CARLOS Tiger without Time

With the number of confirmed U.S. swine flu cases double the 20 it was yesterday, the government says that it is closely monitoring the swine flu outbreak and is preparing for further spread.

“This is obviously the cause for concern and requires a heightened state of alert, but it’s not a cause for alarm,” President Obama said today at the National Academy of Sciences (NAS).

In the U.S., 40 cases have been confirmed by the U.S. Centers for Disease Control and Prevention (CDC) in five different states: New York, California, Texas, Ohio and Kansas. All individuals have recovered, including the one that was hospitalized, Richard Besser, acting director of the Center for Disease Control (CDC), said in a press conference today. Twenty of the cases have stemmed from a New York City preparatory school. Although that’s more than twice the number originally reported, the additional cases were a result of further testing rather than continued spread of the flu, Besser noted. The CDC is distributing kits to test for swine flu in affected states, and as testing ramps up, Besser said, “I expect we will see other cases across the country.”

New cases are being reported in Canada and across the Atlantic, according to a report by the Center for Infectious Disease Research and Policy (CIDRAP) at the University of Minnesota. As of April 26, six confirmed cases of swine flu in Canada and one in Israel had been reported. An informal map of cases worldwide is being collected by a biomedical researcher in Pittsburgh.

Meanwhile, the European Union has issued a travel warning to citizens, urging them to avoid nonessential travel to the U.S. or Mexico, reports The New York Times. The CDC will be distributing information cards at U.S. ports of entry to inform travelers about the flu’s symptoms and precautions that should be taken to avoid it. Later today, the CDC will also issue a travel advisory recommending that all nonessential travel to Mexico be avoided.

“This is a serious event, and we’re taking it seriously,” Besser said. “This situation is evolving very quickly,” he said, and a clear picture of how the disease is spreading may not be available for another week or two.

Although a vaccine for the flu strain, which is similar to those responsible for the 1918 and 1957 outbreaks, is likely months away, biotechnology companies are anxious to get to work, notes FierceBiotech, a biotech industry newsletter. The CDC is discussing whether to include strains of this flu in next year’s flu vaccines.

By dubbing the outbreak a public health emergency yesterday, the government authorized states to release 25 percent of their antiviral drugs from the Strategic National Stockpile, which means that 11 million courses of the drugs are en route to the affected states, said Besser.

Although the drugs could help treat those infected with the virus, Besser noted that, “there’s no single action that will control an outbreak… It starts with personal responsibility, but it doesn’t end there.” He recommended that people take standard precautions such as frequent hand washing, covering coughs and sneezes and staying home from work and school if feeling ill.

At the speech to the NSA, Obama concluded, “If there was ever a day that reminded us of our shared stake in science and research, it is today.”

By Katherine Harmon

Fast treatment manufactured from flu survivors’ antibodies could pave the way to more effectively thwarting pandemics

A new method for swiftly producing proteins to fight infections could mean the difference between life and death during future pandemics. Researchers report in Nature today that they have perfected a way to manufacture monoclonal antibodies capable of destroying diseases such the avian flu, which have the ability to swap genes with human flu varieties and jump from birds to people.

Their research is a dramatic advance, because it marks the first time that scientists were able to rapidly generate the disease-killing proteins, according to study co-author Patrick Wilson, an immunologist at the Oklahoma Medical Research Foundation (OMRF) in Oklahoma City. He says that researchers could one day spare scores of lives and nip potential epidemics in the bud by whipping up a treatment within a month from natural antibodies that survivors developed against the threatening disease.

Until now, he says, it took as long as three months to produce enough monoclonal antibodies to protect huge populations, because the immune system only pumps out small quantities in response to infections.

Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, called the new work a “significant advance,” noting in a statement that it “opens the way to producing [monoclonal antibodies] that potentially could be used diagnostically or therapeutically” for the flu as well as other infectious diseases such as hepatitis C and the human immunodeficiency virus (HIV), which can lead to full-blown AIDS.

