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.
Today, a company called Ion Torrent announced they were going to start selling a DNA-sequencing machine that can sequence an entire human genome for $1,000. It’s just the latest milestone in the long-term crash in the cost of gene-reading. There are lots of benefits that will flow from this ongoing transformation. For one thing, as I wrote in 2010 in the New York Times, it’s getting easier to identify new viruses that could turn to be the next HIV or SARS.
To research my story, I paid a visit to the Center for Infection and Immunity at Columbia University. On the day I dropped by, Ian Lipkin and his colleagues were very busy:
Some researchers were examining New York flu, others African colds. The blood of patients with mysterious, nameless fevers was waiting to be analyzed. There was dried African bush meat seized by customs inspectors at Kennedy Airport. Horse viruses, clam viruses: all told, members of Dr. Lipkin’s team were working on 139 different virus projects. It was, in other words, a fairly typical day.
Some of the research that was going on that day–specifically, the research on JFK bushmeat–was published today in the journal PLOS One. The Columbia researchers collaborated with a network of other scientists at the Centers for Disease Control, the Wildlife Conservation Society, Tufts University, the American Museum of National History, and the EcoHealth Alliance to do the first pilot study of the viruses that are carried from country to country by the wildlife trade.
They undertook the study because many of the world’s worst diseases are the result of pathogens switching from animal hosts to us. HIV started out as a chimpanzee virus, which first infected hunters in Cameroon. SARS started in bats, and then spread to palm civets, which then transmitted the virus to people in Chinese animal markets. There’s no reason to think that we’ve seen the last virus jump to our species. So scientists are starting to set up monitoring programs, in the hopes of reducing the chance that the next spillover is not a complete surprise.
As illustrated by HIV and SARS, a lot of viruses come our way through trade in animals. At first, this trade was small-scale. A hunter might come out of the jungle and barter some monkey meat for shoes. Chinese animal markets bring animals from hundreds of miles away. And today, with planes hopping between continents every day, the wildlife trade is now moving animals–and the viruses they carry–around the planet. About 120 million live animals are illegally imported into the United States every year, along with 25 million kilograms of meat and other wildlife remains. The animals that customs agents seize come most often from countries such as China, Hong Kong, and Nigeria–countries that plagued with some of the most worrisome animals viruses, such as Nipah virus and the H5N1 bird flu. It’s likely that West Nile virus first came to the United States in a bird destined for the pet trade; after first showing up in 1999, it’s now found throughout much of the country. Yet nobody has systematically looked at the viruses being brought into the United States through the bushmeat trade.
The authors of the new study studied wildlife products seized by customs agents at JFK airport between 2008 and 2010, and later also looked at additional seizures in Philadelphia, Washington, Houston, and Atlanta. (The gruesome picture above, from the paper, is a primate head seized at JFK.) All told, they looked at 44 animals. Nine were primates, and the rest of were rats. The scientists isolated DNA from the meat to identify which species it came from. Their sources including chimpanzees and several species of monkeys.
The scientists then fished for genetic sequences of viruses. As they report today, they found a bunch. All nine primates the scientists studied had viruses in them–a variety of simian foamy viruses, cytomegaloviruses, and lymphocryptoviruses, all of which have worried scientists for their potential to cross over from animals to humans.
Since this was just a preliminary study, the scientists did not run experiments to see how well the viruses could infect human cells. So we don’t know if these viruses posed any threat to humans. But that’s no reason to get complacent. The scientists only studied nine primates, after all–a tiny sample of the torrent of primate bushmeat that comes into the country each year. And then there are the swarms of reptiles, mammals, and birds that come into the country as well, carrying potentially dangerous viruses that the scientists didn’t even look at. If people going through customs had to declare all the animal viruses they were bringing into the country, the list would likely be frighteningly long.
This is a story of about how the parts of a puzzle locked into place 800 million years ago. The puzzle is an ion pump that you can find in any mushroom, mold, or yeast. I’ve reproduced a picture of it here.
