I had a primo vantage point for this year’s Cell Slam, ably covered by our intrepid reporter Ewen Callaway here. Cell Slam is a free form poetry and performance art competition for life science geeks. There are few rules to follow — basically three minutes, a mic and no Powerpoint — and the event drew quite a crowd. I was involved (as an absurdly non-illustrious member of an otherwise illustrious panel of judges, including NYTimes’ Natalie Angier, WaPo’s Rick Weiss, NPR’s Joe Palca, Science’s Jennifer Couzin, and NIH director Elias Zerhouni), so I can’t really cover the event in an official unbiased way. Nevertheless, I thought I’d share just a bit of what went on behind the scenes.

For a competition in which the participants were greatly outnumbered by the judges and in which the prizes would be meagre and unevenly distributed, Randy Hampton the evening’s MC, made the obvious comparison to peer review at the NIH. Hampton, a UCSD researcher and former standup comic took lighthearted potshots at “Dr. Z” with little fear of having his funding pulled. “I lost my funding after this last year,” he said, and so had nothing to lose.

Zerhouni did indeed run things like an NIH study section in the hush, hush, closed, door judging section that immediately followed the acts. “I don’t know if you’ve ever heard of something called ‘triage’” he said, pausing for laughter, “But I think we can effectively triage one of the performances right away.” The unlucky performer, Catholic University’s Roland Nardone, used his three minutes, and then another two and half to make an impassioned plea for more diligence in identifying contamination in cell lines. An important topic, to be sure. Nardone was DQ’d because a lot of judges thought he missed the point that Cell Slam is supposed to be fun. Maybe he would have done better with a rap: “Check your cells before you wreck your cells” comes to mind. For what it’s worth, I applaud him for taking the chance to reach out to a packed room, mostly of young researchers, with a message they might have missed had they not been paying attention in, say 1968. Nevertheless, he still got the lowest score I gave last night (nine thumbs up). Sorry, in my book, time limits are sacrosanct. Better luck next year!

I stopped in for a press briefing today on the origins of life. It’s one of the few talks I’ve seen at the American Society for Cell Biology meeting that had no cells in it whatsoever. One of the great questions of our time has been how complex molecules began to aggregate in meaningful ways and pitch forward into something that could be recognized as life. The Stanley Miller experiments helped establish the idea that some primordial soup gave rise to complex interacting organisms. But folks have recongized that in a vast sea – or even a small puddle, interactions wouldn’t be energetically favourable or concentrated enough to get anywhere. So, folks have proposed that early macromolecules were affixed to clay particles or bubbled through porous rocks that would compartmentalize interactions and provide substrate for advancing enzymatic reactions. Helen Hansma, who is a rotating program director for the National Science Foundation, has another idea and she was at ASCB presenting a poster on it.

While looking at a chunk of mica under a microscope one day, she noticed bits of organic gunk growing in between it’s flaky layers and thought, “Hey that would be a neat place for an organism to thrive.” Having spent years tuning atomic force microscopes to observe biomolecules on mica sheets, she knew how amenable the structure of mica is to interaction. Another clue had her hooked on the hypothesis. No one, she says, has ever adequately explained how cells first obtained potassium. All cells tend to keep potassium in and sodium out despite the vast majority of ions that would have existed in primordial seas would have been sodium. But when the nanometer thick sheets of mica separate they do so by breaking covalent bonds and sometimes releasing free potassium. In her vision of this prebiotic model, mechanical forces of water infiltrating mica sheets could produce energy to power little bioreactors for molecules that stick to the surfaces between. RNA, she says, seems somewhat amenable to binding the surfaces within. So Hansma has added to the soup paradigm, a sandwich!

