Here, for your viewing pleasure, is a very important part of a very special flu virus. It may look like an ordinary protein, but in fact it’s been at the center of a blazing debate about whether our increasing power to experiment on life could lead to a disaster. Not that long ago, in fact, a national security advisory board didn’t even want you to see this. So feast your eyes.
For those who are new to this story let me start back at the beginning, in 1997.
In that year, a child in Hong Kong died of the flu. Doctors shipped a sample of his blood to virus experts in Europe, but they didn’t bother taking a look at it for months. When they did, they were startled to discover that it was unlike any flu they’d seen in a human being before.
Each year, several different flu strains circulate from person to person around the world. They’re known by the initials of the proteins that cover their surface–H3N2, for example, is one common strain. The H stands for haemagglutinin, a protein that latches to a host cell so that the virus can invade. The N stands for neuraminidase, which newly produced viruses then use to hack their way out of the cell.
Birds are the source of all our flu strains. Our feathered friends are hosts to a huge variety of H and N type viruses, which typically infect their guts and cause a mild infection. From time to time, bird flu viruses have crossed the species barrier and adapted to human hosts, infecting our airways and then spreading in air droplets. Since flu spreads so fast around the world, a fair amount of the planet’s population has had some exposure–and thus some immunity–to the flu strains in circulation today. But if a new bird flu should manage to make the leap, we could face a very grim situation–a situation that some scientists worry could rival the 1918 pandemic, which killed some 50 million people.
That’s why the scientists in 1997 were so flustered. The Hong Kong boy had died of a strain of bird flu that hadn’t been found in people before. It came to be known as H5N1.
It turned out that around Hong Kong, chickens were rife with H5N1, including the chickens for sale in live open-air markets. Public health workers slaughtered huge numbers of chickens to stop the outbreak, and, for a time, it seemed like they had beaten the virus. In fact, H5N1 had simply gone into hiding. A few years later it was back–and spreading. Birds carried it across Asia, into Africa and Europe. The New World and Australia have been spared so far, but there’s no reason to think that the virus can’t colonize those continents as well. It will just take the right bird.
Doctors found that the majority of patients hospitalized with H5N1 died. The only comforting thing about H5N1 was that it remained a bird flu. Once inside a human being, the virus couldn’t churn out lots of new viruses capable of spreading to another human. But many bird flu experts consider that a cold comfort. Like all flu viruses, H5N1 has been continually evolving. When the viruses replicate they pick up new mutations–some of which help them replicate faster. Sometimes, two H5N1 viruses co-infect a single cell at once and swap some of their genes, producing hybrids. If this high-speed evolution leads to human-adapted H5N1, we could be dealing with a global cataclysm.
Yet some flu experts doubted this grim prospect. It’s been some 15 years since H5N1 was first discovered, and despite all those years of evolution, the virus has yet to nose its way into our species. Perhaps, some scientists suggested, there was something about the biology of the strain that prevents natural selection from transforming it into a human virus. Skeptics have more recently raised another question about the risk of H5N1: is its mortality rate really all that high? In many studies, scientists have estimated the mortality rate of H5N1 based only on sick people who come to hospitals. It’s possible that a lot of people recover from bird flu infections on their own, and go missing from the statistics. (It’s worth bearing in mind, though, that the 1918 flu only had a mortality rate of 2%. If a virus can infect billions of people, even a low rate like that can lead to terrifying numbers of deaths.)
A few years ago, some bird flu experts decided to test the proposition that H5N1 was a potential human scourge. They would tinker with it to see if it could be transmitted from mammal to mammal, instead of bird to mammal. They might be able to see some warning signs for how this transition could happen in nature. The scientists applied for money from the National Institutes of Health, which considered their idea important enough to sink millions of dollars into it.
Two teams of scientists–one in the Netherlands and the other at the University of Wisconsin–got good results. They could infect ferrets with modified H5N1, and the ferrets could cough up droplets that could infect healthy ferrets. They submitted their findings to the world’s biggest scientific journals, Science and Nature, to let the world know of their discovery. One of the Dutch researchers, Ron Fouchier, referred cryptically to the research at a flu meeting in Malta in September.
It occurred to persons unknown that publishing these results might not be such a great idea. What if individuals bent on destruction got the idea of unleashing a pandemic. Maybe they could use the scientific papers–in particular the description of the experimental methods–to replicate the results. Just knowing the mutations might be enough information for a talented virologist to tweak a bird flu virus into a biological weapon.
One smoggy afternoon in the summer of 2010, I took a walk down Xi Zhi Men Wai Avenue in Bejing. The ten-lane thoroughfare was packed with cars, buses, pedalos, and bicycles. But even here, in China’s hyperurbanized core, there were birds to keep me company. Sparrows shot around the roadside trees. Black and white magpies perched in the treetops, issuing their rattling calls. I was walking down Xi Zhi Men Wai Avenue to pay a visit to a museum, where I could take a close look at the fossilized remains of some ancient cousins to the magpies. I was going to see some feathered dinosaurs.