The new technique, pioneered by Wilson and fellow researchers at the Emory University School of Medicine in Atlanta, saves time by using antibodies produced by so-called B cells (white blood cells that produce and then ferry them to infection sites to battle invading germs) in response to vaccines instead of to actual infections.

According to Wilson, monoclonal antibodies from (deliberately infected) animals were routinely used in the first half of the 20th century to try to treat diphtheria (an upper-respiratory illness that killed roughly 15,000 people annually in the early 1920s until a vaccine was formulated against it in 1924) and tetanus (a potentially fatal infection also known as lockjaw, because one of the muscles it destroys is in the jaw). There were, however, compatibility issues: The human immune system in most cases viewed the animal antibodies as alien and rejected them—or lacked the ammunition to destroy them, thereby making patients sicker.

To avoid these problems, researchers have been trying to perfect and speed up procedures for extracting monoclonal antibodies from humans, replicating them in a lab, and then injecting them into victims suffering from the diseases they were formed to fight. The key to collecting these antibodies has been to remove B cells that bear them from survivors of, say, a particular flu strain—or alternatively, someone who has been vaccinated against the flu (because the flu vaccine contains a weakened version of the virus).

Until now, scientist have run into problems trying to recreate large enough quantities quickly enough to spare lives. Wilson says the process traditionally has taken so long that by the time enough new B cells were generated, the flu strain targeted already had mutated into a form no longer vulnerable to the captured crop of antibodies.

In the new method, the researchers isolated B cells from humans who had been vaccinated against—and therefore had built up specific antibodies to—the seasonal flu. But instead of prodding extracted B cells to proliferate, Wilson says, the teams simply plucked the antibody-producing genes from them and inserted those into existing B-cell lines, thereby increasing their protein output.

The type of B cells that the scientists tapped for the coveted proteins are known as antibody-secreting plasma cells (ASCs). ASCs are among the first-line defenders that the immune system sends out when it detects an infection (including weakened vaccine versions). These cells are tasked with scoping out potential danger and signaling the backup germ fighters required to knock out invading armies. ASCs are short-lived, because they serve more as scouts than as combat soldiers.

The teams found that up to 80 percent of the ASCs that they isolated during their peak (seven days after vaccination) contained monoclonal antibodies to the flu strain they had injected.

“The reason this is so exciting is that the same kind of B cell could be present in people [who] have primary infections,” says Wilson, noting that researchers thus far have only showed this works with antibodies created in response to vaccines. The team now plans to test the method on people infected with the flu or another virus.

Antonio Lanzavecchia, director of the Institute for Research in Biomedicine in Bellinzona, Switzerland, stresses that the effectiveness of Wilson’s technique depends on the relatively short time span during which ASCs are active.

Lanzavecchia believes that his own research is more promising: He has harvested antibodies against both severe acute respiratory syndrome (SARS) and avian flu using so-called memory B cells, which are immune cells that store antibodies from all vaccines and previously beaten viruses—and remain in the blood permanently.

“If you have a spontaneous disease, you have only a short window of time where you can get [ASCs],” he says, “so targeting memory B cells [from someone who has beaten the illness] may be an advantage.”

The problem is, Wilson says, that a person has relatively few memory B cells—”on the order of one in thousands”—making the process of extracting antibodies from them a time-consuming task, because they first must be located.

“We are making new antibodies that [are potentially more effective because they] are binding to very specific strains of a virus,” he says. He adds that the new technique might also be employed to pin down the flu strain someone has by testing the effectiveness of extracted antibodies against it.

Wilson says that the new technique could become widely available in a few years if it is proved safe and effective during human clinical trials.

By Nikhil Swaminathan

The two winter respiratory illnesses may look alike, but pay attention to tell them apart

How many times have you dismissed sniffles as “just a cold,” and carried on with a stuffed nose and sinuses assuming that the symptoms would eventually run their course, perhaps a bit more quickly with a few doses of Mom’s homemade chicken soup?

