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.]

The nightmare that is the cholera epidemic of Haiti (2,100 dead so far) has become a little less mysterious. Haiti has not seen cholera for over a cenutry, and so the emergence of cholera in recent weeks has puzzled scientists and led to riots directed at the U.N. for supposedly bringing Vibrio cholerae to the Caribbean nation. Others have pointed to a New World strain as a potential culprit. It triggered an outbreak in Peru in 1991, and has circulated in Central and South America ever since. Perhaps these bacteria washed up on Haiti’s shores.

In the latest issue of the New England Journal of Medicine, Matthew Waldor of Harvard and his colleagues go some distance to settling the debate by finding the Haitian cholera’s place in the tree of life.

“Collectively, our data strongly suggest that the Haitian epidemic began with introduction of a V. cholerae strain into Haiti by human activity from a distant geographic source,” the scientists write. The bacteria belong to a strain that evolved in South Asia. It was probably introduced onto Haiti by a sick person who flew there. We may never know who made the delivery, but it was a terrible blow not just to Haiti but perhaps to other New World countries. The South Asian strain is, unfortunately, deadlier than the Peru strain and resistant to antibiotics to boot. Waldor and his colleagues warn that unless the bacteria are stopped now, they could outcompete the milder Peru strain.

“Clearly, the provision of adequate sanitation and clean water is essential for preventing the further spread of the Haitian cholera epidemic,” they write. Let’s hope we can prune future branches of this deadly tree.

What will the world be like when your genome sequence costs less than a cell phone? A couple days ago I went to Cambridge, Mass. to find out.

The occasion was a meeting called “Genome, Environments, and Traits,” or GET for short. The history of the meeting is in the upper ranks of my list of meetings with strange histories. In 2006, the Harvard geneticist George Church (arguably the smartest, most influential biologist you never heard of) decided to launch a new kind of human genome project. At the time, scientists had only published the sequence of a single human genome, at a cost of $3 billion. And for all that money, the genome was actually a gap-riddled patchwork from several individuals, and only included the DNA from one copy of each pair of chromosomes. Church declared that he would gather the sequenced genomes of 100,000 individuals, along with information about their health, and make all that information available for scientists to study in order to learn more about human biology. Church issued a manifesto of sorts in Scientific American, called “Genomes for All,” which you can read here (pdf) and also talked to Emily Singer of Technology Review here.

To kick off his Personal Genome Project, Church sequenced his own DNA, put it online, and promptly got a message from a doctor on the other side of the country, informing him that he should adjust his cholersterol medication. Church also persuaded nine other people to volunteer to have their genomes sequenced and laid out online for all to see. One of those first ten, the Harvard psychologist Steven Pinker, helped spread the word with this article that in the New York Times Magazine in 2009.

Those early sequencees got together from time to time to talk about the project and their own experiences contending with having a genome available for all to see. This genomic club was an intimate one at first, but its membership is now exploding. With each passing month, the cost of genome sequencing is crashing, companies are gearing up to sequence genomes on a commerical scale, and scientists are starting to think seriously about looking at complete genomes as a regular part of clinical practice. For this year’s meeting, Church decided to try to get as many people with sequenced genomes as possible altogether in one room. It would probably be the last time such an exercise would be possible.

I got pulled into the fun when my phone rang a couple months ago. On the line was Robert Krulwich. Krulwich is the co-host of the show Radiolab, covers science for NPR and ABC News, and is also the go-to guy for live–and lively–interviews with towering figures of science. (Observe him handle both E.O. Wilson and James Watson at once–a bit like juggling torches while riding a unicycle. He doesn’t break a sweat.)

Church had asked Krulwich to come to the meeting and moderate a discussion of a dozen or so sequencees that would take up the first three hours of the meeting. Krulwich decided this was a two-person operation. Wise move. This was heavy lifting.

It would be absurd to have everyone one the stage the whole time, so we came up with a scheme to move people quickly from the front row of the audience to the stage, playing a genomic game of musical chairs. Making it even more challenging was the fact that we had such big subjects to talk about, from the development of next-generation sequencing to the application of genomics to genealogy to the issues of privacy that genome sequencing raises.

