In March, six men entered a London hospital to receive an experimental drug. The men were volunteers, and the drug–a potential treatment for arthritis and leukemia–appeared from animal tests to be safe. But within minutes of the first round of doses, there was trouble. The men complained of headaches, of intolerable heat and cold. The drug made one man’s limbs turned blue, while another’s head swelled like a balloon. Doctors gave them steroids to counteract the side-effect, and managed to save their lives. But several ended up on life support for a time, and they all may suffer lifelong disruptions to their immune systems.

How could such a devastating disaster come from a trial that followed all the rules, including tests on both mice and monkeys? According to a paper published today, the drug developers might have thought twice if they had known more about our evolutionary history.

Humans suffer from a number of immune disorders that don’t bother other primates. HIV evolved from a virus that infects chimpanzees, but when chimpanzees get infected, their immune system doesn’t collapse the way ours does. Chimpanzees don’t get serious inflammation of the liver after hepatitis infecitons, and don’t seem to suffer from lupus or bronchial asthma. All of these disorders are associated with an overreaction by a group of white blood cells known as T cells. This puzzling pattern led scientists at the University of California at San Diego Medical School to see if T cells behave different in humans than in chimpanzees, and if so, why.

They started with one intriguing clue: human T cells don’t make a group of receptors found on many other immune cells. These receptors are known as Siglecs (a nice snappy abbreviation of “sialic acid-recognizing Ig-superfamily lectins.” And breathe.)

No one is quite sure what the function of Siglecs is. It is clear that they bind sialic acids, which are sugary molecules that coat our cells, including immune cells. Scientists have speculated that by recognizing sugars on our own cells and sending a dampening signal, Siglecs might help our immune systems avoid attacking our own tissues.

The scientists decided to compare human T cells directly to those of apes. It turns out that unlike humans apes produce a lot of Siglecs on their T cells. And those Siglecs make their T cells behave differently than ours. The scientists used antibodies to bind to several T cell receptors that are known to play important roles in how the immune system responds to threats. In humans, tickling those receptors caused the T cells to multiply madly. In chimpanzees, by contrast, the response was muted.

Could it be that Siglecs were muffling the response of ape T cells? To test the possibility, the scientists cleared Siglecs off of chimpanzee T cells. The altered chimpanzee T cells responded much more strongly when their receptors were tickled. The scientists also manipulated human T cells, adding Siglecs to their surfaces. Now the human cells were much more muted in their responses.

The scientists detail their results in the Proceedings of the National Academy of Sciences (link to come here). They propose that our ancestors lost their Siglecs some time after our lineage branched off from that of chimpanzees about six million years ago. The scientist also suggest that when the Siglecs disappeared, our lineage became prone to damaging overreactions from T cells that other apes did not suffer.

Why would natural selection favor Siglec-free T cells in the face of these diseases? It’s possible that our ancestors faced some awful pathogen that required a powerful T cell response. Perhaps this reaction even helped our ancestors spread to new environments where they faced new disease.

It’s also possible that natural selection had nothing to do with it. The diseases associated with the overactive human T cell take a long time to develop, and so they may not have interfered with child bearing–and thus with passing on genes from generation to generation.

There’s one particularly intriguing coincidence to consider here: sialic acids have clearly undergone a dramatic evolutionary change of their own. Mammals generally make two kinds of sialic acids. An estimated 3.2 million years ago, our ancestors lost the ability to make one of them. A mutation disabled the gene in some ancestral hominid, and after time that broken gene spread throughout the entire species.

Previous studies have shown that the disappearance of those sugars caused many changes in human Siglecs. New Siglecs evolved, some of which shifted from binding to the old sugars to binding to the new ones. There may have been a shake-up in the whole Siglec-sialic acid system, and the loss of Siglecs from T cells may have been just one side effect.

Now we can return to the unlucky drug volunteers. The drug they got is called TGN1412. It works by binding to a T cell receptor called CD28. Previous research had suggested that binding to CD28 could cause a cascade of events that would ultimately tame an out-of-control immune system. That’s certainly what seemed to happen to mice and monkeys. Since arthritis is caused by out-of-control immune systems, TGN1412 looked like a promising drug. The doctors took care to give the human subjects 1/500 the dose given to the monkeys. Neverthless, it apparently sent their immune systems into a rage, producing massive amounts of inflammation and other sorts of damaging responses.

Guess what one of the receptors was that scientists examined in the new Siglec paper. That’s right–CD28. It’s possible, then, that the drug failed in humans because we have lost the mechanism that keeps a response to CD28 under control.

At this point, this hypothesis is just one possible explanation that needs to be tested. Ajit Varki, one of the authors of the new study, told me that his team has asked for a sample of the drug from its manufacturer to test it on human and ape T cells. So far, the company, Tegenero Inc., has refused.

If it does hold up, it may offer a cautionary lesson about drug tests. Testing a drug on a mouse or a monkey may tell you something about how the drug will work in humans–but only if it acts on biology that we share with those animals. And in some cases, where a drug is affecting proteins that evolved after our split with chimpanzees, no living animal may offer a reliable clue. The more we learn about our evolutionary history, the more we’ll understand about how drugs work.

(Postscript: Last year I wrote about another way in which how this ancient evolutionary event makes a big difference to modern medicine–in this case, stem cell research. If human stem cells are reared with animal tissues, they can pick up the lost sugar and wind up being rejected by our immune systems.)

