Self-Organizing Metabolism and the Origins of Life

The late Leslie Orgel, a pioneering researcher in pre-biotic evolution, has an interesting essay in the most recent issue of PLoS Biology. A long-running debate in origins-of-life research has been over what came first: genetic material or a self-organizing metabolism.

The self-organizing metabolism theory has been most prominently argued by Stuart Kauffman. Orgel doesn't rebut Kauffman's theoretical work, but he does claim it makes unrealistic assumptions about peptide chemistry, and thus is unlikely to be what happened on earth 4 billion years ago.

Orgel makes some reasonable arguments, but what is really needed is more experimental work to figure out just how plausible this self-organizing metabolism idea really is.

An "Irrational Attachment to The Theory of Evolution"?

In Gail Collins' NY Times column today, she says this:

Huckabee seems to be a nice guy, but conservatives are afraid he’d break up the old evangelical-plutocrat Republican alliance and most liberals are restrained by their irrational attachment to the theory of evolution.

Excuse me? I can't quite tell if Collins is being tongue-in-cheek (I frankly don't read her column enough to get where she's coming from), but it looks like Collins is the rationally challenged one here. What she just said is just as absurd as something like: "most liberals are restrained by their irrational attachment to the theory of quantum mechanics."

For people like myself who prefer to reside in the reality-based community, acceptance of the evidence for evolution is in fact an excellent litmus test for people who want my vote. It's a good indication of how decision-makers value evidence versus pet beliefs. Scientific evidence does not necessarily dictate what the correct government policy should be, but it sure as hell can rule out harebrained ones. I view that as a good thing.

This post isn't an endoresement or a slam against any particular political party or candidate - except of course candidates who have an irrational opposition to very successful, fundamental fields of science. The point is, creation vs. evolution isn't just some freak side issue on the fringes of the culture wars - it cuts to the heart of how people respond to the single most successful approach humans have developed for understanding and influencing the reality-based world.

Real Science vs Intelligent Design

If Intelligent Design advocates are so insistent that most of the human genome is functional, why aren't they doing any research like this? Eric Lander's group at MIT devised a way to test whether the thousands of non-conserved, putative protein-coding genes are likely to be spurious or true protein-producing genes.

From the paper, here is their rationale:

The three most widely used human gene catalogs [Ensembl, RefSeq, and Vega] together contain a total of 24,500 protein-coding genes. It is broadly suspected that a large fraction of these entries is simply spurious ORFs, because they show no evidence of evolutionary conservation. [Recent studies indicate that only 20,000 show evolutionary conservation with dog.] However, there is currently no scientific justification for excluding ORFs simply because they fail to show evolutionary conservation; the alternative hypothesis is that these ORFs are valid human genes that reflect gene innovation in the primate lineage or gene loss in other lineages.

Here is what they test:

The purpose of this article is to test whether the nonconserved human ORFs represent bona fide human protein-coding genes or whether they are simply spurious occurrences in cDNAs.

And here is their conclusion:

Here, we provide strong evidence to show that the vast majority of the nonconserved ORFs are spurious.

This is how you do science. If ID advocates were serious about science, they would be testing similar hypotheses and publishing them.

Nature comments on creationism

Tomorrow's Nature issue has an editorial (subscription only) praising the latest NAS book on evolution/creationism. The editorial goes on to suggest that:

"Between now and the 200th anniversary of Charles Darwin's birth on 12 February 2009, every science academy and society with a stake in the credibility of evolution should summarize evidence for it on their website and take every opportunity to promote it."

They also post a link to paeleontologist Kevin Padian's testimony at the Kitzmiller intelligent design trial - it's worth checking out.