Fungus cells, like our own cells, have lots of little pouches inside of them for carrying out special kinds of chemical reactions. In order for those reactions to work, there have to be a lot of positively-charged protons inside the pouches. To get those protons into the pouches, ion pumps like this one force them through membranes.
This pump (which is is offically known as a vacuolar ATPase complex) is a wonderfully complex collection of proteins. They fit together elegantly, and they cooperate to get this vital job done. One particularly cool feature of this pump is the ring lodged in the pouch’s membrane, where it spins around like a wheel. The ring is made up of six proteins–four copies of a protein called Vma3, and a single copy of two other proteins called Vma11 and Vma16–that lock together. If a mushroom can’t make all three types of proteins, its pump won’t work. And without a pump, it’s a dead mushroom. Simple as that.
Joe Thornton, a biologist at the University of Oregon, and his colleagues wondered how this pump came to be. Readers of the Loom may recall a couple previous posts I’ve written about Thornton’s work. He traces the molecular history of life by resurrecting proteins from hundreds of millions of years ago and playing around with them to figure out how they work. This week in Nature, Thornton and his colleagues describe the history of the fungus ion pump. It’s the first time they’ve reconstructed the history of such a molecular “machine” this way. It’s also a useful lesson in the ways complex things evolve–especially things that seem so complex that it’s hard to imagine how they could have evolved step by step from something simpler.
The closest major group of species to fungi are animals. Like fungi, we have vacuolar ATPase complexes in our cells. But they’re different. Instead of three types of proteins in the ring, we only have two types–five copies of Vma3, and one of Vma16. When it comes to ion pumps, at least, we are pretty primitive compared to mushrooms.
The scientists compared the genes for these ring proteins to other genes in order to reconstruct their evoluationary history. They discovered that Vma11, the ring protein unique to the fungi, and Vma3 are closely related. At some point after the ancestors of fungi branched off from the ancestors of animals, an ancestral ring protein duplicated, forming the Vma3 and Vma11 proteins in fungi. Both of the proteins evolved a lot after the duplication. Thornton estimates that 25 amino acids changed between the ancestral protein and Vma3 in fungi, and 31 changed on the way to Vma11.
By comparing Vma3 and Vma11 in yeast, Thornton and his colleagues were able to infer the structure of their ancestral protein. They then created that long-vanished protein (which they dupped Anc.3-11) and ran an experiment to see how it worked 800 million years ago.
To run their experiment, the scientists first shut down the Vma3 and Vma11 genes in yeast cells. Normally, this would stop the yeast from growing. But then they inserted the Anc.3-11 gene into the yeast. The yeast build a two-protein ring instead of its normal three-protein ring, and did just fine with them. Thornton and his colleagues then created yeast strains with just Vma3 shut down. The yeast could combine Vma11 and Vma16 with Anc.3-11 to make a working ring. The same success occurred when they only shut down Vma11.
Based on experiments such as these, Thornton has developed a hypothesis to explain how the ring evolved. This picture illustrates the steps. The ancestral ring in the common ancestor of animals and fungi is shown on the right. It only has two types of proteins. Green is the ancestral form of Vma3 and 11, and red is the ancestral Vma16. The black squares, circles, and triangles represent parts of the proteins that can only lock onto certain parts of other proteins (represented by the matching recesses). As you can seen, the green protein (the ancestor of Vma3 and Vma11) is versatile, able to lock onto several different proteins.
Animals have the same basic ring. In fungi, on the other hand, some important changes happened. First, Anc.3-11 duplicated. (Vma11 is shown in yellow.) Then the links between the proteins changed. None of the proteins gained any new functions, however. Instead, simple mutations caused them to lose an interface. The red dots on the blue and yellow fungal protein show where these interfaces disappeared. These mutations robbed the proteins of their former versatility. As a result, the ring now only fits together if all three types of proteins are present in one particular arrangement.