Influenza is another story. The common cold eventually fizzles, but the flu may be deadly. Some 200,000 people in the U.S. are hospitalized and 36,000 die each year from flu complications — and that pales in comparison to the flu pandemic of 1918 that claimed between 20 and 100 million lives. The best defense against it: a vaccine. Yet barely 30 percent of 4,000 U.S. adults surveyed said they’d been inoculated this season, despite a record supply of flu shots, according to a new RAND Corp. survey. (GlaxoSmithKline, which makes flu vaccine, helped pay for the survey.)

So what is the difference between a cold and the flu – and how can you be sure which one you have?

We asked Jonathan Field, director of the allergy and asthma clinic at N.Y.U. Langone Medical Center/Bellevue Hospital in New York. Following is an edited transcript of our interview with him.

What causes the flu? How is it different from a cold?

The flu is a viral infection caused by the influenza virus, a respiratory virus. The common cold is also a viral infection caused by the adenovirus or coronavirus and there are many, many subsets with a lot of variability. That’s why it’s said there’s no cure for the common cold [and] there’s no real vaccine. The flu is known to be from influenza and is preventable with vaccination.

Colds tend to produce runny nose, congestion, sore throat. Influenza is more pronounced in that it infects the lungs, the joints and causes pneumonia, respiratory failure and even death. It tends to infect the intestinal tract more in kids, with diarrhea and vomiting. Because of the relative immaturity of the gut, they may absorb more virus and that wreaks more havoc on the intestines. Flu causes epidemics and pandemics with the potential for mortality, whereas the common cold is a nuisance for us.

How can someone who’s feeling ill distinguish between cold and flu, or an allergy?

Flu typically starts in early November and can go until March. The peak time is now — November to January. Allergy is typical in spring or fall, and cold more so in winter.

The body can respond in only so many ways, but there are things you can use to differentiate. Allergic symptoms are similar to those of a cold, but [result from] your immune system responding to something benign. Usually there’s no fever, and there’s an allergic manifestation of itch in the back of the throat or the ears. It’s unlikely with allergy to have body aches. With a cold, there’s sometimes a low-grade fever.

You can tell the difference by the length and severity of the illness and whether you’ve had a similar experience in the past. Both colds and flu usually last the same seven to 10 days, but flu can go three to four weeks; the flu virus may not still be there, but you have symptoms long after it’s left. Allergy can last weeks or months.

Are the treatments for these illnesses different?

For any of these things, if it affects the nose or sinus, just rinsing with saline that gets the mucus and virus out is a first-line defense. It’s not the most pleasant thing to do, but it works very well. There are classes of medicines that can help the flu — Tamiflu and Relenza — antivirals that block viruses’ ability to reproduce and shorten the length and severity of the illness. But they have to be taken within 48 hours or the cat is proverbially out if the bag [because by then] the virus has done the most of its reproduction. For a cold or flu, rest and use decongestants and antihistamines, ibuprofen, acetaminophen, chicken soup and fluids.

Zinc supposedly helps the body’s natural defenses work to their natural capacity and decrease the severity and length of a cold. Cells need zinc as a catalyst in their protective processes, so if you supply them with zinc, it helps them work more efficiently. You should also withhold iron supplements. Viruses use iron as part of their reproductive cycle, so depriving them of it blocks their dissemination.

The majority of these infections are not bacterial and do not require [nor will they respond to] antibiotics. My rule of thumb is that a viral infection should go away in seven to 10 days. If symptoms persist after that, you’d consider if it’s bacteria like Strep or Haemophilus influenzae. Those bacteria cause illnesses that are longer lasting.

Is that treatment approach the same for kids?

In general, the same rules apply: Most children will have six to eight colds a year in their first three years of life, and most are viral. It’s very easy to test for strep and for that you should have a [positive] culture [before treating with antibiotics].

Are the strategies for avoiding cold and flu different?

