DARWIN's Surprise

ANNALS OF SCIENCE Darwin’s Surprise

Why are evolutionary biologists bringing back extinct deadly viruses? by michael specter

hierry Heidmann’s office, adjacent manity than viral diseases: yellow fever, composed of broken and disabled retro- to the laboratory he runs at the In- measles, and smallpox have been caus- viruses, which, millions of years ago, stitutT Gustave Roussy, on the southern ing epidemics for thousands of years. At managed to embed themselves in the edge of Paris, could pass for a museum of the end of the First World War, fifty DNA of our ancestors. They are called genetic catastrophe. Files devoted to the million people died of the Spanish flu; endogenous retroviruses, because once world’s most horrifying infectious dis- smallpox may have killed half a billion they infect the DNA of a species they eases fill the cabinets and line the shelves. during the twentieth century alone. become part of that species. One by one, There are thick folders for smallpox, Those viruses were highly infectious, though, after molecular battles that Ebola virus, and various forms of in- yet their impact was limited by their fe- raged for thousands of generations, they fluenza. sars is accounted for, as are rocity: a virus may destroy an entire cul- have been defeated by evolution. Like more obscure pathogens, such as feline ture, but if we die it dies, too. As a re- dinosaur bones, these viral fragments are leukemia virus, Mason-Pfizer monkey sult, not even smallpox possessed the fossils. Instead of having been buried in virus, and simian foamy virus, which is evolutionary power to influence humans sand, they reside within each of us, car- endemic in African apes. H.I.V., the as a species—to alter our genetic struc- rying a record that goes back millions of best-known and most insidious of the vi- ture. That would require an organism to years. Because they no longer seem to ruses at work today, has its own shelf of insinuate itself into the critical cells we serve a purpose or cause harm, these files. The lab’s beakers, vials, and refrig- need in order to reproduce: our germ remnants have often been referred to as erators, secured behind locked doors with cells. Only retroviruses, which reverse “junk DNA.” Many still manage to gen- double-paned windows, all teem with vi- the usual flow of genetic code from erate proteins, but scientists have never ruses. Heidmann, a meaty, middle-aged DNA to RNA, are capable of that. A found one that functions properly in human with wild eyebrows and a beard retrovirus stores its genetic information mans or that could make us sick. heavily flecked with gray, has devoted his in a single-stranded molecule of RNA, Then, last year, Thierry Heidmann career to learning what viruses might tell instead of the more common double- brought one back to life. Combining the us about aids and various forms of can- stranded DNA. When it infects a cell, tools of genomics, virology, and evolu- cer. “This knowledge will help us treat the virus deploys a special enzyme, called tionary biology, he and his colleagues terrible diseases,” he told me, nodding reverse transcriptase, that enables it to took a virus that had been extinct for briefly toward his lab. “Viruses can pro- copy itself and then paste its own genes hundreds of thousands of years, figured vide answers to questions we have never into the new cell’s DNA. It then be- out how the broken parts were originally even asked.” comes part of that cell forever; when the aligned, and then pieced them together. Viruses reproduce rapidly and often cell divides, the virus goes with it. Sci- After resurrecting the virus, the team with violent results, yet they are so ru- entists have long suspected that if a ret- placed it in human cells and found that dimentary that many scientists don’t rovirus happens to infect a human sperm their creation did indeed insert itself even consider them to be alive. A virus cell or egg, which is rare, and if that em- into the DNA of those cells. They also is nothing more than a few strands of bryo survives—which is rarer still—the mixed the virus with cells taken from genetic material wrapped in a package retrovirus could take its place in the hamsters and cats. It quickly infected of protein—a parasite, unable to func- blueprint of our species, passed from them all, offering the first evidence that tion on its own. In order to survive, it mother to child, and from one genera- the broken parts could once again be must find a cell to infect. Only then can tion to the next, much like a gene for eye made infectious. The experiment could any virus make use of its single talent, color or asthma. provide vital clues about how viruses like which is to take control of a host’s cel- When the sequence of the human H.I.V. work. Inevitably, though, it also lular machinery and use it to churn out genome was fully mapped, in 2003, re- conjures images of Frankenstein’s mon- thousands of copies of itself. These vi- searchers also discovered something ster and Jurassic Park. ruses then move from one cell to the they had not anticipated: our bodies are “If you think about this for five min- next, transforming each new host into a littered with the shards of such retrovi- utes, it is wild stuff,” John Coffin told me factory that makes even more virus. In ruses, fragments of the chemical code when I visited him in his laboratory at this way, one infected cell soon be- from which all genetic material is made. Tufts University, where he is the Amer- comes billions. It takes less than two per cent of our ge- ican Cancer Society Research Professor. Nothing—not even the Plague—has nome to create all the proteins necessary Coffin is one of the country’s most dis- posed a more persistent threat to hu- for us to live. Eight per cent, however, is tinguished molecular biologists, and was swarte joost

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TNY—2007_12_03—PAGE 64—133SC. Disabled retroviruses—fossils of molecular battles that raged for generations—make up eight per cent of the human genome.