You might think that life gets more complex as it evolves new features. Our eye can form sharp images, for example, but in order to do so, it first had to evolve a cavity, a pinhole opening, and a lens. In the case of this ring, however, Thornton has found just the opposite. Its simpler ancestor was made up of more versatile proteins. As the proteins duplicated and degenerated, their arrangement became more complicated. No one can say yet how often this kind of evolution happened. We’ll have to wait for some more molecular time travel for an answer.
Today the Huffington Post is launching a new science “channel,” overseen by a full-time science editor. This should be interesting.
The Huffington Post is one of the most popular places for getting news and opinion, attracting well over 30 million views a month. It started out mainly as a blogging network, and then added on a lot of aggregation of news stories, supplemented by slide shows. More recently, they’ve been hiring full-time reporters and editors on subjects like politics and economics.
When it comes to science, this set-up has led to some…well, let’s call it checkered coverage. You could find your way to straight news stories about science from the Associated Press and other outlets, along with some lightly re-written syntheses of articles elsewhere. Some strong voices in the science world paid visits from time to time to share some thoughts. But the Huffington Post has also run some real stinkers in the past–the kind that send readers to the ER with foreheads fractured by particularly powerful desk-slams.
This morning, Arianna Huffington herself introduced the channel with a long post. Here’s its opening:
I’m delighted to announce the launch of our newest section, HuffPost Science, a one-stop shop for the latest scientific news and opinion. From the farthest reaches of space to the tiniest cells inside our bodies, HuffPost Science will report on the world’s greatest mysteries, most cutting-edge discoveries, and most thought-provoking ideas.
The section will also be home to a robust debate on issues great and small — from the Big Questions of our time (are we alone in the universe?), to quirky, fun ones (will they ever create a pill that will let me eat all the pistachio ice cream I want and not gain weight?) There’s no better time than now to launch a venue that explores these questions, given the explosion of truly medieval thinking in our world — and not just on the fringes. It’s a world in which we have senators and presidential candidates who don’t believe in evolution and who think that global warming is a myth. A world in which politicians don’t just have their own set of ideas but their own set of facts.
Science is a subject that has fascinated me for years. I remember, in the mid-70s, being taken by Bernard Levin to meet Arthur Koestler at his flat in London. I had just read his book, The Act of Creation, on the inspirations that propelled great scientists. Koestler, who described scientists as Peeping Toms at the keyhole of eternity, talked about scientific equations with the ease most of us discuss what we had for dinner (or, if you are a HuffPost regular, the Iowa results). I still remember his lyrical analysis of Einstein’s breakthrough equation, E=mc2. The equation’s assurance that nothing in the universe is unrelated to anything else had a real emotional impact on him — as it soon did on me. An emotional impact not usually associated with scientific equations.
It’s the sense of wonder we so often see in our children. I still recall lying on the grass with my then four and two-year-old daughters one night outside our home in Santa Barbara, and Christina looking out into the night sky and asking, “Mommy, what makes it go?” That sense of wonder will be at the core of HuffPost Science. We will explore timeless questions and we will allow our minds to be blown by what is mind-blowing and awe-inspiring.
You can also get a sense of what HuffPost Science will be like by inspecting this morning’s batch of blog posts. There’s some good stuff there, including a piece by Harvard physicist Lisa Randall. They even have a piece by science writer Seth Mnookin on the latest developments in the controversies over vaccines–which is quite something given all the real estate HuffPo has given in the past to people trying to make the false claim that vaccines cause autism.
I for one am ready to give the Huffington Post another look. If they can bring real science to their huge readership, that will be a great thing.
In 2011, the Loom reached its eighth birthday. Thanks to everyone who’s paid a visit or become a loyal reader in that time. With the year coming to a close, I spent a little time this week perusing the Loom’s archive, reflecting on the things that obsessed me during 2011.
More than many years, this one reminded me just how huge science is. Even if you limited yourself to the most important stories of this past year, there was just too much to keep up with. (Here’s Discover’s top 100 picks.) As a science writer, my focus is biology, but that didn’t ease my year-long case of head-spinning. The anchors that kept me from spinning away completely were the very small and the very complicated.
