save link as...' or click to play): http://matrixfiles.com/show-audios/22nd-March-2014.mp3
Talking about the Qur'an and the deception around it using the following references.
Nuggets of Gold - for the 22nd March
- We have the ability to access knowledge and information that is not in the realm of our experience.
- All religions of the world have a tremendous amount of knowledge in them and they all have a calming influence on people.
- There are those who do not want this knowledge to be known so they corrupt the knowledge and create strife.
- Best alternative news sites:
- Circumcision, per the Qur'an, is NOT required of a Muslim.
- Man is made in Perfection.
- Circumcision harms the Man and the Woman (future wife).
- Satan changes the word/knowledge of God. Corrupts Mankind.
- Religions bring order into the environment.
- 2.5% of people on the planet are out to consciously destroy it and it's Peoples. 17.5% of people are at the effect of the 2.5%. 80% of people are good.
- There are as many Universes as there are people.


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Last night marked the final episode in the second series of Black Mirror, the ultra-dark UK show that explores the future of media. This series, like the first, was a set of three short stories (we reviewed the first episode here), each set in the near future. Though this second series was more uneven than the first (the second episode, "White Bear," was a mess), Black Mirror is still one of the very best science fiction shows you will ever see on television.
The final episode, "The Waldo Moment," was fantastically funny, mean, and sad. Set five minutes into the future, it's about a comedian named Jamie whose claim to fame is inventing a character named Waldo, a blue animated bear who likes to scream obscenities and pop boners at his pretentious guests. Waldo is an animation controlled and voiced by Jamie in real time, using a futuristic lo-tech motion capture rig. Waldo rules the interview segment on a popular news satire show, and the hook is that his guests don't realize they'll be talking to a nasty animated bear. The skit blows up into a wildly popular meme when Waldo interviews Liam Monroe, the local Tory candidate for Parliament, and completely freaks the politician out.
Soon the execs want Jamie to spin Waldo up into his own show, and they hit on the idea that Jamie should follow Monroe around in a truck, trolling him with Waldo from a giant flatscreen monitor. Jamie, already a little unbalanced, starts to go into a tailspin when he's pushed to do more political humor. He's not interested in politics, he yells. Still, he agrees to allow the network to do an "Elect Waldo" campaign. That's when things get really dark. Jamie takes Waldo on a news show with the other candidates, and manages to rip into all of them — including the Labour candidate, a young woman who spurned Jamie after sleeping with him for one giddy night. Waldo reaches new heights of popularity on YouTube and Twitter, where people love him for pointing out that all politicians are just as fake as CGI bears.
The bear is such a huge hit that he draws the attention of an American from "the agency," who suggests that Waldo could be a global political entertainment product, the "perfect assassin" in any arsenal aimed at unseating local regimes. In this clip, you can see the show creator Charlie Brooker's satiric genius at work as he has this guy basically explain how to weaponize a meme, turning a foul-mouthed bear into an agent of mass manipulation. The "Waldo Moment" is basically the tipping point when I Can Haz Cheezburger or maybe 4Chan becomes Big Brother. It's the kind of ugly futurist insight that makes Black Mirror such a riveting show.
After that meeting, Jamie gets more and more disenchanted with what's happening to Waldo, and eventually quits in disgust. His producers take over Waldo — they own the intellectual property — and Waldo comes in a close second after the Tory candidate in the local election. Then, in a coda, we flash forward a few years to Jamie living on the streets, being harassed by what seem to be semi-robotic soldiers. Leering down from glowing billboards is Waldo's blue face, surrounded by words like "hope" and "change."
The meme has won. Dystopia wears a cute blue bear's digital face.
Brooker, who wrote this episode, does a brilliant job realizing this genuinely disturbing vision, which comes from an unexpected place. The episode begins as a fairly standard critique of media politics but becomes something far richer — an exploration of how seemingly harmless internet icons who appeal to our sense of nihilistic apathy could be used to exploit us. There is something quite simply haunting about the idea that this glorified LOLbear might trick people into treating politics as fiction, and handing over the (now invisible) reins of their nations to anyone who controls Waldo's joystick.