TNY—2007_12_03—PAGE 65—133SC.—live art r16858_RD one of the first to explore the role of endogenous retroviruses in human evolution. “I understand that the idea of bring- lorca ing something dead back to life is funda- mentally frightening,” he went on. “It’s a The fact that no one had ever seen Lorca run power that science has come to possess had only to do with the legend of his clumsiness, and it makes us queasy, and it should. for one foot was shorter than the other and he was But there are many viruses that are more terrifed to cross the street by himself, dangerous than these—more infectious, though dogs barking in the mountains above him far riskier to work with, and less poten- brought him back to his senses and caused him tially useful.’’ when he was alone to try leaping and skipping Thanks to steady advances in com- the way you did and he tried the hop, skip, and jump puting power and DNA technology, a he learned from the 1932 Olympics talented undergraduate with a decent and loaded the left side of his mouth with green tobacco laptop and access to any university biol- when he was only eleven, for he took comfort ogy lab can assemble a virus with ease. in every form of degradation; and it was Five years ago, as if to prove that point, in John Jay Hall in 1949 researchers from the State University of that Geraldo from Pittsburgh made a personal connection, New York at Stony Brook “built” a polio for they were both housed in Room 1231 virus, using widely available information twenty years apart not counting the months and DNA they bought through the and only one of them heard Eisenhower give his maiden speech mail. To test their “polio recipe,” they in- outside the courtyard entrance, and there were bitter jected the virus into mice. The animals oranges enough for them both and you can imagine first became paralyzed and then died. one of our poets in the hands of our own bastards, (“The reason we did it was to prove that but what is the use of comparing, only the hats it can be done,’’ Eckard Wimmer, who are diferent, though I’m not too sure, the roses led the team, said at the time. “Progress maybe they stufed in our mouths—the Granadas. in biomedical research has its benefits and it has its downside.’’) The effort —Gerald Stern was widely seen as pointless and the justification absurd. “Proof of principle for bioterrorism,’’ Coffin called it. “Noth- One team, at the Aaron Diamond aids genes and viruses. And those viruses ing more.” Then, two years ago, after re- Research Center, in New York, recently helped make us who we are today just as searchers had sequenced the genetic created an almost identical virus. In the surely as other genes did. I am not certain code of the 1918 flu virus, federal scien- past few months, groups at Oxford Uni- that we would have survived as a species tists reconstructed it, too. In that case, versity and at the Fred Hutchinson Can- without them.” there was a well-understood and highly cer Research Center, in Seattle, have also He continued, “The Phoenix virus desired goal: to develop a vaccine that produced results that provide startling sheds light on how H.I.V. operates, might offer protection against future observations about evolution and dis- but, more than that, on how we oper- pandemics. ease. The approaches often differ, but ate, and how we evolved. Many people Resurrecting an extinct virus is an- not the goals. All of these researchers study other aspects of human evolu- other matter. Still, if Heidmann had hope that excavating the molecular past tion—how we came to walk, or the stuck to scientific nomenclature when he will help address the medical complexi- meaning of domesticated animals. But published his results, last fall, few outside ties that we confront today. Almost inci- I would argue that equally important is his profession would have noticed. A dentally, they have created a new disci- the role of pathogens in shaping the paper entitled “Identification of an Infec- pline, paleovirology, which seeks to way we are today. Look, for instance, at tious Progenitor for the Multiple-Copy better understand the impact of modern the process of pregnancy and birth.’’ herv-k Human Endogenous Retroele- diseases by studying the genetic history Heidmann and others have suggested ments,’’ which appeared in the journal Ge- of ancient viruses. that without endogenous retroviruses nome Research, was unlikely to cause a stir. mammals might never have developed Heidmann is on a bit of a mission, though. “ his is something not to fear but to a placenta, which protects the fetus and He named the virus Phoenix, after the celebrate,’’ Heidmann told me one gives it time to mature. That led to live mythical bird that rises from the ashes, dayT as we sat in his office at the institute, birth, one of the hallmarks of our evo- because he is convinced that this virus and which is dedicated to the treatment and lutionary success over birds, reptiles, others like it have much to tell about the eradication of cancer. Through the win- and fish. Eggs cannot eliminate waste origins and the evolution of humanity. dow, the Eiffel Tower hovered silently or draw the maternal nutrients required With equal ardor but less fanfare, sci- over the distant city. “What is remarkable to develop the large brains that have entists throughout the world have em- here, and unique, is the fact that endoge- made mammals so versatile. “These vi- barked on similar or related projects. nous retroviruses are two things at once: ruses made those changes possible,’’