Feathers are one of the marvels of animal evolution–a combination of extreme beauty and extreme usefulness–but for over a century their fossil record stopped with the 145-million-year-old Archaeopteryx. It was a mix of bird anatomy such as wings and older vestiges of a reptilian origins, such as teeth and a long, bony tail. But in the past 20 years, paleontologists have found a series of spectacular fossils of dinosaurs with traces of feathers or feather-like structures on their skin. And most of them have turned up in China. So it only made sense for me to head for Beijing–and in particular, to the Institute for Vertebrate Paleontology and Paleoanthropology. There, a young paleontologist named Xu Xing and his colleagues have built up the most impressive collection of feathered dinosaur fossils on Earth.
When I entered the IVPP, I walked into a badminton game underway on an indoor court. IVPP students sliced at the shuttlecock below the glare of a giant marine reptile fossil bolted high on the wall. I took the elevator to the sixth floor, where I met Xu Xing, a slender middle-aged man. He had just finished playing some badminton himself and was still wearing an IVPP athletic uniform as he sat at his computer, answering email. We shook hands and he ducked out to change into civilian clothes. We then headed into the IVPP’s collection room.
Xu flipped green curtains from the shelves until he found a tray. A student helped him slide it out and set on the floor. Inside the tray was the fossil of a 125-million-year-old dinosaur called Beipiaosaurus. As I looked at the fossil, Xu explained what I was seeing. There were bones from the animal’s legs, skull, spine, and tail. There were also dark streaks surrounding parts of its body. In life, Xu said, they would have been stiff, broad bristles measuring several inches long.
Xu helped me picture Beipiaosaurus in life. “It had a big bulky body, a long neck, and a small head,” he said. Walking on its hind legs, it was as tall as a man. But instead of killing to eat, it probably browsed on plants with grinding teeth. Its entire body would have been covered in soft, short filaments, with tufts of broad, long bristles sprouting off its neck and tail.
“It’s very bizarre,” Xu said, smiling.
In caves around the world, animals and other creatures have adapted to endless night. Cavefish, for example, have lost their eyes and pigment, evolving a greater power in other senses.
In 1954, Syuichi Mori, a biologist at Kyoto University, put flies into a cave of their own. He took eggs from ordinary flies of the species Drosophila melanogaster put them in milk bottles, which he placed in pots and covered in dark cloth. There they lived in utter darkness. He tended to the flies, generation after generation, dividing them into three separate lines. Meanwhile, he reared three lines of flies in normal light for comparison.
Raising flies is not an easy business. They can pick up infections and die in droves. Over the years, all the normal lines of flies died out, as did two of the dark-bred flies. But Mori managed to keep the last line of flies alive in the dark, and after his death, other Kyoto researchers kept the flies going. And today, they are still living in the dark, 57 years since their ancestors last saw light. That’s 1400 generations–which would be some 30,000 years if it were humans living in dark.
Keeping organisms in such weird conditions is one of the most interesting ways to learn about evolution. Scientists create a set of conditions and then allow organisms to grow, breed, and mutate. Mutations that let some individuals survive better and have more offspring become more common in the population due to natural selection. Other mutations can spread thanks to the luck of the genetic dice.
Mori wondered what sort of changes would occur in his dark flies. Would they lose their internal clock, controlling the daily cycles of their bodies? Would they stop responding to light? Would they evolve in other, unexpected ways?
In some respects, the flies haven’t changed much. They still have normal eyes, for example, complete with pigments. Last year, Michio Imafuku and Takashi Haramura reported that the dark flies still had their body clock. If they exposed the flies to three and a half hours of light, the insects became active and sluggish in a 24-hour cycle.
But the Japanese scientists have also found some differences. The bristles on the dark flies became unusually long, for example.
That change might simply be a fluke of rearing flies from a few related insects. To find out if the flies had experienced natural selection, Naoyuki Fuse and colleagues applied modern technology to this venerable invertebrate dynasty.
As they report in PLOS One, there are some tantalizing clues that the flies have indeed adapted to life in the dark.
For starters, the researchers observed how well the flies reproduced. After all, that’s what natural selection is all about. They counted up the eggs that the flies laid, either in the dark or the light, and compared their success to their ordinary relatives. The researchers found a major difference: when kept in the dark, dark-bred flies laid 373 eggs, plus or minus 20. Ordinary flies laid 293 eggs, plus or minus 73. Somehow, in other words, the dark-bred flies had become better at breeding in the dark.
To start hunting for the cause of this change, the Kyoto researchers sequenced the genome of the dark-bred flies and compared it to a genome from normal relatives. They found 220,000 spots in the genome where the DNA had mutated (a single nucleotide polymorphism). In addition, there were 4700 places where a stretch of DNA had been inserted or deleted.