If you want to see where your clicky habits online might lead you, watch "The Waldo Moment" episode of Black Mirror. It will leave your conscience feeling stained, even when you turn off your monitor.
Black Mirror aired on Channel 4 in the UK.


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Kenneth Blackwell
From Conservapedia
Ohio from 1999 through 2007 and was the unsuccessful Republican nominee for Governor in 2006. He is currently Vice Chairman of the Republican National Committee's platform committee and was co-chairman of President George W. Bush's 2004 reelection campaign. A staunch social conservative, Blackwell is "unabashedly pro-life" [1] and led the fight for a state constitutional ban on same sex marriage and civil unions.
Blackwell served as Mayor of Cincinnati from 1979-1980 and later undersecretary of Housing and Urban Development under President George H.W. Bush.


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Want to recreate the gifts from the classic Christmas carol, The 12 Days of Christmas with a sexy twist? Our revamped and refreshed 12 Sexy Days of Christmas will make NIGHTTIME your favorite holiday tradition! Because who isn't looking for a Christmas countdown that's more naughty than nice? The 12 Sexy Nights of Christmas printable download includes everything needed for you and your holiday honey to have yourselves a very Merry Christmas. From the bold bed backdrop to twelve colorful quilt squares, we're sure our calendar is unlike any you've ever seen. This is one sexy Christmas countdown that should be on everyone's list!
Disclaimer: This post contains affiliate links. To learn more about 'em, click here.
A huge holiday thank you to Courtney at Paperelli for creating such wonderfully whimsical images! We couldn't have done it without her! Be sure to check out her Etsy shop!
Ready to trade in those cuddles for something a bit more saucy? Our 12 Sexy Nights of Christmas countdown calendar is the perfect printable to do just that! Not only will its festive design serve to spice up the bedroom, but the hands-on component will leave the two of you feeling a little more than inspired…
Assembly is easy as pie and we're here to help! Simply attach the top and bottom bed pieces, and slip on that Santa hat for an extra holiday vibe!
Let the individual Christmas quilt squares take center stage on your beautiful bed backdrop—just the ticket for a ride (or twelve!) to remember! Simply cut, apply a thin strip of adhesive to the bottom, left, and right sides of each square, and affix to its coordinating outline!
Next, come the inserts – they're as cute as they are clever! Each Christmas themed prompt will have you oh-so-excited for that long winter's nap (no sleeping needed).
Once your calendar is complete, you're ready to do the deeds! Take turns selecting and reading each evening's task and get ready for 12 hot nights of sexy delights! It's going to be a magical Christmas, in more ways than one…
Christmas is my favorite time of the year. I love the smells, the meaning of the season, the giving hearts, and the love that permeates the air! As a rule I try not to get caught up in the busyness of the Christmas season but busyness always seems to sneak in. I have to remind myself that simple is best and it always is! For those of you who are just like me and tend to get busy, you might put quality time with your spouse to the back burner. This year, with Diva Becca's fabulous idea, we are going to change that.
To get these printables… scroll ALL the way to the bottom of this post for the download link!
* * * * *
You are going to make plenty of time for your spouse with The 12 Sexy Days of Christmas!
You will fulfill their wishes, spend plenty of quality time together, and make all their Christmas dreams come true!
Before we begin Becca is going to tell you a little about how this post came about…
"Three years ago, I was trying to come up with a great Christmas present for my husband on a very small budget. I asked him what he wanted and he replied, "You KNOW what I want." I just laughed and said, "No really, what do you want?" He looked me straight in the eye and said, "Why can't I want that? I just want YOU." So I decided that for Christmas, I wanted to give my husband a happy, stress-free wife and a WHOLE lot of lovin'.
And that is how The 12 Lays of Christmas came about!
I sat down and wrote up some flirty poems to add a sexy twist to the 12 Days of Christmas. My friend, Cher, even came up with some fun printables to go with them on her blog, Love Actually. And I have to say- it was a major HIT! Hand downs- his favorite Christmas present EVER! *wink* And I'm SO excited that Michelle has come up with this NEW and IMPROVED version to share with you! Take it away, Michelle!"