And then there was the matter of the line-up. Any one of the speakers could have held the stage on his or her own for an hour. It felt very strange whisking Henry Louis Gates onto the stage and then whisking him off. This, after all, is a guy who can hold an entire TV series together. At the meeting, he talked about getting his father’s genome sequenced as well as his own–becoming the first father-son team to do so. A comparison of the two genomes allowed him to see fifty percent of the genome of his deceased mother–an experience that felt like seeing her come back to life. Gates talked about the experience of seeing so much European DNA in his genome. If you look at my lab results, he said, I’m a white man.

–Well, we’d love to hear all about it, Professor Gates, but we’ve got to move on! A round of applause everyone, and let’s move those chairs!

Krulwich and I also struggled with the challenge of talking about genomics with people who are so uniformly gung-ho about it that they’ve had their genomes sequenced–and of talking to those sequencees in front of an audience made up of genome scientists, people from the biotech sector, venture capital folks, and other assorted people who are, shall we say, already in the genomic tank. Neither Krulwich or I received a fee for our involvement in the meeting, and we were not about to join the ranks those miserable fake journalists you see on infomercials late at night, pitching pre-scripted softballs like, “So tell me again how your company is going to become a raging success in the personal genome business.”

Krulwich and I therefore tried, politely, to nudge the sequencees out of their comfort zone. How on Earth, I wondered, could the sophisticated analysis of genomes become a regular part of everyday medicine when most doctors have office full of old paper records? Was it fair to children to get their genomes sequences when there was nothing immediately wrong with them? What good is getting your genome sequenced if all you get is a laundry list of genetic variations that have obscure relationships to all sorts of diseases that you may or may not get? How can there be a business in genomes if, as Church predicts, the cost of genome sequencing will be dropping to, essentially, free?

In many cases, questioners and answerers ended up talking past each other. Krulwich asked James Watson what he thought about the ethical concerns about genome sequencing. His answer: “Crap.” The other sequencees were more polite when we asked questions that seemed irrelevant to them. When Krulwich asked sequencee Esther Dyson about the potential risks of getting her genome sequenced, Novocell CEO John West pointed out that she was preparing to go to the Space Station. Why were we obsessing about the risks of Dyson’s genome, with no apparent concern that she was about to have herself shot into space on the tip of a rocket?

I think the best answers were deconstructions. Consider this: Widespread genome sequencing will make it possible to test babies for genes associated with intelligence. Isn’t that a horrible thing?

At the meeting, Church pointed out that we already test for intelligence genes, and nobody gets outraged at all. Babies are routinely tested for a genetic disorder known as PKU, in which children are born unable to break down an amino acid called phenylalanine. Phenylalanine builds up to toxic levels in the body, leading to mental retardation. But the mutation that causes PKU does not necessarily cause PKU. Genes are not destiny. If children keep a diet low in phenylaline, they end up with normal intelligence. Knowledge of our genome is not sinister in this case. Ignoring the facts of PKU would be the sinister thing to do.

Church is right, but the story of PKU only carries you so far into the future of genomic medicine. PKU is a rare disorder, affecting an estimated 1 child out of every 13,500 to 19,000 births. It’s also unusual in that it’s caused by the failure of a single enzyme. A single mutation to a single gene is enough to cause it. And the fact that it can be so readily treated is also unusual. Cystic fibrosis, for example, is another single-gene disease. Despite the discovery of its genetic basis 20 years ago, doctors have no cure to offer CF patients.

The genetic roots of common disorders, like high blood pressure and Alzheimer’s disease, have proven to be a lot more complex. It’s possible that the risk for some common diseases may be the result of variations on hundreds of genes, with each variation contributing a tiny fraction of the risk, and different combinations able to cause just as much of the disease. It’s also possible that the risk for some diseases is due to very rare mutations, each of which has very strong effects. There may be a lot of these rare mutations in the world’s population, making it hard to find them all and figure out what they do.

The sequencees at GET didn’t avoid this messy reality. In fact, one of them embodied it. James Lupski, a Baylor College of Medicine geneticist, suffers from a hereditary disease called Charcot Marie Tooth Disease, in which the coating of the long nerves in the limbs starts to fray. He has had to have operation after operation on his feet to treat the symptoms. Lupski studies the cause of the disease, and recently he had his genome sequenced to find its source. He turned out to have some mutations that have been linked to Charcot Marie Tooth Disease before, but he and his colleagues also found a new gene, with a different mutation in his mother’s and father’s copy. The discovery did not point immediately to a cure; instead, it added to the complexity of the disease. Lupski explained his own disease and his difficult research on it in unsentimental detail. Science is hard, Lupski said, and anybody who thinks it isn’t is fooling themselves.