What's The Matter With Texas? Creationism On Its Way Back

Is the State of Texas about to offer Master of Science degrees in creationism? The Institute for Creation Research (ICR), an organization that officially believes the earth sprang into existence less than 10,000 years ago, has applied to offer a state-approved Master's program in science education. Last week, an official advisory committee recommended that the State of Texas approve the ICR's request to offer Master's degrees (read about it here and here). If this request is granted, the ICR has two years in which it can offer state-approved Master's degrees while seeking accreditation for its program from a recognized, outside accreditation organization. Coming on the heels of news that one of the state's science education officials was forced out of her job because she was not "neutral" about standing up for evolution education, this latest event suggests that creationism is about to again become a big issue in the Texas educational system.

It is one thing for a private organization to teach whatever outlandish beliefs it prefers, and for students to attend non-accredited colleges - it's their educational choice, and no big loss to the rest of the educational system. But it's another issue altogether for the state to give its imprimatur to such an organization when intends to train science teachers who will then go out and work such sectarian and unscientific beliefs into public school science classes.

Is it acceptable to accredit a science education program that teaches science students that they can build perpetual motion machines that violate the laws of thermodynamics? That matter is not made up of atoms, and that diseases are caused by 'humours' and not germs? Of course not, and by the same token, it is wrong to give state approval to a Master's program that teaches future science educators that the earth suddenly appeared less than 10,000 years ago, and that today's living species did not descend from a common set of ancestors.

The ICR is free to preach whatever it likes, but it should not be allowed to dress sectarian beliefs up as science and use them to train science teachers who will be hired by the state to teach in public schools. The stuff that institutions like the ICR and the Discovery Institute peddle is not science. Its advocates repeatedly exhibit an extremely poor grasp of the scientific theories they are supposedly critiquing, and in their criticisms they continue to make basic errors about the actual technical content of mainstream science. They love to scour scientific journals and highlight material that they (wrongly) believe undercuts evolution, yet tellingly, they never actually participate in such research themselves. (If Intelligent Design advocate Michael Behe is so convinced that pseudogenes are the product of an intelligent designer and not the accidents of evolution, why isn't he doing any research himself to look for functional pseudogenes?)

The quality of science education in US schools is falling behind that of other industrialized nations, and here we are, taking actions to officially support organizations that are devoting millions of dollars to undercut good science education. Southern states are trying hard to attract scientific talent and biotech dollars to their states, but people who are able to perform top science are generally not very eager to move to a state where their kids are likely to be taught some variant of creationism at school. Texas officials need to show some spine and maintain the integrity of science education in their state.

Intelligent Design's Day in Court on NOVA

Last night the PBS series NOVA featured a two-hour show on the 2005 Dover, PA Intelligent Design trial. If you missed it, go check out clips and some great evolution resources at the show's website. As a creation/evolution junkie, I had previously read all of the trial transcripts, but reading transcripts was no substitute for seeing and hearing the major participants on camera. And while the big players from the Discovery Institute refused to be interviewed, NOVA managed to get just about everyone else on camera, including one of the defense's expert witnesses and the two ex-school board members who started the whole mess. These guys made it abundantly clear in their own words that intelligent design in Dover was not about improving science education - it was all about pushing creationism among the students.

The show was generally well done, in spite of some badly acted (not to mention tacky) courtroom reenactments. There were excellently illustrated segments discussing science's success in some areas where intelligent design advocates have claimed there are problems, such as transitional fossils and the bacterial flagellum. I was happy to see that the show also spent time discussing how the development of genetics, and much later, genomics, were big tests of evolution. Darwin's ideas enabled scientists to make predictions that were borne out decades later in scientific fields that Darwin knew nothing about.

The most entertaining part of the show were the interviews with the two ex-school board members (who were caught lying during the trial) and a local Dover pastor. The founders of intelligent design have gone to great lengths to paint their ideas as serious science, not creationism. And yet on the show we hear Dover's local intelligent design advocates explain that they pushed intelligent design in school because they were concerned that the malleable students of Dover were having their good Christian faith weakened by evolution - not because the board members cared (or knew anything about) a good science education. Alan Bonsell and Bill Buckingham made it repeatedly clear that their main beef with evolution is that it offends their religious beliefs.