Since at least June, NIH peer review, the process by which the bulk of U.S. federal funding for biomedical research is meted out, has been under an intense review process by two groups working in parallel. The reason, funding increases haven’t kept pace with inflation and the biomedical research community is feeling the pinch. With slim funding prospects the approval rate for funding proposals has dropped from a historic 25% to somewhere around 10%. At ASCB Keith Yamamoto of UCSF, Mary Beckerle of the University of Utah, and Katherine Wilson of Johns Hopkins University talked about some of the radical ideas that have been floating around to totally revamp the process by which investigators compete for funding. While Yamamoto emphasized that these were not anything like final recommendations that they would be making, he wanted to offer a glimpse of the ideas they’ve been batting around and invite more feedback from the research community, a process that has officially close, but that these three at least say they are still open to. Incidentally Elias Zerhouni, the head at the NIH intends to implement changes to the review process in the first quarter of 2008. Read on for some specifics.

Continue reading →

There was an interesting session on epigenetics at ASCB this evening. Epigenetics is a term with a slippery definition, but it is basically the study of changes to the way the genome is managed that are heritable but generally don’t affect the genome sequence itself. A lot of research in this area looks at the histone proteins around which DNA wraps, and the specific chemical modifications that can be made to them that in turn appear to affect gene expression in a persistent way.

One talk by David Katz, a postdoc at Emory focused on specific modifcations made to histones in the germline of an organism – that is the cells that become eggs or sperm and lead to future offspring. Katz works with Caenorhabditis elegans, a roundworm. He looked at methylation on Histone H3. Apparently in developing C. elegans practically every cell shows a good deal of methylation of H3 at the fourth lysine residue (K4). H3K4 is not methylated in the germ cells. Without methylation at this specific spot, the genes that wrap around the histones are more likely to be silenced, which is normal for germ cells. They won’t be needed for a while, so why express them. So, Katz looked to see what happened if he disrupted a so-called demethylase gene that removes these methyl marks. It appeared to have absolutely no effect in the first generation, but after following more than 20 generations of the mutant worms, he noticed that their fertility was dropping off to the point that by the 26th generation (if I saw the graph correctly) the worms are practically sterile. Their oogenesis was highly abnormal. If these results are easily confirmed it is another powerful statement for the effects epigenetic changes might have on the germline over a number of generations, a startling testament to the sometimes slow and subtle effects of epigenetics on reproductive health.

A talk later in the evening focused on histone variants associated with DNA damage and how they co-localize with other DNA damage associated proteins. Unfortunately, however, her powerpoint presentation failed to show any red coloured figures. I’ve never seen anyone’s presentation get so derailed by a technical difficulty. Green spots that revealed the location of one DNA repair protein showed up fine, but the red spots that were supposed to show us where the histones appeared in the cell simply weren’t there. It was impossible to understand what she was trying to show. Eventually she got the presentation working. An Apple computer apparently got her back on track, apparently. But during the minor meltdown, someone behind me commented to a colleague, “Now you know what it’s like to be red/green colour blind.” It is amazing to me that so many people present microarray heat maps and cell biological information in red and green with out considering the 7% to 10% of folks (almost all of them male) that can’t distinguish the two.

I talked to Kai Simons today. He’s the fellow who, I think, had some interesting ideas on new approaches to Alzheimer’s disease research last night. He praised the format of the minsymposium on AD that was designed not to present data but to direct approaches and identify future goals in a field that really has stymied researchers for a time. The style allowed for a lot of discussion and argument, and that’s not something that happens a lot in regular talks. Simons had an interesting take on all this calling out the stodgier aspects of the traditional symposium for not engaging in debate. Simons told me he doesn’t even read abstracts anymore. So often the things folks write up are not what they can present, but what they hope they can present by the time the talk comes up.

But here’s some really interesting news. Well, news to me, anyway. Simons is the president of the European Life Science Organization ELSO, a somewhat unique grassroots organization of biologists that contains as many as 40% graduate students. He told me that the efforts of maintaining the organization are no longer feasible and that it would fuse with the much larger European Molecular Biology Organization (EMBO) and eventually disappear. The next ELSO meeting in September in Nice, France is co-sponsored by EMBO in late August and early September. The decision was made in October and announced in EMBO’s most recent newsletter.