It was too bad that the meeting didn’t take place next week instead of this week. Today, the Lancet published a genome paper that included among its co-authors two of the sequencees we spoke with: George Church and Steven Quake of Stanford. At the meeting, Quake explained how he and his colleagues had sequenced his genome last year in a matter of days. That was the easy part, he said. The hard part was analyzing it and interpreting what it meant for Quake’s health. He was referring obliquely to the new paper.

In the paper, Quake, Church, and their colleagues made a close study of Quake’s family (who have suffered from various sorts of heart disease), and then scoured the scientific literature for every mention of the variants they found in Quake’s genome. They considered the risks these variants posed to Quake for various conditions, but they also took into consideration other sorts of complexity. For example, diseases don’t happen in isolation from each other. If you get obese, for example, you increase your risk of type 2 diabetes. The scientists published a marvelous diagram of the diseases they studied in Quake, with the size of each name corresponding to the size of his risk for each.

The geneticist Daniel Macarthur wrote tonight about this new paper on his blog Genetic Future:

…there are the variants that simply can’t be interpreted. This includes virtually everything seen outside protein-coding regions, and the majority of even those variants found inside coding regions. We simply don’t understand the biology of most genes well enough yet to be able to predict with confidence whether a novel variant will have a major impact on how that gene operates; and we have an even less complete picture of how genes work together to affect the risk of disease.

Like Lupski said, science is hard.

I was wiped out by the end of the morning session. I thought we did a pretty good job, although I still felt ambivalent. I scarfed some lunch and then happily settled into the audience for the afternoon. Most of the talks I heard dealt not with humans but with microbes. The genome of a microbe like E. coli is about a thousandth the size of a human genome. As a result, microbiologists can sequence genomes like mad without busting their budgets. Ian Lipkin of Columbia has hunted for the causes of new outbreaks, such as colony collapse disorder in bees, by fishing out new kinds of microbial DNA from sick hosts. Boom, boom, boom, one slide after another documented the discovery of yet another pathogen. The benefits of DNA sequencing were blindingly obvious in Lipkin’s talk.

But even microbes turn out to have fantastic genomic complexity. There may not be a lot of genes in each microbe, but together they can hold a staggering amount of genetic diversity. Rob Knight of the University of Colorado spoke about the surveys he and his colleagues have made of the human microbiome. He described some of the work I’ve blogged about here on the Loom, along with other results. He described, for example, how children become coated with the bacteria that live in their mother’s birth canal as they are born. Women who have a caesarian section give their children the bacteria living on their own skin. Knight is investigating whether the birth canal germs provide any special protection to children. Different people develop different menageries of microbes as they get older, and their experiences–from gaining weight to taking antibiotics–can shift the ecosystem inside their bodies. There’s much left to discover about the thousands of species that share our bodies with us, but Knight raised the prospect of a different kind of personalized medicine: using genomics to survey the microbes in our bodies and then manipulating them for our own benefit.

Then again, maybe you shouldn’t trust me on this score. Everyone knows I’m in the microbial tank.

The day ended with a talk by Anne West, the 17-year-old daughter of John West. The Times of London recently broke the story of how the Wests became the first healthy family to get their genome sequenced. I expected warm and fuzzy blather about what her genome meant to her, but instead, she delivered a hard-core talk that would have fit right into a genetics conference. She analyzed one of her genes involved in blood clotting and determined that she had a few harmless mutations from her mother and one harmful one from her father. Facing an audience full of past and future Nobel-prize winners, biotech barons, and other intimidating grown-ups, she remained impressively poised and calm.

The audience was rightly impressed. One scientist joked that she should drop out of 11th grade and get a job–finishing school would be a waste of her time. But I also had to remind myself of the hothouse atmosphere in which she had done this work, and in which she was delivering her results. Her father had spent upwards of $200,000 on the family’s genomes, according to the Times. This was not your standard science fair project. And as West spoke, I thought about the kids from a local public high school who had come for the morning session. When Krulwich and I asked the audience for questions, a girl stood up and asked how she could get her mother to have their family’s genomes sequenced, when her mother wasn’t even sure what a gene is. Two girls: two very different experiences with genomes. It’s not all about the DNA.