Avoidance is very similar: Strict hand washing, not sharing drinking cups or utensils, and avoiding direct contact with people who are sneezing. As long as someone has a fever, they have the possibility to transmit infection. After they’ve had no fever for 24 hours, they’re not infectious.

The U.S. Centers for Disease Control and Prevention (CDC) now recommends that just about everyone get the flu shot: kids 6 months to 19 years of age, pregnant women, people 50 and up, and people of any age with compromised immune systems. Is the shot beneficial to anyone who gets it?

Unless you have a contraindication, there’s no reason not to get it. Contraindications would include egg allergy (because the vaccine is grown from egg products), any vaccines within a last week or two, and active illness at the time of your vaccine.

By Jordan Lite

Comparisons of the genomes of humans and chimpanzees are revealing those rare stretches of DNA that are ours alone

Six years ago I jumped at an opportunity to join the international team that was identifying the sequence of DNA bases, or “letters,” in the genome of the common chimpanzee (Pan troglodytes). As a biostatistician with a long-standing interest in human origins, I was eager to line up the human DNA sequence next to that of our closest living relative and take stock. A humbling truth emerged: our DNA blueprints are nearly 99 percent identical to theirs. That is, of the three billion letters that make up the human genome, only 15 million of them—less than 1 percent—have changed in the six million years or so since the human and chimp lineages diverged.

Evolutionary theory holds that the vast majority of these changes had little or no effect on our biology. But somewhere among those roughly 15 million bases lay the differences that made us human. I was determined to find them. Since then, I and others have made tantalizing progress in identifying a number of DNA sequences that set us apart from chimps.

An Early Surprise
Despite accounting for just a small percentage of the human genome, millions of bases are still a vast territory to search. To facilitate the hunt, I wrote a computer program that would scan the human genome for the pieces of DNA that have changed the most since humans and chimps split from a common ancestor. Because most random genetic mutations neither benefit nor harm an organism, they accumulate at a steady rate that reflects the amount of time that has passed since two living species had a common forebear (this rate of change is often spoken of as the “ticking of the molecular clock”). Acceleration in that rate of change in some part of the genome, in contrast, is a hallmark of positive selection, in which mutations that help an organism survive and reproduce are more likely to be passed on to future generations. In other words, those parts of the code that have undergone the most modification since the chimp-human split are the sequences that most likely shaped humankind.

In November 2004, after months of debugging and optimizing my program to run on a massive computer cluster at the University of California, Santa Cruz, I finally ended up with a file that contained a ranked list of these rapidly evolving sequences. With my mentor David Haussler leaning over my shoulder, I looked at the top hit, a stretch of 118 bases that together became known as human accelerated region 1 (HAR1). Using the U.C. Santa Cruz genome browser, a visualization tool that annotates the human genome with information from public databases, I zoomed in on HAR1. The browser showed the HAR1 sequences of a human, chimp, mouse, rat and chicken—all of the vertebrate species whose genomes had been decoded by then. It also revealed that previous large-scale screening experiments had detected HAR1 activity in two samples of human brain cells, although no scientist had named or studied the sequence yet. We yelled, “Awesome!” in unison when we saw that HAR1 might be part of a gene new to science that is active in the brain.

We had hit the jackpot. The human brain is well known to differ considerably from the chimpanzee brain in terms of size, organization and complexity, among other traits. Yet the developmental and evolutionary mechanisms underlying the characteristics that set the human brain apart are poorly understood. HAR1 had the potential to illuminate this most mysterious aspect of human biology.

We spent the next year finding out all we could about the evolutionary history of HAR1 by comparing this region of the genome in various species, including 12 more vertebrates that were sequenced during that time. It turns out that until humans came along, HAR1 evolved extremely slowly. In chickens and chimps—whose lineages diverged some 300 million years ago—only two of the 118 bases differ, compared with 18 differences between humans and chimps, whose lineages diverged far more recently. The fact that HAR1 was essentially frozen in time through hundreds of millions of years indicates that it does something very important; that it then underwent abrupt revision in humans suggests that this function was significantly modified in our lineage.

