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Expert's Rating
- Free online photo gallery integration
- Easy photo access and organization
- Extensive feature set rivals iPhoto
- Some bugginess
- Editing tools could use improvement
Our Verdict
When it comes to organizing, editing, and sharing photos, most Mac users know iPhoto. But what happens when you don't feel like plunking down $79 for the latest iLife iteration just to get the snazzy Faces and Places features? Google offers an answer in Picasa, a free photo editing and sharing app that rivals iPhoto '09 ( ), excelling in areas, though it's not without a few shortcomings.
Picasa has only been available for the Mac since January 2009, but it's popular in the Windows world. If you've used iPhoto, Picasa's feature set will be familiar; you can organize and edit photos, add effects, create albums and slideshows, detect faces, tag places, share pics, print photos and contact sheets, and play movies. But Picasa comes with some nice surprises; you can batch edit photos, create collages, sync your Google contacts, set a pic as your desktop, make movies, sync content with Picasa Web Albums, add text to photos, post photos to Blogger, and upload movies to YouTube.
Easy access and organization
Unlike iPhoto, which imports and stores photos in a single iPhoto Library file, making them difficult to access (unless you set iPhoto to not import images), Picasa scans your Mac for images and movies and displays what it finds in its iPhoto-like-but-less-elegant interface, which possesses some scrolling (but designed that way) quirks. Your photos remain in their original locations for easy access. You can tell Picasa which folders to look through (or avoid) and watch, what types of files to find, and even have it search external drives, DVDs, and network servers. You can also import photos from a camera, media card, your iPhone, or other device; upload the pics to Picasa Web Albums; and share them with your Google contacts all at the same time.
Picasa displays all folders that contain images in the Folders section in the left column, organized according to your existing folder array and year; all images contained within a selection appear in the main pane on the right. Like iPhoto, you can double-click any thumbnail to get a bigger view. Unlike iPhoto, you can drag and drop thumbnails within any folder—or to a different folder—to rearrange at whim. Any organizational changes you make affect your actual files, so if you move a photo from one folder to another in Picasa, it moves the corresponding file on your Mac accordingly, and vice-versa.
For better organization, you can create Albums, which appear in the eponymously named section above the Folders at the top of the left column. Albums work kind of like iTunes playlists, letting you group together photos any way you want without moving the actual photos. It's a good way to organize your favorites.
In the Picasa world, People and Places stand in for iPhoto's Faces and Places features. People works a bit differently than Faces, as it automatically starts detecting "people" from the photos it finds, placing them in an "Unnamed" album in the People section, which is sandwiched between the Albums and Folders sections in the left column. It does this a little too well, detecting strangers in a crowd, statues, and other random items, which I ignored. Once you name a person, Picasa creates a new album for that person and adds photos it thinks includes him or her (it can also sync people with your Google contacts). It does a decent job, but it's not perfect (neither is iPhoto), but you can simply drag and drop the pics it misses.
With Places, you get the power of Google maps working for you, letting you geotag photos with the location in which it was taken. It works similarly to iPhoto—select a photo and type an address, city, or landmark to tag its location on Google maps. Or drag a thumbnail directly onto the map. I did experience some weirdness where Picasa couldn't find any location I entered (but iPhoto still could), but this happened only a few times.
Fixing the funk
Picasa includes basic editing tools that make it easy to improve images, and it does this mostly well. The usual accoutrements are here, including tools to fix color, exposure, and contrast, plus tools to retouch (a bit buggy), remove red eye, crop, straighten, and sharpen images. You can also add text (nice!) and effects. And in true Google spirit, there's an I'm Feeling Lucky one-click photo fixer, which did a good job of making less-than-stellar snaps look presentable.
All edits are automatically saved within Picasa—not on your actual photos. When you're ready to commit, you can either save (which moves your original to a hidden folder) or export (which keeps the original in its same location and lets you control quality, size, and watermarking) your pic as a JPEG.
