Cancer evolves. Those two words may sound strange together. Sure, birds evolve. Bacteria evolve. But cancer? The trouble arises from the fact that cancers, unlike birds and bacteria, are not free-living organisms. They start out as cells inside a person’s body and stay there, until they’re either wiped out or the person dies.*

Yet the same forces that drive the evolution of free-living organisms can also drive cancer cells to become more aggressive and dangerous. Evolution becomes our inner foe if mutations disable a cell’s self-restraint. The cell multiplies. Sometimes a new mutation arises in its descendants. If the mutations allow the cancer to grow faster, the cells carrying it will take over the population of cancerous cells. Natural selection and other processes that drive evolution on the outside start driving it on the inside.

Like so many other scientists, researchers who study cancer evolution have jumped on new technology for sequencing genomes on the cheap. They’re now starting to publish fine-grained histories of the disease, tracking individual mutations as they arise and spread. Nature has just published a fine example of this new research. I particularly appreciated the informative pictures they came up with to accompany the paper, one of which I’ve included here. You can click on the picture for a bigger version. And below the picture, I’ll explain what it means.

In the new paper, Li Ding and colleagues at Washington University describe a study they carried out on eight people suffering from acute myeloid leukemia (AML), a disease of the immune system. In people with AML, stem cells in the bone marrow that would normally turn into white blood cells instead become cancerous. Treatments include bone marrow transplants and chemotherapy. Unfortunately, AML has a nasty way of bouncing back from chemotherapy, and the drugs become useless to stop it. As a result, a lot of people who seem at first to be in remission eventually die of the cancer.

The Washington University scientists reconstructed the history of the cancer in each patients by sequencing genomes from a number of cells. To determine the normal, original genome, they sequenced DNA from a healthy skin cell. They then sequenced genomes from cancer cells taken from the patients when they were first diagnosed. And then they looked at genomes of cancer cells that emerged after the patients relapsed. From this survey, they came up with a catalog of new mutations that emerged over the course of the cancer. They could then go back into the blood samples and estimate what fraction of the cancer cells had a given mutation at a given point in time.

This figure illustrates the sad chronicle of one particular woman they studied. When she was in her late 50s, she suddenly came down with a sore throat and began to bruise easily. A bone marrow biopsy confirmed she has AML. She got chemotherapy, and then a stem cell transplant. Although she seemed to go into complete remission, the cancer returned 11 months after her diagnosis. The chemotherapy drugs that had previously been so effective now could not stop the cancer. Other drugs failed, too. Two years after her diagnosis, she died.

On the left of the figure, the cancer begins. A single stem cell mutated and became the founder of the cancerous lineage. we start with normal cells. (The cell is dark, and the grey dot marks its original mutation. HSC stands for hematopoietic stem cells).

The cancer cells grew in number, and as they did, they accumulated a lot of mutations, some of which are listed in the figure next to the star. All of these mutations, one after the other, took over the entire population of cells–a signature of natural selection. When the woman went to her doctor, however, the cancer had diversified into a number of different lineage, each carrying additional, distinctive mutations. Over half of the cells belonged to a lineage marked here in purple, known as cluster 2. Cluster 3, marked in yellow, was made up cells with a separate set mutations. And from within Cluster 3 emerged yet another lineage–Cluster 4, marked in orange. The dots in each circle show the sets of mutations that accumulated in each cluster.

The chemotherapy knocked down all the clusters of cancer cells to such low numbers that doctors couldn’t find them any more. But they were still there. And when exposed to chemotherapy drugs, the most successful cluster was not the one that had been most successful back when the cancer was diagnosed. It was the relatively rare Cluster 4. Apparently, it had mutations that made it better able to withstand the chemotherapy drugs. Some its descendants later picked up new mutations, which enabled them to reproduce quickly and take over the cancer population, as they resisted new chemotherapy drugs as well.

“The AML genome in an individual patient is clearly a ‘moving target,’” the scientists right conclude. “Eradication of the founding clone and all of its subclones will be required to achieve cures.” Easier said than done, of course. The parallels between this research and studies on antibiotic resistance in bacteria are sobering. But at least now we’re starting to see what kind of evolutionary challenge we’re really up against.