A lot of those mutations may not have had any effect on the flies. So the researchers began to sift through the changes for ones that had good evolutionary potential. They found some promising candidates. For example, a gene for a light receptor had acquired a particularly devastating change called a nonsense mutation, which prevents the fly from making a functioning protein. A gene involved in metabolism disappeared. Once the flies were cast into darkness, flies without these proteins may have done better than the ones that held onto them.
The scientists also looked for stretches of DNA that showed signs of having experienced natural selection. Each fly carries two copies of each chromosome, and each chromosome is sprinkled with its own set of mutations. Here and there, however, the DNA on the chromosomes is identical. This close matching is sometimes the result of genes spreading quickly through a population thanks to natural selection. The scientists found 241 new mutations in these identical stretches–potentially giving the flies an advantage in the dark. One of those genes is involved in breaking down toxins. The scientists speculate that flies ordinarily use light to help break down toxins. The dark flies may have evolved a way to do so without the light.
Perhaps Mori envisioned his flies becoming like cavefish, pale and blind in their bottles. That didn’t happen. But now scientists can probe his flies far more deeply, reading their entire genome. And while they may not show obvious signs of evolution, subtler ones may be present by the hundreds.
Whenever I give a talk about my book Parasite Rex, I try to gather together the creepiest images of parasites that I can. Every time, there’s one kind of parasite that summons an instant reaction: a mix of laughter, sucked-in breaths, and gasps of recognition. I speak, of course, of the parasites that eat your tongue.
I only mean you if you’re a fish. Some species of isopods (crustaceans related to the less creepy crabs and lobsters) will swim into the gill of a fish, make their way to its mouth, and devour its tongue. It will jam its legs into the gills to hold itself in place, facing forward, its eyes gazing out of the fish’s mouth, taking the very place of the tongue it just ate.
I was first introduced to these disturbing creatures by Matthew Gilligan, an invertebrate zoologist at Savannah State University. I had come across a disturbing picture of one of these parasitic isopods in a paper he published in 1983 and sent him an email, asking questions about it. I wondered what the isopods did once they were done devouring the tongue. As far as Gilligan could tell, they stopped eating the fish once they had made a place for themselves in its mouth. Perhaps afterwards, they fed on the animals that the fish itself caught. After all, the fish that Gilligan and others had caught with these isopods were still alive and seemed healthy. Gilligan’s response made me wonder if perhaps the fish simply used the hard-shelled back of the parasite as its own tongue.
Since then, a new generation of scientists have studied these mysterious parasites, and it looks as if their dealings with their hosts are not as peaceful as once thought. In 2003, for example, scientists studying isopods in a fish farm off the coast of Turkey found that sea bass with the parasites in their mouths had lower blood counts than ones that still had their tongues intact. It seems that the isopods act like blood-drinking mouth leeches.
In a new paper in the Biological Journal of the Linnean Society, British researchers have followed up on these studies with a big survey of the Mediterranean, inspecting striped sea bream for tongue parasites. They compared two populations of the fish that were closely related to each other but lived in very different environment. One population, off the coast of France, lived in a marine protected area. The other, off the coast of Italy, is heavily fished. In the protected waters, the scientists found, 30 percent of fish had the parasites in their mouth. In the fished waters, 47 percent did.
Take a moment to let that sink in. Almost a third to almost half of these fish open their mouth and look as if they came out of a science fiction movie. Having recently just eaten bream for the first time, I’m relieved to find out that the parasite does not cause human disease. Still, next time I eat fish I may have some disturbing images in my head.
The scientists found not only that there are more parasites in the heavily fished waters. They also found that parasites took a heavier toll there. Fish with tongue parasites ended up smaller and lighter in the heavily fished waters than infested fish in the refuge.
These differences all seem to come down to fishing. A lot of studies on many species of fish have shown that heavy fishing can drive the evolution of small fish. Fish that get to be sexually mature faster may be more likely to have offspring than fish that take their time to reach bigger sizes. In that rush, harvested fish may end up unable to defend themselves against enemies, including tongue-eating parasites.
It would be interesting to see what the rates of tongue parasites are in other heavily fished and protected parts of the world. If this pattern holds up, it may turn out that overfishing has made the world a more alien place.
There are times when I want to retitled this blog The Continuing Adventures of Parasitic Wasps and Their Unfortunate Hosts. Because there are just so many stories of these sinister insects and how they lay their eggs inside other animals. That’s no surprise, really, because there are hundreds of thousands of species of parasitic wasps on Earth, all evolving in different directions as they adapt to their host’s defenses.
Last week, for example, I reported in the New York Times about a newly discovered defense that flies use against certain wasps: when the wasps inject their eggs into the flies, the flies drink alcohol to literally turn the parasites inside out.
