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DNA double helix
Research now suggests that genes overlap each other and share stretches of molecular code.

DNA unraveled

A 'scientific revolution' is taking place, as researchers explore the genomic jungle

The science of life is undergoing changes so jolting that even its top researchers are feeling something akin to shell-shock. Just four years after scientists finished mapping the human genome - the full sequence of 3 billion DNA "letters" folded within every cell - they find themselves confronted by a biological jungle deeper, denser, and more difficult to penetrate than anyone imagined.

"Science is just starting to probe the wilderness between genes," said John M. Greally, molecular biologist at New York's Albert Einstein School of Medicine. "Already we're surprised and confounded by a lot of what we're seeing."

A slew of recent but unrelated studies of everything from human disease to the workings of yeast suggest that mysterious swaths of molecules - long dismissed as "junk DNA" - may be more important to health and evolution than genes themselves.

Meanwhile, a tricky substance called RNA - for decades viewed as the lowly "messenger boy " for genes and proteins - turns out to be a big league player in cell function. It may even represent the cell's command and control system, according to its more vigorous proponents.

In any event, lots of basic biological beliefs are going out the window these days as new discoveries come so rapid-fire that the effect is almost more disorienting than illuminating.

The discoveries have one common theme: Cellular processes long assumed to be "genetic" appear quite often to be the result of highly complex interactions occurring in regions of DNA void of genes. This is roughly akin to Wall Street waking to the realization that money doesn't make the world go 'round, after all.

"It's a radical concept, one that a lot of scientists aren't very happy with," said Francis S. Collins, director of the National Human Genome Research Institute. "But the scientific community is going to have to rethink what genes are, what they do and don't do, and how the genome's functional elements have evolved.

"I think we're all pretty awed by what we're seeing," Collins said. "It amounts to a scientific revolution."

For half a century, the core concept in biology has been that every cell carries within its nucleus a full set of DNA, including genes. Each gene, in turn, holds coded instructions for assembling a particular protein, the stuff that keeps organisms chugging along.

As a result, genes were assigned an almost divine role in biological "dogma," thought to govern not only such physical characteristics as eye color or hair texture, but even much more complicated characteristics, such as behavior or psychology. Genes were assigned blame for illness. Genes were credited for robust health. Genes were said to be the source of the mutations that underlay evolution.

But the picture now emerging is more complicated, one in which illness, health, and evolutionary change appear to be the work of almost fantastical coordination between genes and swaths of DNA previously written off as junk.

The idea that genes possess a singular supremacy took a knock when the human genome was fully sequenced in 2003, revealing that only about 1.5 percent of our DNA consists of actual genes coding for protein.

Another 3.5 percent of DNA is of gene-linked regulatory material whose function isn't well grasped, but which is recognized as vital because it has been precisely duplicated in living things for hundreds of millions of years. "That's smoking gun evidence that nature cares about this stuff," said Eric S. Lander, director of the Broad Institute, a research center affiliated with MIT and Harvard that focuses on applying genomics to medicine.

As for the remaining 95 percent of the genome? "There's this weird lunar landscape of stuff we don't understand," Lander said. "No one has a handle on what matters and what doesn't."

Until recently, the rest of the genome - the murky regions between individual genes - was viewed as occupied by more or less useless glop. Noncoding DNA is the polite term for junk DNA.

But the glop is starting to look like gold. And genes, in a sense, are losing some of their glitter.

"To our shock and consternation, we're learning how little we know about the parts of the genome that may matter most," said Dr. David M. Altshuler, associate professor of genetics and medicine at Harvard Medical School and also a top researcher at the Broad Institute.

"Maybe some of it really is junk. Maybe most of it is junk," he said. "But one shouldn't bet against nature. Maybe it all serves some sort of a purpose. We really don't know."

This is how science goes forward, of course. Not in a smooth march to the future, but with stumbles, back-steps, and wrong turns. Think of soldiers scrabbling on a battlefield, not gleaming ranks in parade. Scientists, like combat infantry, operate in a fog of confusion and hunch.

Altshuler led a team that earlier this year discovered that a common form of diabetes is triggered by changes occurring in sections of DNA hitherto regarded as junk - that is, occupying space on the genome but regarded as having no particular function.

Neither Altshuler nor his co-researchers fully understand the mechanisms involved, but their work revealed that risks for Type 2 diabetes entail more than a mutated gene. Instead, diabetes - as well as heart disease, some cancers, and other deadly ailments - appear to involve processes occurring in noncoding DNA regions as well as in genes.

Such findings represent a sea change for a science that has typically put genes at the center of the universe, much as ancient astronomers believed sun and stars revolved around the earth.