(*For one very cool exception to this rule, consider the case of Tasmanian devil facial tumors, which travel from devil to devil. They evolve too, though.)

I’ve written a few times here about the battle over a virus called XMRV, and its supposed link to chronic fatigue system. I just wanted to point this morning to a few articles by some fine writers about the latest twist: the paper that first claimed a link has been completely retracted.

Ivan Oransky in Reuters

Jon Cohen in Science

Ewen Callaway in Nature

[Image: Wikipedia]

In 1494, King Charles VIII of France invaded Italy. Within months, his army collapsed and fled. It was routed not by the Italian army but by a microbe. A mysterious new disease spread through sex killed many of Charles’s soldiers and left survivors weak and disfigured. French soldiers spread the disease across much of Europe, and then it moved into Africa and Asia. Many called it the French disease. The French called it the Italian disease. Arabs called it the Christian disease. Today, it is called syphilis.

I’ve been intrigued by the murky history of syphilis for a few years now. The text above is from the start of an article I wrote for Science in 2008. At the time, scientists were split between two explanations for sudden appearance of syphilis at the end of the fifteenth century. According to one, it was caused by bacteria that had evolved in the New World and were brought back to Europe by Columbus’s crew. But other researchers found many skeletons with signs of syphilis in Europe, Africa, and Asia that appeared to have been from long before Columbus’s voyage. They argued that it must have started in the Old World, perhaps before people even left for the New World some 15,000 years ago.

As I explained in the article, one way to test these hypotheses is to survey the evolution of the bacteria. A group of researchers based at Emory University came across bacteria infecting Indians in Guyana that was genetically close, but not identical, to syphilis. They suggested syphilis had evolved in the New World from a common ancestor of both pathogens. Columbus’s crew may have picked it up when they visited the New World and then brought it home to Europe. Unfortunately, by the time doctors had gotten the bacteria from the jungles of Guyana to a laboratory where it could be analyzed, the DNA was in bad shape, so they couldn’t come to a firm conclusion.

Recently, I caught up with one of the scientists on the team, Kristin Harper, who is now at Columbia University. She didn’t have any new genetic results to talk about, unfortunately, although she may before long. In the meantime, she pointed me to a new review she has published in the Yearbook of Physical Anthropology. She and her colleagues took a look at the bones that scientists have pointed to as evidence for the antiquity of syphilis in both the New and Old World, and passed judgment about just how good the evidence was that they did, indeed, have syphilis, and not some other disease that can deform bone. The scientists also took a close look at the dating of the bones, since the timing of syphilis’s origin is so crucial to the entire debate.

The trouble with a lot of past research, Harper says, is that scientists have come up with new ways to diagnose syphilis in ancient bones without offering good evidence that their criteria are good. “Paleopathology is kind of the wild west of science, in that the ‘rules’ are still in their infancy,” Harper said. “We set ourselves the challenge of using only evidence-based diagnostic criteria in this paper and tried to be similarly stringent about dating.”

The scientists looked at 54 reports from both hemispheres. Most of the Old World bones failed to meet at least one of the standard requirements for a diagnosis of syphilis, such as distinctive pits on the skull or swelling in the long bones of the arms and legs. But when they looked at the Old World bones that had been dated to before 1492 that did make the grade, they ended up throwing all of those bones out, too. The evidence that these Old World bones were from before 1492 turned out to be weak. They tended to come from coastal regions, where people eat lots of fish. Fish are full of carbon from deep in the ocean, which has a different balance of isotopes than that found on the land. The ocean carbon gets into the bones of coastal people, where it can throw off estimates of their age by centuries. A close examination of these coastal Old World bones led the Emory scientists to conclude that they belonged to Europeans who died shortly after Columbus’s voyage.

“In contrast,” Harper told me, “we found definite cases of treponemal disease [syphilis] hailing from the New World that stretched back thousands and thousands of years.”

Harper and her colleagues conclude that there’s no good evidence for syphilis in the Old World, and plenty in the New World. They continue to argue that syphilis traveled east across the Atlantic.

