a New Look at Very Old Genes.
by Paul Karr
At first, Nathan Bowen didn't believe his eyes. For weeks he had pored over a computer screen, tediously sifting through genetic information about the tiny, primitive worm Caenorhabditis elegans, or C. elegans for short.
The UGA graduate student was studying a group of so-called "retroelements" - virus-like structures that probably lurk in the body cells of every known mammal from birth. He already had determined that the worm definitely contained these quasi-viruses - a surprise in itself, because the worm evolved nearly 500 million years earlier than human beings.
But now, as he pored over computer-generated sequences of the worm's genetic code, he noticed something else: Some of the C. elegans retroelements had a structure that was remarkably similar to that of complex retroviruses, such as the HIV virus that causes AIDS.
"It's something that you don't believe at first," said Bowen, a Ph.D. candidate in genetics who, because of his previous study of HIV proteins, knew what they looked like at the molecular level. "So often you think you've found something, and it doesn't turn out to be true. But this was."
Bowen had not discovered HIV in the worm, not exactly. But he had uncovered what may be some very ancient relatives of that lethal retrovirus, relatives that are possibly much older than humans, mammals or even vertebrates.
That finding, if borne out by further laboratory work, could change the way scientists look at disease research - or perhaps the very nature of evolution.
"These viruses had always been thought to have evolved very recently, within [the history of] mammalian lineage," said UGA genetics department head John McDonald, who supervised Bowen's work and whose Athens lab published the surprising finding in the October 1999 issue of the journal Genome Research. "When you find it in a much more primitive organism such as C. elegans, it's like believing tools were invented by humans and operating on that assumption for awhile, and then finding out one day that tools were used by much more primitive organisms as well."
"They took on quite a difficult task, a full survey of this worm's entire genome, and did very careful analyses of it. Then they became very specific," said Jonathan Eisen, a scientist at The Institute for Genome Research (TIGR) in Rockville, Md. "This is going to be very useful to other researchers, precisely because they took the pains to weed through so much to make sense of these elements.
"And if their conclusion - that these elements were not passed along to the worms recently, but were present in some distant ancestor - bears out, this will become even more useful," he said.
Setting back the clock
Deep inside every living cell are coiled strands of genetic material known as DNA. The arrangement of these strands - which consist of long sequences of four kinds of nucleotide bases, translated into genes - determines what an organism will look like, how its organs will develop from the embryo, whether it will be susceptible to diseases and a great deal more.
What's still unclear to geneticists, however, is why the human genome is made up of so much DNA. Roughly 100,000 genes make up the human genome, but less than 10 percent of that DNA actually plays a function in encoding the protein molecules that serve as the basis for all bodily structures and functions.
In recent years, a public-private race has been touched off to decode and map the entire sequence of those genes. McDonald and Bowen's lab work is part of the public component of that effort, which is funded by The National Human Genome Research Institute - itself an arm of the federal National Institutes of Health. NIH is coordinating dozens of research teams around the globe, some piecing together sequences from human cells and others studying "model organisms" such as mice, worms, fruit flies and yeast that share similar genetic structures with humans.
The McDonald lab began investigating fruit flies as one such model organism more than a decade ago, and its researchers increasingly became interested in the retroelements, free-floating bits of genetic material that replicate themselves in DNA. These retroelements are much simpler than viruses but function essentially the same way, and quite possibly may be their ancestors.
Retroelements have been around for a very long time, and McDonald said they might have played important roles in evolution, from single-celled creatures to the vast array of plants and animals that now inhabit the Earth.
"We already know that these retroelements make up about 50 percent of corn's genome, and up to 90 percent of wheat's and pine's genomes," McDonald said. "They appear to be very abundant."
And not only in plants. It is now known that more than one-third of all human genetic material is composed of these retroelements as well, and new evidence suggests they are major players in genetic mutations. The virus-like bits tend to recombine and disperse rather frequently, and this may nudge along the evolution of their host species.
McDonald's findings about the importance of these transposable elements were controversial at first, but he sees a tide turning in the research. During an October 1999 conference in Athens, Ga., biologists from 11 countries presented growing evidence that these versatile genetic agents not only can cause both mutations and illness, but also may have played a central role in evolution. The recent NIH funding of McDonald's lab is another sign, he said, that the science it is producing is solid.
"In general, the NIH as a funding body can be rather conservative," McDonald said. "That's some indication that either we're moving toward the mainstream or that the mainstream is moving toward us."
Once he knew what to look for, Bowen switched to an examination of the C. elegans roundworm - a simple creature that nevertheless has been widely studied around the globe in recent years. Though the worm lives just two to three weeks and measures approximately 1/32 of inch at full size, its functions are actually quite similar to some essential characteristics of human biology: Scientists consider the worm to have a "brain." It exhibits behavior. It is capable of a very basic kind of learning. Its life cycle begins with embryonic cleavage - just as humans do - and proceeds through growth, development and aging until death. Each of these functions is controlled by genes, but the worm's total genome is much simpler than that of humans.