Update, 5/2/06 3 pm: Fixed up a few late-night errors.

Update 5/2/06 4 pm: In the comments, Nick Matzke reminds me that I’ve already written about how malaria might have had a hand in this immune system disruption here. Memories fade, but blogs are forever.

Today I’ve got an article in the New York Times about the report in Nature that starlings can recognize syntax-like patterns in songs, and what that might mean–if anything–for the evolution of language. The blogs have been buzzing about the study since it came out on Wednesday, with the Language Log logging in several complaints about bad science and bad reporting. (Fortunately, they gave me a pass, and I hope not merely because I’m the brother of one of the bloggers there!)

So why should you now turn to Tuesday’s science section of the Times, days after the wires and the blogs have had their way with this material? I hope that with the luxury of a little extra time, I’ve been able to get the science relatively straight, and to offer a sense of why it is inspiring so much debate. Plus, we’ve got starling songs for you to hear! Check it out.

Update: Tuesday 9 am–article link fixed.

The Loom gathered a bit of dust over the past couple weeks as I grappled with another round of deadlines for work that actually pays the mortgage. Life should now get relaxed enough for more blogging, I hope–starting this evening. And as the articles I’ve been working on come out in the next few weeks, I’ll point you to the links–starting with my recent (brief but free) take
on the new fossil of snakes with legs for the New York Times. And speaking of evolutionary transitions, I’m also happy to bring news of a cool new project, called Kosmos: You Are Here. It’s an e-book on the history of life and the universe. I got to know one of the co-authors, Steven Darksyde, when he contacted me for an interview with me he posted on DailyKos. Steven and his co-authors have put together a fast-paced, engaging look at what we know about the past, from the Big Bang to the Descent of Man. It’s graced with pictures by Carl Buell, who illustrated my first book, At the Water’s Edge and has continued to bring fossils to life (be sure to visit his blog). I provided an introduction in which I muse both about recent advances in science and in the way we communicate about it–including blogs and e-books.

Tomorrow I’ll be on the radio show Science and Society at 4:20 PM EST. It’s my second time on the show. Last time around we talked about the past six million years of hominid evolution (podcast here). This time we’re hoping to cover just a bit more ground: the past 600 million years of vertebrate evolution. We’ll try to hit on the big innovations that our ancestors acquired after we parted ways with the squishy beasts–such as brains, bones, a smart immune system, and hands and feet. You can listen live here, and the podcast should be available here shortly afterwards. is here. (Scroll down a bit to my segment.)

On Thursday I wrote about a new paper reporting the reconstruction of a 450-million year old hormone receptor, and experiments indicating how it evolved into two receptors found in living vertebrates such as ourselves.

On Friday I took a look at the initial response to the paper from intelligent design advocates at the Discovery Insitute. They claim that there exist biological systems that show “irreducible complexity,” which could not possibly have evolved. In response to the new research, intelligent design advocates claimed that hormones and their receptors do not actually make the cut as irreducibly complex systems. But to do so, they had to ignore their own published definition of irreducible complexity.

As I mentioned on Friday, the Discovery Institute promised more, and more they have delivered. Not scientific papers published in peer reviewed scientific journals, of course, but a lot of press releases and such. There’s a lot to wade through as of Sunday evening, and no doubt even more to come. But none of it amounts to much. They spend a lot of time rehashing their claim that irreducible complexity is not touched by this research. And they also use another standard strategy: raising doubts about whether a particular evolutionary scenario could take place, or whether biologists have done enough work to make their case.

It’s odd in a way, that they should go to these lengths. For one thing, they repeatedly claim that the whole experiment has nothing to do with irreducible complexity. For another, they dismiss this evolutionary change as minor stuff that they have no trouble with.

“There is nothing in the paper that an ID proponent would think was beyond random mutation and natural selection,” Michael Behe writes “…Intelligent design proponents happily agree that such tiny changes can be accomplished by random mutation and natural selection.”

Not happily enough, it seems.

Before I get into the objections, let me recap what the scientists found. They compared two kinds of hormone receptors, MR and GR for short. MR binds tightly to a hormone called aldosterone, and plays a role in keeping electrolytes in balance. GR binds to a hormone called cortisol and plays a role in stress, immunity, and other responses. The scientists found that MR and GR evolved from a common ancestral receptor, which was accidentally duplicated in the common ancestor of all fishes and land vertebrates.

When they reconstructed the ancestral receptor, they found that it bound to aldosterone, cortisol, and a third hormone called DOC.

This was surprising, since aldosterone evolved long after this receptor did. The result indicates that the tight link between MR and aldosterone was not there when MR first evolved. Instead, it must have bound DOC, which has a similar structure to aldosterone. Only tens of millions of years later did aldosterone evolve and become associated with MR in land vertebrates.

The reconstructed ancestral receptor revealed an equally suprising story for GR. The main feature of its evolution must have been that it lost its aldosterone sensitivity and retained its sensitivity to cortisol. The scientists found that it changed by two amino acids. They tested out mutant proteins carrying each one of these changed amino acids (known as S106P and L111Q). L111Q on its own reduced the sensitivity of the receptor to all three hormones. S106P did not have the same effect as L111Q. It reduced sensitivity to aldosterone and cortisol, but left DOC response strong. Once the GR receptor had the S106P mutation, the L111Q mutation reduced the aldosterone response even more but then raised cortisol to the sort of sensitivity found in our own cells today. So the scientists suggested that this was the most likely path by which the ancestral receptor could have evolved into the GR receptor.