At the small end of the spectrum were, among other things, the bacteria that call us home. Like every year, 2011 saw outbreaks, such as the E. coli that sickened thousands in Germany. But now that we can read the genomes of these killers, as I noted in Newsweek, we can see how chillingly fast new pathogens can evolve.
But the good germs also gained more recognition in 2011. The science of the microbiome is blooming at an astonishing pace, as you can see in the map I created for the September issue of Wired. As I got more familiar with the microbiome, it became clear to me that scientists won’t be able to handle its complexity without thinking like ecologists. I made that point in a talk this spring called “The Human Lake,” which I turned into a blog post in April. (I was delighted when it was selected as one of the best pieces of 2011 by The Browser and Longreads, and was picked to be including in the 2012 edition of Open Lab.)
The microbiome, I predict, is going to become very intimate in years to come. It’s a strangely thrilling experience to discover 53 species of bacteria living in one’s belly button, as I found out this year. In the future, doctors may check our bug types just as they check our blood types today. But all this new knowledge about the microbiome will bring us unexpected ethical quandaries, some of which I discussed in December in the New York Times.
Bacteria may be small, but they’re positively plus-sized compared to viruses, the subject of my book A Planet of Viruses, which came out in May. (You can read excerpts in Audubon and i09.) Working on the book opened my eyes to just how abundant, diverse, and powerful viruses are–a point I tried to get across in the talks I gave in the spring. The two that I was happiest with were an interview on Science Friday on NPR, and a talk I gave at the Long Now Foundation in San Francisco. As always happens when I write a book about a fast-moving field, the science of virology offered up lots of surprises after the book came out–such as the biggest virus ever, a possible ancestor of hepatitis C in dogs, and signs of a battle between viruses and bacteria in our mouths. When the movie Contagion came out in September, I took a look in Slate at how realistic its story of a new world-wide pandemic was. I found it real enough to be very scary. And in an eerie bit of timing, this fall scientists developed a strain of bird flu that some researchers worry could make the movie a reality.
At the other end of the spectrum from bacteria and viruses is the human brain, those 100 billion neurons that make the universe aware of itself. There seems to be no end of revelatory research coming out of neuroscience and psychology. At the World Science Festival, I talked with three scientists doing extraordinary work on the mystery of sleep (you can watch the video here). In my own stories, I explored genes for language, teen brains, music in the brain, the neuroscience of smiles, how our brains make us capable of both war and peace, and the minds of Neanderthals. A lot of the pieces I wrote first appeared in the New York Times or magazines, but some of them have gotten a new lease on life. I published a new ebook in December, More Brain Cuttings, and my feature on the possibility of uploading our brains to achieve immortality was selected for The Best of American Science Writing 2011.
In 2011, it wasn’t just new science that was in the news. The nature of science was, too. Over the course of 2011, some high-profile papers came under fierce criticism, including arsenic-based life and a link between viruses and chronic fatigue syndrome. These studies prompted a debate about how science gets done in the first place, and how some of it then gets “de-discovered.” I pondered the nature of de-discovery in the New York Times in July, and the emergence of a more transparent discussion of science in Slate.
A lot of that discussion happened on Twitter. Twitter was just one of many new media that became more widespread this year. And just as scientists were getting comfortable with these channels of communication, science writers were too. I spent a fair amount of time in 2011 experimenting with different formats. On Twitter, I went after some egregiously bad science with a hashtag: #Greenfieldism. When I wasn’t on Twitter, I was often on Facebook, Tumblr, and Google+. Each medium has different strengths, I’ve found, which only emerge after playing around with it for a while. Google+ has spurred some fascinating discussions; Twitter is a fast way to spread links. I spent some time working with the folks at Radiolab this year, including the newly minted Macarthur genius Jad Abumrad. It was fascinating to see them turn spoken words into symphonies, such as this episode entitled “Patient Zero.” Another form of storytelling can be found at Story Collider, where people tell tales live in front of an audience. An invitation to be a part of a Story Collider evening led me to talk about how a trip to a war zone made me realize just how deeply science speaks to me. And at the end of the year I published Science Ink, a book born out of a blog-based obsession with science tattoos.
