Hype or hope? Unlocking genes to block diseases

As a child, Larry Weakland watched his grandfather die, painfully, from pancreatic cancer. So when he was diagnosed with the same affliction two years ago, Weakland, 71, resolved two things: He wasn't going to go like that, and his children weren't going to suffer the same legacy.

Days after starting chemotherapy at Mayo Clinic in Rochester early last year, Weakland submitted to genomic testing to determine whether a genetic mutation predisposed him to the cancer risks. He then persuaded his children to do the same.

"I want this thing to end with my family, and my generation," Weakland said.

Weakland's tale was featured last week at a Mayo conference of the nation's leading genomics experts, underscoring how far the field has come since the first human genome was sequenced in 2003 and how far the field has moved beyond research laboratories into applied medicine that is increasingly subject to public scrutiny, expectation and hope.

"Once we touch medicine, it's no longer just a scientific discipline," said Dr. Eric Green, director of the National Human Genome Research Institute. "There are social responsibilities with what we do."

Genetic testing has become commonplace in the past decade: for relatives of patients with pancreatic, breast and other cancers; for mysterious and rare childhood diseases; and for treatment planning in cases of lung cancer and other select conditions.

A rapidly growing discipline called pharmacogenomics is identifying genetic information that predicts how patients will respond to certain drugs.

One reason for optimism on all these fronts is the reduced cost of whole-genome sequencing. The process has become so cheap and repeatable that researchers are able to conduct previously unthinkable studies, and patients can afford to have their genetic histories mapped and mined for potential defects, said Dr. Keith Stewart, director of Mayo's Center for Individualized Medicine.

"I can't believe that we all won't routinely have our genomes sequenced in the not too distant future," he said. "It's so cheap to do now."

Some doctors, though, fear that the promise of genomic medicine has been oversold, and that the stampede to genetics research has come at the expense of other pursuits in health care.

"I like to tell people to drink the Kool-Aid in small doses," said Dr. Michael Joyner, a Mayo anesthesiologist who spoke at the conference. He described a "hype-filled biomedical narrative" that, he argues, has led people to believe that genetic medicine has accomplished more than it really has.

For example, he said, a leading researcher once claimed that the dozen or so genes responsible for diabetes would be discovered by 2008. In reality, a much more complex combination of genes and lifestyle choices are responsible.

"The promise and the ideas of what might happen have just gotten way, way out in front," he said.

Weakland is a believer — especially after losing his grandfather, an uncle and an aunt to cancer and seeing what genetic testing could accomplish for his children. His daughter was considering preventive surgeries, including a hysterectomy and double mastectomy, until the testing found that she didn't share the family's genetic cancer trait — specifically a mutation of the BRCA2 gene.

Weakland's son, on the other hand, carries the genetic trait and will now be monitored closely for physical changes that could be early warning signs.

Weakland, a retired contractor and Vietnam War veteran, has outlived his doctors' expectations when they found his aggressive pancreatic cancer, which had already spread to his liver.

The initial rounds of chemo worked so well that doctors took a follow-up tissue sample from him to learn why.

A concern for skeptics such as Joyner is that genetic testing often identifies only modest increases in disease risks, or negligible differences in the effectiveness of drugs. He pointed to a study of the genetics of Shawn Bradley, a former NBA player who stands 7 feet 6. Researchers found genetic evidence to explain his stature, but it explained only 1 centimeter of his excess height.

Stewart said he agrees that genetic medicine is sometimes oversold but said that shouldn't discourage researchers. Instead, he said, doctors need to challenge their assumptions. For instance, some doctors have questioned whether a pharmacogenomic test really helps in deciding whether to prescribe Plavix for heart patients. So Mayo is participating in a national study involving 5,000 patients to determine whether the testing and medication is ultimately helpful. Mayo also is following 500 patients over a year to determine if spending increases unnecessarily among those who receive whole genome sequencing.

One emerging challenge is simply managing all of the genetic information being collected by clinics and hospitals worldwide so the profession can use it collectively to discover gene types that are more prone to certain diseases or less affected by certain drugs.

Mayo is participating in a study known as All Of Us, in which 100 health care organizations in the United States are collecting the genetic information of 1 million people. Green said there will be as many as 50 million genetic samples in the next 20 years, and that 80 percent of them will be collected by hospitals and clinics in the process of patient care, rather than by researchers.

Another concern, Green said, is making sure these samples represent the nation's diversity, and not just the white majority or people who can afford to pay for them.

David Smith, a genomics cancer researcher at Mayo, acknowledged that scientists might have made unrealistic predictions in the early years, when so much was unknown. But today, he said, predictions need to be more realistic because of the number of people counting on genetic research to save their lives.

"If we continue to do this overhyping," he said, "we're slapping ourselves in the face."