Judge John Jones, who presided over the trial, made a sobering statement towards the end of the show. He said that before this case he would have never have imagined that he would receive threats after an Establishment Clause case. Jones and his family were placed under the protection of the US Marshals for a time after his ruling, due to threats of physical harm Jones received. Of course I'm biased, but I can't imagine that Jones would have received such threats had he ruled the other way. And while I have no doubt that the overwhelming majority of creationists would never, ever make such threats, much less act on them, the incident does expose the hatred that some people feel towards those who work to keep our science curricula untainted by religious dogma. This was a nasty episode in creation/evolution history, but with luck this trial will produce a lull in the battle for a couple of years. Unfortunately, we all know that this controversy is not over.

Evolution's Balancing Act

Evolution carries out an incredibly tricky balancing act: the genetic program of a species has to be resistant to small changes, yet also susceptible to the adaptive remodeling of natural selection. The human genome is so robust that over 6 billion variations give rise to viable organisms that have successfully traversed the complex developmental program that produces a live human infant from a single cell. Yet the human genome is the product of major evolutionary innovation, even over the relatively short period since the human and chimp lineages diverged. How can genomes be robust and malleable at the same time?

A team of researchers led by Andreas Wagner have recently published an interesting theoretical study of this question. This subject can get abstract and tough to follow if you haven’t mastered a lot of technical jargon. However these results are worth the effort to follow the argument, and below I try to explain this study in a relatively jargon-free way.

So how does evolution maintain both stability and the potential for innovation? It’s much easier to study this question by choosing a small model system to study, such as a transcription factor regulatory network. A transcription factor regulatory network is essentially a set of genes that switch each other on or off (via, of course, the proteins that are encoded by these genes). These networks are the subject of Wagner’s research.



Over time, a stable pattern can emerge in a transcriptional regulatory network, with some genes on and others off. This phenomenon, the emergence of a stable pattern of gene expression, is roughly what happens when a stem cell differentiates into another type, such as a nerve or muscle cell - a certain combination of genes are switched on or off to produce a stable pattern that represents the final state in the fully differentiated cell.



A critical point to understand is that different versions of the transcriptional regulatory network can produce the same final, stable pattern of gene expression. In other words, we can rewire some of the connections in our network, but still get the same final pattern of genes switched on or off.



This is one way that evolution produces networks that are stable to change - small variations don’t radically alter the end result of the transcription factor network. Andreas Wagner and his colleagues used simulations to test just how much rewiring can happen in a network that still produces the same final gene expression pattern. The answer is that you can in fact do a lot of rewiring and still have your network carry out its proper function. Naturally some rewiring is going to produce catastrophic change, but the point is that evolution has many different ways to produce the same final pattern of gene expression. Once nature has hit on a great way to make a stem cell differentiate into a nerve cell, it’s not that difficult to keep making nerve cells, even in the face of significant evolutionary change.

Thus this group of researchers has used simulations to come up with a theoretical understanding of how the complex systems in a lineage of organisms remain stable over long periods of evolutionary change. But if these systems are so stable, how does evolution ever produce something new? If it is so stable, how can a transcriptional network which produces a stable pattern of gene expression in a nerve cell ever be rewired to produce an expression pattern for a new cell type?

The answer to this question is paradoxically tied to the very features that make transcriptional networks so stable. Wagner and his colleagues found in their simulations that networks which are structured in very similar ways can be mutated to produce only a few limited, new patterns of gene expression. But we learned just a moment ago that transcriptional networks can be structured in very different ways yet still produce the same final effects; these different networks can evolve in different ways and thus increase the potential for evolutionary innovation.

An example can make this idea clear. Let’s say we a dozen different but closely related species; each of these species produces its nerve cells using very similar transcriptional regulatory networks. The networks can only be changed in certain, limited ways, thus the potential for evolutionary innovation is limited.