"We're realizing that things happening 'somewhere else' in the genome, not in genes, are playing critical roles" in sickness and in health, Altshuler said.

Although biological dogma has held that organisms - whether human or hydrangea - are largely controlled by a tidy collection of independent genes, scientists were aware of other factors. A curious chemical called RNA has been under scrutiny, but usually only as a bit player, a carrier of messages.

These days, RNA is emerging as a superstar, a prime mover and shaker in cellular processes hitherto attributed mainly to genes. Indeed, major research suggests that a primary purpose of junk DNA might be to create various forms of RNA that, in turn act as regulators for protein-coding genes.

"Instead of running errands, RNA appears to be running the whole show," said Isidore Rigoutsos, a lead scientist at IBM's Thomas J. Watson Research Center in Yorktown Heights, N.Y.

Rigoutsos published startling research last year that pegged the number of different RNAs performing some sort of labor in cells at about 37,000, compared with only 22,000 genes. Since RNA is an "active molecule" - meaning it's usually up to something, although scientists aren't always sure what - the variety of RNAs suggests an importance to life and health.

"The picture that's emerging" of how living cells actually operate and evolve "is so immensely more complicated than anyone imagined, it's almost depressing," Rigoutsos said.

Not all biologists accept the vision of RNA as secret puppetmaster of genes, although most now accept that RNA's role in cellular biochemistry goes well beyond running errands for genes.

In June, a consortium of 80 research institutions in North America, Asia, Europe, and Australia completed the first comprehensive effort to plumb all the inner workings of the DNA molecule, not just the genetic portions.

The Encode study shattered the view that genes carry out their labor in relative isolation.

Instead, genes appear to overlap each other and share stretches of molecular code. Moreover, genes and nongenetic DNA appear to work in close, if mysterious, conjunction and also seem to communicate across relatively vast genomic distances in ways not understood.

Scientists have long understood that small numbers of RNAs act as "dimmer knobs" that adjust the intensity of genes, thus regulating biological processes.

But few had predicted the complex orchestration of genes and nongenetic DNA suggested by the Encode research. Even more sunning was the Encode finding that most "junk DNA" is transcribed, or copied, into more RNA molecules than can be accounted for by most prevailing theories.

No one knows what all that extra RNA is doing. It might be regulating genes in absolutely essential ways. Or it may be doing nothing of much importance: genetic busywork serving no real purpose.

Many researchers believe the truth falls somewhere in between.

"Half of it may be doing something very useful," said Lander, who is also a professor of biology at MIT. "The other part may turn out to be, well, just junk - doing neither great good nor great harm."

If the surprising amount of RNA transcribed from genomic "junk" proves to be a powerful regulator of genes, understanding it will be critical in the fight against genetic disease, medical researchers predict. A big push is underway, for example, to develop so-called "RNA interference" drugs, designed to turn off gene activity by mimicking the effects of RNA.

"For medicine, it could be good news if disease is mainly caused by 'regulators' " in the genome, not mutations in genes themselves, said Lander. "It suggests that [cures] might be a matter of tweaking the controls - turning them up here, dialing them down there. Nothing about the gene is broken, but the dial may be powered up too high or turned low."

Meanwhile, scientists are tantalized by the possibility that organisms may be defined more by differences in their "junk" than in their actual genes.

One riddle of evolution is why humans possess far fewer genes than scientists had long imagined, about 22,000 or so - not dramatically different from less complicated organisms. If genes alone can't account for the differences between sea anemones and humans, for example, what can?

"The only consistent difference between higher and lower organisms - say, humans and worms - is the extent of noncoding DNA sequences," the so-called junk DNA, said John S. Mattick, a molecular biologist at Australia's University of Queensland.

Mattick is a maverick, but his view that RNA represents a command and control system for cells seems less outrageous than it once did. "The genetic programming of higher organisms has been misunderstood for the past 50 years," he said. "The majority of the human genome [is operated] by a hidden RNA regulatory system that directs differentiation and development."

That's a bigger leap than most scientists want to make.

However none dispute that biology is at an extraordinary pivotal point - one in which the pace of discovery seems faster than the ability of even the most brilliant minds in the field to comprehend.

"Partly it's the very power of new technology," said Zhiping Weng, a biomedical engineer at Boston University who is involved in the ongoing Encode studies. "It used to be a university laboratory might spend 10 years or more just trying to puzzle out the secrets of a single gene. Now in a week, we can scan a genome."

"We were looking at droplets," she said. "Now we're suddenly viewing the ocean. It will take time just to get our bearings."

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