It was a strange year indeed when a traditional book felt like a fresh new format. And it makes me eager for the surprises waiting for us in 2012.
Recently I blogged about a new strain of potentially dangerous flu that evolved during experiments in the Netherlands and Wisconsin. There I tried to counter the misconception that scientists had intentionally concocted this particular strain. Because these new flus actually evolved pretty quickly in laboratories, we now know we should take seriously the possibility that this transformation may happen in the outside world someday.
But there’s a second issue at play with this new virus: should the world get to see its genome?
As Martin Enserink reported last month, both teams of scientists have submitted their papers for publication. Normally, such a paper might include the entire genome of the new viruses. This was a touchy subject, so the papers went under review by the U.S. National Science Advisory Board for Biosecurity (NSABB).
Today, the editors at Science passed on the NSABB’s reccommendations. I’ll quote them here in full:
The National Science Advisory Board for Biosecurity (NSABB) made the following
recommendations regarding the publication of two manuscripts on highly pathogenic avian
1. Neither manuscript should be published with complete data and experimental details.
2. Conclusions of the manuscripts be published but without experimental details and
mutation data that would enable replication of the experiments.
a) Text should be added describing: 1) the goals of the research, 2) the potential
benefits to public health (including informing surveillance efforts, pandemic
preparedness activities, and countermeasure development and stockpiling efforts), 3)
the risk assessments performed prior to research initiation, 4) the ongoing biosafety
oversight, containment, and occupational health measures, 5) biosecurity practices
and adherence to select agent regulation, and 6) that addressing biosafety, biosecurity,
and occupational health is part of the responsible conduct of all life sciences research.
b) The NSABB should develop a statement that explains their review process and
rationale for the recommendations. This statement will be provided to the journals to
consider for publication.
c) The USG should encourage the authors to submit a special
communication/commentary letter to the journals regarding the dual use research
In essence: “Delete the recipe and the mutations.”
The editors at Science released a statement of their own, which I’ll quote in part:
The resulting virus is sensitive to antivirals and to certain vaccine candidates and knowledge about it could well be essential for speeding the development of new treatments to combat this lethal form of influenza. The NSABB has emphasized the need to prevent the details of the research from falling into the wrong hands. We strongly support the work of the NSABB and the importance of its mission for advancing science to serve society. At the same time, however, Science has concerns about withholding potentially important public‐health information from responsible influenza researchers. Many scientists within the influenza community have a bona fide need to know the details of this research in order to protect the public, especially if they currently are working with related strains of the virus.
Science editors will be evaluating how best to proceed. Our response will be heavily dependent upon the further steps taken by the U.S. government to set forth a written, transparent plan to ensure that any information that is omitted from the publication will be provided to all those responsible scientists who request it, as part of their legitimate efforts to improve public health and safety.
Science supports the 2003 joint Statement on Scientific Publication and Security, published in Science, Nature and PNAS. The statement notes that “open publication brings benefits not only to public health but also to efforts to combat terrorism.” It further emphasizes the need to publish “manuscripts of high quality, in sufficient detail to permit reproducibility,” and it recognizes that there may be occasions when a paper “should be modified, or not be published.”
In essence, “We haven’t decided yet. It would be nice if you let us know how responsible scientists could get hold of the data.”
Vincent Racaniello, a virologist at Columbia University, thinks taking this path is a bad idea. Here’s how he put it to me when I sent him the statements:
It doesn’t make any sense to publish Fouchier’s paper without complete data and experimental details. The point of a science paper is to enable others to duplicate the findings. Are we going to set a new precedent, where security matters override the reason for publication? This is setting a very dangerous precedent for virology and biological sciences in general.
