Recently I blogged about how the mere existence of whales might be an important clue to treating cancer.  That post has drawn many readers, and many questions in the comment thread.

Happily, the authors of the review I described–Carlo Maley of the University of California, San Francisco, and Aleah Caulin of the University of Pennsylvania–have joined the thread. They’ve answered the first set of reader questions and promise to come back to respond to the rest. Further proof of the majesty of blogs…

[Update: Here's their next batch of answers.]

Last summer I wrote in the New York Times about a controversy over one of the most influential concepts in the recent history of evolutionary biology. Known as inclusive fitness, it basically says that helping relatives can be a good way to pass on your genes, because they’ve got your genes too.

In August, Nature published a lengthy paper by Martin Nowak, E.O. Wilson, and Corina E. Tarnita in which they argued that inclusive fitness was mathematically flawed and basically superfluous. I had no trouble finding other scientists who were ready to say all sorts of scathing things about Nowak et al. I’m no fan of ginning up fake debates, but when somebody says, “This paper, far from showing shortcomings in inclusive fitness theory, shows the shortcomings of the authors,” the story writes itself.

Seven months later, Nature has finally published some “Brief Communication Arising” letters from some of these critics. The first letter alone has 137 co-signers.

Their ranks include plenty of major players in the field of evolution (including John Alcock, Tim Clutton-Brock, Stephen Emlen, Paul Sherman, Mary-Jane West Eberhard, and Richard Wrangham). The tenor of the letters is more dignified than the comments I got for my story, but the message is unchanged:

We believe that their arguments are based upon a misunderstanding of evolutionary theory and a misrepresentation of the empirical literature.

The authors of the first letter argue that Nowak et al don’t get inclusive fitness. They claim it needs lots of stringent assumptions, when, in fact, it’s a general theory. They also challenge the idea that inclusive fitness doesn’t provide any more insights into biology. They offer a list of such insights, such as why animals cooperate with each other, why they can act spitefully, and why mothers produce different ratios of males and females. Inclusive fitness has proven particularly useful for addressing last question–what’s known as sex allocation. It explains how the ratio of males to females changes with the density of females, the mortality rate, and many other factors–and it does so for species as varied as mammals, birds, spiders, and plants.

Nowak et al respond to all the criticism and don’t budge in their own stand. They claim that their critics have misinterpreted their own argument. And they claim that sex allocation does not require inclusive fitness. Oddly, though, they never explain why it doesn’t, despite the thousands of papers that have been published on inclusive fitness and sex allocation. They don’t even cite a paper that explains why. They conclude by writing,

Inclusive fitness theory is neither useful nor necessary to explain the evolution of eusociality or other phenomena. It is time for the field of social evolution to move beyond the limitations of inclusive fitness theory.

[Image from Alex Wild]

Today I’ve got a story about some new research into evolvability–the potential to reach new adaptations. Scientists have explored the possibility of evolvability for some time now, but mostly through analyzing mathematical equations. Now a new study offers a fine-grained picture of evolvability in action.  Richard Lenski of Michigan State and his colleagues have watch evolvability help one line of bacteria beat out another one. It’s a Darwinian story of the tortoise and the hare. Check it out.

(For more on evolvability, check out this review by Massimo Pigliucci [pdf])

[Image: Wikipedia]

Charles Darwin pictured evolution as a grand tree, with the world’s living species as its twigs. Scientists identify 10,000 new species a year, but they’ve got a long, long way to go before finding all of Earth’s biodiversity. So far, they have identified 1.5 million species of animals, but there may be 7 million or more in total. Beyond the animal kingdom, our ignorance balloons. Scoop up some sea water or a cup of soil, and there will likely be thousands of new species of microbes lurking there. Fortunately, a lot of the species that scientists discover each year are fairly close relatives to species we already know about. There may be plenty of beetle species left to be discovered, for example, but they will all end up as tufts sprouting from the same beetle branch.