A critical clue to the function of HAR1 in the brain emerged in 2005, after my collaborator Pierre Vanderhaeghen of the Free University of Brussels obtained a vial of HAR1 copies from our laboratory during a visit to Santa Cruz. He used these DNA sequences to design a fluorescent molecular tag that would light up when HAR1 was activated in living cells—that is, copied from DNA into RNA. When typical genes are switched on in a cell, the cell first makes a mobile messenger RNA copy and then uses the RNA as a template for synthesizing some needed protein. The labeling revealed that HAR1 is active in a type of neuron that plays a key role in the pattern and layout of the developing cerebral cortex, the wrinkled outermost brain layer. When things go wrong in these neurons, the result may be a severe, often deadly, congenital disorder known as lissencephaly (“smooth brain”), in which the cortex lacks its characteristic folds and exhibits a markedly reduced surface area. Malfunctions in these same neurons are also linked to the onset of schizophrenia in adulthood.

HAR1 is thus active at the right time and place to be instrumental in the formation of a healthy cortex. (Other evidence suggests that it may additionally play a role in sperm production.) But exactly how this piece of the genetic code affects cortex development is a mystery my colleagues and I are still trying to solve. We are eager to do so: HAR1’s recent burst of substitutions may have altered our brains significantly.

Beyond having a remarkable evolutionary history, HAR1 is special because it does not encode a protein. For decades, molecular biology research focused almost exclusively on genes that specify proteins, the basic building blocks of cells. But thanks to the Human Genome Project, which sequenced our own genome, scientists now know that protein-coding genes make up just 1.5 percent of our DNA. The other 98.5 percent—sometimes referred to as junk DNA—contains regulatory sequences that tell other genes when to turn on and off and genes encoding RNA that does not get translated into a protein, as well as a lot of DNA having purposes scientists are only beginning to understand.

Based on patterns in the HAR1 sequence, we predicted that HAR1 encodes RNA—a hunch that Sofie Salama, Haller Igel and Manuel Ares, all at U.C. Santa Cruz, subsequently confirmed in 2006 through lab experiments. In fact, it turns out that human HAR1 resides in two overlapping genes. The shared HAR1 sequence gives rise to an entirely new type of RNA structure, adding to the six known classes of RNA genes. These six major groups encompass more than 1,000 different families of RNA genes, each one distinguished by the structure and function of the encoded RNA in the cell. HAR1 is also the first documented example of an RNA-encoding sequence that appears to have undergone positive selection.

It might seem surprising that no one paid attention to these amazing 118 bases of the human genome earlier. But in the absence of technology for readily comparing whole genomes, researchers had no way of knowing that HAR1 was more than just another piece of junk DNA.

Language Clues
Whole-genome comparisons in other species have also provided another crucial insight into why humans and chimps can be so different despite being much alike in their genomes. In recent years the genomes of thousands of species (mostly microbes) have been sequenced. It turns out that where DNA substitutions occur in the genome—rather than how many changes arise overall—can matter a great deal. In other words, you do not need to change very much of the genome to make a new species. The way to evolve a human from a chimp-human ancestor is not to speed the ticking of the molecular clock as a whole. Rather the secret is to have rapid change occur in sites where those changes make an important difference in an organism’s functioning.

HAR1 is certainly such a place. So, too, is the FOXP2 gene, which contains another of the fast-changing sequences I identified and is known to be involved in speech. Its role in speech was discovered by researchers at the University of Oxford in England, who reported in 2001 that people with mutations in the gene are unable to make certain subtle, high-speed facial movements needed for normal human speech, even though they possess the cognitive ability to process language. The typical human sequence displays several differences from the chimp’s: two base substitutions that altered its protein product and many other substitutions that may have led to shifts affecting how, when and where the protein is used in the human body.