[PS--Thanks to all the Twitterers who acted as a note-taking collective. Their assembled chronicle is here.]

Measles looks to be 1000 years old. It jumped from cattle. And you can read more about it here.

Can the bacteria in our bodies control our behavior in the same way a puppetmaster pulls the strings of a marionette? I tremble to report that this wonderfully creepy possibility may be true.

The human body is, to some extent, just a luxury cruise liner for microbes. They board the SS Homo sapiens when we’re born and settle into their assigned quarters–the skin, the tongue, the nostrils, the throat, the stomach, the genitals, the gut–and then we carry them wherever we go. Some of microbes deboard when we shed our skin or use the restroom; others board at new ports when we shake someone’s hand or down a spoonful of yogurt. Just as on a luxury cruise liner, our passengers eat well. They feed on the food we eat, or on the compounds we produce. While the biggest luxury lines may be able to carry a few thousand people, we can handle many more passengers. Although the total mass of our microbes is just a few pounds, the tiny size of their cells means that we each carry about 100 trillion microbes–outnumbering our own cells by more than ten to one.

It’s important to bear in mind that you can carry this galaxy of microbes around and enjoy perfect health. These microbes, for reasons that are not entirely clear, behave like well-mannered passengers. They do not barge into the kitchen, take a cleaver to the cooks, and then eat all the food. Aboard the SS Homo sapiens, the crew includes a huge staff of security guards armed with lethal chemical sprays and other deadly weapons, ready to kill any dangerous stowaway (also known as the immune system). For some reason, the immune system does not unleash its deadly fury on the microbes–even when the microbes are fairly close relatives to truly dangerous pathogens.

In fact, our microbial passengers may actually help out the cruise liner’s crew. They can close up the ecological space in our bodies, so that invading pathogens can’t get a solid foothold. Some species in our guts can break down our food in ways that we can’t, and synthesize certain vitamins and other compounds beyond our biochemistry. The genes that the microbes carry–millions of them–expand our biochemical powers enormously.

To understand the human microbiome better, scientists have been cataloging the microbes in and on people’s bodies, and they’ve been sequencing their DNA. (Listen to my recent podcast with biologist Rob Knight for more.) Yesterday, Nature published a head-spinningly huge study on the microbiome from a team of European and Chinese researchers. Lurking in the stool of 124 volunteers, the scientists found, were 3.3 million microbial genes. The scientists identified a core of bacteria species carried in most people’s guts, as well as other species that varied from person to person.

As Ed Yong rightly points out, this study is most impressive as a titanic database. It is not the Theory of Everything for the human microbiome. That will take a lot longer to build, because the microbial ecosystem inside of us is so complex. Individual species don’t just sit in isolation, surviving in their own special way. Microbes cooperate with one another to get the food they need and produce the conditions in which they can thrive. In Microcosm, for example, I write about research suggesting that E. coli–a minor member of the gut ecosystem–may keep oxygen levels low enough for other species to invade and dominate. And it’s not as if there is some Platonic ideal of a microbiome that we all carry around with us from birth to death. The diversity of microbes I carry is different from the one you carry, and they both change over our lifetimes. Every time we take a dose of antibiotics, for example, the balance can change dramatically. And as the diversity of microbes changes, so do its ecological functions.

Which brings me, at last, to the possibility that the human microbiome can become our puppetmaster.

First some background. A lot of parasites have evolved the ability to manipulate their hosts for their own benefit. (I get into more detail about this in my book Parasite Rex and in this segment of the show Radio Lab.)

Very often, the parasites cause hosts to do things that help the parasites, instead of themselves. For example, a protozoan called Toxoplasma needs to get from rats to cats, and to help the process along, it makes rats lose their fear of cats. Parasites can also change the diet of their host as well as the way in which their hosts digest their food. Parasitic wasps living inside caterpillars, for example, cause catepillars to convert the plants they eat into compounds that supply quick energy (good for wasp larvae growing quickly) instead of storing them as fat for their own metamorphosis.