Unfortunately, I had no luck fixing high contrast photos. Picasa provides three sliders to adjust exposure, but using them is a one-way street. You can increase the Fill Light, brighten Highlights, and darken Shadows, but can't go the other way. When I exposed details in the shadows, I overexposed highlights. When I toned down bright spots, I shrouded my subjects in darkness. A proper color corrector is also needed, as Auto Color and the Natural Color Picker (kind of a white balance fixer) don't always work suitably.
The wow factor
There are several things that make Picasa stand out. I love the Collage feature, which automatically arranged my photos into a designed or messy layout, which I could then fine-tune. Movie Maker lets you make basic movies (including time lapse) and slideshows. While it doesn't provide nifty prefab themes or Charlie Brown music to create slick productions (and it exhibited some bugginess when moving photos around the timeline), it does the job well, and the caption feature is especially useful.
For photo sharing, Picasa integrates with Google's own Picasa Web Albums, which gives you 1GB of free Web space, unlike paying $99 a year to integrate iPhoto with MobileMe. Once you sign up for a free account (you'll need a Google account), you can upload photos, slideshows, and movies to your Picasa Web Albums site. Even better, you can sync Albums and Folders with your site to automatically keep your online and offline collections in sync anytime you edit a photo, add images, or delete them. Your visitors can view your latest adventures, play slideshows, leave comments, make collages and movies of your photos, and order prints. Sure, Picasa Web Albums doesn't have the eye candy of MobileMe, but I don't really miss that.
Macworld's buying advice
If you use an older version of iPhoto but want the newer features, switching to Picasa is a no-brainer. If you use Photoshop or another image editor, Picasa makes a great photo-management companion. It's free, so why not give it a go?
[Kris Fong is a freelance writer.]


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Scott Henderson Uses Variax to Record with Jazz Fusion Supergroup
At first it might seem strange that one of the most innovative and influential jazz fusion guitarists of our time is actually a blues player—but there's more to Scott Henderson than meets the ear. From his work as founding member of Tribal Tech to collaborations with Jean-Luc Ponty, Chick Corea, Joe Zawinul and others, Henderson has developed a unique style that combines the progressiveness of jazz fusion with the soul of the blues.
Over the years, Henderson has garnered countless accolades from Guitar Player, Guitar World and other publications while developing a dedicated worldwide following. For his latest project, he teamed up with fellow veteran musicians Jeff Berlin (bass) and Dennis Chambers (drums) to form supergroup HBC—and took to the studio with Variax in hand.
In the Studio with HBC
At first, HBC focused exclusively on performing. "Live gigs were definitely the priority," explains Henderson. "We did three tours before ever deciding to enter the studio. When we finally did, I thought it would be cool to cover tunes by keyboard players like Joe Zawinul and Herbie Hancock—but without a keyboardist. It was challenging to make the songs sound as big and textural as the original recordings without the help of synths and keyboards."
It turns out that HBC's experience as a performance-focused group spilled over into the studio. "We recorded the record in one day," relates Henderson. "For us it was just like playing another gig. I took the tracks home and spent about a week on each of the tunes that needed the most layering. It took a while to find the right guitar tones for the parts, especially when trying to come as close as possible to the keyboard sounds. I used lots and lots of pedals.
Variax—Just What the Tone Doctor Ordered
HBC's self-titled debut album features a wide range of guitar sounds, from the high-gain blues vibe on "Wayward Son of Devil Boy" to the funky clean tones on "Actual Proof." When recording the Wayne Shorter classic "Footprints," Henderson wanted to approach the track as a traditional jazz tune—problem is, he doesn't own a traditional jazz guitar.
"Instead of borrowing an archtop—which I've never really enjoyed playing—I decided to use my Variax," he relates. "The Jazzbox model provided great tone, and the guitar was very easy to play. That tone made me play much differently than usual, so the song sounds completely different from the others, and I got to be a traditional jazz guitarist for one tune. I received some nice compliments from my friends who play hollowbody jazz guitars—they were quite surprised it was a Variax."