A recent finding has shed some light on when the speech-enabling version of FOXP2 appeared in hominids: in 2007 scientists at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, sequenced FOXP2 extracted from a Neandertal fossil and found that these extinct humans had the modern human version of the gene, perhaps permitting them to enunciate as we do. Current estimates for when the Neandertal and modern human lineages split suggest that the new form of FOXP2 must have emerged at least half a million years ago. Most of what distinguishes human language from vocal communication in other species, however, comes not from physical means but cognitive ability, which is often correlated with brain size. Primates generally have a larger brain than would be expected from their body size. But human brain volume has more than tripled since the chimp-human ancestor—a growth spurt that genetics researchers have only begun to unravel.

One of the best-studied examples of a gene linked to brain size in humans and other animals is ASPM. Genetic studies of people with a condition known as microcephaly, in which the brain is reduced by up to 70 percent, uncovered the role of ASPM and three other genes—MCPH1, CDK5RAP2 and CENPJ—in controlling brain size. More recently, researchers at the University of Chicago and the University of Michigan at Ann Arbor have shown that ASPM experienced several bursts of change over the course of primate evolution, a pattern indicative of positive selection. At least one of these bursts occurred in the human lineage since it diverged from that of chimps and thus was potentially instrumental in the evolution of our large brains.

Other parts of the genome may have influenced the metamorphosis of the human brain less directly. The computer scan that identified HAR1 also found 201 other human accelerated regions, most of which do not encode proteins or even RNA. (A related study conducted at the Wellcome Trust Sanger Institute in Cambridge, England, detected many of the same HARs.) Instead they appear to be regulatory sequences that tell nearby genes when to turn on and off. Amazingly, more than half of the genes located near HARs are involved in brain development and function. And, as is true of FOXP2, the products of many of these genes go on to regulate other genes. Thus, even though HARs make up a minute portion of the genome, changes in these regions could have profoundly altered the human brain by influencing the activity of whole networks of genes.

Beyond the Brain
Although much genetic research has focused on elucidating the evolution of our sophisticated brain, investigators have also been piecing together how other unique aspects of the human body came to be. HAR2, a gene regulatory region and the second most accelerated site on my list, is a case in point. In 2008 researchers at Lawrence Berkeley National Laboratory showed that specific base differences in the human version of HAR2 (also known as HACNS1), relative to the version in nonhuman primates, allow this DNA sequence to drive gene activity in the wrist and thumb during fetal development, whereas the ancestral version in other primates cannot. This finding is particularly provocative because it could underpin morphological changes in the human hand that permitted the dexterity needed to manufacture and use complex tools.

Aside from undergoing changes in form, our ancestors also underwent behavioral and physiological shifts that helped them adapt to altered circumstances and migrate into new environments. For example, the conquest of fire more than a million years ago and the agricultural revolution about 10,000 years ago made foods high in starch more accessible. But cultural shifts alone were not sufficient to exploit these calorie-rich comestibles. Our predecessors had to adapt genetically to them.

Changes in the gene AMY1, which encodes salivary amylase, an enzyme involved in digesting starch, constitute one well-known adaptation of this kind. The mammalian genome contains multiple copies of this gene, with the number of copies varying between species and even between individual humans. But overall, compared with other primates, humans have an especially large number of AMY1 copies. In 2007 geneticists at Arizona State University showed that individuals carrying more copies of AMY1 have more amylase in their saliva, thereby allowing them to digest more starch. The evolution of AMY1 thus appears to involve both the number of copies of the gene and the specific changes in its DNA sequence.

Another famous example of dietary adaptation involves the gene for lactase (LCT), an enzyme that allows mammals to digest the carbohydrate lactose, also known as milk sugar. In most species, only nursing infants can process lactose. But around 9,000 years ago—very recently, in evolutionary terms—changes in the human genome produced versions of LCT that allowed adults to digest lactose. Modified LCT evolved independently in European and African populations, enabling carriers to digest milk from domesticated animals. Today adult descendants of these ancient herders are much more likely to tolerate lactose in their diets than are adults from other parts of the world, including Asia and Latin America, many of whom are lactose-intolerant as a result of having the ancestral primate version of the gene.