Making matters more complicated is that the tree is, in some ways, more like a web. Genes sometimes slip from one species to another, especially among microbes. There are lots of ways this can happen. Viruses can ferry these genes from species to species; in other cases, microbes may just slurp up naked DNA. In the process, they blur genealogy.

This can be a hard concept to grok, so let me offer a blogger’s analogy. Let’s say that Ed Yong and I meet up at a conference. We shake hands. Little do I know that Ed has perfected his Yong-o-matic Horizontal Gene Transfer Injector. A portion of his genes invade the skin on my hand, slip into my cells, and replace some of my own genes. Later, I decide to pay for a DNA ancestry test, curious to find out exactly where I come from. The tests come back, indicating that my ancestors are not, as I once thought, from Europe, but from China.

It’s not just individual genes that can slip from one species to another, either. On rare occasions, entire cells have merged together, creating entirely new kinds of life (like us). Cell fusions and horizontal gene transfer are probably best portrait by interconnected branches, rather than diverging ones. The base of the tree seems especially tangled, more like a mangrove rather than an oak.

With all those caveats in mind, here’s a rough picture of the tree of life that Norman Pace of the University of Colorado offered in a scientific review he published in 2009. It shows life divided up into three domains: eukaryotes (that’s us), bacteria, and archaea.

There’s a lot of debate about whether eukaryotes actually split off from within the archaea, or just branched off from a common ancestor. Nevertheless, the two forms of life are quite distinct. For one thing, the common ancestor of living eukaryotes acquired oxygen-consuming bacteria that became a permanent part of their cells, called mitochondria. They’re keeping you alive right now.

A lot of scientists wonder how all the new species that scientists are discovering are going to change the shape of this tree. Will its three-part structure endure, with each part simply growing denser with new branches? Or have we been missing entire swaths of the tree of life?

It’s possible–but just possible at this point–that we have missed a big part of it.

One clue came to light in December. A team of French scientists have been studying weird bunch of viruses officially called Nucleocytoplasmic Large DNA Viruses (NCLDV). I’m just going to call them giant viruses, because they are quite huge. Grotesquely so. As I write in my upcoming book, A Planet of Viruses, they were mistaken for years as bacteria. They were a hundred times bigger than any virus known at the time.. Giant viruses are indeed viruses, however. They hijack host cells the way all viruses do, for example.

But giant viruses also explode a lot of conventional ideas of what viruses are supposed to be. Not only are giant viruses monstrously big, but they are overloaded with genes. A flu virus has just ten genes, for example, but a number of giant viruses have well over a thousand. Giant viruses even get infected by viruses of their own.

For years, researchers have been finding that the diversity of genes in viruses is tremendous. It turns out that giant viruses are particularly bizarre, genetically speaking. Didier Raoult and his colleagues compared one set of genes in giant viruses to their counterparts in other lineages. Here’s the evolutionary tree they came up with. (The giant virus genes are shown in red.)

The genes are so different, the scientists argue, that giant viruses represent a fourth domain of life. Here’s an impressionistic figure they created to show how the four domains emerged from the web of gene-trading early on in the history of life (from left to right, archaea, bacteria, eukaryotes, and giant viruses).

Today Jonathan Eisen of UC Davis and his colleagues publish still more evidence for a possible fourth domain. (Some of the evidence can be found in a paper in PLOS One; the rest is in a shorter note at PLOS Currents.) Their evidence comes from a voyage Craig Venter and his colleagues took in his yacht, scooping up sea water along the way. They ripped open the microbes in the water and pulled out all their genes. The advantage of this approach is that it allowed the scientists to amass a database of literally tens of millions of new genes. The downside was that they could only look at the isolated genes, rather than the living microbes from which they came.

Eisen and his colleagues decided to compare the versions of a few genes that are found in all living things and are very useful for reconstructing evolutionary trees of the grandest scale. (The genes are called small subunit rRNA, recA, and rpoB). They found that a lot of the genes they analyzed belonged to species that are closely related to species that scientists already know about.