The Road Ahead
So what's next for a guitarist who's spent the better part of four decades on the forefront of the fusion scene? "Tribal Tech is touring Asia in March, and hopefully Europe in the summer, and then I'll be touring with my trio right after that," explains Henderson. "I'll also be doing a recording project with Alan Hertz on drums and Travis Carlton on bass. My number one priority is to finish writing songs for that new album and get into the studio."
For more info, visit http://www.scotthenderson.net

subset: commoncrawl


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Republicans: the Charlie Browns of politics
NRO has little daily polls. Today's asked if House Republicans are blowing in on the fiscal cliff. The voting divide as of now is pretty close:
I voted yes, but not because I was thinking about the substantive issues (taxes increases, spending cuts, etc.). Instead, my "yes" vote resulted because I think the House Republicans blew it on a much more fundamental level: Budget talks should have been done in public.
Having John Boehner sneak into smoke-filled rooms with Obama (both, after all, do smoke), had two terrible consequences. First, it made Republicans look weak because, every time Obama made a ridiculous offer, Boehner came back with a counter offer. Second, and this is the important one, Boehner utterly deprived Republicans of the chance to make their fiscal arguments out loud, directly to the American public. Worse, by giving Obama the shelter of closed doors, Boehner protected him and his fellow Demos from having to defend a demand for more money without any significant spending cuts.
As it is, Republicans are now stuck with headlines that make it look as if they're unwilling to tax bazillionaires, even though the principle driving their refusal to vote for Plan B revolves around Obama's unwillingness to cut spending.
When will Republicans ever learn that Democrats don't play fair, whether in back-room negotiations or on the front pages of the American media? Honestly, if Democrats are bad because they're dishonest and manipulative, Republicans are proving that they're worse, because they're too dumb to live.


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PHOENIX (AP) — Clayton Kershaw isn't sure why he's off to a rough start in spring training, but he's not happy about it.
"Not fun to deal with," the Los Angeles Dodgers ace said, looking glum in the clubhouse Monday after his outing against the Athletics.
Kershaw allowed five runs on two hits and three walks during Oakland's 7-3 victory. He was unable to get an out in the third inning.
The two-time NL Cy Young Award winner gave up three runs and five hits in two innings last Wednesday in his first start of the spring. He looked strong in his first two innings Monday, retiring the A's in order, but opened the bottom of the third with back-to-back walks to Daric Barton and Derek Norris.
Sam Fuld and Nick Punto had run-scoring hits, with another walk in between, and Kershaw's day was done. He struck out two.
The A's scored all seven runs in the inning and sent 12 batters to the plate.
Asked if he is concerned, Kershaw said there is always concern for him when he struggles. The left-hander signed a $215 million, seven-year contract in the offseason, the richest ever for a pitcher.
"Physically, feel great. I don't have any excuses," he said. "Searching for answers right now. I know it's spring training and it doesn't matter, but it matters to me. So I've got to figure it out."
Dee Gordon drove in the Dodgers' first two runs with a triple in the second off starter A.J. Griffin. Andre Ethier added two hits and an RBI.
Los Angeles committed four errors and walked nine.
"It was one of those games you like to forget," manager Don Mattingly said. "It tells you that we're not ready, so we've got to keep on working. Just tells us we're not there yet."
Dodgers: Kershaw was relatively short with the media after his outing and clearly is unhappy with how his spring has gone so far. He said even his bullpen sessions haven't been up to his standard.
"I don't believe you come in to get ready. You're supposed to be ready every time you pitch," he said. "Hopefully I'll figure it out here pretty quick."
Athletics: Griffin gave up two runs and four hits in two innings, striking out two.
"First time out, I thought he threw the ball well. I thought his breaking stuff was really good," A's manager Bob Melvin said.
Dodgers right-hander Zack Greinke won't pitch in the team's season-opening series against the Arizona Diamondbacks in Australia, Mattingly said. Greinke's schedule has been thrown off by a calf injury and he won't be ready to throw the planned 90 pitches in a game by March 22, when the Dodgers open a two-game series Down Under.
Right-hander Ross Stripling, a top prospect, left the Dodgers to return to Los Angeles for an MRI on his right elbow. He has thrown two innings in spring training games but might need major surgery for ligament damage.
