Friday, July 25, 2008

Remnants of Viruses Past

One of the most surprising developments in modern biology has been the discovery of just how tenuous the wall between species is. Primitive organisms apparently trade bits of genetic material back and forth with wild abandon. This is, among other things, one way bacteria acquire resistance to antibiotics. An infectious agent will acquire a snippet of genetic material from a harmless strain the way a friend might slip me a CD with the latest software patch.
Just as surprising is how much of the DNA of higher animals -- ourselves included -- is from another species.
A retrovirus stores its genetic information in a single-stranded molecule of RNA, instead of the more common double-stranded DNA. When it infects a cell, the virus deploys a special enzyme, called reverse transcriptase, that enables it to copy itself and then paste its own genes into the new cell’s DNA. It then becomes part of that cell forever; when the cell divides, the virus goes with it. Scientists have long suspected that if a retrovirus happens to infect a human sperm cell or egg, which is rare, and if that embryo survives—which is rarer still—the retrovirus could take its place in the blueprint of our species, passed from mother to child, and from one generation to the next, much like a gene for eye color or asthma.

When the sequence of the human genome was fully mapped, in 2003, researchers also discovered something they had not anticipated: our bodies are littered with the shards of such retroviruses, fragments of the chemical code from which all genetic material is made. It takes less than two per cent of our genome to create all the proteins necessary for us to live. Eight per cent, however, is composed of broken and disabled retroviruses, which, millions of years ago, managed to embed themselves in the DNA of our ancestors. They are called endogenous retroviruses, because once they infect the DNA of a species they become part of that species. One by one, though, after molecular battles that raged for thousands of generations, they have been defeated by evolution. Like dinosaur bones, these viral fragments are fossils. Instead of having been buried in sand, they reside within each of us, carrying a record that goes back millions of years. Because they no longer seem to serve a purpose or cause harm, these remnants have often been referred to as “junk DNA.” Many still manage to generate proteins, but scientists have never found one that functions properly in humans or that could make us sick.

How much of the remnants can be found in our DNA?
Enough.
Then, last year, Thierry Heidmann brought one back to life. Combining the tools of genomics, virology, and evolutionary biology, he and his colleagues took a virus that had been extinct for hundreds of thousands of years, figured out how the broken parts were originally aligned, and then pieced them together. After resurrecting the virus, the team placed it in human cells and found that their creation did indeed insert itself into the DNA of those cells. They also mixed the virus with cells taken from hamsters and cats. It quickly infected them all, offering the first evidence that the broken parts could once again be made infectious.

It's now possible to recreate viruses from the description of its genome. Polio has been built from parts in this way, as has the strain of flu responsible for the 1918 epidemic. The study of ancient retroviruses in human DNA could lead to the resurrection of old plagues, but it also shines a light on the process of evolution.

...a new discipline, paleovirology, which seeks to better understand the impact of modern diseases by studying the genetic history of ancient viruses.

“This is something not to fear but to celebrate,’’ Heidmann told me one day as we sat in his office at the institute, which is dedicated to the treatment and eradication of cancer. Through the window, the Eiffel Tower hovered silently over the distant city. “What is remarkable here, and unique, is the fact that endogenous retroviruses are two things at once: genes and viruses. And those viruses helped make us who we are today just as surely as other genes did. I am not certain that we would have survived as a species without them.”

He continued, “The Phoenix virus sheds light on how H.I.V. operates, but, more than that, on how we operate, and how we evolved. Many people study other aspects of human evolution—how we came to walk, or the meaning of domesticated animals. But I would argue that equally important is the role of pathogens in shaping the way we are today. Look, for instance, at the process of pregnancy and birth.’’ Heidmann and others have suggested that without endogenous retroviruses mammals might never have developed a placenta, which protects the fetus and gives it time to mature. That led to live birth, one of the hallmarks of our evolutionary success over birds, reptiles, and fish. Eggs cannot eliminate waste or draw the maternal nutrients required to develop the large brains that have made mammals so versatile. “These viruses made those changes possible,’’ Heidmann told me. “It is quite possible that, without them, human beings would still be laying eggs.”

H·I.V., the only retrovirus that most people have heard of, has caused more than twenty-five million deaths and infected at least twice that number of people since the middle of the twentieth century, when it moved from monkey to man. It may be hard to understand how organisms from that same family, and constructed with the same genes, could have played a beneficial, and possibly even essential, role in the health and development of any species. In 1968, Robin Weiss, who is now a professor of viral oncology at University College London, found endogenous retroviruses in the embryos of healthy chickens. When he suggested that they were not only benign but might actually perform a critical function in placental development, molecular biologists laughed. “When I first submitted my results on a novel ‘endogenous’ envelope, suggesting the existence of an integrated retrovirus in normal embryo cells, the manuscript was roundly rejected,’’ Weiss wrote last year in the journal Retrovirology. “One reviewer pronounced that my interpretation was impossible.’’ Weiss, who is responsible for much of the basic knowledge about how the AIDS virus interacts with the human immune system, was not deterred. He was eager to learn whether the chicken retroviruses he had seen were recently acquired infections or inheritances that had been passed down through the centuries. He moved to the Pahang jungle of Malaysia and began living with a group of Orang Asli tribesmen. Red jungle fowl, an ancestor species of chickens, were plentiful there, and the tribe was skilled at trapping them. After collecting and testing both eggs and blood samples, Weiss was able to identify versions of the same viruses. Similar tests were soon carried out on other animals. The discovery helped mark the beginning of a new approach to biology. “If Charles Darwin reappeared today, he might be surprised to learn that humans are descended from viruses as well as from apes,” Weiss wrote.

(Here, it should be noted: This is a real case of a maverick scientist going against the conventional wisdom, and winning through in the end. He did so because he was able to make specific predictions -- in this case that the same endovirus fragments would be found in other fowl, separated from any possible infection in chicken coops in the US by thousands of miles.)

And the field is yet another proof of human descent from apes:

nothing provides more convincing evidence for the “theory” of evolution than the viruses contained within our DNA. Until recently, the earliest available information about the history and the course of human diseases, like smallpox and typhus, came from mummies no more than four thousand years old. Evolution cannot be measured in a time span that short. Endogenous retroviruses provide a trail of molecular bread crumbs leading millions of years into the past.

Darwin’s theory makes sense, though, only if humans share most of those viral fragments with relatives like chimpanzees and monkeys. And we do, in thousands of places throughout our genome. If that were a coincidence, humans and chimpanzees would have had to endure an incalculable number of identical viral infections in the course of millions of years, and then, somehow, those infections would have had to end up in exactly the same place within each genome. The rungs of the ladder of human DNA consist of three billion pairs of nucleotides spread across forty-six chromosomes. The sequences of those nucleotides determine how each person differs from another, and from all other living things. The only way that humans, in thousands of seemingly random locations, could possess the exact retroviral DNA found in another species is by inheriting it from a common ancestor.

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