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TNY—2007_12_03—PAGE 66—133SC. Heidmann told me. “It is quite possi- common ancestor, it was a revolutionary the viruses mutate with such speed. ble that, without them, human beings idea, and it remains one today. Yet noth- H.I.V. can evolve a million times as fast would still be laying eggs.” ing provides more convincing evidence as the human-immune-system cells it in- for the “theory” of evolution than the vi- fects. (Such constant change makes it I.V., the only retrovirus that most ruses contained within our DNA. Until hard to develop antiviral drugs that will • people have heard of, has caused recently, the earliest available informa- remain effective for long, and it has also moreH than twenty-five million deaths tion about the history and the course of presented a significant obstacle to the de- and infected at least twice that number of human diseases, like smallpox and ty- velopment of an aids vaccine.) people since the middle of the twentieth phus, came from mummies no more There are retroviruses (like H.I.V.) century, when it moved from monkey to than four thousand years old. Evolution that do not infect sperm or egg cells. man. It may be hard to understand how cannot be measured in a time span that Because they are not inherited, they organisms from that same family, and short. Endogenous retroviruses provide leave no trace of their history. “We can constructed with the same genes, could a trail of molecular bread crumbs leading have a fossil record only of the viruses have played a beneficial, and possibly millions of years into the past. that made it into the germ line,’’ Paul even essential, role in the health and de- Darwin’s theory makes sense, though, Bieniasz told me. “And, of course, most velopment of any species. In 1968, Robin only if humans share most of those viral did not.” Bieniasz is a professor of retro- Weiss, who is now a professor of viral fragments with relatives like chimpan- virology at the Aaron Diamond aids oncology at University College London, zees and monkeys. And we do, in thou- Research Center and the chief of the found endogenous retroviruses in the sands of places throughout our genome. retrovirology laboratory at Rockefeller embryos of healthy chickens. When he If that were a coincidence, humans and University. He has long been interested suggested that they were not only benign chimpanzees would have had to endure in the way complex organisms interact but might actually perform a critical an incalculable number of identical viral with viruses and adapt to them. “With function in placental development, mo- infections in the course of millions of flu virus, you can watch it change in lecular biologists laughed. “When I first years, and then, somehow, those infec- real time,’’ he said. “You can watch the submitted my results on a novel ‘endog- tions would have had to end up in exactly antibodies develop and see when and enous’ envelope, suggesting the existence the same place within each genome. The how it dies out. But with these others of an integrated retrovirus in normal em- rungs of the ladder of human DNA con- you are looking back tens of millions of bryo cells, the manuscript was roundly sist of three billion pairs of nucleotides years, so it is hard to know how a virus rejected,’’ Weiss wrote last year in the spread across forty-six chromosomes. functioned.’’ journal Retrovirology. “One reviewer The sequences of those nucleotides de- While Heidmann was working with pronounced that my interpretation was termine how each person differs from the Phoenix virus in France, Bieniasz and impossible.’’ Weiss, who is responsible another, and from all other living things. two colleagues at Aaron Diamond initi- for much of the basic knowledge about The only way that humans, in thousands ated a similar project. (At first, neither how the aids virus interacts with the of seemingly random locations, could team was aware of the other’s work.) Bi- human immune system, was not de- possess the exact retroviral DNA found eniasz rebuilt the youngest extinct retro- terred. He was eager to learn whether the in another species is by inheriting it from virus in the human genome—one that chicken retroviruses he had seen were re- a common ancestor. was still active a few hundred thousand cently acquired infections or inheritances Molecular biology has made precise years ago—because it had the fewest mu- that had been passed down through the knowledge about the nature of that inher- tations. The team took ten versions of centuries. He moved to the Pahang jun- itance possible. With extensive databases that virus (we carry more than thirty) and gle of Malaysia and began living with a of genetic sequences, recon- compared the thousands of group of Orang Asli tribesmen. Red jun- structing ancestral genomes nucleotides in the genetic gle fowl, an ancestor species of chickens, has become common, and sequence of each version. were plentiful there, and the tribe was retroviruses have been found They were almost identical, skilled at trapping them. After collect- in the genome of every ver- but where they differed the ing and testing both eggs and blood sam- tebrate species that has been researchers selected the nu- ples, Weiss was able to identify versions studied. Anthropologists cleotides that appeared most of the