Without any further ado, allow me to introduce you to the…
My husband and I have one very important Christmas tradition that was started our first year of marriage. The only gift we are allowed to exchange with each other is a love letter that reflects upon the year, our growing love, and the excitement we have for next year. Now what does that have to do with this post?! Thanks to Becca's idea and Paige's help I'm adding the 12 Sexy Days of Christmas to our Christmas traditions because I love it THAT much!!! After you read this post you are going to want to add this to your traditions too!!!
The Gift
Grab a cute little box, I used a snowflake take-out box, to place all of your lovely, sassy, flirty, and teasing ornaments into. Place the first day of Christmas ornament, any additional items, and the note card into the box. Put on the finishing touches by tying the 12 Days of Sexy Christmas tag to the box with a ribbon. Place the gift next to your tree for your spouse to discover. Upon opening the gift place the ornament on the tree as a reminder of what's in store! Each day you will prepare a sexy rendezvous for the two of you. On each new day place the ornament into the box for your excited spouse to open!
The Ornaments
Aren't these ornaments beautiful?! A big shout out to Sameeha of The Inked Leaf for making these printables. She is divine to work with and always makes what I've imagined ah-maz-ing. Head on over and take a peek at her lovely designs, you will see why we love her so much!
To make each ornament or tag into a hanging ornament, punch a hole at the top and tie a ribbon through.
Each ornament has an accompanying little gift to help you fulfill your sexy deeds.
The items needed are:
Day 1: One Pear Sugar Scrub or any body scrub will do
Day 2: Two chocolate turtles or Dove chocolates
Day 3: Three hershey kisses
Day 4: One Whistle
Day 5: Five golden rings tied with a ribbon around a several lingerie outfits.
Day 6: Six Rolo's
Day 7: One bottle of Temptations Dreamy Bubble Bath or Feeling Smitten Bath Bombs (these were on Oprah's favorite things, they are ah-maz-ing!!!) along with Crayons and Finger Paints
Day 8: One box of Milk Duds
Day 9: A romantic CD
Day 10: One Mountain Dew
Day 11: One toy pipe/flute Whistle
Day 12: A ticket for a private drumming session and the note finishing the 14 Sexy Days of Christmas (these are found on the last page of the printables)
The Tree
Thanks to my hubbies snipping skills we put together this twig tree. Making your own tree will be simple and easy all you need to do is find a tree with pretty twigs, snip them off at the length you would like, and carefully arrange the twigs to look like a pretty tree! Place your twig tree into a mason jar that you've covered with burlap and ribbon. Place in your room in a cozy place that is easily seen by the two of you.
Some of you might be thinking this is way too much work for just one gift. I completely agree with you! Keep this tree up all year round and create a sexy countdown for different occasions. On Valentines replace the red ribbon with a pink one and make sexy coupons out of hearts to hang from the tree. In March write reasons they are "lucky" on shamrocks and use a green ribbon. For April, use a pastel ribbon and hang easter eggs with steamy gifts inside them. In July use stars to hang on the tree and tie with a patriotic ribbon. When Halloween arrives hang treats on the tree with little coupon notes wrapped around them and use an orange ribbon. For November hang leaves from the tree and tie with a brown or white ribbon. And we all know what to do in December! See how much fun this twig tree made just for the two of you will become!!!
The End
On the last day of the Sexy Days of Christmas, after you have fulfilled your treat, present this little enticing note.
Is it the end? No this is just the beginning!!! As long as you keep your spouse a priority, the two of you will enjoy countless love making sessions!!!
The Printables
Grab your 12 Sexy Days of Christmas printables. Print onto glossy sheets of cardstock for a very shimmery look! To make the card follow the instructions on the page with the card.
To keep up the sexy fun during Christmas check out Merry Kiss-mas, Santa's Cookies Bedroom Game, and The Sexy Stocking.
No more stalling, gather all your items and fill your Christmas season with lovin', in and out of the bedroom!