I disagree with the NSABB recommendations, because they have no scientific basis…one cannot conclude that the mutations selected by Fouchier [the head of the Dutch research team] will have effects on transmission of the virus among humans. I understand that if you publish the plans for a nuclear weapon, that may enable a terrorist to make one, but the Foucher finding doesn’t enable anything except more experiments. And that is why the paper should be published – to allow virologists to extend his findings and determine what controls transmission of H5N1 viruses. Often the best experiments are done by scientific unknowns who take an interest in a problem and apply a fresh view. If you restrict dissemination of this information, you are limiting our eventual understanding of the problem.
Update: Looks like Racaniello’s concerns have fallen upon deaf ears. Martin Enserink reports that the virus researchers have decided to redact the contested parts of the papers, which are being considered by Science and Nature.
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.
[Update, 12/19 7 pm: Some of the comments prompted me to edit this piece for clarity.]
Long before Darwin published The Origin of Species, there was talk of evolution. The more acquainted naturalists became with the major groups of animals, the gaps between them grew smaller. Once it seemed as if mammals were profoundly different than other vertebrates, for example. And then European explorers encountered the platypus, a mammal that laid eggs. Perhaps the major groups of animals had not been separately created, some naturalists suggested. Perhaps life had changed over time.
In 1837, a profoundly paradoxical creature was shipped from West Africa to London, packed in clay. It was destined for Richard Owen, the greatest British anatomist of his age. He picked away the clay, to reveal a creature that looked like a fish. It has a knife-shaped body, gills, and fins. “If indeed the species had been known only by its skeleton,” Owen wrote, “no one could have hesitated in referring it to the class of Fishes.”
But inside its body, Owen found what he could only call lungs. Its whisker-like fins had a chains of bones that faintly resembled arms. Owen was a fierce opponent of all the transformationists of his day, and he was determined to find a way to push this creature–what Owen called Lepidosiren and what we today commonly call a lungfish–to one side of the divide or the other. He finally found an antidote to evolution in its nose.
Owen’s examination led him to conclude that the nostrils of the lungfish did not connect to its mouth. They seemed to end in a blind pouch. That was a hallmark of fish, and the trait banished lungfish from the tetrapods–the land vertebrates such as reptiles, birds, and mammals. “According to this test, Lepidosiren is a Fish…simply by its nose,” he wrote.
As I write in my book At the Water’s Edge, Owen turned out to be wrong. In 1860, a year after Darwin published his theory of evolution, an Irish anatomist named Robert M’Donnel discovered a passageway from the lungfish’s nose to its mouth. It was, he concluded, a transitional creatures, with some traits from our fishy past mixed with traits also found in tetrapods. “I know of no animal more calculated leading to the adoption of the theory of Darwin, than the Lepidosiren,” he wrote.
Since then, scientists have amassed an overwhelming amount of evidence that lungfish are close kin to tetrapods. Their kinship is inscribed in their DNA, for example: genetic tests consistently show that of the 30,000-odd species of fish, lungfish are the closest (or among the closest) relatives to tetrapods.
On the other hand, we shouldn’t rush to the conclusion that the lungfish is a living fossil, a snapshot of our own ancestry. Lungfish and tetrapods share a common ancestor that lived some 400 million years ago. Since then, the lungfish lineage has gone through drastic changes. Some 350 million years ago, rivers and coastal waters were loaded with a diversity of lungfishes, including massive predators the size of sailboats. Today, lungfish are a whisper of that former glory, a few species eking out an existence in Australia, Brazil, and Africa. The living lungfishes are different from each other in some important ways. The lungfish in Africa have wispy fins and dig into the mud to survive droughts. The lungfish of Australia have stout lobe-shaped fins and never escape droughts in the mud.
Once scientists can sort out what’s new about lungfishes, they can then take a look at what’s old. And therein lie some intriguing clues about our own origins. Today, scientists at the University of Chicago published a study of lungfish that sheds light on the origin of one of the most essential behaviors for a tetrapod: the ability to walk. In their own weird way, lungfish can walk, too.