Behe describes these mutations this way:

“In the ‘most promising’ intermediate protein (the one that has just the S106P alteration) the protein has lost about 99% of its ability to bind DOC and cortisol, and lost about 99.9% of its ability to bind aldosterone.”

You get the notion that the receptor has been crippled in some devastating way. Indeed, Behe suggests, “One would think that the hundred-fold decrease in the ability to bind a steroid would at least initially be a very detrimental change that would be weeded out by natural selection.”

There’s really no reason to think that. The response of receptors to hormones is not some simple one-to-one relationship that you can summarize with a single number. Here’s the graph. Aldosterone is green, DOC is blue, and cortisol is red.

You can see how L111Q just pushes the response curve flat. Flood it with all the aldosterone, cortisol, or DOC you want, and you won’t get any significant response. But S106P receptors still respond to the hormones. They just need a higher concentration. In fact, DOC responds much more strongly in S106P than in the ancestral form at high concentrations. But these concentrations are not abnormally high. Indeed, they’re typically of many receptors in living animals.

This graph offers no indication then that natural selection must have weeded out S106P mutants. Even if the shift in the DOC response did affect ancient fish, we can’t forget that these fish also had the other kinds of receptors, MR, which are very responsive to DOC.

In fact, the S106P might have even been able to survive even if it had been moderately harmful. Moderately harmful mutations can withstand natural selection if they are linked to beneficial genes, for example, if they exist in a small population where natural selection is weak. So nothing in what scientists know about how natural selection works says that the S106P pathway is prohibited by natural selection.

But that’s still not enough for intelligent design folks, of course. Behe writes,

“The authors do not test for that [that S106P would be weeded out by natural selection]; they simply assume it wouldn’t be a problem, or that the problem could somehow be easily overcome. Nor do they test their speculation that DOC could somehow act as an intermediate ligand. In other words, in typical Darwinian fashion the authors pass over with their imaginations what in reality would very likely be serious biological difficulties.”

Is it me, or is it strange that intelligent design advocates are telling biologists that they aren’t working hard enough, that they are not getting enough results from their lab work? Remember, this is the same Michael Behe whose sole peer-reviewed paper in the past eight years was a computer model (and a pretty poor one, it turned out). Compare that to the work of Joe Thornton, the principal investigator on the new paper. In the past eight years he’s published twenty papers on hormones and their evolution: he’s been sequencing hormone receptor genes, working out how they respond to different hormones, determining how they’re related to one another, and even resurrecting them after 450 million years of oblivion. All Behe is doing is complaining that Thornton hasn’t done enough, without even bothering to explain how a scientist could even set up the sort of test he demands. The fact of evolution, which Discovery Institute folks like to ignore, is that natural selection is tough to measure precisely even in living populations. The challenge gets far greater after millions of years have passed. Scientists can detect the fingerprint of natural selection on various genes, but they may never be able to recover the precise chain of events that drove the evolution of a new kind of gene.

Yet that doesn’t mean that scientists can know nothing about evolutionary history. Here we have tightly integrated systems (MR, GR, and their hormones) which appear to have evolved stepwise from a common ancestor. Even though the receptors and their hormones are tightly integrated today, that doesn’t mean that they couldn’t have functioned without their partners. MR evolved long before its aldosterone partner did, and it just happened to have a structure that would allow it to latch on. As for GR, Thornton and co. have even showed which parts of the ancestral gene mutated, and offered a sequence of events by which those mutations may have taken place.

And guess what? Thornton is now back in his lab right now, working with his colleagues to test their own hypothesis. The folks at the Discovery Institute folks might want to take a break from their empty complaints and give it a try.

Update 4/10 3 pm: Ian Musgrave at Panda’s Thumb explores yet another way in which Behe contradicts himself (even under oath!).

Yesterday I blogged about a new study in which scientists reconstructed 450 million year old proteins in order to trace the evolution of some receptors for hormones. The paper itself does not comment on the implications these results have for intelligent design, which claims that some biological systems are too complex to have evolved. But in the accompanying commentary, Chris Adami does. (Adami is the brains behind Avida, an artificial life program that I wrote about in Discover in 2005.) He writes,

Although these authors have not directly addressed this controversy in the discussion of their work–because the work itself is intrinsically interesting to biologists–such studies solidly refute all parts of the intelligent design argument. Those “alternate” ideas, unlike the hypotheses investigated in these papers, remain thoroughly untested. Consequently, whatever debate remains must be characterized as purely political.

In a press release from the University of Oregon, Joe Thornton, the lead author, also raised the connection.

The stepwise process we were able to reconstruct is entirely consistent with Darwinian evolution,” Thornton said. “So-called irreducible complexity was just a reflection of a limited ability to see how evolution works. By reaching back to the ancestral forms of genes, we were able to show just how this crucial hormone-receptor pair evolved.

The intelligent design advocates responded quickly with a statement. Michael Behe, author of Darwin’s Black Box, says:

“The authors (including Christoph Adami in his Science commentary) are conveniently defining “irreducible complexity” way, way down. I certainly would not classify their system as anywhere near irreducibly complex (IC). The IC systems I discussed in Darwin’s Black Box contain multiple, active protein factors. Their “system”, on the other hand, consists of just a single protein and its ligand. Although in nature the receptor and ligand are part of a larger system that does have a biological function, the piece of that larger system they pick out does not do anything by itself. In other words, the isolated components they work on are not irreducibly complex.”