same viruses. Similar tests were and biologists have used frequently. That permitted soon carried out on other animals. The them to investigate not only them to piece together a discovery helped mark the beginning of the lineage of primates but the relation- working replica of the extinct retrovirus. a new approach to biology. “If Charles ships among animals—dogs, jackals, “If you have a person with a lethal defect Darwin reappeared today, he might be wolves, and foxes, for example—and also in the heart,’’ Bieniasz explained, “and an- surprised to learn that humans are de- to test whether similar organisms may in other with a lethal defect in the kidney, scended from viruses as well as from fact be unrelated. you could make one healthy person by apes,” Weiss wrote. Although it is no longer a daunting transplanting the respective organs. That Darwin’s surprise almost certainly technical task to find such viruses, or is what we did. would be mixed with delight: when he their genes, figuring out the selective “In the past, you got sick and you suggested, in “The Descent of Man” evolutionary pressures that shaped them keeled over and died,’’ he said. “Or you (1871), that humans and apes shared a remains difficult. Partly, that is because survived. Nobody could make much

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TNY—2007_12_03—PAGE 67—133SC.—live spot art r16843B, pls inspect and report on quality at the Massachusetts Institute of Tech- nology, simultaneously discovered reverse transcriptase, the special enzyme that can do exactly what Temin predicted: make DNA from RNA. The discovery has had a profound impact on modern medicine. It not only explained how cancer can be caused by a virus but provided researchers with the tools they needed to understand the origins and natural progression of diseases like aids. It also created a new field, retrovirology, and, more than that, as the Nobel committee noted when it awarded the 1975 Prize in Medicine to both Baltimore and Temin, it began to erase the tenuous borders between viruses and genes. Retroviruses cause cancers in chickens, sheep, mice, and other animals, but their effect on humans became clear only in the late nineteen-seventies, with the identification of two viruses that cause forms of leukemia. Retroviral proteins are particularly abundant in certain kinds of tumor cells, and scientists won- “I’m afraid that’s a wrap for this session!” dered to what degree they might be a cause of cancer. They were also curious about how retroviruses that infect us •• today differ from their ancestors. Work- ing with mice in 2005, Thierry Heid- sense of it. But almost ten per cent of our cancer. Rous, who as a young man mann found that endogenous retrovi- DNA consists of old retroviruses, and worked on a Texas cattle ranch, was ruses were present in large quantities in that says to me that it’s pretty clear they mystified. He extracted cancer cells tumor cells. Similar viruses have been played a major role in our evolution. We from the sick bird, chopped them up, associated with many cancers (and other evolved remarkably sophisticated de- and injected the filtered remains into diseases). It is still not clear how they fenses against them, and we would have healthy chickens: they all developed tu- function, but they may help subvert the done that only if their impact on human mors. A virus had to be the cause, but immune system, which would permit populations had been quite severe. It’s for years no one could figure out how cancer cells to grow without restraint. very likely that we have been under threat the virus functioned. Endogenous retroviruses also may actu- from retroviruses many times through- Then, in the nineteen-sixties, How- ally protect us from viruses that are even out human history. It is eminently pos- ard Temin, a virologist at the University worse. Experiments with mice and sible that this is not the first time we of Wisconsin, began to question the chickens have shown that they can block have been colonized by a virus very much “central dogma” of molecular biology, new infections by viruses with a similar like H.I.V.” which stated that genetic instructions genetic structure. Nonetheless, endoge- moved in a single direction, from the nous retroviruses are parasites, and in t the end of the nineteenth cen- basic blueprints contained within our most cases the cells they infect would be tury, a mysterious series of cancer DNA to RNA, which translates those better off without them. There is, how- epidemicsA devastated American poultry blueprints and uses them to build pro- ever, one notable exception. farms. One bird would fall ill and the teins. He suggested that the process The earliest mammals, ancestors of entire flock would soon be dead. In could essentially run in the other direc- the spiny anteater and the duck-billed 1909, a desperate farmer from Long Is- tion: an RNA tumor virus could give rise platypus, laid eggs. Then, at least a hun- land brought a chicken with a tumor to to a DNA copy, which would then insert dred million years ago, embryos, instead the laboratory of Peyton Rous, a young itself into the genetic material of a cell. of growing in a shell, essentially became cancer researcher at the Rockefeller In- Temin’s theory was dismissed, like most parasites. While only balls of cells, they stitute for Medical Research, in New fundamental departures from conven- began to implant themselves in the lin- York City (which became Rockefeller tional wisdom. But he never wavered. ing of the womb. The result was the pla- University). Cancer was not supposed to Finally, in 1970, he and David Balti- centa, which permits the embyros to take spread by virus, but the bird clearly had more, who was working in a separate lab, nourishment from the mother’s blood,