Tetrapods walk in many different ways. Lions race, sloths lumber, salamanders squirm. But all tetrapod walks are built on the same foundation. A tetrapod typically alternates its forelegs and hind legs, pushing each limb against the ground to propel itself forward. Early tetrapods bent their trunks from side to side as they moved, and amphibians like salamanders still do today. Other tetrapods modified their walks; most mammals keep their trunk from bowing out to the sides, instead flexing it up and down.
That’s a far cry from the typical way fishes move. They propel themselves forward through the water with their tails, adjusting their fins to help them control their movements. They mainly flap their pectoral fins (which correspond to our arms). One glaring exception to this kind of locomotion is a deep-water fish known as the coelacanth. It swims by alternating its lobe-shaped fins. And it just so happens that the coelacanth is the only other aquatic animal that shares the same close kinship to tetrapods as lungfish.
Some researchers who have observed lungfishes in the wild have noticed that they also seem to move their fins in an alternating pattern. To see whether that was actually true, Heather King of the University of Chicago and her colleagues have been filming lungfish in lab tanks and then analyzing their movement on computers.
King found that the lungfishes regularly moved around their tank by pushing off the bottom with their pelvic fins (which correspond to hind legs). They alternated between the fins in a walk-like pattern, sometimes switching to a bounding, synchronous gait. With each step, the lungfishes lifted their bodies up and forward, much like tetrapods do while walking. (The movie below shows a few samples of her footage.)
It’s pretty remarkable that lungfish can come so close to walking. They have no pelvis to help them transmit the force they generate pushing off the bottom of the tank to the rest of their body. Their their fins contain thin chains of bones, with no foot or ankle. King’s research suggests that an animal doesn’t need all that much tetrapod anatomy to walk.
This discovery offers a new way to interpret some enigmatic track marks dating back to the time when the first tetrapods evolved. These trackways seem to have been formed by a limbed animal with an alternating gait. But there are no toe marks preserved with them. It’s possible, King suggests, that early relatives of tetrapods made them, with limbs as simple as those of lungfishes.
It also underscores one of the most counterintuitive facts about how our ancestors evolved into land-walking vertebrates. Our limbs are so well-adapted for moving around on land that it’s tempting to think that they must have first evolved expressly for that purpose. Indeed, for much of the 1900s, many scientists believed tetrapods evolved when fish had to crawl from pond to pond to survive droughts. It’s clear, however, that many of the key elements of a walking body–such as limbs that an animal could move in an alternating gait to push itself forward–evolved long before our ancestors came on land. The lungfish, M’Donnel might say, is more calculated than ever to lead to the adoption of the theory of Darwin.
King et al, Behavioral evidence for the evolution of walking and bounding before terrestriality in sarcopterygian fishes. PNAS. http://www.pnas.org/cgi/doi/10.1073/pnas.1118669109
[Photo by Joel Abroad Flickr/Creative Commons]
When it comes to viruses, we humans like to pretend we know much more than we really do. It’s understandable. The influenza virus, for example, has only ten genes. It is just a shell that delivers genes and proteins into a host cell, where it hacks the biochemistry to manufacture more viruses. It seems like such an easy biological problem to solve.
Yet the flu and other viruses hide a complexity which virologists have only partly uncovered. The idea that someone could intentionally design a super-lethal virus from scatch–as plausible as it may seem–is, for now, a delusion.
If you’ve been following the news this past week, you may think I’ve just been proven wrong. Reports have surfaced about two teams of scientists producing flu viruses that could potentially kill millions if they escaped from the labs. The scientists have the viruses locked up tight for now, and government officials are debating whether they can publish their results. (New Scientist and Science have excellent reports.)
So is this evidence that scientists have become viral Frankensteins, who can engineer pathogens at will? Hardly.
The new research is part of a long-running struggle to understand how new flu strains arise. It’s clear that all flu viruses that infect humans ultimately evolved from viruses that infect birds. From time to time, people can pick up these viruses, which infect their airway. Depending on the strain, bird flu may be harmless or lethal to humans. But for the most part, it can’t get from one human to another. It’s too well adapted for life in birds.