But now let’s say we have a hundred different (more distantly related) species, and they all produce nerve cells (with similar stable patterns of gene expression), but they do so using a wide variety of transcriptional network structures. The pool for evolutionary innovation is now much larger, meaning that it’s much more likely that a new and useful cell variant will evolve.

If all of these hundred species had to produce their nerve cells in exactly the same way, using very similarly structured transcriptional networks, this potential for evolutionary innovation would not be possible. Thus Wagner’s group demonstrated how it’s possible for regulatory networks to be both stable, and yet malleable at the same time.

Ancient Microbes Revived from Antarctic Ice May Be Spreading Their Genes

After being encased in Antarctic ice for 8 million years, ancient microbes thawed by a team of researchers revved up their metabolic engines again and began making proteins and replicating. These are the oldest organisms ever brought back to life after a deep freeze.

The research team, a group primarily from Rutgers, looked at the microbial population in some of the oldest ice known on earth, obtained from Antarctica’s Beacon Valley. Using microscopy, the researchers could see that these samples had a variety of bacteria encased inside. But microscopy can only tell you so much; to learn more, the research team turned to DNA sequencing.

The standard way of identifying what you have in a mixed population of bacteria is to sequence the 16S ribosomal DNA - a gene encoding an important component of the protein-synthesizing machinery. This gene is plays such an important functional role that it changes very slowly over evolutionary time, thus allowing scientists to easily compare DNA sequences among organisms that have diverged from each other for hundreds of millions of years. The 16S rDNA sequences from these ice samples revealed nearly a dozen different types of bacteria in the 8 million-year-old ice; that’s not much compared to a fresh, modern sample of seawater, but that's great for very old ice.

Some of these ancient bacteria were alive. When the researchers melted the ice (but keeping it still cold and dark - these are sensitive bacteria), they found that at least some of the bacteria were able start up their metabolism, which was measured using radioactive metabolites that the bacteria could ingest and incorporate into their protein or DNA.

16S rDNA can tell you what kinds of bacteria you have, but another intriguing question is what genes do these bacteria have? Are most of their genes similar to those of today’s known bacteria? After sequencing as much of the bacterial genomes as they could, the researchers found that a substantial 46% of the genome sequence did not match any known genes. This is not actually so surprising - in spite of all of the DNA sequence from thousands of organisms stored in GenBank, we know that we have sampled only a fraction of the different types of genomes on earth. The genomes of multicellular organisms are relatively similar to each other, but that bacterial world represents a vast, poorly explored genetic resource. We know most of the genes on our planet are in fact missing from our databases; we best understand the biology of that small subset of bacterial and archaebacterial genes that was present in the ancestors of all eukaryotic organisms.

While scientists may not know much about most bacterial genes, evolution is not blind to them. Bacteria are remarkably generous with their genes; they pass them on not only to their descendants, but to their neighbors as well. This phenomenon of lateral gene transfer, or LGT, makes the evolutionary analysis of bacteria fiendishly difficult. The authors of the ice microbes paper raise another fascinating (or depressing, if you study bacterial evolution) possibility: that ancient ice is a “gene popsicle,” facilitating gene transfer not only across species, but also across time. With the onset of an ice age, microbes, harboring a given set of genes, get preserved for thousands or millions of years, until the ice melts. That’s when these ancient bacteria return to the local ecosystem, where they can pass on their ancient genes via LGT to modern bacterial species. These modern species then, with luck, use these recently revived genes to better adapt to their environment. As the authors of the paper put it:

“Our analysis suggests that melting of polar ice in the geological past may have provided a conduit for large-scale... LGT, potentially scrambling microbial phylogenies and accelerating the tempo of microbial evolution.”

This is a mind-boggling prediction, which will be difficult to test without a lot more bacterial genome sequencing. However, the idea again demonstrates the tremendous resources evolution has to work with. As the biologist Leslie Orgel reportedly once said, “Evolution is cleverer than you are.”

