One Size Doesn’t Fit All

parallel lines of different thicknessOver the last two decades, genetics researchers have made dramatic advances in their understanding of the human genome, which has laid the groundwork for precision medicine: therapies and preventive strategies that can be customized to an individual’s unique genetic makeup.

Telomere Pioneer

The science of telomeres made international headlines in 2009, when Johns Hopkins molecular biologist Carol Greider received the Nobel Prize for Physiology or Medicine for her pioneering research on their structure. Together with Elizabeth Blackburn and Jack W. Szostak, Greider discovered that telomeres are protected from progressive shortening by the enzyme telomerase — an enzyme she discovered in 1984 while a graduate student in Blackburn’s lab. 

Greider joined Johns Hopkins in 1997 and served for many years as the Daniel Nathans Professor and director of molecular biology and genetics. In 2014, she was named a Bloomberg Distinguished Professor. Greider left Johns Hopkins in October to join the University of California, Santa Cruz as a distinguished professor of molecular, cell and developmental biology.

Johns Hopkins genetic epidemiologist Rasika Mathias is excited by the speed with which her field has advanced. But she has long been troubled by a disturbing reality: Much of what geneticists have learned until now has been based on “interrogating” enormous sets of data on people of European ancestry. In fact, until recently, non-European participants represented less than 5 percent of research study subjects. “This has led to big gaps in our understanding of the genetic predictors of diseases in minority populations, such as African Americans and Hispanic/Latino individuals,” she notes.

Mathias is committed to filling that gap. A decade ago, she led the first genomewide association study on the genetics of asthma in a population of African ancestry. Today she leads the Consortium on Asthma among African-ancestry Populations in the Americas, which is dedicated to bridging the gaps in our understanding of the health disparities surrounding asthma.

Most recently, Mathias has turned her attention to aging. Her focus? The telomere, a “cap” at the end of each strand of our DNA that protects our chromosomes, like the plastic tips at the end of shoelaces [see “Telomere Pioneer”]. Our telomeres get shorter as we age, and telomere shortening is involved in all aspects of aging at the cellular level. While the shortening process is impacted by environmental factors, such as stress, obesity, smoking and diet, genetics also plays a role. All of this holds out a tantalizing possibility for scientists: If we could somehow stop or reverse the telomere shortening process, perhaps we could slow the biological aging process and extend the number of years that people could live in good health.

Until recently, non-European participants represented less than 5 percent of research study subjects.

“But to date, there are major holes in our understanding of the genetic predictors of this dynamic part of the human genome,” notes Mathias. What’s more, “the field of telomere genetics is crippled by the issue of health disparities,” she says.

“Telomere length differs between human populations, but there has been little science in African American and Hispanic/Latino populations in this area. This limits not only the validity and generalizability of current knowledge but also, more importantly, seriously hampers our ability to translate the research into clinical practice in an equitable manner.”

So Mathias, who was recently named the Sarah Miller Coulson CIM Human Aging Project Scholar, has embarked upon an ambitious, multiyear study, which she hopes will bridge these gaps and ultimately lead to precision medicine opportunities for healthier aging — solutions that are ancestry specific.

To do that, she and her team are tapping into enormous sets of genetic data made available through the TOPMed Program (Trans-Omics for Precision Medicine) of the National Heart, Lung, and Blood Institute. “We have the opportunity to leverage the information from 100,000-plus samples to evaluate the association between ancestry and telomere length — and home in on the genetic underpinnings that can explain differences,” she says. “This study will be the single largest effort to examine telomere length across the most diverse representation of minority populations.”

Once the scientists have identified promising genetic determinants, they will move on to generating polygenic risk scores, a crucial tool in the arsenal of precision medicine that uses an individual’s genetic makeup to predict future health outcomes. “This gives us the ability to stratify patients by their risk for aging related outcomes, which will potentially make it possible to target early interventions,” she says.

The bottom line: “Our patients are diverse,” notes Mathias, “so it’s crucial that we develop tools, like polygenic risk scores, that are designed by considering the diversity in human populations. We need to be leaders in building those tools, in an equitable manner.