But some are different. Very different. In fact, they represent some of the oldest branches on the tree of life. In this figure, for example, they compare versions of the RpoB gene in giant viruses (red), bacteria (purple), eukaryotes (blue), and archaea (green). Two branches that turned up in the global ocean survey are in cyan. Unknown 2 seems to be like the giant viruses, but Unknown 1 is just off the map.

Eisen and his colleagues consider it possible that these genes come from a fourth domain. Analyzing the ancient history of genes is notoriously tricky, with lots of opportunities for spurious results to crop up, so this possibility might soon evaporate. But scientists have a number of tools at their disposal to test the results. In this case, the first order of business will be to find more of these exotic genes to see if they continue to fall into a distinct domain of their own. TIf they do, scientists will need to track down the actual organisms that carry them. Are they viruses, or are they true cells? That discovery might show how this possible fourth domain got its start. Did it start out as ordinary cellular life, and then some of its genes ended up in viruses? Or is the fourth domain another sign that life as we know it actually originated as viruses? Answering those questions will be tough. And redrawing the tree of life will probably be even tougher.

[Update: For lots more, go to Eisen's own blog post.]

Last week I wrote in the New York Times about a fascinating new paper in which scientists described a lamp shell embryo that is, in effect, a swimming eyeball. The paper itself, however, comes in two parts. Along with the part on the swimming eyeball, the scientists also described a later stage of the lamp shell embryo in which it developed simple eyes connected to neurons. It’s primitive version of our own eyes that reveals some interesting things about evolution–particularly about the different photoreceptors that evolved over half a billion years ago for sensing light. At the time, I was struck by the fact that this one paper had two newsworthy insights. So I was glad to see PZ Myer takes up the other half of the story in excellent detail over at Pharyngula. Check it out.

Tomorrow’s Science Times section of the New York Times has a special package of articles all about animals–the relationship between humans and the animals we raise, what makes us separate from animals, and so on. I took the opportunity to take a big step back and look at how animals came to be in the first place. The answer–or at least part of it–lies among some weird creatures, such as this tentacled creature that dwells inside snails. Check it out.

If you’ve just been bitten by a venomous snake and your flesh is starting to rot and you can’t breathe, you may not be in the mood to hear how beautiful snake venom can be. But from a safe distance, it really is a marvel to behold.

Snake venom is a blend of molecules, many of which are exquisitely adapted for wreaking havoc. Some are enzymes that slice muscles apart. Some grab onto proteins that normally form clots, so that a snake’s victim can’t stop bleeding. Many snake venoms attack the nervous system with molecular precision that’s so good that neuroscientists have snakes to thank for some of their biggest discoveries.

In the 1950s, two researchers in Taiwan–CY Lee and CC Chang–decided to study the venom of the banded krait. A bite from the snake, native to Taiwan, caused paralysis and shallow breathing–suggesting to the scientists that the snake’s venom must interfere in an interesting way with the nervous system’s control of muscles.

Nerves trigger muscles to contract by releasing the neurotransmitter acetylcholine. At first Lee and Chang assumed that the snake venom must cut acetylcholine apart, but they found it had no effect. Instead, they discovered, the banded krait venom prevented neurons from responding to acetylcholine and from releasing their own. These two changes were caused by two different proteins in the venom of the banded krait, which Lee and Chang dubbed α-bungarotoxin and β-bungarotoxin.

In 1970, Lee went to Paris. He wanted to present his results to Jean-Pierre Changeux, a neuroscientist at the Pasteur Institute in Paris who was at the forefront of deciphering the molecular structure of neurons. He was thrilled by Lee and Chang’s research, because it looked as if that α-bungarotoxin was latching onto a receptor for acetylcholine. Scientists assumed that such a receptor existed, but no one had found it yet.

Lee collaborated with Changeux and Michiki Kasai to test out the toxin on neurons from electric eels. Just as Changeux had hoped, the krait venom latched onto one receptor in particular. Using the venom as their guide, the scientists could purify a big enough supply of the receptors to figure out its structure–the first time such a feat had ever been accomplished for a receptor on a neuron.