Since then, I’ve become obsessed with another species of wasp that attacks aphids. The battle between these two species–and their many allies–makes the story of the boozy flies seem positively pedestrian.
The wasp is known as Aphidius ervi, and its hosts are aphids. Because aphids are major pests on farms and in gardens, researchers have turned A. ervi into a biological weapon against them. If you so desire, you can order 250 mummified aphids with wasps ready to emerge through the mail for $69.95.
To find an aphid host, A. ervi wasps take advantage of the struggle between the aphids and the plants they eat. When a plant gets nibbled by an aphid, it releases a cocktail of molecules into the air. The wasp detects those chemicals, sniffing its way to the plant–and to the aphid.
The wasp may lay only a single egg inside an aphid, or it may choose to lay additional ones. Along with her eggs, the wasp will also inject a venom that stunts the growth of the aphid’s own ovaries–thereby stopping the host from wasting energy on its own reproduction so that there’s more food for the wasps. The wasp eggs have no yolk, so they depend entirely on their host from the start. When the wasp egg hatches, the larva develops a thick, tentacled blanket of cells that extends out into the aphid’s body and draw in nutrients–in other words, a placenta. The placenta also buds off a special class of cells that swim through the aphid’s body, releasing enzymes that degrade the aphid’s cells and bind fatty acids, making it easier for the wasp to feed on its host.
But there’s a big puzzle about A. ervi’s strategy. No matter how many eggs it lays in an aphid, only a single adult wasp at most emerges from a host. Why the extra eggs?
In many cases, no wasp emerges at all. That’s because the aphids have defenses of their own. Their immune cells go after the wasp larvae. And in addition to their own defenses, many aphids are home to allies–namely a species of bacteria called Hamiltonella defensa. Some aphids are infected with the bacteria and pass it down from parents to offspring (or spread it by sex). The bacteria produce a toxin that sickens the wasps and keeps them from developing. Weirdly, Hamiltonella defensa only protects the aphids if they are, in turn, infected by a virus of their own, which carries the wasp-attacking toxin gene. (See Ed Yong’s post for details.)
That would be remarkable enough. But now scientists have discovered another dimension in this multi-species battle. A team of researchers led by Kerry Oliver at the University of Georgia has found that the wasps can tell the difference between aphids that are protected by bacteria, and the ones that are defenseless. Into the defenseless aphids, they lay only a single egg. And into the protected aphids, they are more likely to lay two or more. Oliver found that the wasps seem to boost their odds of surviving against the bacteria by boosting their numbers. It’s possible that the extra venom and enzymes let the wasps grow despite the poison supplied by the bacteria and their viruses. No matter how exactly the extra eggs help, Oliver’s finding hints at an answer to the puzzle of the wasp’s egg laying patterns.
How the wasps can figure out that the aphids have friends inside, the scientists cannot say. It’s possible that when the wasps lay the first egg, they can probe the chemistry of the aphid and figure out if it’s infected with H. defensa. Oliver and co. raise an even more intriguing possibility. The aphids infected with H. defensa seem to release fewer alarm pheromones in times of trouble. Perhaps they are blase about parasites because of their protection. It’s possible that the wasps have evolved to use that clue to tell whether they need to lay extra eggs.
Regardless of which trick they actually use, Aphidius ervi is my favorite parasitic wasp. But it will probably not keep the trophy for long.
Reference: Parasitic wasp responses to symbiont-based defense in aphids. Kerry M Oliver, Koji Noge, Emma M Huang, Jamie M Campos, Judith X Becerra and Martha S Hunter. BMC Biology (in press)
(For much more on the wasps, see my book Parasite Rex)
If not for a virus, none of us would ever be born.
In 2000, a team of Boston scientists discovered a peculiar gene in the human genome. It encoded a protein made only by cells in the placenta. They called it syncytin.
The cells that made syncytin were located only where the placenta made contact with the uterus. They fuse together to create a single cellular layer, called the syncytiotrophoblast, which is essential to a fetus for drawing nutrients from its mother. The scientists discovered that in order to fuse together, the cells must first make syncytin.
What made syncytin peculiar was that it was not a human gene. It bore all the hallmarks of a gene from a virus.
Viruses have insinuated themselves into the genome of our ancestors for hundreds of millions of years. They typically have gotten there by infecting eggs or sperm, inserting their own DNA into ours. There are 100,000 known fragments of viruses in the human genome, making up over 8% of our DNA. Most of this virus DNA has been hit by so many mutations that it’s nothing but baggage our species carries along from one generation to the next. Yet there are some viral genes that still make proteins in our bodies. Syncytin appeared to be a hugely important one to our own biology. Originally, syncytin allowed viruses to fuse host cells together so they could spread from one cell to another. Now the protein allowed babies to fuse to their mothers.