In an article in the New York Times, Behe is reported to have commented that

a two-component hormone-receptor pair was too simple to be considered irreducibly complex. He said such a system would require at least three pieces and perform some specific function to fit his notion of irreducibly complex.

Time for a fact check!

I looked at the index of Darwin’s Black Box for “Irreducibly complexity, defined.” It directed me to page 39, where I found the following passage:

By irreducibly complex I mean a single system composed of several well-matched, interacting parts that contribute to the basic function, wherein the removal of any one of the parts causes the system to effectively cease functioning.

Hm.

Behe’s own definition does not refer to active protein factors, just parts. So that’s not a valid objection.

It does not specify “at least three” pieces must be involved. While he uses the word “several,” he offers no explanation for why a two-part system is not complex. It certainly does meet his specification that removing one part makes the system non-functional.

What’s more, a hormone and its receptor certainly do carry out a function: they relay a signal from outside a cell to inside a cell. That signal is indeed carried further into the cell by other proteins. But Behe does not explain why that fact means that the two molecules studied by Thornton don’t have a function. And in fact, as was revealed in the recent Dover intelligent design trial, Behe himself is happy to look at a part of a system. In the trial, the plaintiff’s lawyer explored Behe’s claim that blood-clotting is a complex system. Behe ignored part of the blood-clotting response in his argument. It just so happens that some proteins in the part he ignored are missing from some species, but they can still form blood clots. That raises doubts about whether the system is irreducibly complex.

So, to recap: this system appears to match Behe’s own original definition of irreducible complexity, while Behe’s comments yesterday do not. And Thornton and his colleagues have presented evidence about how this irreducibly complex system could have evolved. The intelligent design statement promises more comments from others today. We’ll have to see how well they hold up to a fact check as well.

Update 4/10: Not so well, it turns out.

Over the last few years, scientists have figured out how to recreate biological molecules that were last seen on Earth hundreds of millions of years ago. Until now, scientists have reconstructed ancient proteins to gather clues about life was like long ago. But now some scientists at the University of Oregon have done something new with these old proteins: they used them to figure out how evolution produces complex systems–exactly the sort of systems that creationists would have us believe cannot evolve.

Scientists reconstruct an ancestral protein by tracing its evolution into new versions carried by living species. Along each lineage, the gene for that protein picks up mutations, some of which alter the structure of the protein. Scientists can determine many of those mutations, and by working backwards up the evolutionary tree, they can determine what the original gene looked like. Thanks to powerful statistical techniques, they can determine how much confidence they can have in each letter in the genetic sequence they reconstruct. If they find a lot of statistical confidence in the overall sequence, they can then go to the lab and use it as a guide to build the corresponding protein. And once they have the protein in hand (or in beaker), they can see how it works. In this 2004 paper, University of Oregon biologist Joe Thornton reviewed the latest advances in this molecular resurrection. Scientists have recreated one of the light-gathering proteins from the eyes of the common ancestor of birds, crocodiles, and dinosaurs that lived 240 million years ago. The protein still catches light in its resurrected form–and turns out to be particularly good in dim light, suggesting that this ancient reptile was a nocturnal creature.

Thornton and his colleagues have now used this same method to learn about the evolution of signals our cells use to talk to one another. In particular, they look at hormones and the receptors on the surface of cells to which they attach. Hormones coursing through our body maintain harmony between our cells, keeping levels of various molecules in balance while allowing our bodies to respond quickly to challenges–the most famous example being the fight-or-flight rush of adrenalin.

This communication can be ruined by misunderstanding. “Did you say boost glucose levels up a little? Sorry–I thought you meant it was time to utterly freak out.” To avoid that confusion, the structure of hormones only allow them to latch onto certain receptors, a bit like keys fitting into certain locks. (Only a bit, though–something I’ll get back to in a little while.)

The genes for hormone receptors in humans and other vertebrates show clear signs of having evolved from common ancestor. Take the mineralocorticoid receptor (MR for short). In our bodies it responds to a hormone called aldosterone that regulates our electrolytes in the kidneys. We’ve got MR, dogs have it, birds have it, snakes have it, frogs have it. In fact, all known land vertebrates have various versions of MR. Even ray-finned fish have it. Even skates (a kind of cartliginous fish) have it. The MR gene we carry is more like the MR gene carried by frogs than it is to ray-finned fish or to skates. And if you look at two MR genes carried by fish, they’re more similar to each other than they are to ours. But ray-finned fish MR genes look more like ours than they do to those of skates.

This fits perfectly with what the fossil record tells us. The ancestors of skates and other cartilaginous fish branched off from other living vertebrates about 450 million years ago. Ray-finned fish and land vertebrates descend from a more recent ancestor. And all land vertebrates descend from an even more common ancestor. The MR genes reflect that ancestry.

A few years ago Thornton discovered where the original MR receptor came from. He found that MR genes all bear a striking resemblance to another sort of receptor, the glucocorticoid receptor (GR for short). GR responds mainly to cortisol, and is important for coping with stress and infection. It does not respond to aldersterone, the signal for MR.

Thornton hypothesized that MR and GR are the product of an ancient gene duplication. An ancestral gene for a hormone receptor was accidentally copied, and two version of the receptor began to be produced on ancient fish. Over time, each gene acquired mutations that altered how its receptor responded to hormones, and eventually the two versions evolved into MR and GR.

