Mark McCarthy: Type 2 diabetes, genetics and the modern world

Type 2 diabetes is a growing medical problem, but unlike many complex diseases there is an easily identifiable foundation for its cause—our modern lifestyle. Its emergence as a serious threat to health therefore poses significant challenges in a variety of fields beyond clinical medicine, including research and public health.

HUGO Council member Mark McCarthy is on the front lines of both the research and clinical fronts. His dual roles are effectively captured in his two U.K. bases of operations in buildings about 400 meters apart in Oxford: at the Oxford Centre for Diabetes, Endocrinology and Metabolism and at the Wellcome Trust Centre for Human Genetics. In the lab at the Wellcome Trust he works to tease out the root genetics of susceptibility to type 2 diabetes, seeking pathways that can be targeted for improved therapies. In the clinic he specializes in diabetes, helping patients manage their existing disease.

One recent late spring morning McCarthy discussed the behavioral versus genetic aspects of type 2 diabetes, how technology advances are aiding his work, the difficulty of capturing the human condition in the lab, and much more.

Q: You originally trained as a medical doctor. How did you become so involved in genetics research?

A: I was doing the equivalent of a residency and received a fellowship to do some research in diabetes genetics. At the time I was mostly looking to move up the medical ladder, and a higher degree in research would help. But I enjoyed it, and in the mid 1990s went on to do post-doctoral work with Eric Lander at the Whitehead Institute before returning to the U.K. to continue my research using family-based studies to find genes associated with diabetes. I still practice medicine, but over the years I’ve done progressively more basic research and less clinical work.

Q: Type 2 diabetes is strongly correlated with behavior and environment—what techniques are you using to find the genetic associations?

A: We are focused on finding the components of disease risk, which is driven by genetic differences. We are using a range of different approaches to identify this genetic component. Over the past few years, genome wide association studies have provided a powerful approach to identifying genetic loci, and we’ve identified around 65 for type 2 diabetes. Given these associations, we’re now increasingly trying to understand the whole chain of causation from variant to disease, something that has proven quite challenging.

Q: Have model organism studies been effective?

A: Well, we’ve seen over and over again that we struggle to recapitulate the true disease situation in model organisms. We can use them to discover basic biology and test pathways, but type 2 diabetes is so heterogeneous that we have to bring it back to the human for most clinical discovery.

Q: Heterogeneous? Part of the promise of genomic medicine is to treat patients as individuals, not part of large population averages. How does this figure in to type 2 diabetes therapies?

A: Type 2 diabetes is the result of multiple factors coming together, and it is likely that the balance of factors involved differs subtly from individual to individual. That opens the door to more precise, personalized approaches to treatment and prevention. One of the main challenges is that, once people have diabetes, the disease and/or its treatment gets in the way of characterizing the changes that led to the diabetic state. So those kinds of studies need to be done in people before they develop diabetes, for example by performing detailed phenotyping of the earliest stages of disease.

Q: Much of the blame for the type 2 diabetes epidemic rests in behavioral and environmental factors, and some people say we should put our effort and investment into education and behavioral modification instead of genetics and pharma research. What are your thoughts?

A: In principle, we know how to stop the diabetes epidemic in its tracks—through changes in diet and exercise for example. However, in practice those behavioral modifications are incredibly hard to sustain. We can already identify many of the individuals destined to develop diabetes based on their family history and ethnicity, but it has proven very difficult to achieve the sustained lifestyle changes that might reduce their risk.

In terms of more specific interventions, it might be possible to target energy-dense foods as one possible culprit contributing to the rise in diabetes. It’s also possible that research will turn up other factors that have contributed to the rise in diabetes worldwide. Could it be, for example, that widespread antibiotic use in early life has led to changes in the gut microflora that are important? That’s purely speculative at the moment, but indicates the kind of factor—amenable to intervention—that might emerge from ongoing research.

Q: But losing weight has such a direct impact . . .

A: It’s clear that humans generally do a great job of matching energy input and output. And even in those who become obese, the imbalance between those two factors is relatively modest. 

Q: How has HUGO contributed to your work?

A: My research depends a great deal on international collaboration, and many of our projects use samples collected in diverse parts of the world. HUGO has contributed hugely to good practice in this area, and in the promotion of genomic research across the globe. This has really opened doors to new international collaborations that would not otherwise have been possible.

Q: Looking ahead, is there any chance we’ll be able to find a cure for type 2 diabetes?

A: It is certainly possible. The best hope lies in identifying the processes most fundamentally involved in diabetes pathogenesis, such as those revealed by genetic studies, and then by developing novel preventative and therapeutic interventions which can reverse those changes.

Q: What about using genetics to predict onset?

A: On their own, the predictive power of genetic variants is modest, and it may well be that genetics alone will never provide a sufficiently strong predictive signal for clinical purposes.  But by combining genetics with measures of other contributors to disease risk—such as epigenetic changes, or the cumulative effect of environmental exposures collected on hand-held devices—I am hopeful that clinically useful stratification of risk will be possible in the years to come.