Therefore, when scientists recently announced that they had cracked the entire sequence of genes in the worm's genome - chains of genetic material totaling nearly 100 million nucleotide bases in all - there was great excitement among geneticists. For the first time, a creature's entire genetic blueprint was known. That, the scientists knew, would make it much easier to focus on specific areas of interest within the worm - and then draw conclusions that could be applied to the much more complex human genome.
Bowen began analyzing the C. elegans data and located a dozen families of retroelements, a much more abundant and divergent collection of them than he'd expected to find. Their close correspondence to the lentivirus family, to which HIV belongs, convinced him that retroelements evolved along with primitive worm-like creatures a very long time ago - long before humans. He speculates they may have arisen during the early Metazoan period, generally agreed to be about a half billion years ago. By contrast, human beings evolved perhaps 120,000 years ago. For illustration, if the time that has elapsed since this early Metazoan period is considered to be a feature film running for two hours, then human beings flicker onto screen only during the last 1 1/2 seconds before the credits roll.
"As a result of this work, I've developed the philosophy that these elements have been there from the start, that our own genomes are constantly evolving around them and with them," Bowen said. "Many of these elements have no doubt gone extinct, and we'll never know about them, but plenty of them have survived too. They're worth studying because of that, because they've figured out how to survive."
Such an ancient origin would not only mean that virus-like organisms long pre-date us. It also could mean that they have coexisted in the body cells of most living organisms through much of life's history, perpetuating themselves without killing off the species that host them.
"These elements clearly can be lethal to some individuals and yet not lethal to the species," McDonald said. "What we don't know, yet, is the full significance of this fact to the evolution of these viral elements and to their hosts."
Rethinking viral therapies
What does this finding mean for medical science? While the practical applications of their work remain to be developed, McDonald said he believes one day it could pave the way for new therapies to treat retroviruses like HIV.
"If we understand the processes behind retroviral evolution," he said, "we could get to the point where we can make educated guesses about where these viruses might be evolving, about what they might be like in the future. That, in turn, could lead to new approaches to preventing or treating them."
Although their structures are different from viruses, it's useful to draw a parallel with what happens to bacteria as new antibiotics are developed to combat them. New bacteria mutate and evolve, outfoxing the drugs developed to stop them. The same thing almost certainly is happening with HIV and other pathological viruses and retroviruses.
"A lot of current solutions to stop virus replication could be providing selective pressure for them to become stronger instead. That would be having the opposite of the intended effect," McDonald said. "We're dealing with evolving, living systems, and these systems are always going to be looking for [evolutionary] ways to escape therapeutic control. They are driven by the same force as we are; they want to replicate."
Complicating the issue, retroviruses use a particularly insidious method to ensure their replication and survival: Since they can't reproduce by themselves, they commandeer living cells to produce viral nucleic acid and proteins, reassembling those substances into new virus particles. Essentially, their life cycle becomes closely enmeshed with that of our own body cells. As a result, drugs that simply attack the virus's copying mechanisms also are likely to harm us in the process.
"The more we know about these types of [retroelements], the better," said TIGR's Jonathan Eisen. "They are scattered throughout genomes, they move around, they have the potential to jump into genes where you don't want them to be. And they are clearly closely related to pathogens. Yet it's very hard to study these things in humans, and if you can find and study them in another, simpler organism, you can learn a lot about their function in humans."
Beyond the practical applications of their research, McDonald and Bowen also are aware that what they are proposing uproots mankind's traditionally self-centered view of the biological world. Yet the growing evidence from molecular biologists, they argue, almost demands a philosophical shift in point of view.
"The real shift," McDonald said, "comes when you go back to the very earliest 'bubbling pool,' when the first molecule figured out how to replicate itself. That was selfish, by definition; it was virus-like. At some point in time, part of this whole viral replication sequence became devoted to the task of performing a simple cellular function - which was sort of an 'altruistic function' juxtaposed with the selfish one. At that point, a battle began within the simplest organism.
"Biologists have always thought of these viral-like elements as being of recent origin, but it looks now like they've been with life from the very beginning. It looks like our own mammalian DNA may have evolved within the context of this selfish viral DNA."
What McDonald is suggesting, then, is that viruses may not have evolved by accident and then chanced upon animals to perpetuate their existence. Instead, it's possible some of these ancient viruses have contributed to the evolution of higher organisms as a way to more efficiently keep themselves living through generations - an argument that flies in the face of both traditional evolutionary theory (which speculates that evolutionary change occurs by natural selection operating on essentially random mutations) and conventional religious ideas about the human place in things.
"This goes to the way we fit in the world around us, something ecologists have been saying for awhile," McDonald said. "It says that, rather than being the center of universe, we are part of a larger whole."
Paul Karr is an award-winning science writer and writing consultant who divides his time between Athens, Ga., and Europe.