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SAMJ: South African Medical Journal
versão On-line ISSN 2078-5135
versão impressa ISSN 0256-9574
SAMJ, S. Afr. med. j. vol.100 no.7 Pretoria Jul. 2010
Misplaced trust? Gaping flaws in drug approval and licensing
When a medical practitioner writes a prescription, he or she takes it on faith that the substance he or she is prescribing is safe (within the bounds of disclosed potential adverse effects) and efficacious by virtue of its having been rigorously tested, approved and registered by a statutory regulatory agency such as the Medicines Control Council (MCC) in South Africa, the Medicines and Healthcare Products Regulatory Agency (MHRA) in the UK, or the Food and Drug Administration (FDA) in the USA. The FDA mandate as stated on its website echoes that of other regulatory agencies, namely to be 'responsible for protecting the public health by assuring the safety, efficacy, and security of human and veterinary drugs, biological products ... [and] medical devices'.
But questions have long lingered regarding the integrity and reliability of the system by which new drugs are evaluated, regulated and promoted, bolstered by revelations of inconsistencies and dubious conclusions in the evidence (clinical trials) used to support the licensing of certain drugs already on the market. The power and influence of drug companies in the registration process is a continuing source of much disquiet among honest clinical researchers and medical journal editors. The clinical trials used to support drug registration are almost always funded and directed by the manufacturer, with a huge financial interest in the outcome. More often than not, such evidence is shrouded in secrecy on the excuse of protection of intellectual property.
The FDA requires just two placebo-controlled trials with positive results to approve a drug indication, regardless of how many other trials fail to corroborate this outcome. As a rule, negative trials are rarely published in medical journals. And it doesn't matter if the difference in effectiveness between the drug and a placebo is slight, as long as it is statistically significant.
The soft underbelly of clinical trials
For some years now, oseltamivir (Tamiflu), a neuraminidase inhibitor, has been the mainstay of treatment for influenza, and was accordingly stockpiled by many nations at a cost of billions of US dollars in the wake of the H1N1 pandemic. Tamiflu was said to prevent secondary complications such as bronchitis, pneumonia and sinusitis by 67% in otherwise healthy persons infected with the influenza virus, thus helping to reduce hospitalisations by over 60%. This reputation stemmed from a highly influential meta-analysis of clinical trials published by Kaiser et al.1 showing that oseltamivir had these benefits. But when a Cochrane Collaboration group sought to replicate Kaiser's review in 2009, it transpired that the review had been based on 10 clinical trials held by the manufacturer, 8 of which had not been published or peer reviewed.2 Furthermore, the Kaiser review was funded by the company. Four of Kaiser's co-authors were employees of the manufacturer, and one a paid consultant. Curiously, the key authors of the two trials that were published were not named in documents submitted for registration purposes, and those named in these documents were not listed as authors in the published papers.
Concerted attempts by the Cochrane group to get access to these company-held trials ran up against a brick wall. When the BMJ and the UK's Channel 4 News launched a joint investigation into this matter and attempted to gain access to the original registration trials, they too were frustrated by 'a complex interplay between politics, public health planning, availability of trial data, publishing, and drug regulation'.3
In 1998 Kirsch and Sapirstein4 upset the pharmaceutical applecart with the publication of their article entitled 'Listening to Prozac but hearing placebo'. The authors analysed 38 published clinical trials involving more than 3 000 depressed patients, and found that placebos were 75% as effective as the antidepressant drugs studied, whereas the drugs incurred serious adverse effects that included sexual dysfunction and suicide risk. Kirsch and co-workers followed up this work with an analysis of the original trials (obtained with great difficulty) submitted to the FDA for purposes of licensing, and found an even larger placebo effect. Their findings have been replicated by others such as Fournier et al.5 who, as recently as early 2010, concluded that there is little evidence that antidepressants have a specific pharmacological effect relative to placebo.
Conflict of interest and self-aggrandizement are pervasive in the business of drug trials, with many investigators and institutions standing to make tons of money from the drug industry. Former NEJM editor Marcia Angell asserts bluntly that 'it is often possible to make clinical trials come out pretty much any way you want, which is why it's so important that investigators be truly disinterested in the outcome of their work'.6
The point of this editorial is not about the cited examples, but rather about flaws in the drug regulatory system that made these detractions possible. There is a crying need for greater transparency, integrity and independence from big pharma if the regulators are to earn the complete trust of the practitioner and the consumer.