Junk DNA in the Opossum Genome

Vertebrate genomes are full of junk. Despite the occasional confusing magazine article, the spurious claims by creationists, or obfuscatory statements by some scientists, we know that our genomes are stuffed full of DNA sequence that serves no functional role for the organism. The vast bulk of this junk sequence consists of molecular parasites, called transposable elements, whose only 'function' is to replicate themselves. While our genomes obviously contain critical information required to build and maintain ourselves, they are also vast ecosystems of virus-like parasites that have colonized our DNA.

A recent paper in the journal Genome Research describes the DNA ecosystem of the opossum genome. "Ecosystem" is not an exaaggeration; more than 52% of the opossum genome is comprised of transposable elements, which can be classed into nearly 500 different families. Transposable elements are similar to viruses; they are, one way or another, able to replicate themselves within an organism's genome and get passed on to the next generation. These elements have variety of survival strategies; some elements get transcribed into RNA and then 'reverse transcribed' back into DNA and inserted somewhere in the genome, while other elements never go through an RNA stage. Some transposable elements encode proteins that enable them to spread through the genome more efficiently; other elements don't bother to code for any proteins and instead hijack the proteins produced by those elements that can code for them.

Why do transposable elements exist in our genomes? Because they can. If a DNA element in an organism's genome can get itself passed on into the next generation, whether that element is beneficial to the organism or not, then obviously it will remain in the genome of that species. Since these elements don't generally serve any functional role, there is no reason for natural selection to preserve them, and we thus see piles of defective copies of transposable elements scattered around our genomes. These elements no longer have the ability to spread through the genome and they serve no function - they are pure junk. While our cells do have systems that try to stop these elements from spreading, we, and most animals, have not evolved effective ways to get rid of the junk elements once they are there; these elements therefore hang around and bulk up our genomes with non-functional material. About 45% of the human genome consists of these elements; that fraction rises to 52% for the opossum (which has a genome slightly larger than ours).

Transposable elements are not completely useless. For one, biologists love them because they can be helpful for studying evolutionary history - one approach to teasing out relationships among various species is to reconstruct a rough history of transposable element activity in various genomes. We have also known for some time that these elements can occasionally be recruited for a functional role (such as telemoeres in flies, X-chromosome inactivation in mammals, and centromeres in various organisms).

The opossum paper offers even more tantalizing, although not wholly unprecedented, evidence of a larger role for transposable elements. The authors of this paper looked at transposable elements, common to both opossum and human, that were present in known or suspected regulatory regions of the genome. Transposable elements in these regions are obvious candidates for a functional role. And remarkably, the researchers found that a handful of transposable element families were highly abundant in these regulatory regions - in one case, 70% of all the individual elements of one family were found in regulatory regions of the genome. It is possible that this particular family of transposable elements somehow contains a useful 'regulatory module,' some sequence that has been recruited through evolution to control the expression some genes. If this is true, than this would be a case of transposable elements providing the raw genetic material to create new layers of regulation in the genome.

So while most of the self-perpetuating transposable element ecosystem is undoubtedly junk from the perspective of the organism hosting it, our genomes are occasionally able to scoop up some of the detritus and put it to good use.

Our Genomes, ENCODE, and Intelligent Design

What has the ENOCODE project done, and how do their results change our understanding of the human genome? In the last post I put this project into perspective by briefly outlining some past concepts of the gene and highlighting some of the ENCODE findings. Now it's time to take a closer look at the results of the ENCODE project and their significance for our understanding of the human genome. ENCODE's genome snapshot is unquestionably fascinating, and it suggests that some features of genome regulation that were previously viewed as exceptions to the norm are really quite common. But are these results revolutionary? Do they overturn any long-cherished notions about genes that scientists have heavily relied on in their understanding of gene regulation, as some have suggested? And do they support intelligent design? I don't think so.

What ENCODE Did

In one sense, the ENCODE project can be thought of as the third big Human Genome Project - the first project being the actual genome sequencing, and the second being the HapMap Project to extensively study genome variation in different human populations. The ENCODE project is an effort to find and study, on an encyclopedic scale, all of the functional elements in the human genome.