I was reminded of this sinister manipulation by a paper that was published in Science today by Rob Knight and his colleagues. They built on previous research that revealed that mice genetically engineered to be obese have different kinds of microbial diversity in their guts than normal mice. Scientists have found that if they transfer microbes from an obese mouse to a regular mouse that has had all its own germs stripped out, the recipient mouse will develop extra fat. In the case of these obese mice, it appears that the microbes become less efficient at helping the animals digest food, triggering a series of changes that leads the mice to be fat.

Knight and his colleagues discovered a different–and more disturbing–way that microbes can make mice fat. They started out by engineering mice so that they didn’t produce a protein normally found on the surface of gut cells, called TLR5. TLR5 can recognize bacteria, and some studies suggest that the cells can then pass along signals to the immune system, possibly sending a stand-down command so that the immune system doesn’t start trying to kill the microbes (and end up killing gut cells too).

Born without TLR5, mice got 20% fatter than normal. Not only that, but the mice had lots of other familiar symptoms that go along with being overweight, such as high levels of triglyceride, cholesterol, and blood pressure. Without TLR5 exerting its soothing influence, the mice suffered from chronic inflammation, probably thanks to the low-level war they were waging on their microbes. And things got worse for the mutant mice when they had to eat a high-fat diet. They gained more weight on a high-fat diet than regular mice, suffered even more inflammation, and even ended up diabetic.

The obesity of these TLR5-deficient mice was not the result of inefficiency, as in previous studies. Instead, the mice wanted to eat more–about 10 percent more than regular mice. Knight and his colleagues restricted the diet of the mutant to what the regular mice ate. A lot of their symptoms went away. So the change in their behavior was critical to their weight change.

The scientists also discovered that the make-up of the microbial diversity changed significantly in the mutant mice. Were the microbes giving the mice their symptoms? To find out, Knight and his colleagues knocked out the microbes with antibiotics. The mice ate less, put on less fat, and showed less diabetes-like symptoms.

To isolate the effects of the microbes even more, the scientists transferred them from mutant mice into the bodies of ordinary mice that had first had all their own germs stripped out. Remember–these mice have a normal set of TLR5 receptors. The scientists found that the microbes made the recipient mice hungry–and also made them obese, insulin resistant, and so on.

So here we are. Mice with a genetic make-up that alters the diversity of their gut microbes get hungry, and that hunger makes them eat more. They get obese and suffer lots of other symptoms. Get rid of that particular set of microbes, and the mice lose their hunger and start to recover. And that distinctive diversity of microbes can, on its own, make genetically normal mice hungry–and thus obese, diabetic, and so on.

When I first learned of this work, I asked Knight–with a mix of dread and delight–whether the microbes were manipulating their hosts, driving them to change their diet for the benefit of the microbes. He said he thinks the answer is yes.

This discovery doesn’t just have the potential to change the way we think about why we eat what we eat. (Am I really hungry? Or are my microbes making me hungry?) It also provides a new target in the fight against obesity, diabetes, and related disorders. What may be called for is some ecological engineering.

[Update: Links to papers fixed.]

It’s been nearly ten years since President Bill Clinton stood on the White House lawn with a team of scientists to announce the completion of the first survey of the human genome. “Today, we celebrate the revelation of the first draft of the human book of life,” he said. It’s a pleasing metaphor, but it’s deeply flawed. There is not a single Human Book of Life. If there were, after all, Clinton and the scientists and all the rest of us would all be identical clones.

There is a vast amount of genetic variation from person to person, and from one continent to another. The survey that Clinton was announcing was a cobbling-together of DNA from several individuals. Since then, researchers have produced much higher-quality reads of the genomes of actual people. They’ve learned a lot from those studies, but, in the scope of human genetic diversity, these studies have been timid ventures. If you compare someone from South Korea to someone of northern European descent, you’re only capturing a small sliver of the variation in our species. If you really want to get into the thick of it, there’s really one place to go: Africa.

This chart helps to illustrate why. If you trace the origins of the genetic material in our species, you end up in Africa. One reason we know this is that human populations outside of Africa share some genetic markers that Africans lack. That’s consistent with the hypothesis that Homo sapiens evolved in Africa, and then a small group of Africans migrated off the continent and gave rise to all the other populations of humans alive today. Another clue is in the genetic diversity of Africans themselves. Looking at relatively small collections of DNA, scientists have found much more genetic diversity in Africa than elsewhere. That would make sense if African populations have existed longer than populations elsewhere, giving them more time to accrue new mutations.