Soon, this discovery bore medical fruit, by allowing scientists to understand a disease called myasthenia gravis. Myasthenia gravis slowly weakens the muscles, making it hard to swallow, talk, and keep one’s eyelids open. In 1973 scientists at Johns Hopkins applied radioactive α-bungarotoxin to muscle tissue from people with myasthenia gravis. The radioactive venom latched onto their acetylcholine receptors, allowing the scientists to count them up. They discovered that people with the disease had fewer receptors than normal.

Researchers wondered if the immune system was mistakenly attacking the receptors and destroying them. If that were true, then you’d expect people with myasthenia gravis to have antibodies to the receptors. In 1976, scientists from the Salk Institute mixed together radioactive α-bungarotoxin and acetylcholine receptors and then added them to serum from people with myasthenia gravis. Just as the researchers had predicted, the serum was loaded with antibodies that attacked the receptors. Today, neurologists use α-bungarotoxin to diagnose the disease. There’s no point in trying to make a better probe, when snakes have evolved such a good one already.

In a review to be published in the journal Bioessays, Freek Vonk of Leiden University (picture above with a king cobra) and his colleagues describe how venom is continuing to make its way into the clinic. A crucial part of this translation is understanding how snakes evolved such a rich pharmocopeia. By comparing the genes for venom with other genes, scientists have found that they’ve been borrowed away from other functions. Many animals–ourselves included–make enzymes that attack microbes. In snakes, this molecule evolved into a structure that let it attack muscle. It doesn’t attack the snake’s own muscles, however, because the gene for it only becomes active in the cells of the snake’s venom gland.

This transformation has occurred many times over, and, as Vonk and his colleagues explain, it is made possible by several different kinds of mutations. In some cases, the genes are duplicated, so that one copy can go on doing its original job, while the other is free to evolve to do a beter job at a new one–in this case, killing prey. It’s also possible for cells to use one gene to make two different proteins. Genes are made of segments, and cells can use different combinations of segments to make different proteins (a process called alternative splicing). The DNA from gene segments can also get swapped from one venom gene to another, adding new loops and pockets to proteins to give them new opportunities to attack.

This creative evolution didn’t just turn non-venom into venom. It also let venom evolve into new forms. Snakes, scientists are finding, often carry venoms fine-tuned for their prey of choice. Some species of saw-scaled vipers make arthropods their prey, while others attack mammals. The venom of the mammal-specialists is useless against arthropods like scorpions.

As a result of this evolution, scientists have lots of different venoms to explore to see if they’re useful in medicine. Millions of people rely on venom to keep their blood pressure in check, for example. ACE inhibitors were isolated from Brazilian pitvipers, which use the molecule to make their prey black out from a drop in blood pressure. Saw-scaled vipers make blood-thinning venoms, which have been turned into an anticoagulant drug called tirofiban. A number of venom drugs are now in the pipeline to treat cancer, bacterial infections, and other ailments.

Scientists are developing ways to test out venoms faster. Instead of trying them out on mice, for example, some researchers are figuring out how to inject venom into zebrafish eggs. And Vonk and his colleagues think that there are a vast number of venoms for these scientists to investigate. While scientists have been studying venoms for decades, they’ve focused their attenion on the ones that are dangerous to humans. Yet most snakes–even seemingly harmless ones without fangs or complicated venom glands–turn out to produce venom. You won’t get killed by a garter snake’s venom, but it may be enough to slow down a rat that the snake wants to eat. And the molecules made by these “harmless” snakes are just as interesting, chemically speaking, as anything made by a king cobra.

Of course, Vonk and other snake experts won’t be able to study those venoms if the snakes become too rare to find. A lot of the habitats where snakes live are under siege, and some preliminary surveys suggest that snakes may be in a worldwide decline. If they go of into that dark night of extinction, they’ll take their medicines with them.