For the first phase of this project, the ENCODE researchers examined a small but reasonably representative chunk of the human genome (roughly 1%, or 30 million DNA bases) by running that chunk through a battery of experimental tests and computational analyses. Most of the experimental techniques and results are unfortunately beyond the scope of this little summary. This first round of the ENOCDE project produced a big paper in Nature, and the journal Genome Research has devoted its entire June issue to papers from the ENCODE project. I'm going to winnow down this mass of material to two of the most interesting topics: transcription and evolution.

Transcription (if you don't know what transcription is, look here):

The researchers attempted to identify regions of DNA that were transcribed. Why? Because our presumption has generally been that most (note the qualifier!) transcripts contain some functional material, such as protein-coding genes or non-coding RNAs that have some functional role (such as miRNAs, snoRNAs, rRNAs, etc.). Therefore by looking for transcribed regions, we can find new functional portions of the genome.

The transcribed regions were identified using tiling arrays, which are DNA-chips, or microarrays, that cover the entire genome and thus can detect transcription from any place in the genome. This is in contrast to more traditional microarrays that only detect the transcription of known genes. Thus by using tiling arrays and a handful of other complementary techniques, the ENOCDE researchers found that a large fraction of the genome region in the study was transcribed, including many places that have no recognizable genes. They estimate that up to 93% of the genome is transcribed, although the evidence for much of this is indirect and other explanations of the experimental results are possible. The actual transcribed fraction may be substantially lower, although it is still likely to be large.

The most interesting finding of these transcription studies is that a lot of strange stuff is ending up in these RNA transcripts. We have long known that different protein-coding regions (exons) from a single gene can be spliced together in various combinations to create many different proteins. The ENCODE researchers confirmed this (the protein-coding genes they studied produce on average 5.4 differently spliced forms), but they also found that chunks of other sequence end up in the transcripts, such as coding and non-coding portions of neighboring genes. Why this is happening is not yet clear, although part of the explanation is surely that the transcription and splicing machinery are more noisy than we previously (and naively) appreciated.

Another major part of the ENOCODE project is to find out just where transcription starts. Transcription start sites (TSSs) are important, because key regulatory events take place there. Regulatory sequences in the DNA, together with regulatory proteins, act at TSSs to control the protein machinery that carries out transcription; this control is critical for deciding which genes in the cell are 'on' or 'off'.

The ENCODE researchers found many new TSSs, sometimes very far away from known genes. Interestingly, the TSSs far away from known genes had different characteristics from those close to known genes, suggesting two distinct functional roles. One possible role for these distant TSSs is to control the higher-order structure (i.e., chromatin structure) of big regions of the genome, and thus to some degree regulating entire sets of genes. This work lays a good foundation for studying these control systems.

Evolution

The ENCODE researchers searched for regions of the human genome that have changed little throughout mammalian evolutionary history; these are the regions that have been constrained by natural selection. They compared portions of the human genome with the genomes of 14 other mammalian species, and found that 5% of the genome is under evolutionary constraint, a result that agrees with earlier studies.

The immediate question then is, how much of the 5% consists of known functional elements? The ENCODE researchers reported the following breakdown:

Of the 5% of the genome that is evolutionarily constrained:
- 40% consists of protein-coding genes
- 20% consists of known, functional, non-coding elements
- 40% consists of sequence with no known function

The sequence with no known function is not too surprising. Functional DNA elements other than protein-coding genes are difficult to find, and in spite of many recent studies we know we're missing a lot. These results tell us roughly how much more functional, non-coding sequence we need to find, and where it is probably located.

The ENCODE researchers also looked at evolutionary conservation from another angle: how much of known, functional DNA falls into conserved regions? Protein-coding genes and their immediate flanking regions are generally well-conserved, while known, non-coding functional elements are less conserved. Again, this is nothing too surprising; non-coding elements tend to be very short and have what is called 'low information content', and they are more easily created and destroyed by by random mutations.