OK, I’ve got to admit. I’m a little excited about being a judge at the ASCB 2007 cell slam tomorrow night. For the uninitiated, a cell slam is kind of like a poetry slam — which are geeky enough on their own — but adds the extra geeky element of being all about biology. The basic remit is “three minutes, one microphone, no AV.” For the record and in interest of full disclosure, I’ve participated something akin to this before. My colleague Erika Check Hayden caught the action last year, and it sounds like it was quite a trip.

John Fleischman, an information officer for the meeting who’s been promoting the event, tells me that last year he walked up to find the room they’d reserved for the event filled spilling out into the hallway. It was 180 person occupancy room. He cleverly thought, I’ll just open the room divider and instantly double the space. When he went to draw the wall back, he found that the other room was already filled. “The fire marshal was not happy,” he said.

Apparently selling beer was a major draw. This year the event may even get a spotlight. The organizers didn’t have a budget for it. But apparently ASCB found some money for it. Events that popular can’t go unlit. I’m excited to see the acts, but even more excited to query co-judge Elias Zerhouni on the revamp NIH peer review is getting. More on that later.

I had a chance to ask ASCB president Bruce Alberts what had him excited about this year’s meeting. He directed me to a session (actually two sessions) that take a bit of a departure from the usual format. I went to the working group symposium on the cell biology of Alzheimer’s disease (AD). Rather than present data, we got outlines of future prospects and directions from two established experts in AD research and two cell biologists who have come to study AD from different directions. Audience participation was encouraged, and it made for some good arguments that I daresay seemed the slightest bit productive. I’ll warn you that there’s a bit of alphabet soup coming, but bear with me, there are some neat new ideas here.

The proposition that Amyloid Beta (AB) plaques are a causative entity in Alzhiemer’s disease generated some lively debate. AB plaques are one of several types of proteinaceous clumps that are closely associated with brains affected by AD. They’re made when a protein of unknown purpose called Amyloid Precursor Protein (APP) is cut in two very specific places releasing an AB protein fragment that aggregates in the spaces between neurons and appears associated with said neurons atrophying and wasting away, but there are doubts that the plaques themselves are causing the problems.

There are good reasons to believe that AB-aggregate formation is causative. Several mutations associated with increased risk for the disease appear in APP itself or the proteins that process it. Nevertheless, it’s clear this isn’t the whole story. It may be intermediate building blocks of of the plaques, so called soluble AB aggregates. Or AB formation might be a response to some other pathological factor. A presentation by AD expert Gopal Thinakaran, from the University of Chicago, drew some sharp critiques that AB has really become a ‘lamp post.’ This is a reference to an old joke about a drunk searching for his keys under a streetlight. A policeman comes along and asks, “Did you lose them here?” The drunk replies, “No, but the light’s better here.” AB may not be the best target, but it’s one of the most studied aspects of AD.

Nevertheless, I believe a lot of light came out in this meeting. AD specialist Lennart Mucke of the Gladstone Institute challenged the group with a number of imperatives, but in a more offhand statement he opined how AB clustering around blood vessels is “vastly understudied.” Kai Simons, a self proclaimed AD amateur from Max-Planck-Institute of Molecular Cell Biology and Genetics in Dresden, talked about how his specialty, investigating the dynamics of lipid rafts in cell membranes, could point to new therapeutic targets in minimizing the production of AB fragments. The implication of lipids jives with a well known variant of the ApoE gene known to increase risk for AD. William Balch, of Scripps Research Institute in La Jolla Calif., talked about the program of aging. (We’ve got a neat story on an institute devoted to this kind of research in our current issue.) Apparently interfering with an insulin growth factor receptor protein in C. elegans not only extends life in worms, it reduces the toxicity of aggregating proteins. Surprisingly (or not surprising to some, I suppose), the reduction in toxicity didn’t necessarily mean that the worms faced fewer heavy protein aggregates. He made a plea for more cell biologists to start looking into the problems of AD.