(For more on venom, see my articles in the New York Times here and here. And also check out Vonk giving snakes the Steve Irwin treatment )

Here’s one of the weirder things I’ve come across in biology. When lamp shells are just tiny 36-hour-old embryos–just a clump of a few hundred cells–they can see. Many cells on their outer surface express a photoreceptor gene, and they show evidence of being able to swim towards light. In other words, these lamp shells are swimming eyeballs.

Aside from the surrealism, this discovery is also cool because it might be a model for how our own eyes evolved. Perhaps they started out in a similar way. For more details, check out my story in today’s New York Times.

[Image: Coreldraw]

Strictly speaking, there should be no blue whales.

Blue whales can weigh over a thousand times more than a human being. That’s a lot of extra cells, and as those cells grow and divide, there’s a small chance that each one will mutate. A mutation can be harmless, or it can be the first step towards cancer. As the descendants of a precancerous cell continue to divide, they run a risk of taking a further step towards a full-blown tumor. To some extent, cancer is a lottery, and a 100-foot blue whale has a lot more tickets than we do.

Aleah Caulin of the University of Pennsylvania and Carlo Maley of the University of California, San Francisco, have done some calculations of the risk of cancer for blue whales thanks to their huge size. We don’t know a lot about cancer in blue whales, because blue whale oncology wards would be a wee bit awkward for everyone involved. So Caulin and Maley extrapolated up from humans.

About thirty percent of all people will get cancer by the end of their life. Scientists have been able to build good models for the odds of developing certain forms of the disease. For example, Peter Calabrese and Darryl Shibata of USC put one together last year for colorectal cancer. The colon is made up of a series of pockets called crypts. Inside of each crypt are a few stem cells that continually produce new cells that act as the lining for the colon.Calabrese and Shibata reasoned that the odds of getting colorectal cancer at a certain age depend on the odds of mutation at each cell division, the number of stem cell divisions a person has experienced, how many mutations are required to develop full blown cancer, the number of stem cells in each crypt, and the numuber of crypts in the colon.

Calabrese and Shibata found that their equation churns out results that are close to actual medical records. (Five percent of people get colon cancer by the time they’re ninety.) Their equation doesn’t just match the overall rise in colorectal cancer through life for the population as a whole. It also accurately predicts that tall women are more prone to colorectal cancer than short women–because they’ve got longer colons.

In a review in the journal Trends in Ecology and Evolution, Caulin and Maley took Calabrese and Shibata’s model and ramped it up to blue-whale scale. They found that the huge size of the animals means that by the age of fifty, about half of all blue whales should have colorectal cancer. By age 80, all of them should have it. It’s likely that blue whales should have far higher rates of other kinds of cancer, too.

Blue whales do get cancer, but it’s hard to believe that they get it at the rates that come out of Caulin and Maley’s calculations. Blue whales are known to live well over a century. Bowhead whales have reached at least 211 years. If blue whales really did get cancer as fast as the models would suggest, they ought to be extinct.

The failure of the model means that blue whales must have some secrets for fighting cancer. “The mere existence of whales suggests that is possible to suppress cancer many-fold better than is done in humans,” Caulin and Maley write.

The mere existence of whales is the most glaring example of what biologists call Peto’s Paradox. There seems to be no correlation between body size and cancer rates among animal species. We run a thirty percent risk of getting cancer over our life time. So do mice, despite the fact that they’re 1000 times smaller than we are. All animals studied so far have cancer rates in that ballpark. (And yes, sharks do get cancer.)

Caulin and Maley argue that when animals evolve to larger sizes, they must evolve a better way to fight against cancer. It’s possible that a blue whale simply has a souped-up version of our own defenses. We have proteins that monitor our cells for over-eager growth, for example; they can kill or zombify cells that on the road to cancer. When the genes for these gatekeeper proteins mutate, a cell becomes more likely to become cancerous. The opposite also seems to be true: Scientists have engineered mice to have extra copies of these gatekeeper genes, and they’ve found that the animals become more resistant to tumors.