Many potentially functional elements, picked up in the experimental data analyzed by the ENOCODE groups, are not evolutionarily constrained - about 50%, when these elements are compared across all mammalian genomes in the study. This means that there are regions of the genome that are bound by regulatory proteins or that are transcribed, but which have not been constrained by natural selection.

Intelligently Designed Transcription?

I need to pause here and answer the obvious question here that those of you who aren't molecular biologists are probably asking: So does this mean that evolution can't explain much of the functional parts of the genome? Intelligent design advocates are already on the web, misreading the ENCODE work and claiming that it somehow supports the fuzzy claims of intelligent design. My advice: don't believe what you hear about this from people who only have the vaguest understanding of how ENCODE's experiments and analyses work (and that includes biochemist Michael Behe).

The ENCODE results do not cast doubt on evolution. Here are some of the reasons why:

1. Just because something is transcribed or bound by a regulatory protein does not mean that it is actually functional. The machinery of the cell does not literally read the DNA sequence like you and I do - it reads DNA chemically, based on thermodynamics. As I mentioned before, DNA regulatory elements are short, and thus are likely to occur just by chance in the genome. An 8-base element is expected to show up just by chance every 65,000 bases, and would occur randomly over 45,000 times in a 3 billion base pair genome. Nature does work with such small elements, but their random occurrence is hard to control. In a genome as large and complex as ours, we should expect that there is a significant amount of random, insignificant protein binding and transcription. Incidentally, such random biochemical events probably make it easier for currently non-functional events to be occasionally recruited for some novel function. We already know from earlier studies that this kind of thing does happen.

2. To say that something is truly functional requires a higher standard of evidence than the ENCODE research provides. The ENCODE researchers did a fine job detecting transcription and regulatory protein binding with state-of-the-art experimental and computational techniques, but confirming a functional role for these elements will require more experiments aimed at addressing that issue.

3. Some of the functional elements that don't appear to be conserved really are conserved. When you're comparing a small functional element in a stretch of DNA between say, humans and mice, it is often difficult to find the corresponding region in each species. The mice and humans may have the same functional element, but in slightly different places. Thus conserved elements can be missed. The ENOCODE researchers note this, and people like myself who study these small elements know from experience that this happens frequently.

4. Despite what you may read, there is still a lot of junk DNA. The ENOCDE project does not "sound the death-knell for junk DNA." Our genomes are filled with fossils of genetic parasites, inactive genes, and other low-complexity, very repetitive sequence, and it's extremely clear that most of this stuff no functional role. Much of this sequence may be transcribed, but remember that the ENCODE evidence for most of this transcription is indirect - their direct measurements only detected transcripts for ~14% of the regions they studied. Even if much of it is transcribed, this mainly suggests that it is not worth expending energy to actively repress this transcription, since there are so many other controls in place to deal with unwanted transcripts in the cell.


Enlightening but not revolutionary

Moving on from intelligent design, some people, around the web and in a few journals, are making the ENCODE results out to be more revolutionary than they really are. For example, writing in a Nature piece stuffed with exaggerated claims about what our "preconceptions" supposedly are (subscription required), John Greally states that "Now, on page 799 of this issue, the ENCODE Project Consortium shows through the analysis of 1% of the human genome that the humble, unpretentious non-gene sequences have essential regulatory roles," and "the researchers of the ENCODE consortium found that non-gene sequences have essential regulatory functions, and thus cannot be ignored."

Every biologist I know could have told you that "non-gene sequences have essential regulatory roles," years ago, before ENCODE. Larry Moran, over at Sandwalk says that he hasn't "had a 'protein-centric' view of a gene since I learned about tRNA and ribosomal RNA genes as an undergraduate in 1967." Where has Greally been all this time? I'm not sure why he is so surprised.