People seemed genuinely excited by the debate and discussion. Hats off to Alberts for the great suggestion. I wonder if the other working group session he suggested (on the nature of cytoplasm) was as lively. If anyone made it, I’d love to hear how it went.

This week, somewhere in the neighbourhood of 7500 biologists descend upon Washington DC for the American Society for Cell Biology. I made it here today just in time to hear a lecture given by Alejandro Sanchez Alvarado, a Howard Hughes Medical Institute Investigator at University of Utah, who’s been using the planarian Schmidtea mediterranea as a model for regeneration. His website has beautiful pictures. Planarians are regenerative heroes — long know for their ability to completely redevelop from pieces as small as 1/279th of the original. And even though they’re strange – they have a mouth that doubles as an anus that Sanchez Alvarado calls a “manus” – they are actually surprisingly complex. Thomas Hunt Morgan studied them and did a great job of characterizing their regenerative abilities, but when genetics came on the scene at the turn of the 20th century, the planarian was left behind in favour of more genetics friendly organisms like Drosophila.

But developments in the past decade have changed that. The 800 Mb genome of planaria has been sequenced, and manipulating genes is possible thanks to RNA interference. His group can shut down any gene they want just by feeding it bacteria engineered to produce short RNA strand specific to that gene. I’ve spoken with Sanchez Alvarado before, and I find his work fascinating. He talked about a number of projects he’s been exploring with the tiny worms, including investigating the properties of so-called neoblasts, a population of stem cells that exists almost everywhere in the organism and appears responsible for its regenerative prowess. A particularly interesting project, however, was a follow up from an 1898 paper written by Morgan. Morgan cut a very thin slice from the middle of a planarian and watched it regenerate. For a piece cut from the middle of the worm, normally the head end (anterior) would regenerate a head and the tail end (posterior) would regenerate a tail. Instead these slices grew into worms with two heads and no tail. Morgan called them ‘janus,’ not to be confused with the worm’s ‘manus.’ And he apparently wrote in the paper: “There is something here that is important to find an explanation for.”

Using RNA interference to tinker with genes known for their roles in setting up anterior/posterior polarity (these are genes from the Wnt pathway, which was discovered in Drosophila), Sanchez Alvarado’s group has recreated the janus worms. When they fed the worms RNA designed to block the production of beta catenin and cut the worms up, pieces from the middle grew two heads. By blocking a gene that is known to work antagonistically with beta catenin, known as APC, the group was able to produce these freakish worms with no heads – just two tails. The videos Sanchez Alvarado showed were great … the two tails battled against one another in a pushmepullyou fashion.

For folks who know their fly genetics this probably isn’t too surprising, but I’m fairly amazed at how well the pathways are conserved and that they work not only in the early development of the organism, but in the maintenance of developed organ structures and their ‘re-development’ in the regenerative program. Also, when silencing a gene very high up in the pathway, the group found they got no phenotype, which suggests that there may be another sequence of genetic events running the pathway in this instance. The E.E. Just lecture is a minority in science award to honour Sanchez Alvarado, a native of Venezuela, for his pioneering work in rejuvenating this classic model for regeneration. What a great first lecture to fall into!

Today, scientists were told that an epic battle is raging – and they must don their armor, head for the trenches and join the fight.

The battleground: America’s schools, churches and airwaves. Yes folks, we’re talking about the fight over evolution. And if you thought yesterday’s news on evolution wasn’t pretty, this is a lot uglier.

Continue reading →

I never would have guessed that a cell biology meeting would be such a carnival of vice: singing, dancing, unnatural sex in hotel rooms…all before noon on a Sunday morning!

Continue reading →