So this left Thornton with a puzzle: how is that that an ancestral receptor 450 million years ago gave rise to two such different sorts of receptors, one (MR) sensitive to aldosterone and used to regulate electrolytes, and the other (GR) an immunity-linked receptor sensitive to cortisol and not sensitive at all to aldosterone?

The puzzle only gets deeper when you consider the evolution of aldosterone, the hormone that attaches to MR. Only land vertebrates like ourselves make it. So it must have evolved after our ancestors branched off from the ancestors of living fish, about 400 million years ago. In other words, the lock evolved 50 million years before the key.

Some might argue that this means that these receptors and their hormones could not have evolved by mutation and natural selection. They only have their own personal disbelief to go on, however. Thornton took another tack: he did some tough science.

Thornton and his colleagues reconstructed the ancestral receptor that gave rise to both GR and MR. They figured out the sequence of its gene by comparing the genes for MR and GR in land vertebrates and fish, and also looking at other related receptors. They focused their attention on a 247-nucleotide-long section of the receptor gene. This stretch encodes the part of the receptor to which the hormone attaches. The scientists ended up with a sequence of DNA that had a 94% probability of being the ancestral sequence. Two-thirds of the sequence had a 99% probability. They focused their attention on a section of the receptor where the hormone attaches, measuring 247 amino acids long. They calculated that their reconstruction had a 94% probability of being correct, with two-thirds of the amino acids getting at 99% rating.

The scientists synthesized a gene with this sequence and inserted it into cells. The cells used the new gene to make the ancestral receptor, which the scientists could then test. They discovered–weirdly enough–that the ancestral protein was sensitive three different hormones: aldosterone (the hormone specific to MR), cortisol (the GR hormone), and a third, called DOC.

It may seem surprising that the ancestral receptor would respond to aldosterone, a hormone that did not evolve until tens of millions of years later. But it’s not so surprising when you compare them to living fish. Living fish don’t make aldosterone, and yet it can still attach to fish MR anyway. Obviously, the fish aren’t making these receptors to snag hormones they don’t make. Instead, it seems that in fish, MR are responding to DOC, which is very similar to aldosterone. In the ancestors of tetrapods, DOC evolved into aldosterone and took on its function that it has in our own bodies.

Here’s where the lock and key metaphor can cause mischief. Receptors are not built out of metal. They’re loops and spirals of atoms that can flex. So a receptor that is adapted to respond to one hormone may have the capacity to respond to another one. Scientists call such molecules promiscuous. The promiscuity of proteins is a big area of research these days. It explains, for example, why bacteria can feed on pollutants that were nearly nonexistent a century ago. Some of their proteins evolved for other functions, but had the potential to be used to eat a new kind of food. Thorton’s work suggests that MR was preadapted to respond to aldosterone, much like fish with fingers were preadapted for walking on land.

But if these three hormones could all latch onto the ancestral protein, why is it that today its descendant receptors are specialized only for certain hormones? MR can still respond to cortisol, but it doesn’t appear to get the chance to. That’s because kidneys and other tissues that produce MR also make enzymes that destroy cortisol.

GR is different. It does not respond at all to aldosterone. So somehow it had to lose its ability to latch to aldosterone after it evolved from the ancestral receptor. Thornton and his colleagues found that GR differs from the ancestral receptor by two significant mutations. The scientists tinkered with the ancestral receptor to see how each of these mutations affected it.

One mutation (called L111Q) was devastating. It rendered the receptor unable to latch onto any of the three hormones (aldosterone, cortisol, or DOC). But the other mutation (called S106P) only reduced the ability of aldosterone and cortisol to latch onto the receptor. Its respond to DOC was unaffected. And here’s where things get extremely cool. Thornton took some of these S106P mutant receptors and then added the L111Q mutation. Now the mutation was not devastating at all. The receptors completely lost their ability to respond to aldosterone but recovered their ability to respond to cortisol.

Scientists have discovered this odd feature of mutations in other genes in other species. The effect of a mutation depends on the other mutations that have already affected a gene. Depending on which mutations are already there, a mutation may be harmful, neutral, or even beneficial. So it would have been unlikely that the ancestral receptor could have experienced the L111Q mutation first. Fish that carried it might have lost their ability to respond to any of the hormones. But they could have survived the S106P mutation, and afterwards the L111Q mutation would have had a different effect altgoether. Instead of making the receptor useless, the mutation would have fine-tuned it to respond to cortisol but not to aldosterone.

This study took me quite by surprise. I had been so fascinated by resurrected proteins as a sort of molecular Jurassic Park that it never occurred to me that somebody might use them to work out a step by step hypothesis for the molecular changes that can produce complex systems. I can only wonder how many other proteins–perhaps even precursors to the proteins that give us language or autobiographical memory–will return to tell us their stories.

(This paper will appear tomorrow appears today in Science, but here’s a press release from Oregon.)

Update, Friday 4/7: Here’s my take on the Intelligent Design response to Thornton’s work.

Update, 4/10: And the final take.

Mark Siddall, the leech hunter, is on another quest. He’s posting updated from his journeys through Australia in search of new leeches. Read them at Blood Lust II.

Tiktaalik: music to my ears.