It turned out that syncytin was not unique to humans. Chimpanzees had the same virus gene at the same spot in their genome. So did gorillas. So did monkeys. What’s more, the gene was strikingly similar from one species to the next. The best way to explain this pattern was that the virus that gave us syncytin infected a common ancestor of primates, and it carried out an important function that has been favored ever since by natural selection. Later, the French virologist Thierry Heidmann and his colleagues discovered a second version of syncytin in humans and other primates, and dubbed them syncytin 1 and syncytin 2. Both virus proteins seemed to be important to our well-being. In pre-eclampsia, which gives pregnant women dangerously high blood pressure, levels of both syncytin 1 and syncytin 2 drop dramatically. Syncytin 2 also performs another viral trick to help its human master: it helps tamp down the mother’s immune system so she doesn’t attack her baby as a hunk of foreign tissue.
In 2005, Heidmann and his colleagues realized that syncytins were not just for primates. While surveying the mouse genome, they discovered two syncytin genes (these known as A and B), which were also produced in the same part of the placenta. This discovery allowed the scientists to test once and for all how important syncytin was to mammals. They shut down the syncytin A gene in mouse embryos and discovered they died after about 11 days because they couldn’t form their syncytiotrophoblast. So clearly this virus mattered enormously to its permanent host.
Despite their name, however, the primate and mouse syncytins didn’t have a common history. Syncytin 1 and 2 come from entirely different viruses than syncytin A and B. And the syncytin story got even more intricate in 2009, when Heidmann discovered yet another syncytin gene–from an entirely different virus–in rabbits. While they found this additional syncytin (known as syncytin-Ory1) in a couple different species of rabbits, they couldn’t find it in the close relative of rabbits, the pika. So their own placenta-helping virus must have infected the ancestors of rabbits less than 30 million years ago.
Now Heidmann has found yet another virus lurking in the ancient history of mammals. This one is in dogs and cats–along with pandas and hyenas and all the other mammals that belong to the so-called carnivoran branch of the mammal tree. In every carnivoran they’ve looked at, they find the same syncytin gene, which they named syncytin-Car1. In every species it is strikingly similar, suggesting that it’s experienced strong natural selection for an important function for millions of years. But it’s missing from the closest living relative of carnivorans, the pangolins. The diagram here, from the authors, shows how they see this evolution having unfolded. After the ancestors of carnivorans split from other mammals 85 million years ago, they got infected with a virus which eventually came to be essential for their placenta.
The big picture that’s now emerging is quite amazing. Viruses have rained down on mammals, and on at least six occasions, they’ve gotten snagged in their hosts and started carrying out the same function: building placentas. The complete story will have to wait until scientists have searched every placental mammal for syncytins from viruses. But in the meantime there is something interesting to consider. Some mammals that scientists have yet to investigate, such as pigs and horses, don’t have the open layer of cells in their placenta like we do. Scientists have come up with all sorts of explanations for why that may be, mainly by looking for differences in the biology of each kind of mammals. But the answer may be simpler: the ancestors of pigs and horses might never have gotten sick with the right virus.
[Top image: Leonardo da Vinci's sketch of a human fetus. From Universal Leonardo]
Michael Osterholm, his face a pink-cheeked scowl, looked out across the table, beyond the packed room at the New York Academy of Sciences, and out through the windows. The New York Academy of Sciences is housed on the fortieth floor of 7 World Trade Center, and their endless bank of windows affords a staggering view of Manhattan, Brooklyn, and New Jersey. One reason that its view is so magnificent is that there’s a huge gap in the skyline–and a huge gouge in the ground–where the Twin Towers once stood.
Osterholm had come here from Minnesota, where he runs a research center for infections diseases and terrorism, to talk Thursday night about the threat of a new kind of flu sitting in labs in the Netherlands and Wisconsin. In nature, it’s a flu that spreads easily between birds but doesn’t travel well from human to human. The Dutch and Wisconsin scientists had found ways to get this bird flu, known as H5N1, to move between ferrets. For Osterholm, ferrets were uncomfortably close to humans on the evolutionary tree. And so he, along with other members of an advisory board, issued a recommendation in December that key information in the papers about the research should be left out.
Osterholm looked out at the empty space beyond the windows. “Who would have imagined that you could use box cutters to take down the World Trade Center?” Osterholm asked. The risk from the new bird flu might seem equally unlikely, he warned, but it could end up being far more devastating. “We can’t afford to be wrong.”
The bird flu controversy first started to bubble up in September, when Ron Fouchier of the Erasmus Medical Center in Rotterdam described some of his unpublished results at a scientific meeting in Malta. It kicked into high gear when the National Science Advisory Board on Biosecurity issued their ruling, which Fouchier and Yoshihiro Kawaoka have agreed to. In January, the researchers agreed to stop doing any H5N1 research for two months, during which time the scientific community would try to come up with a plan about how to deal with such controversial research.