Caulin and Maley suggest that nature has carried out this experiment as well. We have one copy of a gatekeeper gene called TP53, for example. Elephants–which are at a greater risk for cancer–have a dozen copies of the same gene.

Other defenses might include a more powerful immune system that can destroy new tumors. Big animals may have also lost some genes that make them particularly prone to developing cancer. And anatomy itself can offer a defense, Caulin and Maley point out. As the cells in each colon crypt divide, for example, the older ones get pushed up to the top and get sloughed off. As a result, there are few steps from stem cell to the final cell in a lineage. With fewer steps, we run a lower risk of developing cancer. Bigger animals may have evolved even more effective architectures.

It’s also conceivable that big animals enjoy defenses to cancer merely by being big. Big animals have a lower metabolic rate for their weight than smaller animals. With a lower metabolic rate, big animals produce fewer harmful byproducts that can cause mutations. One pretty wild benefit of being big has been proposed by John Nagy and his colleagues: big animals can kill cancer with cancer. Nagy’s idea is that tumors can develop “hypertumors”–cancer cells that parasitize their fellow cancer cells. Hypertumors would slow down their host tumors, making them less harmful to an animal. And since big animals can handle bigger tumors, their bodies would allow cancer enough time to develop hypertumors. It’s an interesting idea, but Caulin and Maley note that it has yet to be tested.

Then again, few of the other ideas they offer have been tested yet. But Caulin and Maley lay out a roadmap for doing so. Scientists could look at closely related species that span a big range of sizes, searching for telling differences in their cancer defences. Whales and dolphins would be a good pick, since blue whales are 2,000 times bigger than the petite Commerson’s dolpin.

But such an undertaking would have to overcome a lot of inertia in the world of cancer research. Cancer biologists don’t look to big animals as models to study–which is one reason there’s not a single fully-sequenced genome of a whale or a dolphin for scientists to look at. For most cancer researchers, mice are the animals of choice.

But if we want to find inspiration for cancer-fighting medicines, mice are the last animal we’d want to consider. It’s like learning how to play baseball from a bench-cooler at a Little League game, when Willie Mays is waiting to dispense his wisdom.

[Image: Photo by Ryan Somma]

[Update: various typos fixed, and a link to the paper added.]

Behold the Japanese white-eye, considered an invasive species in its new home in Hawaii. Yet the bird does something that conservation biologists might considered useful for sustaining ecosystems: it spreads the seeds of native Hawaiian plants. Get rid of the Japanese white-eye, and you get rid of its service.

In Yale Environment 360 this morning, I take a look at a controversial proposal that’s making its way into the peer-reviewed biology literature: some introduced species are actually beneficial. I wrote about the complicated relationship between non-native species and biodiversity a couple years ago in the New York Times. In my new article, I focus on two new papers (here and here) in which scientists are advancing these ideas further. Reconsidering exotic species is just one part of a bigger vision they’re offering: in a human-dominated world, we will often have to give up the idea of restoring ecosystems to a pre-human state; instead, we should focus on ensuring the ecosystems are as resilient as possible, because they’re going to be facing even tougher times in years to come.

As one of the scientists say, the idea is now edgy, but not nuts. Not nuts, maybe, but certain one that continues to draw the ire of many critics, some of whom I interview in the article. Check it out.

[Image: Tristan Shears/Flickr via Creative Commons]

Here’s the video of the lecture I gave last week at Stony Brook University, which was the basis of my recent blog post. I’ve uploaded the slides as a pdf here. (You can read the slides online or download them by going to the File drop-down menu.) I’m not sure what the ideal combination of video and slides would be…if anyone has any suggestions, let me know.

[Update--the video url got switched around. This should work now...]

If you’re interested in language, computers, and human cognition, check out my brother Ben’s first piece for the Atlantic, in which he pops the hype balloon that has inflated around the Watson computer’s performance on “Jeopardy.” Suddenly, my stash of Simpsons trivia has become profound!