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TNY—2007_12_03—PAGE 68—133SC.—live art a12850 while preventing immune cells or bac- simply takes that protein into the cellu- he was testing out his course on me. I teria from entering. The placenta is es- lar equivalent of a trash can; if not for liked it and decided to apply to graduate sentially a modified egg. In the early that gene, H.I.V. might have been a triv- school—although I had less than a tenth nineteen-seventies, biologists who were ial disease. “To even think about the of the required biology courses. I had scanning baboon placentas with an elec- many million-year processes that caused very little hope.’’ But he had excellent test tron microscope were surprised to see that sort of evolution,” Malik said, shak- scores and in 1993 was accepted at the retroviruses on a layer of tissue known as ing his head in wonder. “It’s dazzling.” University of Rochester, as a graduate the syncytium, which forms the princi- Malik grew up in Bombay and studied student in the biology department. He pal barrier between mother and fetus. chemical engineering at the Indian Insti- visited his new adviser as soon as he ar- They were even more surprised to see tute of Technology there, one of the rived. “He looked at my schedule and that all the animals were healthy. The most prestigious technical institutions in said, ‘I see that you are doing genetics.’ I same phenomenon was soon observed in a country obsessed with producing engi- had no clue what he was talking about, mice, cats, guinea pigs, and humans. For neers. He gave no real thought to biol- but I said sure, that sounds good. I had many years, however, embryologists ogy, but he was wholly uninspired by his never taken a course in the subject. He were not quite sure what to make of other studies. “It was fair to say I had lit- gave me the textbook and told me that these placental discoveries. Most re- tle interest in chemical engineering, and the class was for undergraduates, which mained focussed on the potential harm a I happened to tell that to my faculty ad- made me feel more comfortable.’’ It retrovirus could cause, rather than on any viser,’’ he recalled. “He asked me what I wasn’t until the end of the conversation possible benefit. Cell fusion is a funda- liked. Well, I was reading Richard that Malik realized he would be teaching mental characteristic of the mammalian Dawkins at the time, his book ‘The the class, not taking it. placenta but also, it turns out, of endog- Selfish Gene’ ”—which asserts that a The Hutchinson Center encourages enous retroviruses. In fact, the protein gene will operate in its own interest even its research scientists to collaborate with syncytin, which causes placental cells to if that means destroying an organism colleagues in seemingly unrelated fields. fuse together, employs the exact mecha- that it inhabits or helped create. The Malik and Michael Emerman, a virolo- nism that enables retroviruses to latch on concept fascinated Malik. “I was think- gist at the center’s Human Biology and to the cells they infect. ing of becoming a philosopher,’’ he said. Basic Sciences Divisions, have been “I thought I would study selfishness.” working together for four years. Malik’s he Nobel Prize-winning biologist Malik’s adviser had another idea. The principal interest is historical: why did Joshua Lederberg once wrote that university had just established a depart- evolutionary pressures shape our de- theT “single biggest threat to man’s contin- ment of molecular biology, and Malik fenses against viruses, and how have they ued dominance on this planet is the virus.” was dispatched to speak with its director. done it? Emerman studies the genetic Harmit Malik, an evolutionary geneticist “This guy ended up teaching me by him- composition and molecular pathology at the Fred Hutchinson Cancer Research self, sitting across the table. We met of the AIDS virus. “Together, we are try- Center, acknowledges the threat, yet he is three times a week. I soon realized that ing to understand what constellation of confident that viruses may also provide one of our greatest scientific opportuni- ties. Exploring that fundamental para- dox—that our most talented parasites may also make us stronger—has become Malik’s passion. “We have been in an evolutionary arms race with viruses for at least one hundred million years,’’ he told me recently, when I visited his laboratory. “There is genetic conflict everywhere. You see it in processes that you would never suspect; in cell division, for instance, and in the production of proteins involved in the very essence of maintain- ing life. “One party is winning and the other losing all the time,” Malik went on. “That’s evolution. It’s the world’s defini tive game of cat and mouse. Viruses evolve, the host adapts, proteins change, viruses evade them. It never ends.” The Aids virus, for example, has one gene, called “vif,” that does nothing but block a protein whose sole job is to stop the virus from making copies of itself. It “These maps are old, so pay no attention to the borders.”