Gordon is the leading contender to open the season at second base for Los Angeles should the club decide untested Alex Guerrero is not ready. Gordon helped his cause with a two-run triple in the second inning. A shortstop most of his career, the 25-year-old Gordon has long been known for his speed more than his bat. He hit .234 in 38 major league games last season and .228 in 87 games in 2012.
A's center fielder Billy Burns, a prospect acquired in an offseason trade with Washington, drew a walk, scored a run, singled and stole a base as he pushes for a roster spot. He has five stolen bases in spring training.
Punto, a key reserve and fill-in starter for the Dodgers last season, stung his former club with a two-run single off Kershaw. Punto played third base, shortstop and second base for Los Angeles last season and started at second for Oakland on Monday.
"We got him for a reason and he's a great fit here," Melvin said.
The Dodgers send reliever Brian Wilson to the mound to start against Seattle on Tuesday. Wilson takes the place of Greinke. Left-hander Hyun-Jin Ryu makes his second spring training start Wednesday against Cincinnati.
The A's have split-squad games Tuesday against Milwaukee and the Chicago Cubs, with right-hander Dan Straily going against the Brewers, and left-hander Tommy Milone facing the Cubs.


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Google Glass Reasons Why Google Glass Is Worth the Wait
Google Glass – Reasons Why Google Glass Is Worth the Wait
Spectacles and eyeglasses also have their own share of story when talking about innovation and technology. In fact, it's no ordinary innovation, it's something from Google. Google Glasses is the new product developed by the biggest search engine. It appears like the typical eyeglasses, only in a sleeker built. By late 2013, this item will scatter in the market, but what many people ask now is "is it really worth the buy?"
Prior to its release date, developers already publicized the price we can expect, a whopping $1,500. Now that's expensive for just a pair of glasses. Well it also has unique features that ordinary glasses don't have that need to be considered. Here's some of it.
Design and outer image
As mentioned, Google Glass has a sleek design fit for every character. Its battery, which happens to be the most important part of the glass, is located at the rightmost part of the glass, almost touching the ears. A small and thin tube-like part is also at the right part. Inside it is where the CPU, micro speakers and microphone are placed. At the front part of this tube, which ends at the middle half of the glasses, the camera and prism are built. Glass also has an adjustable nose pads for a more comfortable fit. This item may look fragile, but its makers made sure that it will survive even the toughest hands.
Special features
The high definition display of Glass is equal to a 25-inch HD screen from about 8 feet away. It has 5 MP for photos and 720 MP for videos. Both photos and videos can be taken from the small, almost invisible, built in camera. This gadget also has a bone conduction transducer for better audio. It allows you to connect to the Internet with its 802.11b/g wifi and Bluetooth feature.
Compatibility and more
It just looks small, but Google Glass has a sizable storage of 12 GB, and a total of 16 GB when synced with Google cloud storage. When talking about battery life, you can almost say this device is much like a mobile. It allows you to enjoy one full day of use without worrying about charging. However, other features like video recording and Hangouts may consume more battery life. Just bring its Micro USB cable and charger to be sure.
As for the compatibility, Google Glass can work with any bluetooth-compatible mobile phone. The MyGlass companion app necessitates an Ice Cream Sandwich Android 4.0.3, and this app enables SMS sending and GPS. Now, what more can you ask for?
Purchasing a useful gadget like this should really be considered. Where else can you find a device that allows you to take pictures and videos, hands-free? Glass is also capable of answering just any questions, with the help of Google, of course; not to mention translating into different languages. Lastly, Google Glass is voice-operated, which means you don't have to put your groceries down just to take a photo of a Primadonna shoes stacked on the store's racks.


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Lyrics Depot is your source of lyrics to Power by Ice-T. Please check back for more Ice-T lyrics.