Daniel J Ncayiyana
References available from the Editor at email@example.com


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Mac OS X has several amazing features that are hidden from the user. If you have been using Mac for a couple of years then, we are sure you would have stumbled across a few Mac hidden features. Many users are unaware of these secret Mac functions even after several years of using the Mac OS X. In this article, we have gathered 15 useful, lesser known Mac features that are sure to surprise you.
Merge Folders
You can easily merge the contents of two identically named folders but dragging one folder onto another prompts a Replace dialog message. So, the trick to merge two folders is to use Option – Dragging the folder which prompts an additional choice to merge folders. One folder containing contents of both source and destination folders will be created.
Create a Signature in Preview
It is easy to add a signature to your document in Mac. Open the document in preview and open the Annotations toolbar. Click on the Signature button and choose the Create Signature from Built-in iSight option. Follow the on-screen instructions to add a signature to your document. You can save your signature for future use as well.
Quick Dictionary Access
You can quickly access the dictionary in Mac systems with these shortcut options. In older version of Mac OS, use ⌘⌃D to bring up the definition of the world while hovering over the word. You can find the definition of a word by double tapping with three fingers in Lion version. Quick access to dictionary helps users find meanings to obscure words immediately.
Restoring Scroll Bars
Scroll bars by default are hidden in Lion version and are visible only when a user begins to scroll the page. This could be confusing at times and hence many users prefer to have the scroll bars on. You can have the scroll bars visible always by changing the default setting. Go to System Preferences, under General Category; select Always under Show Scroll Bars option.
Built-in emoji Support
It is extremely easy to insert emoticons in Mac OS X. It comes with a built-in emoji which allows users to insert special characters. Press ctrl +⌘ + space to open the window. This window contains an exhaustive list of special characters. You can choose the special characters and emoticons that you need from this window.
Speech-to-Text Conversion
Dictation-typing in Mac OS works amazing well. You can convert your speech-to-text by pressing the function (fn) key twice and begin speaking. Your voice gets converted to text when you press function (fn) key one more time. The OS X types out as you speak.
Easy Volume and Brightness Control
With this shortcut, volume and brightness control can be achieved quite easily. Hold ⇧ + ⌥ together to change the brightness in small increments. You can change your volume control without affecting the brightness control by just holding the ⇧ key.
Auto Complete of Words
Do you have trouble with spellings? This hidden feature will help you spell difficult words correctly as you type in iChat or TextEdit. Press F5 or Option + Escape to bring up an auto complete menu that provides a list of possible spellings to the word that you have started typing. This feature is extremely useful when you are typing official documents.
Quick Duplicate Open File
Many of the apps on Mac lack the option of "Save As" to duplicate an open file. There is a way to achieve duplication of an open file without opening the File menu. Click on the filename at the top. This drops down a menu of options. Click on the option Duplicate which allows you to replicate the file.
Hot Corners
This feature allows you to trigger certain events by touching the corner of your screen. You can enable hot corner setting by navigating to System Preferences -> Desktop & Screen Savers ->Screen Saver Tab -> Hot Corners. It is a very useful feature which allows you to disable screensaver, launch notification center and open applications.
Close Running Apps
Running apps take up a lot of RAM space and slow down your system. Here is a quick solution to close your running apps on Mac. Simply hold ⌘ + tab and continue holding ⌘ and tab through all open apps. When you reach the app that you want to quit, press Q. If you want to hide the app, press H.
Turn Off Notifications
Open your Notification Center and scroll down the side-loading bar until you find Do Not Disturb toggle feature. Turn it on and you will not receive any notifications for a day. It is a convenient way to focus on your work without being disturbed by notifications that pop-up quite often. You can also schedule Do Not Disturb feature to be turned on for a specific period of time or for a particular event. For example, you can have it turned off when display is mirrored to a projector output.
Delete Apps in Launchpad
Deleting apps using Launchpad is an easy way to cleanup old apps. Open Launchpad interface and hold down Option to launch the iOS –style wiggle mode. This will activate the close icons on apps installed through Mac App Store. You can click on the cross icon to delete unused old apps from the system.
