A recent study shows why genetic advances in medicine are so challenging.
By Michael White
(Photo: samazgor/Flickr)
The Human Genome Project was both a spectacular success and a frustrating disappointment. It has revolutionized the science of biology and spawned a multi-billion dollar industry. It has also failed to deliver on the ambitious promise that genome science will, as President Bill Clinton stated 16 years ago, “revolutionize the diagnosis, prevention and treatment of most, if not all human diseases.”
But hype springs eternal. The human genome is now old news; today scientists study tens or even hundreds of thousands of human genomes. We now hear promises about the imminent benefits of personalized medicine, medicine that is tailored to an individual’s unique genetic make-up. President Barack Obamahopes that “10 years from now we can look back and say we have revolutionized medicine,” from cancer to Alzheimer’s. To achieve this, the White House has launched another large research effort: the Precision Medicine Initiative, which will devote hundreds of millions of dollars to advance the use of genomics and other cutting-edge science in medical practice.
It’s an admirably ambitious vision, but in 10 years we shouldn’t expect to look back and see a revolution. Scientifically, this is the right direction — over the long-term, genomic discoveries will certainly drive major medical advances. But it’s going to be a long slog. The major challenges that lie ahead are laid bare in a recent genetic study of Type 2 diabetes. This study, published in Nature earlier this month, shows that the genetics of diabetes is a mess — and it illustrates why the big promises of genetic medicine won’t be realized any time soon.
Known mutations account for only 10 percent of the estimated genetic contribution to the disease. After more than a decade of large, high-tech studies, the genetic basis of diabetes remains, for the most part, unexplained.
Type 2 diabetes is one of the major diseases that biomedical scientists hope to conquer with genomics. It’s one of our most common diseases — the Centers for Disease Control and Prevention estimates that nearly 10 percent of all Americans have it. Diabetes is also expensive: It accounts for an estimated $176 billion in medical costs each year. And while most of us have the impression that diabetes is something you prevent with a healthy diet and exercise, the disease also has a strong genetic component.
By understanding the genetics of diabetes, we hope to combat the disease in three big ways. First, we’ll be able to identify people with a high genetic risk, and make them the focus of prevention efforts. Second, we might recognize and specifically treat different molecular forms of the disease — different people likely have different underlying genetic mutations, which means that not all diabetics respond the same way to a one-size-fits-all therapy. And third, genetics will help us understand the disease’s molecular underpinnings, and guide us toward better treatments that directly target those molecules. If we achieved all three goals, we would indeed revolutionize the treatment of diabetes.
And so, for the past decade, researchers have conducted large genetic studies, involving at first thousands, and now tens of thousands of diabetics. The results have been somewhat disappointing: Though researchers have linked dozens of mutations with diabetes, we’re clearly still missing much of the picture. Known mutations account for only 10 percent of the estimated genetic contribution to the disease. After more than a decade of large, high-tech studies, the genetic basis of diabetes remains, for the most part, unexplained.
To find the missing mutations in diabetes, scientists of two large international research consortia performed a deeper DNA analysis of a large set of study subjects. Earlier studies used a lower-cost, coarse-grained scan of the subjects’ DNA. These scans only had the power to detect mutations that are relatively common in the population. In this most recent study, the researchers decided to survey the subjects’ genomes much more comprehensively.
The hypothesis behind this approach is that diabetes is a bit like Leo Tolstoy’s famous claim about unhappy families: Each case of diabetes is affected by genetics in its own way. In other words, although diabetes is a common disease, its genetic component might not be caused by a set of relatively common mutations. Rather, each person’s genetic risk could be the result of distinctly different, and relatively rare, mutations.
If that were true, this new, more comprehensive study should have turned up many of these hypothetical rare mutations. But that’s not what the researchers found. After analyzing the DNA of over 100,000 diabetics and healthy volunteers, the researchers largely re-discovered the same set of common mutations that had been previously found. They discovered few rare mutations.
The hypothesis behind this approach is that diabetes is a bit like Tolstoy’s famous claim about unhappy families: Each case of diabetes is affected by genetics in its own way.
Why is this bad news? Because it means that finding the genetic risk factors for diabetes is going to be very hard. If rare mutations were important genetic drivers of diabetes, then the task of understanding diabetes genetics would likely be easier. Rare mutations are expected to have larger effects, and therefore a person’s individual genetic risk for the disease would come down to just one or a few mutations. If we knew what mutations to look for, we could easily test for them in a routine, clinical genetic test.
Mutations that are common in the population, on the other hand, tend to have smaller effects on disease. (Mutations with large effects tend not to become common, thanks to natural selection.) This latest study suggests that the genetic basis of diabetes involved the combined effects of many mutations, each one only making a small contribution. These small contributions are statistically challenging to detect in a scientific study, and much harder to evaluate in a clinical genetic test. This is why the study authors argue that “Genome sequencing in much larger numbers of individuals than included in the current study are needed.” As one scientist put it: “Once dubbed ‘a geneticist’s nightmare,’ diabetes seems to be living up to its reputation.”
Fortunately, with today’s technologies, very large genetic studies are becoming feasible. Obama’s Precision Medicine Initiative proposes to put together a study cohort of one million Americans over the next several years. And given the hundreds of billions of dollars that diabetes costs America each year, such large studies, if successful, are clearly worth the expense.
The challenging genetics of diabetes and other common diseases, however, means that the benefits of such studies will mostly arrive in the long term. We are laying an important foundation for the medicine of the future — but people also need care today. Fortunately, even without the genetics, we understand a lot about how to prevent diabetes though lifestyle changes. Investing in large efforts to help people change their diet and exercise habits may not sound as exciting as high-tech genetic medicine. But, just as we shouldn’t overhype the near-term prospects of genetics, we shouldn’t undersell the value of the effective care we can provide today.