On rare occasion, a bird flu does manage to adapt to humans. It may experience natural selection, it may pick up some genes from human flu viruses, or both. Scientists are still trying to figure out what it takes for a flu virus to make this transition. It’s an important question, not just as a matter of fundamental biology but as a matter of global health. When new bird flus jump to humans, we lack immune defenses against them, and they can thus cause worldwide pandemics.
Flu experts have had their eye on one strain of bird flu in particular for a while now: H5N1. It’s proven extraordinarily lethal, and yet, since it first came to light in 1997, it hasn’t managed to make the big leap and start spreading from person to person. If you get H5N1, you’re in big trouble. But not many people get it. Yet.
Does this mean that H5N1 just doesn’t have what it takes to become the next great pandemic? Or does it mean the virus simply hasn’t evolved the right recipe yet?
Scientists have tried to answer this question by tinkering with the virus. Instead of trying to make a virus that spreads among people, they infected ferrets, which turn out to have much the same experience with the flu as we humans do. In April, CDC scientists published the latest of these studies. They focused their attention on a protein called hemagglutinin, which flu viruses use to get into host cells. Based on earlier experiments, the CDC scientists reasoned that the right tweak to the structure of hemagglutinin in H5N1 could switch it from binding strongly to bird cells to mammal cells.
But their rational tweaks failed. They concluded that there was a lot more to becoming a human flu that we don’t yet understand.
The studies that have now hit the news have succeeded where other experiments have failed. The difference is that instead of trying rational tweaks, the scientists sat back and let evolution do the tweaking.
According to the news reports, the scientists used a tried-and-true method known as serial passage. You infect an animal. It gets sick. You wait for the virus to replicate inside its animal host–as new mutants arise and natural selection favors some mutants over others–and then take some viruses from the sick animal and infect a healthy one. You repeat this, moving the virus from host to host.
Interesting things can happen when you let viruses evolve under these conditions. Natural selection can produce viruses with many new mutations, which together let them reproduce faster in the lab than their ancestors. And those viruses, in some cases, can be a lot more dangerous than their ancestors.
Back in 2007, for example, a virologist named Kanta Subbarao and her colleagues transformed the SARS virus this way. SARS evolved from a bat virus, crossing over into humans in 2003. It killed over 900 people before it mysteriously disappeared. Subbarao wanted to find a way to study SARS in lab animals, such as mice. Mice normally don’t get sick from human SARS viruses, though, even though the virus can replicate at a low rate inside them. Even when mice are genetically engineered so that they can’t develop an immune system, SARS can’t harm them.
So Subbarao and her colleagues that instead of changing the mice, they’d change the virus. They inoculated mice with the SARS virus, gave it a chance to replicate inside them, and then isolated the new viruses to infect new mice.
Over the course of just 15 passages, it changed from a harmless virus into a fatal one. One sniff of SARS was now enough to kill a mouse.
As Martin Enserink reports in Science, the new experiments on bird flu were similarly effective. They turned H5N1 into a ferret flu in just 10 generations. By the time the scientists were done, they no longer had to ferry the flu from one ferret to the next. A healthy ferret just had to be placed near a sick one; the virus could travel through the air. When they examined the new strain, they discovered five mutations in two genes. All five mutations have been found in natural H5N1 viruses–just not all in one virus.
A mammal-ready flu virus was beyond human reason, in other words, but it was fairly easy for evolution to find, given the right condtions. That suggests that H5N1 may not have far to evolve to make us its host. Of course, a serial passage experiment is not identical to the flu’s natural world, where it circulates among millions of birds and sometimes encounters people. But it’s disturbingly close.
And if it’s so easy for mutations to turn H5N1 into a human flu, the experimental viruses have a lot to tell us about what we may be facing in the future. There’s no point in condemning the scientists for tampering with nature. They were watching nature do what it does disturbingly well.
[Update: The excellent podcast This Week in Virology discusses the new research. They think the hype to reality ratio is very high.]