Tiktaalik is the lilting name of a newly discovered fossil fish with fingers. It lived 380 million years ago in the northern reaches of Canada, back when the northern reaches of Canada were tropical coastal wetlands not far from the equator. Tiktaalik’s discoverers (Ted Daeschler, Neil Shubin, and Farish Jenkins) detailed their discovery in back-to-back papers in today’s issue of Nature. In some ways Tiktaalik is big news. It may prove to be the single most important fossil for telling us how our ancestors changed from fish to land vertebrates complete with legs, arms, fingers, and toes. But in other ways, Tiktaalik is no news at all–and its non-newsworthiness makes it just as important.

The history of research on this transition is one of the most fascinating episodes in science. I may be biased in that judgment, having spent half of my book At the Water’s Edge exploring that history. But judge for yourself. Before Darwin, the divsion between fish and land vertebrates (tetrapods) was considered by many to be the most profound split in nature. It was proof positive that life could not have evolved. There was one fish, however, that raised some troubling questions–the lungfish of Brazil. It had lungs and other features once thought unique to tetrapods. Richard Owen, Britain’s great Victorian anatomist, dispatched the lungfish to the realms of Fish by its nose. Its nostrils were closed off from its mouth–like the nostrils of other fish and not like any known tetrapod. It was a fish “simply by its nose,” he wrote.

But in 1860, a year after the Origin of Species, an Irish anatomist Robert M’Donnell, examined a lungfish from Africa and reported that its nostrils actually did connect to its mouth. It was a confusing blur of tetrapod and fish features. “I know of no animal more calculated leading to the adoption of the theory of Darwin than Lepidosiren [the lungfish],” M’Donnell wrote.

Over the next few decades scientists came to recognize that lungfish and coelacanths were the two surviving members of a large group of fish that were more like tetrapods than they were like shark or trout or other fish. They came to be known as lobe-fins, for their peculiar appendages. Today there’s no doubt that lobe-finned fish are the closest living relatives to tetrapods. Scientists have made many comparisons of the DNA of tetrapods, ray-finned fish, lobe-finned fish, and other vertebrates, and again and again, the lobe-fins turn up as close kin.

But in the late 1800s, before anyone knew what DNA was, it was much harder to make the case. The most compelling evidence came from the fossil record. One particularly important fossil was of a lobe-fin called Eusthenoperon, which had some limb-like bones in its fins. And then, for about a century, the discoveries came very slowly.

In the 1920s, scientists exploring Greenland found a 360-million year old fossil of a barrel-chested, flat-headed tetrapod that had a fish-like tail, complete with slender rays along its top. They named it Ichthyostega. They also found a few fossils of what looked like a smaller tetrapod, but the bones remained a puzzle until the 1980s. That’s when Cambridge paleontologist Jenny Clack organized a trip of her own back to Greenland and found bones from several individuals, which came to be known as Acanthostega.

I got interested in Clack’s work in the mid-1990s, as she and Michael Coates of the University of Chicago began publishing the results of their painstaking work. Acanthostega was wonderfully mind-blowing. For starters, it had eight fingers, rather than the standard five that everyone thought was the rule for tetrapods. It’s now clear that the developmental genes that controlled digit growth were not tightly locked into the five-fingered rule when tetrapods first evolved. Perhaps even more remarkable was the fact that Acanthostega would have been a miserable land-walker, despite having nicely formed feet and digits. It didn’t have the hips or shoulders to support its weight, and it had rays on the top and bottom of its tail. It also had bones that likely supported gills. It suggested that the tetrapod body adapted first for life underwater and then was adapted for life on land.

If I remember correctly, my article about Acanthostega, which appeared in Discover way back in 1995, was the first major magazine feature about the beast. I decided to make it a central part of At the Water’s Edge. But then other fossils started turning up.They were just scraps–a jaw here, a shoulder bone there–but they were helping to fill in the transition. Most remarkable I thought was an isolated fin of a lobe fin that was not all that closely related to Acanthostega and land tetrapods. Sauripterus, found by Daeschler and Shubin, had lots of finger-like elements in its fin. It was proof that a lot of independent experiments in limb-like fins were going on around 360 to 380 million year ago.

Writing books about science is massive fun, but it is always followed by an unpleasant aftertaste, as you watch all your work become quaint and dated. But after At the Water’s Edge came out in 1998, I thought the tetrapod section held up pretty well. Acanthostega remained the best known fossil from the transition from lobe-fins to tetrapods. Further down the tree, it was mostly scraps until the Eusthenopteron branch.

Well, that’s all over now, thanks to Tiktaalik. Deschler, Shubin, and Jenkins found three individuals of this species (its name comes for the word for a large freshwater fish in the Inuktitut language). Tiktaalik was a fair-sized creature, perhaps three feet long. It was far more fish-like than Acanthostega or any other tetrapod. It had scales across its back, rays in its fins, and a lot of less visible but no less important traits seen in lobe-fins but not tetrapods. But it also has surprising number of features found in tetrapods, such as a neck on which its head could turn, throat bones that could pump air into its lungs, and some bones inside its fishy fins that were remarkably tetrapod-like.

The scientists dedicate an entire paper just to those limb bones, because the fossils are so good that they can determine how the bones articulated and moved around each other. Unlike Sauripterus, which was a separate experiment in limbs, Tiktaalik’s bones share a clear common ancestry with our own arms and legs. More primitive lobe-fins had shoulder bones that only allowed them to paddle back and forth in the water. Tiktaalik could support itself, bending its wrists to lay its hand-like bones flat on the water bottom. Its powerful ribs and spine gave it more support, and with its eyes stuck right on top of its head, it could look at prey (or predators) swimming overhead.