Power Lyrics
Artist: Ice-T
Album: Power
I'm livin' large as possible posse unstoppable
Style topical vividly optical
Listen you'll see'em sometimes I'll be'em
Cops critics and punks necer ever wanta see me in POWER
Well that's too bad Apocalypse Now I'm back and I'm mad
We're comin' you're runnin' cold and cunning
Ice T on the mic TopGunning
After your neck checkin' respect makin' you sweat
Rhyme Syndicate boy in effect
The rap motivator teacher talker night rhyme stalker
Words thrillin',so real they're chillin',the hit author
Gettin' louder than a shot gun,you don't want none
RHYME PAYS was the name of the album
But that was number one,this is the number two
The posse grew,we're gonna break through
Somebody line up the suckers who refuse to recognize the truth
Tie up the punks who refuse to understand the youth
My posse's growin' and it's gettin' larger every day
Come on,come on,come on,toys,let's play
Circle the calendar,perpetrator doomsday
ICE T fool man of my own full grown
I cause havoc when I speak upon the microphone
I'm outspoken,no jokin',get in my face your jaw will get broken
Layin' it,sayin' it,then you're playing it
Lyrics so heavy that you might try weighin' it
Hated by many but I hate'em back
Loved by troopers who know where it's at
You might like me,might think I'm wack
But don't step to me 'cause the boy stays strapped
I'm taking no shorts,hatin' the courts,hatin' the judges
Punk DA's with their personal grudges
I hate the clubs that think with their butts
No hats,no jeans,no sneakers,no what?
No beepers,no gold? Yo kiss my ass
We'll wait and see who gets the last laugh
We'll have the power
Power (x3)
Power it starts with P like pussy
She knows she's got it,she doesn't worry,does she?
Spendin' your cash,leavin' you in the trash
While your little head's thinkin',they're gone in a dash
They got it,know it,that's why they show it
The power of sex,if man could overthrow it
He'd be king in a day,no way.We get rich,hard,give it away
We're weak and as we speak,the girls are hawkin'
Sizin' me up straight out as I'm talkin'
But you gotta have control if you want the gold
I don't wanta be alone like Stallone
So I keep my mind thinkin' 'bout the green
And stop dwellin' on the in-between
I got the power
I'm on a mission mackin' hard as a hammer
Take my picture,I might take your camera
My posse might move,and they move fast
A fool's move could be a punk's last
Ain't no criminal although I used to be
Ain't no new jack rappin' ain't new to me
I been makin' records on wax since 1982
Now it's 1988 finally I'm coming through
That adds up to six years of makin' ok jams,but now I'm mad
Here comes the body slam
Turnin' out concerts,house'n the industry
Lovin' all the fly girls screamin' for ICE T
Rollin' with the Syndicate my unstoppable battalion
38 Solid gold my medalion
Gainin' velocity,momentum and energy
ICE Capital T
I got the power
So you say that I'm a fake think,you really must be a fool
I been to jail more times than you have probably been in school
Shot at,shot back,hit,and seen my buddies killed
That's the foundation upon the raps of ICE-T are built
I say what I think,the system does stink
Money you walk,you short,you're writin' from the klink
Come on,what's up,you know the laws are full of bull
Prey on the lame,release those with pull
Power!I know you wanta try it
Well check out money can buy it
Control and mold the world to do your wishin'
The knowledge of power is mine,so just listen
Money controls the world and that's it
And once you got it,then you can talk shit
You have the power
You have the power
I got the power(fade out)
Ice-T Lyrics
Ice-T Power Lyrics
More Ice-T Music Lyrics:
Ice-T - CJ Mac (Interlude) (featuring CJ Mac) Lyrics
Ice-T - Don't Hate The Playa Lyrics
Ice-T - Eye Of The Storm (featuring Buckshot Shorty) Lyrics
Ice-T - It's Goin' Down Lyrics
Ice-T - Sex Lyrics
Ice-T - Shit Hit The Fan (featuring Shawnie Shawn) Lyrics
Ice-T - Shut Up Be Happy Lyrics
Ice-T - The Girl Tried To Kill Me Lyrics


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Advanced Search
Open source learning management system Moodle is gaining additional Web conferencing capabilities thanks to a new open source plugin from Remote-Learner that integrates the LMS with the Adobe Acrobat Connect Pro service.