Africa is, of course, a huge continent, with a billion people and 2000 distinct ethno-linguistic groups. Some of those groups, including some of the most populous ones, are relatively young. In some cases, they expanded over large areas as they developed agriculture. Some smaller ethnic groups are only distantly related to other Africans, since their ancestors split off a long time ago. Those groups are crucial to a full-spectrum picture not just of African diversity, but the diversity of all humanity.

So it’s heartening to find that today scientists are publishing a genome of a man from one of those deeply diverging groups–the Khoisan of southern Africa, also known as the Bushmen of the Kalahari.

The Khoisan are not a single group of Africans, but a large number of small groups. They originally probably spanned much of southern Africa, making a living by hunting and foraging for food. Bantu farmers moved into southern Africa much later, taking up a lot of the arable land. Most Khoisan live now in Botswana and Namibia, eking out a precarious existence.

A team of scientists from the United States, Australia, and Africa sequenced the complete genome of a Khoisan named !Gubi (far left in the top photos). They also sequenced portions of the genomes of three other Khoisans from Namibia to gauge the diversity within the group. And, for comparison, they also sequenced the genome of a Bantu from South Africa. Not just any Bantu, mind you, but none other than Archbishop Desmond Tutu.

The survey confirmed the conclusion of earlier studies: Khoisans have a lot of genetic diversity. On average, each pair of the Khoisans differed at 1.2 out of every 1000 nucleotides (the “letters” of DNA). On average, a European and an Asian differ at 1 out of every 1000.

Khoisans lack some key adaptations that arose in Africans who have taken up agriculture. For example, they lack a mutation that allows adults to digest milk. They also lack a common mutation that provides resistance to malaria–a disease that took off when parasite-carrying mosquitoes could lay eggs in farm fields and bite farmers sleeping in nearby huts. But these absences don’t mean that Khoisans are primitive cavemen, or that their genomes are a time capsule from antiquity. Most of the distinctive features of their genomes arose only after their ancestors split off from the ancestors of other humans. A number of those new mutations show some indications of being adaptations for life in the desert, such as controlling levels of salt in the blood.

Understanding the genome of Khoisans is not just interesting in itself, but important to the well-being of all people on Earth. To figure out the effects of genes on our health, scientists scan DNA from lots of people, looking for variations that are strongly linked to certain diseases. As I wrote last year in Newsweek, it’s been a struggle. One reason is that the list of genetic variations we’ve been using has, until now, been too short. In the new study, the scientists found 1.3 million differences between Khosians and the reference human genome against which all human DNA is compared. Just as intriguing are some of the variants that Khoisans have that are found in other populations. Some of these familiar variants have been linked to serious diseases. Yet all the Khoisans who were tested in the new study were around 80 years old and in excellent physical shape. The effect of these variants may actually depend on variations in other genes. To figure out what any one human genome means for a person’s health, scientists need to look at a full spectrum of human genomes. The Book of Life is not enough. We need to read the Library of Life.

[Images: Schuster et al, "Complete Khoisan and Bantu genomes from Southern Africa," Nature, doi: 10.1038/nature08795, Campell and Tishkoff]

Deep down, we are all cannibals. In tomorrow’s issue of the New York Times, I take a look at the science of autophagy: how our cells destroy themselves to live again. It turns out that this cellular cannibalism is crucial for our well-being in many ways. Scientists are now trying to improve our ability to destroy ourselves as a potential treatment for diseases like cancer and Huntington disease, and perhaps even to slow the process of aging itself. Check it out.

(Note to link-lovers: the article takes you directly to some of the primary literature. Progress!)

[Image: Royal Academy of Arts]

Congratulations to Elizabeth Blackburn, Carol Greider, and Jack Szostak, who just won the Nobel Prize in Physiology or Medicine this morning. They won for their discovery of telomeres, the caps on the ends of chromosomes that keep them from degrading and ward off aging. The Nobel site has posted some useful information about why this was such a profound discovery.

As a science writer, I often find it sobering to read scientific history. Science works slowly, even though we wish it would work in nanosecond breakthroughs.

In 1913, for example, a Russian scientist named Nikolai Anichkov ran an experiment in which he had egg yolks fed to rabbits. On this cholesterol-heavy diet the rabbits developed atherosclerosis. The more cholesterol the rabbits ate, the bigger the deposits on their blood vessels became. It was a tremendous discovery, considered by some one of the greatest in medical history.