TNY—2007_12_03—PAGE 69—133SC.—live art a12815 viruses we are susceptible to and why,’’ don’t get infected,’’ he said. Every pri- and Emerman stressed that this day will Emerman told me. “We know at least mate has some version, but it works not come soon. “First, we have to estab- that it is all a consequence of infections differently in each species—customized lish what part of trim5a is actually re- our ancestors had. So from there we to fit the varying evolutionary require- sponsible for protecting monkeys against want to try and derive a modern reper- ments of each. In the rhesus monkey, H.I.V.,” Malik said. “Then we would toire of antiviral genes.” that single gene provides complete pro- have to try and make it as a drug”—and They focussed on chimpanzees, our tection against H.I.V. infection. In hu- one that the human body won’t reject. closest relatives. Chimpanzees are easily mans, it does nothing of the kind. “When “The challenge is to find out how little infected by the AIDS virus, but it never Michael and I started to get into this you can change the human version and makes them sick. That has remained one business, people had never thought much still make it effective against H.I.V. That of the most frustrating mysteries of the about the evolutionary meaning of that is really what drives this whole story of epidemic. How did nearly identical ge- gene. But we wondered, Is trim5a just re-creating that extinct virus and doing netic relatives become immune to a virus an anti-H.I.V. factor or is there some- these experiments. Nobody is doing this that attacks us with such vigor? The most thing else going on here?” as a gimmick. This virus could open dramatic difference between the chimp Like the two human retroviruses doors that have been closed to us for mil- genome and ours is that chimps have that were reconstructed in France and in lions of years. And if we can learn how to roughly a hundred and thirty copies of a New York, PtERV has long been extinct; do that we have a chance to find a very virus called Pan troglodytes endogenous Emerman and Malik realized that they effective response to one of the world’s retrovirus, which scientists refer to by the would have to assemble a new version if most incredibly effective viruses.” acronym PtERV (pronounced “pea-terv”). they hoped to learn how we became im- Gorillas have eighty copies. Humans mune to it. They took scores of viral se- he Oxford University zoology de- have none. quences and lined them up to see what partment is housed in a forbidding “We can see that PtERV infected goril- they had in common. The answer was concreteT structure that looks like an las and chimps four million years ago,’’ almost everything. When there were Eastern European police station. The Emerman told me. “But there was never differences in the sequence, the research- building is named for the Dutch ethol- any trace of its infecting humans.” It is ers used a statistical model to predict the ogist Niko Tinbergen, whose work— possible that all infected humans died, most likely original version. Then they with wasps and gulls, among other but it is far more likely that we developed put the virus back together. (Like Bien- species—won him a Nobel Prize and a way to repel the virus. Nobody knew iasz, in New York, they did so in such a helped establish the study of animal be- why until Emerman, Malik, and Shari way that the virus could reproduce only havior as a science. Tinbergen’s most fa- Kaiser, a graduate student in Emerman’s once.) They modified the human trim5a mous student, Richard Dawkins, has lab, presented evidence for a startling the- protein so that it would function like the carried on the university tradition of ory: the evolutionary process that protects chimp version. After that, the protein no aggressive independence, and so have us from PtERV may be the central reason longer protected humans against the re- the younger members of the faculty. I we are vulnerable to H.I.V. constructed copy of the virus. Next, they stopped by the department a few months “We thought we must have a defense tested this modified version against ago to have lunch with two of them, against this thing that they don’t have,’’ H.I.V. Emerman placed it in a dish, first Aris Katzourakis and Robert Belshaw, Malik told me, picking up the story the with H.I.V. and next with PtERV. What both evolutionary biologists who have following day. Evolutionary biologists he found astonished him. No matter made the new field of paleovirology a are not given to emotional outbursts—by how many times he repeated the test, the specialty. Just before I arrived, Kat- definition, they take the long results never varied. “In every zourakis had lobbed a bomb into the view. Malik is an engaging and case, the protein blocked ei- field. voluble exception. When an anti- ther PtERV or H.I.V.,” Emer- Nobody knows what chain of evolu- viral protein excites him, he man told me. “But it never tionary factors is required to transform doesn’t hold back. “Where but in protected the cells from both an infectious virus—like H.I.V.—into evolutionary history can you see a viruses.” one that is inherited. Such a virus would story like this, with PtERV and the There are several possible have to invade reproductive cells. H.I.V. chimps?’’ he asked, leaping up ways to interpret the data, doesn’t do that. It belongs to a class from his chair to begin sketching but the one favored by the recalled lentiviruses (from the Latin for viral particles on a whiteboard. “It’s sim- searchers is that because humans devel- “slow”), which are common in mam- ply amazing.’’ oped an effective defense against one mals like sheep and goats. Because len- He launched into a description of the virus, PtERV, at about the time we split tiviruses had never been found in any complex interactions between viruses and off from the chimps, five million years animal’s genome, most virologists as- the proteins that we have developed to ago, we were left vulnerable to a new one, sumed that they evolved recently. Until fight them. There is one particular gene, H.I.V. “If we can develop a drug that acts this summer, the oldest known lentivi- called trim5a, that in humans manufac- the same way the monkey version of this rus was “only” a million years, and al- tures a protein that binds to and destroys protein acts—so that it recognizes H.I.V. most no one thought that a lentivirus PtERV. “Our version of this gene is highly and neutralizes it—we could have a very could become endogenous. effective against PtERV, which is why we effective therapy,’’ Malik said. Both he In a paper titled “Discovery and

