Malcolm Ritter, Associated Press

March 31, 2008 — Scientists are scanning human DNA with a precision and scope once unthinkable and rapidly finding genes linked to cancer, arthritis, diabetes and other diseases.

It’s a payoff from a landmark achievement completed five years ago — the identification of all the building blocks in the human DNA. Follow-up research and leaps in DNA-scanning technology have opened the door to a flood of new reports about genetic links to disease.

On a single day in February, for example, three separate research groups reported finding several genetic variants tied to the risk of getting prostate cancer.

And over the past year or so, scientists have reported similar results for conditions ranging from heart attack to multiple sclerosis to gallstones. The list even includes restless legs syndrome, a twitching condition best known as "jimmy legs" in an episode of "Seinfeld."

Interviews with scientists at the center of this revolution and a review of published studies over the past six months make clear the rapid adoption of the new technology and the high expectations for it.

Since 2005, studies with the gene-scanning technique have linked nearly 100 DNA variants to as many as 40 common diseases and traits, scientists noted this month in the Journal of the American Medical Association.

"There have been few, if any, similar bursts of discovery in the history of medical research," two Harvard researchers declared last summer in the New England Journal of Medicine.

What does all this excitement mean for ordinary people? Not so much just yet. Simply finding the genes that can raise the risk of an illness doesn’t mean you can prevent the disease.

But there have been some payoffs already.

One involves a leading cause of blindness in older people, age-related macular degeneration. A series of genome-wide scans, the most recent in 2005, "led to huge breakthroughs in understanding" that disease, said Stephen Daiger, a Houston scientist.

When scientists implicated a particular gene that’s involved in a system of disease-fighting proteins in the blood, it gave scientists a "slap-on-the-forehead kind of insight…into the biology of what’s going on," said Daiger, a vision genetics expert at the University of Texas Health Sciences Center.

That galvanized research into the disease. And at least one new drug is being tested in patients now.

What’s made this and other hopeful findings possible is the "genome-wide association study," which lets scientists scan the entire complement of DNA from thousands of people in unprecedented detail. While the basic technique is not new, its popularity has exploded recently because of cost-cutting advances in technology and discoveries about the genome.

"It lets you go searching for that needle in the haystack," says Michael Watson, executive director of the American College of Medical Genetics.

It’s a big haystack. DNA is made up of long sequences of building blocks, sort of like sentences composed from a four-letter alphabet: A, C, G and T. The human genome contains about 3 billion letters, about as many as the total number of letters and digits in more than 100 Manhattan phone books.

Scientists have identified the order of the letters in the human genome, a feat the government declared accomplished in 2003. But of course, different people have slightly different DNA sequences. People commonly differ in what letter they have at about 10 million positions along the full genome. Some folks may have a T where most people have a C, for example.

And those single-letter variations are key to the genome-wide scans. Basically, scientists compare DNA from a large number of people, some sick with a particular disease, and others healthy. They can look at a half-million or more positions to see what letter appears. If sick people tend to show a different result than healthy ones — say, if they tend to have a T in some spot more often than healthy people do — it’s a red flag.

It suggests that some genetic influence on the risk of that disease comes from that spot or nearby. So it gives scientists a specific place to look more closely for a disease-promoting gene.

In practice, genome scans can be big undertakings.

Scientists in Iowa and Denmark are searching blood samples from 7,000 babies and new mothers in the United States and Denmark for genetic variations that raise the risk for premature birth.

DNA will be extracted, and early this summer, more than half a million spots on the microscopic strands from each mother and baby will be assessed for clues to where the genetic variations may lie.

The DNA will be analyzed at the Center for Inherited Disease Research at Johns Hopkins University in Baltimore. Robots will put a tiny drop of DNA-bearing solution from each person onto a clear glass slide roughly the size of a business card, with four drops per slide.

The lab’s DNA scanners, blue boxes each about twice as big as a desktop printer, will reveal what DNA "letter" appears in more than 580,000 spots in the genetic material, said lab director Kimberly Doheny.

This scan takes about half an hour per sample. Once the results are available, the scientists will use statistical tests to find the telltale signs of a possible gene affecting risk of premature birth. They’ll double-check to make sure any such signal shows up in more than one population.

Even five years ago, such a detailed examination of DNA from so many people would have been inconceivable.

Genome scans offer some major advantages over previous gene-hunting techniques. Scientists don’t have to start by guessing what genes might be involved in a disease, or confine themselves to families where a tendency to an illness is inherited.

And the genome-scan approach reveals genes with only subtle influence on the risk of getting sick, too slight to be found by earlier methods. That’s just the kind of gene that plays a role in common illnesses like heart disease.

Even if its impact on risk is small, a newly found gene can be a bonanza to scientists if it reveals something new about the biology of a disease. That in turn can give hints for finding new treatments.

For non-scientists, the most direct payoff of finding new disease genes may be in devising tests to identify people at elevated risk for a particular disorder.

Most genetic variants found in the genome scans boost a person’s risk by around 50 percent. If the disease risk is fairly low, that’s "not something you’d lose much sleep over," Watson said.

More useful, he said, is the notion of finding variants in maybe a half-dozen genes that affect the risk for a disease, then testing a person for all of them at once to come up with a more powerful indicator.

Related Links:

National Human Genome Research Institute

Center for Inherited Disease Research

Gene-Scanning Technique

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