Tiktaalik’s fins are important not just for what they say about how our fish ancestors lived, but about how any sort of new structure evolves. If you compare your hand to the fin of a fish that’s studied a lot by biologists–zebrafish, for example–it’s hard to see much in common. The fin rays are not made of skeletal bones, and the few skeletal bones they do have don’t correspond in any clear way to our own limbs. So even quite recently some scientists saw the tetrapod limb as a major innovation. But zebrafish are separated from our own ancetry by 400 million years or more of diverging evolution. Now Tiktaalik makes clear that the evolution of arms and legs was not such a big transformation after all. The fins of fish like Titaalik had already evolved much of the limb equipment–down to individual wrist bones–that would emerge in later tetrapods as so important for moving around on land.

So why is Tiktaalik big news and not news at all? It is big news because it blurs the distinction between fish and tetrapod more spectacularly than ever before. It is no news at all, because it is just the sort of creature that one would predict from previously discovered fossils. Its place on our family tree has been cleared and waiting for some time now. And now it’s filled.

A couple weeks ago I wrote about the 98,000 viruses that have permanently pasted their genes into our genome over the past 60 million years. What makes these viruses doubly fascinating is that scientists are making new discoveries about them all the time. Over at the open-access journal PLOS Pathogens, two new papers add some pieces to the puzzle of how these viruses get into our genomes, and how they affect our health along the way.

The first paper offers a striking portrait of a virus hopping species. Researchers at the Cleveland Clinic stumbled across the virus as they were studying prostate cancer that runs in families.

It turns out that some forms of prostate cancer are associated with mutations in a gene called RNASEL. Some studies indicate that one mutation in particular is behind 13% of all prostate cancer cases. If one copy of the gene is mutated, a man’s chances of getting prostate cancer go up fifty percent. If both copies are mutated, his chances double. And yet–as is often the case–other studies on RNASEL failed to make this link. So the scientists wondered if the mutation was just one ingredient in the recipe for prostate cancer, and if some other factor in the environment might have to come into play as well.

A clue to what that factor may be comes from RNASEL itself. When it’s not crippled by a mutation, the gene produces an enzyme that shreds virus genes (in particular, viruses that carry genes on single-stranded RNA as opposed to double-stranded DNA). Viruses are known to play a role in many cancers, triggering cells to replicate like mad. So the scientists wondered if the RNASEL mutation weakened defenses to a particular virus that could contribute to prostate cancer.

To find out, the scientists embarked on a virus hunt. They isolated cells from prostate tumors linked to the RNASEL mutation, and split them open. They placed the contents of the cells on a glass slide studded with 20,000 molecular probes, each tailored to snag a particular fragment of a virus gene. The probes on this so-called Virochip are based on genes of known viruses, but they can also snag genes from previously unknown viruses. That’s because closely related viruses share relatively similar genes.

The scientists discovered virus genes. And not just any virus genes. These genes belonged to a new virus whose closest relatives are found in mice. The biggest genetic fragment the scientists extracted from the cancer cells is 96% identical to murine leukemia virus. It belongs to the remarkable group of viruses that become part of their host’s genome (known as endogenous retroviruses). As I wrote in my earlier post, over the generations these viruses tend to lose their ability to make new copies of themselves and infect other hosts. But murine leukemia virus can still break out. Until now, the virus had only been found infecting rodents. Now, however, it turns out that it is infecting humans as well.

Exactly how the virus turned up in the cancer cells is a mystery. The scientists doubt that the people who developed these particular tumors all got the virus from direct contact with mice. Instead, they suggest that the virus originated in mice, acquired mutations that allowed it to infect other vertebrate animals, and then–some time in the past–infected some people. Then the virus began to spread from human to human. The precise connection between the virus and prostate cancer remains to be discovered. The virus turns out to infect not the cancerous prostate cells themselves but surrounding cells, called stromal cells. It’s possible that infected stromal cells send out signals that cause other prostate cells to turn cancerous. In any case, it would explain the strange mismatch of studies on the link between RNASEL and prostate cancer. A mutation to the gene weakens a person’s defenses, allowing the virus to infect successfully. If the virus is found among some people and not others, association studies will yield different results.

Will this mouse virus find a home within our species as well? It may take hundreds of thousands of years to find out. The virus will need to infect a sperm cell or an egg, so that it can spread from one generation to the next without having to infect a new host. After it makes that transition, only time will tell whether its genes spread through the human population or eventually reach a dead end. That’s how the thousands of in-house viruses we carry have made the transition.

If the mouse virus actually does help cause prostate cancer, treating it may prove to be a major medical advance. Over 30,000 men die of prostate cancer annually, and so blocking the virus might save several thousand lives each year. And understanding these viral shifts may also help in the fight against a more devastating pathogen, namely HIV.

HIV is also a retrovirus, meaning that it inserts its genes into our own. But it is not a live-in virus. It primarily infects one class of white blood cells, and then spreads to other people through shared needles, sex, and other forms of contact. HIV leads to the collapse of the immune system, otherwise known as AIDS. Growing evidence suggests that it does so not by killing cells directly, as once thought, but by chronically overactivating the immune system. As the immune cells divide madly, they eventually start malfunctioning and even committing suicide.