Viruses very often spark controversies, but often the controversy is between the scientists who study them and groups of people beyond the academy. Think of HIV denialism, of the non-existent link between vaccines and autism, of the purported connection between the XMRV virus and chronic fatigue syndrome. The new bird flu controversy is different. It’s split the scientific community wide open. I’ve written about this controversy in recent weeks over at Slate, as well as here at the Loom. Like most reporters covering the story, I’ve sampled the sharply opposing viewpoints of scientists over the phone or via emails. But on Thursday night, we got to see this debate in person. The New York Academy of Sciences brought together a group of experts to talk about new virus, and whether self-censorship is a prudent protection or a dangerous precedent. I wasn’t sure what to expect; I was a bit worried it might have turned out to be a fairly dry discussion of how to inspect the hood equipment in virus labs. Instead, we witnessed explosive confrontation between scientists who think we may be facing a world-destroying catastrophe, and others who think our fear of non-existent threats is going to destroy science’s power to help us out of clear and present dangers.
The panel included two members of the National Science Advisory Board on Biosecurity: Michael Osterholm and Arturo Casadevall of Albert Einstein College of Medicine. They both made it clear that they were speaking at the meeting as individuals, rather than as official spokesmen for the board. But they presented a fairly united front. The board has been around for eight years, and it has only considered issuing a recommendation twice. The first time was in 2005, when scientists unearthed the bodies of victims of the 1918 flu epidemic, which killed an estimated 50 million people. The researchers isolated the 1918 virus and sequenced its genes. The board decided they had no objections about publishing the research. But six years later, they decided that, as bad as the 1918 flu might have been, the risk of an H5N1 outbreak was worse.
One big factor in their recent decision was the mortality rate when H5N1 gets into people. The World Health Organization’s official estimate is 60%. The 1918 flu, by contrast, had a death rate of about two percent. If H5N1 could gain the ability to spread among humans–either naturally, or through a lab experiment–it could bring that fearsome death rate to the entire world. “It’s the lion king of infectious diseases,” Osterholm said, no doubt dismaying Disney lawyers across the country.
Sitting a few seats down the panel from Osterholm was Peter Palese, one of the world’s leading experts on flu, who works at Mount Sinai Medical School. Palese disputed Osterholm’s apocalyptic warnings. Where Osterholm burned hot, Palese kept cool, but he did not hide his utter rejection of the board’s decision. Just because a flu virus can be transmitted by another mammal species, he argued, doesn’t automatically mean it can spread among humans. In fact, ferrets are rather delicate in the face of a flu infections, easily suffering from brain damage. Our closer relatives among the primates, by contrast, don’t get sick from flu at all. (Jon Cohen explores the ferret question in depth in a news article for Science.)
Palese also questioned whether H5N1 is all that dangerous. He argued that the World Health Organization based its mortality rate only on the people who came into hospitals and tested positive for H5N1. But this particular strain of bird flu mostly strikes people in poor countries, especially in southeast Asia, where medical services are scarce. The people who make it to a hospital could well be a small fraction of all the people who come down with H5N1.
“The asymptomatic people are not being counted,” Palese said. If those extra people only got sick for a few days and then got on with their lives, the true mortality rate might be far less than 60% “It’s really much lower,” he said, pointing to surveys in Thailand and other countries that revealed evidence that a fair number of people had been exposed to H5N1 at some point in the past. (Palese recently published this same argument in the Proceedings of the National Academy of Sciences.)
This argument positively enraged Osterholm. He had clearly read Palese’s recent PNAS commentary and had prepared a rebuttal. “What you’re saying is just propaganda,” he told Palese. The trouble with Palese’s numbers were that they came from lousy studies, Osterholm argued. There are many ways to overestimate how many people have been exposed to a particular virus. A common test involves fishing for antibodies in blood samples. If your test isn’t precise enough, you may end up dredging up antibodies to other viruses. Osterholm had gone through surveys of H5N1 exposure, setting aside the lousy studies and tallying up the results from the best of the bunch. He came up with an estimate of .6% or less. If very few people have been exposed, the recorded deaths from H5N1 represent a frighteningly high rate.
Casadevall granted that perhaps H5N1 wasn’t 60% fatal. But it could be half that and still be a planetary nightmare. Even if it was ten times lower, it would still be far worse than the 1918 flu. “The numbers of unbelievable, any way you look at it,” he said.
Palese was unmoved. The new H5N1 viruses might pose a risk–a small one, in Palese’s mind–but scientists could handle it. All the research that had triggered the controversy wasn’t conducted in someone’s backyard. It was carried out in well-protected labs. Palese noted that the board doesn’t seem to have any objections to the work that’s done these days on smallpox, a virus that killed millions of people every year until it was eradicated in the 1970s. If scientists can in fact safely experiment with dangerous viruses, there is no need to paralyze the scientific community over bird flu. “You can always assume the worst,” Palese said. “But where do we stop being afraid?”