Moodle is generally recognized as the most popular learning management system available, with nearly 1.2 million teachers using it and more than 33.5 million users participating in more than 3.3 million courses at more than 46,000 validated sites worldwide. Moodle supports both small and large deployments (with several sites well beyond 100,000 users) and includes course management tools, various Web 2.0 technologies, online assessments, and other features common to learning management systems.
Adobe's Connect is a family of online conferencing, whiteboarding, and collaboration tools available on a subscription basis (along with a free version called ConnectNow). Connect Pro integrates a number of electronic learning features, including content authoring and management, curriculum management and tracking, and live virtual classrooms.
The new plugin "allows users to create Adobe Connect Pro meetings by adding an activity instance and providing the meeting name, URL (optional), start time, end time, meeting template and a public or private meeting setting," according to the documentation provided by Remote-Learner.
Remote-Learner has donated the source code for the plugin under the GNU General Public License (GPL). The company is also offering "enterprise support" for the plugin.
The Acrobat Connect Pro plugin for Moodle is available now at no cost on Moodle's download site here.
About the Author
David Nagel is editorial director of 1105 Media's Education Technology Group and editor-in-chief of THE Journal and STEAM Universe. A 29-year publishing veteran, Nagel has led or contributed to dozens of technology, art and business publications.
He can be reached at [email protected]. You can also connect with him on LinkedIn at or follow him on Twitter at @THEDavidNagel (K-12) or @CampusTechDave (higher education).
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Did you know that Google Workspace for Education offers four different licenses, all bursting with tools and features to elevate teaching and learning? Now the question is, "which one best suits teachers, admins, and students at my school?"
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25mm-electrical-tee switzerland
Home » 25mm-electrical-tee switzerland
Our 25mm-electrical-tee switzerland all through China regions as well as other nations. They may be selling to Southeast Asia, Japan, Korea, the Middle East and Europe. We use new technologies to make 25mm-electrical-tee switzerland goods to achieve high accuracy, high intelligence and high speed control. Considering the fact that the enterprise was founded, under the leadership of Chairman, 25mm-electrical-tee switzerland has has been extensively praised in China industries. We adhere to customer initially, quality initially, continuous improvement, mutual advantage and win-win principles. When cooperation using the client, we supply consumers with all the highest excellent of service. Established superior enterprise relations with the China consumer in the market, we've established personal brand and reputation. In the very same time, wholeheartedly welcome new and old customers to our organization to stop by and negotiate business enterprise. Sincerely hope to cooperate with good friends from all circles to create a 25mm-electrical-tee switzerland industry leader.


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Waiting on Wednesday startades av Jill från Breaking the spine. Det är till för att visa upp kommande böcker man längtar lite extra till.
Three Dark Crowns av Kendra Blake
20:e september 2016
Every generation on the island of Fennbirn, a set of triplets is born: three queens, all equal heirs to the crown and each possessor of a coveted magic. Mirabella is a fierce elemental, able to spark hungry flames or vicious storms at the snap of her fingers. Katharine is a poisoner, one who can ingest the deadliest poisons without so much as a stomachache. Arsinoe, a naturalist, is said to have the ability to bloom the reddest rose and control the fiercest of lions.
But becoming the Queen Crowned isn't solely a matter of royal birth. Each sister has to fight for it. And it's not just a game of win or lose…it's life or death. The night the sisters turn sixteen, the battle begins. The last queen standing gets the crown.
If only it was that simple. Katharine is unable to tolerate the weakest poison, and Arsinoe, no matter how hard she tries, can't make even a weed grow. The two queens have been shamefully faking their powers, taking care to keep each other, the island, and their powerful sister Mirabella none the wiser. But with alliances being formed, betrayals taking shape, and ruthless revenge haunting the queens' every move, one thing is certain: the last queen standing might not be the strongest…but she may be the darkest.
Kommentarer: Jag har inte läst någon av Kendra Blakes böcker tidigare men den här låter bara för bra för att låta bli!