Also, as I mentioned above, not all (or maybe not even most) of the transcribed, intergenic sequences found by ENCODE are believed to have "essential regulatory roles." Non-coding DNA regulatory elements have been the subject of intense study by many groups for many years now. To claim that we have not paid enough attention to them is wrong. None of the types of transcripts discovered by ENOCDE are really novel; we've seen examples in earlier studies of they found. What is significant about the ENCODE results is the extent of this unusual transcription; what were once thought to be exceptions are now seen to be much more common.

I'm happy to see the ENCODE results; many of us will use their results in our own research, and projects like this certainly help to make the human genome much less of a black box. But they haven't shattered any paradigms that weren't already on their way out, or revolutionized the field of genomics.

Sean Carroll's Smackdown of Michael Behe

This week's issue of Science has a book review (subscription required unfortunately) of Michael's Behe's latest effort to defend Intelligent Design Creationism. Michael Behe's latest book, The Edge of Evolution, contains Behe's latest incarnation of his idea of irreducible complexity. A few years ago he put forward this latest argument in a paper in Protein Science (a journal which one of my mentors dismissed, maybe a little unfairly, as a "junk journal"), and he elaborates on this argument more extensively in his new book. (See a response to Behe's Protein Science paper here.)

The argument is this: Any novel function in a protein that requires two simultaneous amino acid changes is so unlikely to occur by chance that the novel function must have been designed. Since most beneficial changes in protein function would require a change of two or more amino acids, most of the varied functional proteins we see in nature must have been designed and not evolved. So for example, if a receptor for a certain hormone were, over the course of evolution, to evolve a new specificity for a different hormone, and if that new specificity required at least two amino acid changes, then such change is incredibly unlikely to occur under just natural selection and random mutation.

In making this argument, Behe makes this explicit assumption: an 'intermediate' protein with only one amino acid change (so in other words, it's only halfway evolved towards a new function that requires two certain amino acid changes) is non-functional, and thus is not subject to selection for the new function. So in order for natural selection to act, the protein would need both amino acid changes simultaneously, arising by chance mutation in the same individual organism (an event which Behe calculates to be unlikely).

Sean Carroll takes on this argument by pointing out that Behe's assumption of non-functional intermediate proteins is contradicted by vast amounts evidence. Single amino acid changes in a protein do in fact cause beneficial changes that are favored by natural selection, and over time these single changes accumulate in a lineage to create a more robust novel function. This is the norm in evolution, not the exception as Behe would have it. The scientific literature supporting this is extensive.

Carroll goes on to make this important point: "Behe seems to lack any appreciation of the quantitative dimensions of molecular and trait evolution." This is because Behe, like me, is a biochemist - biochemists learn about the physics and chemistry of proteins. The kind of math we use to do our work consists primarily of differential equations that describe the kinetics and thermodynamics of proteins and nucleic acids. Biochemists generally do not study mutation rates, evolving populations, or the heavy statistics behind natural selection. That's a whole separate field, called quantitative genetics, founded primarily by the pioneering scientists Sewall Wright and Ronald Fisher, whose work is usually not that familiar to biochemists. (As someone who did a PhD in a biochemistry department, but now works in a genetics department, and in a lab that does serious quantitative genetics, I have acutely, even painfully, experienced this difference in training firsthand.)

Behe's problem is that he's tried to jump into this field without any serious background knowledge; it's like a chemist or engineer trying to tackle research problems in quantum gravity - the chances of producing anything worthwhile are essentially zero. Behe's efforts at modeling mutation and selection on protein function have thus been amateurish, and not taken seriously by people who work on these problems professionally.

On a different note, it's great to see Sean Carroll join the evolution/intelligent design fray. Many distinguished scientists write well and effectively against the weak claims of Intelligent Design, but few have the stature, as scientists, that Carroll has. He's a very big player in the field of evo-devo, a field which is directly relevant to the claims made by ID creationists. It's nice to see such a heavy-hitter get involved.