It’s intriguing if Harper turns out to be right. Europeans brought smallpox and other pathogens to the New World which decimated its residents. Syphilis, it seems, is one pathogen that went the other way.

[Image of Columbus voyage: Wikipedia]

[Update, 12/19 7 pm: Some of the comments prompted me to edit this piece for clarity.]

Story Collider is a monthly performance where people tell stories about science. (Think The Moth in a lab coat.) The organizer, Ben Lillie, invited me to tell a personal story about the place of science writing in my life. I decided to talk about a memorable night in South Sudan, when I wondered what I was living for.

I told the story to a great crowd at Union Hall in Brooklyn last week. And you can hear the podcast at the Story Collider web site. Check it out.

I’ve devoted a few posts (here and here and here) to the saga of a disputed link between chronic fatigue syndrome and a virus called XMRV. This week marks the next chapter in the story, with more evidence that the original results were at least partly due to contamination and a partial retraction of the original paper. Two great writers at Science, Martin Enserink and Jon Cohen, have put together an epic telling of this affair, from the first reports two years ago to the latest developments. The magazine has wisely put the piece out in front of their paywall. Do read it.

As Enserink and Cohen note, this is not the final word. That will probably come early next year, when a larger study led by Ian Lipkin of Columbia. We’ll see then if the link is buried at last, or lives to see another day.

In tomorrow’s New York Times, I have a profile of Arthur Horwich, a medical geneticist who has spent a quarter century trying to figure out the workings of this beautiful molecular box. Today he won the Lasker Award, a prize for medicine that has often gone to scientists who later won the Nobel. Why all accolades for a little box? Because without it, you’d be dead. And as Horwich and others have discovered what goes on inside, they’ve helped change the way we understand the biology of the cell. Check it out.

[Image of GroEL from Molecular Chaperone Group, Birkbeck College]

In the wake of last year’s earthquake in Haiti, cholera arrived on the island for the first time in 60 years. According to the World Health Organization, 419, 511 Haitians got sick with cholera as of July 31, of which 5,968 died. The infection rate is dropping right now, but the arrival of Hurricane Irene could change that.

As I wrote in December, scientists applied evolutionary biology to find clues to how cholera–or, more precisely, the bacteria Vibrio cholerae– came to Haiti. They compared the DNA in the strain in Haiti to ones that have been found in other parts of the world. From this analysis, they drew a tree, which I’ve reprinted below.

The bacteria in Haiti was more closely related to strains in South Asia than ones from South America. So it was unlikely that cholera came to Haiti floating by water from a nearby country. The evolutionary tree led credence to idea that U.N. peacekeeping troops, some of whom came from Nepal, brought it with them by plane. An outbreak of cholera hit Nepal in September 2010, shortly before a battalion of Nepalese peacekeepers left for Haiti.

This analysis was a bit like a picture taken from 10,000 feet in the air. The bacteria that the scientists analyzed were just a small selection of the many strains that have made people sick over the past few decades. Notably missing from the tree were any bacteria from Nepal. That’s because those strains had not made their way into bacteria collections.

To get a picture up close–and to test the idea that U.N. peacekeepers brought cholera to Haiti–a team of Nepali, American, and Danish researchers collected 24 samples in Nepal at the end of last year. They sequenced the entire genomes of bacteria and compared them to the genomes of Haitian cholera. They reported their results today in the journal mBio.

And here’s their close-up tree. It clearly shows that the Haitian cholera strain evolved from one of four related lineages of V. cholerae circulating today in Nepal. It differs from the Nepalese strain by a single mutation.

It’s amazing that genome-sequencing methods have gotten so powerful that scientists can now use entire genomes to reconstruct an intercontinental outbreak. Yet ten months passed from the outbreak to the publication of this paper. In a blog at the mBio site, co-author Paul Keim explains why: politics. Governments can be reluctant to give up samples that might make them look bad. Building an evolutionary tree of a deadly outbreak takes more than data: it can take a lot of diplomacy, too.

Update: Martin Enserink, writing in Science, raises the question of whether the United Nations should compensate Haiti for the outbreak that this study now clearly lays at their doorstep. Hoo boy!

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.]

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 )

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.]