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Press release
7 October 2002
The Nobel Assembly at Karolinska Institutet has today decided to award
The Nobel Prize in Physiology or Medicine for 2002 jointly to
Sydney Brenner, H. Robert Horvitz and John E. Sulston
for their discoveries concerning "genetic regulation of organ development and programmed cell death"
The human body consists of hundreds of cell types, all originating from the fertilized egg. During the embryonic and foetal periods, the number of cells increase dramatically. The cells mature and become specialized to form the various tissues and organs of the body. Large numbers of cells are formed also in the adult body. In parallel with this generation of new cells, cell death is a normal process, both in the foetus and adult, to maintain the appropriate number of cells in the tissues. This delicate, controlled elimination of cells is called programmed cell death.
This year's Nobel Laureates in Physiology or Medicine have made seminal discoveries concerning the genetic regulation of organ development and programmed cell death. By establishing and using the nematode Caenorhabditis elegans as an experimental model system, possibilities were opened to follow cell division and differentiation from the fertilized egg to the adult. The Laureates have identified key genes regulating organ development and programmed cell death and have shown that corresponding genes exist in higher species, including man. The discoveries are important for medical research and have shed new light on the pathogenesis of many diseases.
Sydney Brenner (b 1927), Berkeley, CA, USA, established C. elegans as a novel experimental model organism. This provided a unique opportunity to link genetic analysis to cell division, differentiation and organ development – and to follow these processes under the microscope. Brenner's discoveries, carried out in Cambridge, UK, laid the foundation for this year's Prize.
John Sulston (b 1942), Cambridge, England, mapped a cell lineage where every cell division and differentiation could be followed in the development of a tissue in C. elegans. He showed that specific cells undergo programmed cell death as an integral part of the normal differentiation process, and he identified the first mutation of a gene participating in the cell death process.
Robert Horvitz (b 1947), Cambridge, MA, USA, has discovered and characterized key genes controlling cell death in C. elegans. He has shown how these genes interact with each other in the cell death process and that corresponding genes exist in humans.
Cell lineage – from egg to adult
All cells in our body are descendents from the fertilized egg cell. Their relationship can be referred to as a cellular pedigree or cell lineage. Cells differentiate and specialize to form various tissues and organs, for example muscle, blood, heart and the nervous system. The human body consists of several hundreds of cell types, and the cooperation between specialized cells makes the body function as an integrated unit. To maintain the appropriate number of cells in the tissues, a fine-tuned balance between cell division and cell death is required. Cells have to differentiate in a correct manner and at the right time during development in order to generate the correct cell type.
It is of considerable biological and medical importance to understand how these complicated processes are controlled. In unicellular model organisms, e.g. bacteria and yeast, organ development and the interplay between different cells cannot be studied. Mammals, on the other hand, are too complex for these basic studies, as they are composed of an enormous number of cells. The nematode C. elegans, being multi-cellular, yet relatively simple, was therefore chosen as the most appropriate model system, which has then led to characterization of these processes also in humans.
Programmed cell death
Normal life requires cell division to generate new cells but also the presence of cell death, so that a balance is maintained in our organs. In an adult human being, more than a thousand billion cells are created every day. At the same time, an equal number of cells die through a controlled "suicide process", referred to as programmed cell death.
Developmental biologists first described programmed cell death. They noted that cell death was necessary for embryonic development, for example when tadpoles undergo metamorphosis to become adult frogs. In the human foetus, the interdigital mesoderm initially formed between fingers and toes is removed by programmed cell death. The vast excess of neuronal cells present during the early stages of brain development is also eliminated by the same mechanism.
The seminal breakthrough in our understanding of programmed cell death was made by this year's Nobel Laureates. They discovered that specific genes control the cellular death program in the nematode C. elegans. Detailed studies in this simple model organism demonstrated that 131 of totally 1090 cells die reproducibly during development, and that this natural cell death is controlled by a unique set of genes.
The model organism C. elegans
Sydney Brenner realized, in the early 1960s, that fundamental questions regarding cell differentiation and organ development were hard to tackle in higher animals. Therefore, a genetically amenable and multicellular model organism simpler than mammals, was required. The ideal solution proved to be the nematode Caenorhabditis elegans. This worm, approximately 1 mm long, has a short generation time and is transparent, which made it possible to follow cell division directly under the microscope.