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TNY—2007_12_03—PAGE 70—133SC.—live spot art r16843C, pls inspect and report on quality Analysis of the First Endogenous Len- tivirus,’’ published last spring in Proceed- ings of the National Academy of Sciences, Katzourakis, along with collaborators from Oxford, Stanford University, and Imperial College London, showed oth- erwise. They discovered the fossilized remains of an ancient lentivirus—the same type that causes AIDS—within the genome of the European rabbit (Orycto- lagus cuniculus). “At first, I just assumed it was a mistake,’’ Katzourakis told me over lunch in the building’s cafeteria, Darwin’s Café. “We checked it twice, three times. But we kept seeing genes that are found only in lentiviruses.’’ They named their discovery “rabbit endogenous lentivirus type K,” or RELIK. An obvious next step for Katzourakis and his group will be to work with virologists who can assemble a functional version of the ancient virus—as the researchers in Paris, New York, and Seattle have done. “It’s the most promising way to explore the evolution and the impact of H.I.V.,” he said. It might be more than that. AIDS researchers have always been handicapped by the absence of a small-animal model in which to study the effects of the disease. It is not easy to use monkeys or sheep. They are expensive and difficult to obtain, and, for reasons of ethics, many experiments on them are proscribed. “Al- though RELIK is an ancient lentivirus and only defective copies were identified in this analysis,’’ the authors wrote, “recent research has shown that it is possible to reconstruct infectious progenitors of such viruses,” which, they concluded, could potentially “provide a small animal model for experimental research.” The discovery has already changed the way scientists think about viral evolution, and about H.I.V. in particular. “The most obvious implication is that we can no longer say that H.I.V. could not become endogenous,’’ John Coffin, of Tufts, told me, though he still considers that unlikely. “It opens the field to a whole new level of examination.” It also considerably alters the phylogenetic tree. RELIK is at least seven million years old, which makes it the oldest known lentivirus. “It is possible that primate lentiviruses such as er H.I.V. and S.I.V.’’—its simian cousin— dn

ro “are much older than people ever thought,” b Coﬃn said. Hillary Clinton and Mitt Romney, who hope for a rich harvest in Iowa, ﬁnd steve steve We can’t be certain when endoge- themselves in the tall corn with Barack Obama and Mike Huckabee.

TNY—2007_12_03—PAGE 71—133SC.—live art r16863_Alt_RD, pls pull kodak for color guidance nous retroviruses entered our genome, retrovirus must have spread to Australia have to do is put the genes together, and because it is impossible to watch a five- recently and is entering the genome back it comes. million-year process unfold. Yet in Aus- now. That offers virologists and evolu- “The knowledge you gain from res- tralia a retrovirus seems to be evolving in tionary biologists their first opportunity urrecting something that has not been front of our eyes. Beginning in the late to learn how a virus transforms itself alive for a million years has to be im- nineteenth century, koalas on the main- from something that can simply infect mensely valuable,’’ Harmit Malik told land were hunted nearly to extinction. (and kill) its host to an organism that me in Seattle. “We didn’t take it lightly, To protect them, as many as possible will become a permanent part of that and I don’t think any of our colleagues were captured and moved to several is- host. Persistent viruses tend to grow did, either.’’ He repeatedly pointed out lands in the south. In the past hundred weaker over the years. They couldn’t that each virus was assembled in such a years, those koalas have been used to re- live for long if they killed everything way that it could reproduce only once. plenish the population on the mainland they infected. How they adapt, though, “If you can’t apply the knowledge, you and on several other Australian islands. is a mystery. “Events like this have ob- shouldn’t do the experiment,” he said. In many cases, though, they have be- viously occurred in human evolution,’’ Malik is a basic research scientist. His come infected with a retrovirus that Paul Bieniasz told me—even with vi- work is not directly related to drug de- causes leukemia, immune disorders, and ruses like H.I.V. “We might be able to velopment or treating disease. Still, he other diseases. It can even kill them. see how the koala infection settles into thinks deeply about the link between The epidemic presents a significant the genome, and whether it plays a role what he does and the benefits such work threat to the future of the species, and in helping its host fend off other vi- might produce. That is an entirely new scientists have followed it closely. One ruses,” he continued. “Whatever we way to look at the purpose of scientific group, from the University of Queens learn will be useful, because we could research, which in the past was always land, looked for the virus in koala never have learned it in any other way.” propelled by intellectual curiosity, not DNA—and, as one would expect with utilitarian goals. Among élite scientists, a retrovirus, found it. The team also no- n 1963, Linus Pauling, the twentieth it was usually considered gauche to be ticed that some of the babies, known as century’s most influential chemist, obsessed with anything so tangible or joeys, were infected in the same loca- wroteI an essay, with Emile Zucker- immediate; brilliant discoveries were tions on their DNA as their parents. kandl, in which they predicted that it supposed to percolate. But that para- That means that the virus has become would one day become possible to re- digm was constructed before laborato- endogenous. Yet, when the scientists construct extinct forms of life. It has ries around the world got into the busi- examined the koalas on Kangaroo Is- taken half a century for scientists to ac- ness of reshaping, resurrecting, and