But it did not lead overnight to a treatment for heart disease. In fact, it did not even lead, on its own, to a clear understanding of how cholesterol ends up in the blood vessels. Instead, it focused the attention of later scientists on the question of cholesterol. It took many years for scientists to figure out the steps by which enzymes produce cholesterol molecules. Then scientists began searching for drugs that might interfere with those enzymes.

In 1971, six decades after Anichkov ran his egg-yolk experiments, Akira Endo of Tokyo Noko University and his colleagues, decided to see if microbes made natural cholesterol-fighting compounds (free pdf). They reasoned that such a compound would be a potent weapon against microbial competitors, since cholesterol and related molecules are essential for building cells. In 1973 they found a fungus that blocks a key enzyme in the cholesterol pathway. It took more than another decade before drugs based on Endo’s explorations, known as statins, reached the market. Today drugs like Lipitor are prescribed to millions of people.

If a journalist wrote an article on Anchikov’s intial research, the most accurate headline would have been something like: “RUSSIAN SCIENTIST DISCOVERS LINK BETWEEN MOLECULE AND HEART DISEASE. WILL LEAD TO POWERFUL NEW MEDICINE IN EIGHTY YEARS.”

Of course, it would be a rare journalist who would be able to see eighty years in the future like that. And headlines about events readers won’t be alive to see can seem awfully remote. Anchikov’s discovery did not change the lives of the people who could have read about it at the time. Their grandchildren, yes.

I’ve been thinking about Anchikov recently, after having read a letter to the New England Journal of Medicine. It’s by Joel Hirschhorn of Harvard, on the subject of genomes.

A decade ago a complete sequence of the human genome was still a dream, although a dream close to becoming real. In a typical article from 1999, a reporter wrote that “scientists hope to treat diseases in much the same way that software engineers fix faulty computer programs, by isolating flaws in the code.” Once we could read the entire human genome, the article promised, nothing would be the same: “By identifying the genetic roots of illnesses like cancer and heart disease, some experts say, the science of the genome, or genomics, may make it possible for a child born today to live to 150–or, some say, much longer.”

What a difference a decade makes. Scientists have been finding many genetic markers for common diseases like heart disease and diabetes, but they’re not pointing the way to obvious treatments. The falling cost of DNA is letting scientists sequence genomes left and right–not just people’s genomes, but the genomes of their cancer cells and their microbes. And for now, scientists are drowning in data rather than plucking out new cures.

Hirschhorn wants the growing number of skeptics to keep history in mind. In his NEJM letter he writes,

New biologic insights do not guarantee a rapid translation into clinical practice; the latter will require great effort by basic, translational, and clinical researchers. The difficulty in translation is not unique to genetic discoveries: nearly a century and three Nobel Prizes separate the determination of the chemical composition of cholesterol from the development of statins. Each discovery of a biologically relevant locus is a potential first step in a translational journey, and some journeys will be shorter than others. With a more complete collection of relevant genes and pathways, we can hope to shorten the interval between biologic knowledge and improved patient care. 

In the next issue of Newsweek, I consider the near-term and the long-term future of genomes. My essay is called “The Gene Puzzle.” Check it out.

[Animation: Wikipedia]

Here’s a vision of how science may work in the future.

Last month I scrambled to write a story about the evolution of swine flu for the New York Times. I talked to some of the top experts on the evolution of viruses who were, at that very moment, analyzing the genetic material in samples of the virus isolated around the world. One scientist, whom I reached at home, said, “Sure, I’ve got a little time. I’m just making some coffee while my computer crunches some swine flu. What’s up?”

All of the scientists were completely open with me. They didn’t wave me off because they had to wait until their results were published in a big journal. In fact, they were open with the whole world, posting all their results in real-time on a wiki. So everyone who wanted to peruse their analysis could see how it developed as more data emerged and as they used different methods to analyze it.

Now, a little over a month later, they’re publishing their results in the journal Nature. Normally we press folks would get a press release about the paper a week before publication, and it would be under strict embargo till it appeared in the journal. This morning, however, I got a press release pointing me to the published paper. And while Nature normally requires you to subscribe to read a paper, the flu paper is published under a Creative Commons license, which means anyone can get it and use it under the license’s terms.

