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.
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.]