Preview Files
Previewing files is really simple with this trick. Hold down the space bar when you select a file to preview the file. You can even preview image and video files with this option. You can switch between files while in preview by pressing the arrow keys.
Create a New Desktop
Mission Control is a cool new feature in Lion. In Mission Control, you can create a new desktop easily. A '+' tab appears at the top right while you hover your mouse in Mission Control. If you want to move a window to a new desktop, you can drop them into the '+' tab. You can have a dedicated desktop by simply dragging and dropping windows into this tab.


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OP/TECH USA Hood Hat, Large Overview
The black, large OP/TECH USA Hood Hat is designed to fit a lens and shade with a diameter from approximately (10.2 to 11.4 cm). Simply placing the Hood Hat onto the front of the hood while in place will provide just as much protection for the critical front lens elements as would be provided by a traditional lens cap. The neoprene material will adjust to fit both round and elliptical "petal-type" shades.
Lens hoods with significantly larger opening than the lens diameter may require larger model hood hat. This item is made in the USA.
Neoprene stretches for a custom fit on round or elliptical "petal-type" shades
Protects lens and shade against dust, moisture and impact
Cylindrical design for better fit


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In organic photochemistry, the terms singlet and triplet refer to the configuration of two coupled electrons in the outer or valence orbital of a molecule and, by extension, to the two unpaired electrons in a radical pair. In the singlet state, shown in Figure 1, the two electrons are in a "spin paired" or "anti-parallel" configuration, meaning that both are spinning about opposite vectors.
A vector is a geometric object in the shape of a line with both a magnitude (its length) and a direction. Think of each electron as a ball spinning in a clockwise (when viewed from below) direction about a vector, with the direction of the vector indicated by the arrow at its tip. In addition to spinning about a vector, the electrons "precess" around an axis, labeled "z" in Figure 1. Precession is analogous to the motion of a gyroscope or, if you will, a wobbly top.
While precessing, the vector arrow traces out a circular path about the z axis. The spinning, precessing electrons exert a force called angular momentum along the z axis, either up or down depending on the orientation of the arrow. In the opposite direction, they exert a magnetic force called a magnetic moment.
In the singlet state, the two electrons not only spin about opposite vectors, they also precess "out of phase," meaning their vector arrows are always opposed. As a result, the angular momenta and magnetic moments exerted by the two electrons cancel each other out. Thus, there is no net spin, no net angular momentum, and no net magnetic moment. This is the single (one and only) configuration in which two electrons can occupy the same atomic orbital, and is known as the singlet state.
In the triplet state, shown in Figure 2, the two electrons are always "orbitally unpaired." There are three possible configurations of the triplet state. In one, found to the left of Figure 2, both electrons are spinning about "up" vectors and precessing "in phase," meaning their vector arrows are always pointed in the same direction. In the opposite case, to the right in Figure 2, both electrons are spinning about down vectors and again precessing "in phase." The third triplet configuration, found in the center of Figure 2, has the two electrons spinning about opposite vectors but precessing "in phase." Though there are subtle differences between them, all three produce a positive net spin and angular momentum. Most importantly, all three configurations are "spin unpaired" and look and behave as highly reactive radicals.
If involved in absorption of a photon, two electrons in the singlet state separate into different orbitals, i.e., they become "orbitally unpaired," but at least initially maintain the singlet ("spin paired") configuration. This spin-paired, orbitally unpaired state is called the singlet excited state. Unless something–an outside magnetic force, for example–causes one electron to "flip" its spin or change its phase, the singlet pair will quickly return to the stable singlet configuration in the same orbital. In this context, "quickly" typically means in a billionth of a second (10-9 seconds).
If an outside force does cause one of the singlet pairs to flip or re-phase, then they enter the triplet state. If that happens, the triplet pair is in a metastable (semi-stable) state that keeps the two electrons from orbitally re-pairing, i.e. occupying the same orbital. Therefore, they can persist in the triplet state for some time, or until an outside force causes one of the electrons to "flip" or "re-phase" and return to the singlet state. "Some time" in this context typically means thousandths of a second or even longer. And within that time lag lies the most significant difference between the singlet and triplet states.