Osterholm glowered at Palese. “You do not represent the mainstream of influenzologists when it comes to this issue on influenza,” he said. I glanced at some of the other journalist in the audience, wondering if Osterholm could see us scribbling notes.
Osterholm stressed that he was not against research on bird flu in general. He just wanted the scientific community to balance the potential costs and benefits. He didn’t see very much significance in the new bird flu work. It wouldn’t help public health workers monitoring H5N1 viruses for lineages that might be evolving into a human pathogen. Nor did he see any benefit for developing vaccines or antivirals. On the other hand, he saw a risk–a small one, possibly–of tremendous devastation.
But when it comes to viruses can we really calculate such ratios of costs to benefits? Vincent Racaniello, a Columbia University virologist who was also on the panel, doesn’t think so. We’re bad at estimating risks. In 1981, for example, Racaniello and his colleagues pioneered a method for making polio viruses: they stuck the virus’s genes on a ring of DNA called a plasmid, which they then inserted into E. coli bacteria. The engineered E. coli spewed out polio genes, which Racaniello could insert into human culture cells, which then made full-blown polio viruses. People worried that Racaniello’s bacteria would get into people’s guts and start a polio epidemic. (It didn’t.)
We’re also bad at determining the benefits of research. Racaniello recalled how microbiologists in the 1950s discovered that E. coli defend themselves against invading viruses by chopping up their genes. Nobody thought much of that discovery for over a decade. But then in the late 1960s, a few researchers realized that they could use E. coli’s enzymes to cut up DNA and then paste them into new combinations. The entire biotechnology industry was born from that late eureka.
“You could have never predicted that,” said Racaniello. “You never know who will do the right experiment. So that’s why you need to give the information to everyone.”
The way things stand right now, everyone will not be getting that information. I tried to follow the reasoning for holding back key parts of the studies, but, honestly, I can’t recount it in a way that makes sense. As far as I could tell, the thinking was somebody just fooling around out of curiosity would be able to use the full information to create a deadly flu. But the fact is that the scientists who produced the new bird flu used standard methods that have been published many times over. I was also confused by how Nature and Science, the two journals where the redacted papers are to be published, will handle distributing the information to those who need to know about it. An editor from Nature talked about how hard it would be to set up a system. I had been expecting them to have a system to unveil for us.
“None of us ever wants to see a redaction again,” said Casadevall. The most sensible way to avoid that would be to figure out a way to make decisions about risks and benefits much earlier in the life cycle of an experiment. If the mission of an experiment is to create a deadly virus, just to see if it can be done, the panelists agreed that that is probably not a study to run. But what kind of system can stop not just these experiments, but other experiments that might present unexpected dangers? Casadevall worries that every graduate student may have to fill out 100-page forms for even the most harmless of experiments. “You’ll kill science,” he said.
Casadevall was expressing a concern that all the scientists on the panel shared: they worry that this affair will keep them from doing research. For now, they’re trying to work out a fairly self-regulating system to handle this sort of controversial research, perhaps in the hopes that the government won’t come sweeping in. But there was one non-scientist on the panel who did her best to make the scientists aware of the world outside their community.
Laurie Garrett, an award-winning health reporter who now works at the Council on Foreign Relations, pointed out that the flu is not just something that American scientists study in their labs. It’s a global problem. There’s a huge amount of resentment in poor countries where bird flu is the biggest threat, not just to humans, but to the poultry industry. “Poor people are killing their chickens for you,” Garrett said. “They’re going bankrupt.”
Making matters worse, as Garrett has recently written, is the distrust that has developed in the developing world towards Western medical research and the pharmaceutical industry. Indonesia, where many of the H5N1 deaths have occurred, has been reluctant to share bird flu samples with Western scientists, for fear that they would make huge profits from vaccines developed from them. The World Health Organization has set up an international agreement for the exchange of wild bird flu strains between different countries, but it’s in fragile shape.
So for all the sparks that flew in New York Thursday night, the real fireworks over the flu are yet to come.
[Update 2/3 9 am: Corrected description of Racaniello's experiment. Thanks to Matt Frieman. 2:50 pm Fixed Fouchier's institution name and month of his talk. Thanks to Jon Cohen. 8 pm: Expanded Osterholm's "mainstream of influenzologists" quote after seeing his objection to a similarly truncated version in Christine Gorman's story for Scientific American and reviewing my own recording. It's a valid clarification .]
A fair number of scientists like to get a tattoo to celebrate their research. Ryan Carney, a biologist at Brown University has taken the practice one step further. He’s gotten a tattoo that shows the key finding of a paper he and his colleagues have just published today. They studied a fossil feather from Archaeopteryx, the iconic bird (or almost-bird). They conclude it looked just like this tattoo.