While that’s all very exciting, the paper itself is an anxiety-triggering read. The new swine flu (which the authors now call S-IOV S-OIV) is only distantly related to other known swine flus, which means that there are a lot of flu viruses circulating around about which we know very little. And, as I mentioned in my article, it had already entered the human population several months before it came to light earlier this spring. Be sure to check out figure 1 (I’m inserting it below from the wiki–thanks, Creative Commons!), which shows how lots of bird, swine, and human season flu viruses mixed together to produce the new beast. The authors warn that the pattern of evolution they see is the sort of pattern the big flu pandemics followed when they emerged in the past.

With this sort of urgent situation at hand, the patient process of old-fashioned science publishing may have to be upgraded.

[Image: CDC]

3quarkdaily just picked up my little rant about an awful piece of science writing. They accompanied their post with a picture of the scientist profiled in the article, Hina Chaudhry. That juxtaposition made me a bit queasy–let me just make clear that I was not criticizing Dr. Chaudhry, just the article about her. Dr. Chaudhry is doing what scientists should: running experiments and getting her results published in peer-reviewed journals. Here’s a free link to a 2007 paper of hers on regenerating heart tissue. It’s up to us science writers in turn to find a better way to describe a scientist than as a “a pretty lady.”

Cancer is not just a terrible disease but a strange one. Tumor cells must switch on certain genes in order to thrive and multiply. You might expect that natural selection would have eliminated those genes, because they kill off their owners. Far from it.  A number of cancer genes, known as oncogenes, have actually been favored by natural selection over the past few million years. Oncogenes, in other words, have boosted the reproductive success of their owners, and have even been fine-tuned by evolution.

Humans are not alone in getting cancer. In fact, it seems to be a pretty inescapable risk of being an animal. As cells divide and mutate, some mutations may make cells ignore the needs of the body and multiply madly. That’s too bad for other animals, but there’s a silver lining for us: by studying other animals, scientists can get some clues to how cancer evolves in us.

The delicate swordtail (Xiphophora cortezi) is particularly prone to getting melanomas (the bottom picture here shows a fish with a tumor in its tail). When Andre Fernandez and Molly Morris of Ohio University went fishing for delicate swordtails in mountain streams in Mexico, they found six fish with melanomas in a single day’s catch. These melanomas are particularly nasty–instead of striking old fish that are going to die soon anyway, they turn up in young breeders and kill them over a few months.

Melanomas develop from pigment-producing cells in the skin. As these tumors develop, the cells inside them produce lots of extra proteins from a gene called Xmrk. Despite Xmrk’s harm, it has survived in good working order for a long time. Functioning versions of Xmrk exist not just in delicate swordtails, but in related swordtail speices that descend from a common ancestor that lived a few million years ago.

How does such a dangerous gene continue to survive for so long? Fernandez and Morris have just published an experiment that might solve the mystery.  A lot of delicate swordtails have large dark spots on their tails, like the one shown on the top fish here. Xmrk is essential for producing those spots. Other fish have been shown to use stripes, spots, and other visual patterns to attract mates. So Fernandez and Morris wondered what the female delicate swordtails thought of the Xmrk spots on males.

Turns out, they like them a lot. When offered a chance to pay a visit to one of two male fish, female delicate swordtails from two populations in Mexico spent more time with spotted males than spotless ones. And they also preferred to consort with males with big spots over males with little ones.

The Xmrk gene definitely imposes an evolutionary cost on fish. But that cost may be erased by the benefit it gives male fish through sexual selection. By the time a male delicate swordtail dies from an Xmrk tumor, he may have mated with a number of females, which will pass down the gene to their young.

We humans may also be shaped by the trade-off between sexual selection and the cost of cancer.  Testosterone and related hormones latch onto androgen receptors on the surface of some cells. It’s important for the development of men’s bodies, for example, and the growth of body hair. It also plays a role in the production of sperm. These kinds of traits can affect the success men have in finding mates and having children. But the androgen receptor gene also becomes active during prostate cancer. In fact, versions of the gene that increase sperm count in men also raise the risk of cancer.

For more on the sexy side of cancer, check out my article in Scientific American which, I’m happy to report, was selected by author Sylvia Nasar to be included in The Best American Science Writing 2008, which has just been published. (Take a browse online here.)