LCT is not the only gene known to be evolving in humans right now. The chimp genome project identified 15 others in the process of shifting away from a version that was perfectly normal in our ape ancestors and that works fine in other mammals but, in that old form, is associated with diseases such as Alzheimer’s and cancer in modern humans. Several of these disorders afflict humans alone or occur at higher rates in humans than in other primates. Scientists are currently researching the functions of the genes involved and are attempting to establish why the ancestral versions of these genes became maladaptive in us. These studies could help medical practitioners identify those patients who have a higher chance of getting one of these life-threatening diseases, in hopes of helping them stave off illness. The studies may also help researchers identify and develop new treatments.

With the Good Comes the Bad
Battling disease so we can pass our genes along to future generations has been a constant refrain in the evolution of humans, as in all species. Nowhere is this struggle more evident than in the immune system. When researchers examine the human genome for evidence of positive selection, the top candidates are frequently involved in immunity. It is not surprising that evolution tinkers so much with these genes: in the absence of antibiotics and vaccines, the most likely obstacle to individuals passing along their genes would probably be a life-threatening infection that strikes before the end of their childbearing years. Further accelerating the evolution of the immune system is the constant adaptation of pathogens to our defenses, leading to an evolutionary arms race between microbes and hosts.

Records of these struggles are left in our DNA. This is particularly true for retroviruses, such as HIV, that survive and propagate by inserting their genetic material into our genomes. Human DNA is littered with copies of these short retroviral genomes, many from viruses that caused diseases millions of years ago and that may no longer circulate. Over time the retroviral sequences accumulate random mutations just as any other sequence does, so that the different copies are similar but not identical. By examining the amount of divergence among these copies, researchers can use molecular clock techniques to date the original retroviral infection. The scars of these ancient infections are also visible in the host immune system genes that constantly adapt to fight the ever evolving retroviruses.

PtERV1 is one such relic virus. In modern humans, a protein called TRIM5α works to prevent PtERV1 and related retroviruses from replicating. Genetic evidence suggests that a PtERV1 epidemic plagued ancient chimpanzees, gorillas and humans living in Africa about four million years ago. To figure out how different primates responded to PtERV1, in 2007 researchers at the Fred Hutchinson Cancer Research Center in Seattle used the many randomly mutated copies of PtERV1 in the chimpanzee genome to reconstruct the original PtERV1 sequence and re-create this ancient retrovirus. They then performed experiments to see how well the human and great ape versions of the TRIM5α gene could restrict the activity of the resurrected PtERV1 virus. Their results indicate that a single change in human TRIM5α most likely enabled our ancestors to fight PtERV1 infection more effectively than our primate cousins could. (Additional changes in human TRIM5α may have evolved in response to a related retrovirus.) Other primates have their own sets of changes in TRIM5α, probably reflecting retroviral battles that their predecessors won.

Defeating one type of retrovirus does not necessarily guarantee continued success against others, however. Although changes in human TRIM5α may have helped us survive PtERV1, these same shifts make it much harder for us to fight HIV. This finding is helping researchers to understand why HIV infection leads to AIDS in humans but not in nonhuman primates. Clearly, evolution can take one step forward and two steps back. Sometimes scientific research feels the same way. We have identified many exciting candidates for explaining the genetic basis of distinctive human traits. In most cases, though, we know only the basics about the function of these genome sequences. The gaps in our knowledge are especially large for regions such as HAR1 and HAR2 that do not encode proteins.

These rapidly evolving, uniquely human sequences do point to a way forward. The story of what made us human is probably not going to focus on changes in our protein building blocks but rather on how evolution assembled these blocks in new ways by changing when and where in the body different genes turn on and off. Experimental and computational studies now under way in thousands of labs around the world promise to elucidate what is going on in the 98.5 percent of our genome that does not code for proteins. It is looking less and less like junk every day.

By Katherine S. Pollard