Technology speeds hunt for disease-linked genes
Wanted: Information leading to the identification of genes that may put you at risk.
In a nutshell, that's the endgame of genomic research. Scientists are hunting for genes—or gene variants—that play a role in causing disease. New discoveries could improve screening and diagnosis or point toward more effective treatments. For instance, quieting a troublesome gene or activating a potentially helpful one may be a way to stop some cancers.
Genomic researchers also want to know which genetic variations affect how people respond to drugs. Such knowledge is already being applied: In some cases, for instance, doctors use a genetic test to predict how a patient will respond to the anticlotting drug warfarin. Too much of the drug could result in bleeding; too little could allow dangerous clots to form. Knowing the patient's genetic profile makes it easier to set the right dose from the outset.
This type of "personalized medicine" is the fruit of genomic research. The more researchers learn about the effects of different genetic variations, the greater the extent to which doctors will be able to tailor care for people based on their individual DNA. There's only a small portion of our DNA—less than one percent—that's of special interest to researchers. That's where variations called SNPs (pronounced "snips") occur. SNPs—short for single nucleotide polymorphisms—are changes in one of the chemical bases that make up the DNA sequence, such as guanine or cytosine. They are what give us unique traits.
Searching for a million genetic variations at a time
Some of these changes might be of little consequence. Others might raise our risk for a serious disease. There are millions of these SNPs—among the three billion chemical base pairs that make up our DNA—so finding the critical ones is like finding the proverbial needle in the haystack. But thanks to futuristic robots, laser scanners and "bead array" technology, researchers are making progress.
"We can do in a few weeks what we couldn't do in years," says Steven Schichman, MD, PhD, director of the Pharmacogenomics Analysis Lab at the Little Rock VA Medical Center. "We're using technology that enables you to simultaneously detect a million SNPs at a time in the genome [the entire genetic material] of a person."
Detecting SNPs in an individual patient is one thing. Solving the mystery of which SNPs impact disease risk—or have other critical health effects—is another.
There's only a small portion of our DNA—less than one percent—that is of special interest to researchers.
"That's a huge biological question," says Anjanette Stone, a biomedical technician who helps run Schichman's lab. "You have to study hundreds of patients to see if there's a 'phenotypic' effect to a particular SNP. That polymorphism [SNP] may not do anything. It may not change a thing in your body. Or it could: What if it changes an amino acid sequence in a protein, and it totally changes the function of that protein? Once again, that may not do anything, or it may change how you metabolize a drug, for example. There could be many effects of a polymorphism, and the only way to understand them is to do these studies with huge numbers of patients."
The studies Stone refers to are called genome-wide association studies. Here's how they work: DNA samples are obtained from large numbers of people with and without a particular disease. SNPs that show up more commonly in the affected population become prime suspects in the hunt for disease-related genes. The SNP could be in a gene—for example, patients with the disease might be more likely than healthy controls to have one or two copies of a gene variant—or the SNP could lie near a troublemaking gene in the genome. Either scenario can provide valuable clues for researchers.
Among other such studies now under way in VA, the Little Rock lab is part of research on Lou Gehrig's disease, or amyotrophic lateral sclerosis (ALS). The team is helping genetic epidemiologists at the Durham, N.C., VA Medical Center learn which genes may contribute to ALS risk. DNA from veterans with ALS who have agreed to be part of a registry is being compared with DNA from patients without ALS.
"The people in Durham take all the data sets and compare them with one another to find SNPs associated with ALS," says Schichman. "They'll take a million SNPs and try to find a small subset, maybe less than 20, associated with the disease."
The Durham group, led by Eugene Oddone, MD, is also looking at other environmental and health factors that may be part of the picture: diet, family and medical history, medications, exposures to toxins, and more. A similar approach is being used by other VA teams studying the genetic and environmental triggers of other diseases.
Such studies will become increasingly common in VA in the next few years. The agency already has a biorepository in Boston that stores frozen DNA samples from veterans who consented for their genetic material to be analyzed as part of clinical trials in which they took part. That facility may expand in the future as VA ramps up its genomics program. Based on an extensive survey of veterans, the agency is now exploring the best ways to widen efforts to collect DNA samples from consenting veterans in research and patient-care settings. The goal: Build a huge database of their genetic results. Such a storehouse of genetic information—combined with information extracted from the patients' VA electronic health records, a rich source of health and clinical data—would be the world's largest and could fastforward the field of genomic research.
Long-term clinical relationships would enhance VA's genetic database
According to Ronald Przygodzki, MD, associate director of genomic medicine for VA, the long-term relationship that veterans have with the VA health care system would make the genetic database an especially valuable research tool.
"Our advantage is that we have a tremendously loyal, supportive group of veterans," he says. "These people come to the VA medical center, to the CBOC [Community-Based Outpatient Clinic] and receive care there. They're long-standing patients. They're altruistic. They're willing to get involved to help themselves, their fellow veterans and the greater community. That's a plus that nobody out there has."
Notwithstanding all the potential for progress, genomic researchers have their work cut out for them. Learning about the health effects of millions of SNPs and thousands of genes—itself a mammoth task—is only the first step in unraveling a huge mystery.
Schichman: "Once the associations are pinpointed, the science needs to be done to show mechanistically how those associations may lead to, for example, higher susceptibility to a certain cancer." Only then, he says, can the information be used to its full clinical potential.
Another hurdle to climb: figuring out how to weave veterans' genetic information into their electronic health records so it's helpful to clinicians.
"Even if we had the entire genome of each patient, just placing that information into the electronic medical record would have no meaning for doctors. It has to be translated into a usable format," explains Schichman.
Every day, labs like his generate hundreds of gigabytes of raw data, including hefty image files, from DNA studies. After quality-control checks and preliminary analyses, reports get sent to other researchers who comb through the data on millions of SNPs and try to find answers.
Schichman says genomic researchers are undeterred by the vast amount of genetic information that is increasingly available to them, or by the equally vast challenge of learning how to use it to improve medical care.
"All the information we have may not make sense right now, but as it accumulates, and as we have bright people putting it together in new ways, we discover more and more," he says.
"It's like a huge jigsaw puzzle—you may not have any idea how all the pieces are related until the whole puzzle is assembled. We're just assembling pieces of the puzzle, and we're able to do it much faster now thanks to the technology."