Most chemical reactions (even very fast ones) need at least a millionth of a second (10-6 seconds) to proceed, so few can compete with the much shorter-lived singlet state. However, many chemical reactions proceed from the long-lived triplet excited state. These chemical reactions are always destructive to the molecules involved in them. If the molecules happen to be the UV filters in sunscreens, then their destruction causes the sunscreen to lose its ability to protect the wearer from the damaging rays of the sun. Formulators must understand singlet and triplet quenching to create photostable sunscreens, which was described in more detail in an article by this author that appeared in the February 2010 edition of Cosmetics & Toiletries magazine.


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Camping Saarburg
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Publications Search
This publications portal is a repository of all IOM migration health publications from 2006 to present where IOM was a primary contributor.
Publications include peer-reviewed scientific papers, technical reports, training guides/manuals, policy briefs/discussion papers, factsheets, newsletters, research reviews, conference and poster presentations. These are categorized by topic, author, country/region covered as well as by year, language, and type of publication. The map reflects the countries covered by the publications.
To browse or search: simply use the filter options on the left-hand side. Alternatively, you can enter keyword/s in the search box. Selecting a specific publication will lead to a 'download' link or link to the website where the document is housed. Here is the step-by-step guide for your reference.
Migration and Health in South Africa: A review of the current situation and recommendations for achieving the World Health Assembly Resolution on the health of migrants
Author/s: IOM South Africa
A review of the current situation and recommendations for achieving the World Health Assembly Resolution on health of migrants. November 2010.
- Executive summary
- Introduction
- Migration, development and health in South Africa
Multiple forms of migration: internal and cross-border migration are global realities: Internal migration within South Africa…
Migrants' Right to Health in Southern Africa
Author/s: IOM South Africa
The review reveals that the law in all the SADC member states contains either expressly or implied provisions that guarantee migrants rights to health. While in some states, the law is more direct than others in its protection of migrant rights to health, it has emerged that an interpretation of the domestic law in consonance with the States' international legal obligations accords migrants right to health.
- …


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Project details: Textile automation at Inman Mills
Inman Mills is the sixth of seven textile manufacturing facilities Patti Engineering Inc. has modernized with custom designed automation technology. Technologies used include...
Inman Mills is the sixth of seven textile manufacturing facilities Patti Engineering Inc. has modernized with custom designed automation technology. Patti Engineering is a control systems integration company based in Auburn Hills, Mich., with offices in Massachusetts and Texas, with expertise in the textile industry.
Patti Engineering is a certified Siemens Solution Partner with extensive Siemens expertise, and it restored the Siemens S5 PLC to full functionality for the the bobbin stripper.
Inman Mills plant manager Bill Hightower said, "Patti Engineers were very professional and knowledgeable about the complete automation system where the software was installed. They provided exceptional communication at all times during the installation, training, and implementation of the system. We are pleased as this installation by Patti Engineering has performed exceptionally since implementation. As we continue in our learning mode, if we have any questions about the system, Patti Engineering has been very quick to respond. I would not hesitate to recommend Patti Engineering based on the excellent results we experienced on this project."
Patti Engineering's first experience with this type of equipment laid the foundation for expertise in this market segment. On the original textile plant retrofit, the ring spinning system with a PC-based control systems and hardware and software was no longer supported. With complicated code written in German, Patti Engineering had to build the new software program from the ground up.
According to Steve Palmgren, senior electrical controls engineer and Patti Engineering's Texas branch manager, "upgrading the controls on ring spinning equipment in textile mills is a real sweet spot for us now; our engineers understand the systems and we are well versed on designing the best controls software solutions to have the equipment operate at peak efficiency."
Also read: Textile automation adds to thread-thin profits for more project details and six more photos.
– Georgia H. Whalen is director of marketing for Patti Engineering Inc. Edited by Mark T. Hoske, content manager CFE Media, Control Engineering and Plant Engineering.
Do you have experience and expertise with the topics mentioned in this content? You should consider contributing to our CFE Media editorial team and getting the recognition you and your company deserve. Click here to start this process.