Carney collaborated on the research with a team of scientists who have developed a method to reconstruct colors from fossils. One source of colors in animals is a cellular structure called a melanosome. Depending on the size, shape, and spacing of melanosomes, they can produce a range of hues. It turns out that melanosomes are incredibly rugged, sometimes enduring for millions of years.
As I wrote in the New York Times in 2009, the scientists first found melanosomes in the ink sac of a fossil squid and then went on to look at a 47-million-year-old bird feather. Then they went on to look at the feathers and feather-like structures of dinosaurs, reconstructing some of the colors of their plumage. The color pattern, which included stripes and tufts, hints that dinosaurs may have been using their feathers to show off to each other long before they evolved flight. (More details can be found in this story I wrote for National Geographic last year.)
No examination of feather evolution would be complete, of course, without Archaeopteryx. For over 150 years, it’s been at the center of debates about the history of birds–not to mention evolution itself.
The first fossil of Archaeopteryx was a single feather–the one that Carney has turned into a tattoo. It was discovered in 1861 in a limestone quarry near the town of Solnhofen and brought to Hermann von Meyer, one of Germany’s leading paleontologists at the time. As scientists would later determine, this exceptional feather was 145 million years old. Despite its antiquity, the feather looked much like the feathers on the wings of living birds.
The fossil was so extraordinary that Von Meyer wondered if some forger had etched it. After all, Solnhofen limestone was prized for making finely detailed lithographic prints. But then von Meyer compared the slab and the counterslab and found them to be identical.
“No draughtsman could produce anything so real,” he declared.
Even as von Meyer was studying the feather, the quarry at Solhofen yielded another spectacular fossil: an entire animal cloaked in feathers. Word of the fossil spread fast, but only a few scientists got to glimpse the fossil in person. Its owner, a local doctor, was carefully managing the access to his fossil to fuel a bidding war for his entire fossil collection. Those few glimpses were enough to electrify scientists across Germany and beyond. The animal looked in some ways like a bird. It had wing feathers draped from its arms, for example. But other parts of its body looked more like a reptile’s, such as its long bony tail. It was unlike anything alive today.
At the end of 1861, Von Meyer came up with a name to describe both fossils: Archaeopteryx lithographica—the lithographic first bird.
The debut of Archaeopteryx 150 years ago was a case of beautiful timing. Just two years earlier, Charles Darwin had published The Origin of Species, in which he claimed that living animals had evolved from transitional ancestors. “Had the Solenhofen quarries been commissioned – by august command – to turn out a strange being a la Darwin – it could not have executed the behest more handsomely – than in the Archaeopteryx,” wrote the paleontologist Hugh Falconer.
Darwin agreed. “It is a grand case for me,” he confided to a friend.
In later years, more fossils of Archaeopteryx emerged, and it became even more of a chimera. Like a bird, it had feathers on its entire body. But unlike living birds, it had teeth in its mouth and claws on its wings. Darwin’s followers continued to argue that it marked a transition in the origin of birds. But opponents of Darwin and his followers argued that a single species—especially one with feathers no different than those on living birds—did not establish a full-blown transition.
“Their views must be at once rejected as fantastic dreams,” the German paleontologist Andreas Wagner declared.
Wagner turned out to be wrong. A number of bird-like dinosaurs have come to light in the years since the discovery of Archaeopteryx, and researchers have been able to work out many of their relationships to each other. There’s still plenty of debate about just how well Archaeopteryx itself could fly, as well as its precise place in the dinosaur-bird tree of life. Last July fellow Discover blogger Ed Yong wrote about a new study suggesting other dinosaurs were more closely related to living birds than Archaeopteryx.
In a study funded by the National Geographic Society, Carney and his colleagues were able to sample tiny bits of the original, lone Archaeopteryx fossil, housed in a museum in Germany. They examined its melanosomes, comparing them to the melanosomes in 115 living birds. As they report today, the feather was most likely straight black, as you see it in Carney’s tattoo.
While a single feather isn’t enough to reconstruct Archaeopteryx’s entire appearance, it does provide some interesting clues about the animal. The feather was what’s known as a covert, meaning that it was sandwiched in the middle of the wing, covering the primary flight feathers but covered in turn by the feathers at the wing’s leading edge. As a result, it was mostly hidden from sight. So its black color couldn’t have served to attract the opposite sex or to camouflage it from enemies. It’s possible that the whole wing was black, and this particular covert just went along on the evolutionary ride. It’s also possible, Carney and his colleagues speculate, that the melanosomes were serving another function in this particular feather. In living birds, melanosomes can block bacterial infections, and they can also make feathers hard, preventing them from breaking under the forces of flight.
As for the function of black pigmentation on the shoulders of biologists–well, that’s another story.
Reference: R.M. Carney et al, “New evidence on the colour and nature of the isolated Archaeopteryx feather.” Nature Communications 2012 doi: 10.1038/ncomms1642