Brenner provided the basis in a publication from 1974, in which he broke new ground by demonstrating that specific gene mutations could be induced in the genome of C. elegans by the chemical compound EMS (ethyl methane sulphonate). Different mutations could be linked to specific genes and to specific effects on organ development. This combination of genetic analysis and visualization of cell divisions observed under the microscope initiated the discoveries that are awarded by this year's Nobel Prize.
Mapping the cell lineage
John Sulston extended Brenner's work with C. elegans and developed techniques to study all cell divisions in the nematode, from the fertilized egg to the 959 cells in the adult organism. In a publication from 1976, Sulston described the cell lineage for a part of the developing nervous system. He showed that the cell lineage is invariant, i.e. every nematode underwent exactly the same program of cell division and differentiation.
As a result of these findings Sulston made the seminal discovery that specific cells in the cell lineage always die through programmed cell death and that this could be monitored in the living organism. He described the visible steps in the cellular death process and demonstrated the first mutations of genes participating in programmed cell death, including the nuc-1 gene. Sulston also showed that the protein encoded by the nuc-1 gene is required for degradation of the DNA of the dead cell.
Identification of "death genes"
Robert Horvitz continued Brenner's and Sulston's work on the genetics and cell lineage of C. elegans. In a series of elegant experiments that started during the 1970s, Horvitz used C. elegans to investigate whether there was a genetic program controlling cell death. In a pioneering publication from 1986, he identified the first two bona fide "death genes", ced-3 and ced-4. He showed that functional ced-3 and ced-4 genes were a prerequisite for cell death to be executed.
Later, Horvitz showed that another gene, ced-9, protects against cell death by interacting with ced-4 and ced-3. He also identified a number of genes that direct how the dead cell is eliminated. Horvitz showed that the human genome contains a ced-3-like gene. We now know that most genes that are involved in controlling cell death in C. elegans, have counterparts in humans.
Of importance for many research disciplines
The development of C. elegans as a novel experimental model system, the characterization of its invariant cell lineage, and the possibility to link this to genetic analysis have proven valuable for many research disciplines. For example, this is true for developmental biology and for analysis of the functions of various signaling pathways in a multicellular organism. The characterization of genes controlling programmed cell death in C. elegans soon made it possible to identify related genes with similar functions in humans. It is now clear that one of the signaling pathways in humans leading to cell death is evolutionarily well conserved. In this pathway ced-3-, ced-4- and ced-9-like molecules participate. Understanding perturbations in this and other signaling pathways controlling cell death are of prime importance for medicine.
Disease and programmed cell death
Knowledge of programmed cell death has helped us to understand the mechanisms by which some viruses and bacteria invade our cells. We also know that in AIDS, neurodegenerative diseases, stroke and myocardial infarction, cells are lost as a result of excessive cell death. Other diseases, like autoimmune conditions and cancer, are characterized by a reduction in cell death, leading to the survival of cells normally destined to die.
Research on programmed cell death is intense, including in the field of cancer. Many treatment strategies are based on stimulation of the cellular "suicide program". This is, for the future, a most interesting and challenging task to further explore in order to reach a more refined manner to induce cell death in cancer cells.
|Using the nematode C. elegans this year's Nobel Laureates have demonstrated how organ development and programmed cell death are genetically regulated. They have identified key genes regulating programmed cell death and demonstrated that corresponding genes exist also in higher animals, including man. The figure schematically illustrates the cell lineage (top left) and the programmed cell death (below) in C. elegans. The fertilized egg cell undergoes a series of cell divisions leading to cell differentiation and cell specialization, eventually producing the adult organism (top right). In C. elegans, all cell divisions and differentiations are invariant, i.e. identical from individual to individual, which made it possible to construct a cell lineage for all cell divisions. During development, 1090 cells are generated, but precisely 131 of these cells are eliminated by programmed cell death. This results in an adult nematode (the hermaphrodite), composed of 959 somatic cells.
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