In an opinion piece in PLOS Pathogens, Viktor Muller and Rob J. De Boer point out that most of HIV’s cousins, which infect other primates, don’t do anything of the sort. I’ve reproduced a tree they put together, showing the relationship of HIV-like viruses in apes and monkeys. (Go here for a closer view.) HIV, marked in red, is not a single lineage of viruses. One form, HIV-2, jumped from sooty mangabey monkeys into people several times. The more common form, HIV-1, descends from chimpanzee viruses, which have moved into humans many more times. As the tree shows, lots of primates get infected by their own HIV relatives, and this appears to have been going on for millions of years. But if you look at sooty mangabeys or some other monkey, you generally find abundant amounts of the virus without any sign of an overactive immune system. It’s not that the virus carried by sooty mangabeys is weak. Scientists have injected it into other monkeys, and it has triggered a strong immune response. The blue arrows on the tree mark the rise of new virus strains in macaques that came from sooty mangabeys. This shift appears to have happened at primate research centers in the past few decades. In their new hosts, these viruses cause lots of nasty symptoms.

Muller and De Boer propose an intriguing hypothesis to explain all of this: perhaps apes and monkeys don’t suffer ill effects from these viruses because they carry copies of the viruses in their own genome. After all, the authors point out, HIV’s genes have been isolated in human sperm DNA, so these viruses clearly have the potential to make their way into a host genome. Muller and De Boer suggest that primate viruses got into their hosts’ genome. The young primates then began making proteins from the virus, which their developing immune system recognized as part of their “self.” When the primates then got infected with new copies of the virus, they didn’t mount an attack or become overstimulated. The viruses infected the primate’s immune cells, but they were only a minor burden to the primates compared to a collapsed immune system. Natural selection would have favored the primates who carried these in-house viruses, as those without them died from viral infections.

Muller and De Boer point out that scientists have created a similar kind of tolerance by injecting viruses into mice–specifically into the thymus, the finishing school for immune cells. It would be nice if Muller and De Boer could also point to the DNA of HIV-like viruses sitting in the genomes of primates. They did look at the published sequences and came up dry. But the absence of evidence in this case definitely does not mean the evidence of absence. Only a couple primate genomes have been sequenced so far, and it is possible that simple searches may miss virus genes that have become fragments and have acquired a lot of mutations. Muller and De Boer propose that scientists should closely examine the genes that are expressed in developing immune cells in a wide range of primates. Some of these genes may turn out to be similar to the genes of the HIV-like viruses that infect their species. Another way to the test the hypothesis is to run an experiment in which the tolerance to the virus is blocked. Theoretically, these harmless viruses should become as vicious as HIV.

It’s cool but a little frightening to imagine if Muller and De Boer are on to something. It would mean that primates have not survived their own HIV epidemics by destroying the virus. Nor would it mean that the virus had become more benevolent, in order to spare its host. It would mean that they simply evolved to ignore the virus altogether. I’m not sure I would agree to gene therapy to insert HIV genes into the genome of my children to protect them from HIV. But it might turn out to be the best way to come to an evolutionary truce with the viruses.

Check out Pharyngula on the new paper that uses penguin fossils to time the evolution of living bird groups. In October I posted this picture of a reconstruction of the penguin in question, which now has a name: Waimanu. I’d just add to PZ’s run down that this fossil is also important because it is part of the transition from flying ancestors to flightless living penguins. Its wings could still bend at the elbows.

Randy Olson, who sparked a massive discussion here a couple weeks ago in connection to his movie, Flock of Dodos and how to explain evolution, sends an update:

Hello Carl -

Big news here — the official World Premiere of “Flock of Dodos: the evolution-intelligent design circus,” will be at Robert De Niro’s Tribeca Film Festival on the evening of Sunday, April 30 in New York City, followed by three more screenings during the following days. We will have details on our website next week on how to get tickets. Here’s the Tribeca announcement: http://www.indiewire.com/ots/2006/03/tribeca_fest_un.html

Now before P.Z. Myers and everyone else recoils with, “Oh, no, Robert De Niro’s festival — now he’s REALLY gone Hollywood,” I want to clarify one detail.

Your review of the advance screening at Yale on Feb. 13 produced a wonderful round of discussion on at least eight evolution blogs. And quite a few evolutionists took issue with some of my ten suggestions for improving the communication of evolution. Probably the biggest misperception of what I said was the confusion between “concision” (what I am advocating) and “dumbing down,” (which is rightfully the fear of all good evolutionists).

Concision is the essence of effective mass communication, and its not as simple as dumbing down. Think of it as being similar to solving a mathematical proof. The mathematical clod (like myself) takes 100 steps to make the proof. The skilled mathematician achieves the same proof in three steps. And therein lies the beauty and even art of great mathematics. Its all about simplicity.

Simiarly, the communications clod takes twenty minutes to explain something. The skilled communicator takes three minutes to explain the same thing. And I mean EXACTLY the same thing. And therein lies the beauty of great communication.

Some people are naturally better than others at communication, but everyone can get better by raising it up as a higher priority. I have given sloppy. poorly thought out and unrehearsed talks as a scientist, and I have given carefully structured, concise, well rehearsed talks as a scientist. The former were all very easy. The latter took a lot of work and a prioritization of almost as much effort in the communicating of the science as in the doing of the research.

Its not clear how much the research environment has changed over the past thirty years. But what is undeniable is that the communication environment has changed drastically. And this is the central point of my film. So at the risk of annoying a lot of very nice scientists (like P.Z. Myers), I look forward to continuing this discussion over the upcoming year. And hopefully see you all at Tribeca.

- Randy Olson