land, in the south, they discovered quire the information necessary to mas- creating various forms of life. something they had not anticipated: ter most of the essential molecular biol- The insights provided by recent ad- none of the koalas were infected. ogy and genetics, but there can no longer vances in evolutionary biology have al- That could mean only one thing: be any doubt that Pauling was right. ready been put to use, particularly in since the infected animals had all been Once you are able to assemble the ances- efforts to stop the AIDS virus. One of the moved just in the past century, the koala tral sequence of any form of life, all you main reasons that endogenous retroviruses can enter our genome without kill- ing us is that they make many errors when they reproduce. Those errors are genetic mutations. The faster a cell re- produces (and the older it is), the more errors it is likely to make. And the more errors it makes the less likely it is to be dangerous to its host. “Viruses are accu- mulating and becoming more decrepit with every passing million years” was the way Malik described it to me. That real- ization has led AIDS researchers to con- template a novel kind of drug. Until recently, antiviral medications had been designed largely to prevent H.I.V. from reproducing. Various drugs try to inter- fere with enzymes and other proteins that are essential for the virus to copy itself. There is a problem with this approach, however. Because the virus changes so rapidly, after a while a drug designed to stop it can lose its effective “Making a difference doesn’t make a difference.” ness completely. (That is why people

TNY—2007_12_03—PAGE 72—133SC.—live art a12791 take cocktails of H.I.V. medications; the combinations help slow the rate at which the virus learns to evade those interventions.) Scientists at a company called Koro- nis Pharmaceuticals, just outside Seattle, are taking the opposite approach. They hope that by speeding up the life cycle of the AIDS virus they can drive it to extinction. The goal is to accelerate the virus’s already rapid pace of mutation to the point where it produces such an enor- mous number of errors in its genome that it ceases to pose a threat. Like endogenous retroviruses, H.I.V. would become extinct. Earlier this month, researchers at the University of California at San Francisco and at the University of Toronto announced an even more fasci- nating way to use the fossils in our genome. H.I.V. infects immune-system cells and alters them so that they can produce more H.I.V. In doing so, they stimulate endogenous retroviruses, “We ask only that you be discreet around the celebrities.” which then produce proteins that act as a sort of distress signal. Those signals can •• be detected on the surface of H.I.V.-infected cells, and in theory it should be possible to develop vaccines that target are molecular genetic parasites and are protect people against the virus. (For them. In essence, such a vaccine would mostly recognized for their ability to in- H.I.V. to infect immune cells, for exam- act like a smart bomb, homing in on duce disease.” Yet he goes on to argue ple, it must normally dock with a recep- a signal transmitted from within each that they also represent “a major creative tor that sits on the surface of those cells. H.I.V.-infected cell. The team in San force’’ in our evolution, driving each in- There are people, though, whose genes Francisco found strong evidence of those fected cell to acquire new and increasingly instruct them to build defective receptors. signals in the immune cells of fifteen of complex molecular identities. Villarreal Those with two copies of that defect, one sixteen volunteers who were infected was among the first to propose that en- from each parent, are resistant to H.I.V. with H.I.V. In an uninfected control dogenous retroviruses played a crucial role infection no matter how often they are group, the signals were far weaker or in the development of the mammalian exposed to the virus.) The process might were absent altogether. “For a vaccine placenta. He goes further than that, take tens, or even hundreds, of thousands against an infectious agent, this is a com- though: “Clearly, we have been observing of years, but Darwinian selection would pletely new strategy,’’ Douglas Nixon, evolution only for a very short time. Yet ultimately favor such mutations, and pro- the immunologist who led the team, we can witness what current viruses,” such vide the opportunity for the evolution of said. It’s one that could not have emerged as H.I.V., “can and might do to the a fitter human population. “If this were to without the recent knowledge gained human population.” be the outcome,’’ Villarreal wrote, “we through experiments with endogenous Villarreal predicts that, without an would see a new species of human, retroviruses. effective AIDS vaccine, nearly the entire marked by its newly acquired endogenous population of Africa will eventually per- viruses.” The difference between us and here may be no biological process ish. “We can also expect at least a few hu- this new species would be much like the more complicated than the relation- mans to survive,’’ he wrote. They would difference that we know exists between shipsT that viruses have with their hosts. be people who have been infected with humans and chimpanzees. Could it be that their persistence made it H.I.V. yet, for some reason, do not get For Villarreal, and a growing number possible for humans to thrive? Luis P. sick. “These survivors would thus be left of like-minded scientists, the conclusion Villarreal has posed that question many to repopulate the continent. However, is clear. “Viruses may well be the unseen times, most notably in a 2004 essay, “Can the resulting human population would be creator that most likely did contribute to Viruses Make Us Human?” Villarreal is distinct” from those whom H.I.V. makes making us human.”  the director of the Center for Virus Re- sick. These people would have acquired search at the University of California at some combination of genes that confers newyorker.com Irvine. “This question will seem prepos- resistance to H.I.V. There are already ex- terous to most,’’ his essay begins. “Viruses amples of specific mutations that seem to An audio interview with Michael Specter.

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