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Dr. Elizabeth Speliotes

Tuesday, May 19, 2015

Elizabeth Speliotes is the lead author of the largest study of genetic variation related to obesity ever published. Appearing in a recent issue of Nature, and making headlines worldwide, the paper describes 97 different areas of the genome—56 of them new to science—that affect obesity and may be future targets for individualized treatment. Publishing a landmark study such as this in an influential journal would be a gratifying accomplishment for any scientist. However, Speliotes, who is a 2012 recipient of the Doris DukeDr. Elizabeth Speliotes Clinical Scientist Development Award, contends that, like many physician scientists today, getting to this point has not been easy and that, even with these commendable achievements under her belt, her future as a researcher is not assured.

“When I look at my colleagues, I see our numbers as physician scientists diminishing,” said Speliotes. “There are a lot of pressures to put aside work as a researcher to focus solely on clinical work.”

Speliotes’ observations are backed by statistics: Only 1.6 percent of active physicians currently claim research as their primary activity compared with a peak of 4.7 percent in 1984.[1] With the strong conviction that physician scientists provide a vital bridge between laboratory experiments and patient care, the Doris Duke Clinical Scientist Development Award was created in response to this trend, in an effort to encourage early-career physician scientists to build successful clinical research careers. Much would be lost without the important perspective that physicians bring to unraveling the mysteries of human disease.

“Physicians are very in tune with what people care about,” said Speliotes. “People show up to your clinic and ask questions that give you important insights into what they want and what’s needed in the medical community, which allows you to better direct research towards meeting some of those needs.”

Early on in Speliotes’ career as a physician scientist, it is this kind of in-person interaction that first gave her a hunch that obesity had a genetic component. She had completed her Ph.D. in genetics at MIT and was at Harvard Medical School finishing her M.D. In the clinic she noticed that many patients were obese and suffering from related complications, such as type 2 diabetes and liver disease. Intrigued, Speliotes saw an opportunity to use her training to investigate the genetic causes of obesity.

Like many new ideas that challenge the status quo, Speliotes’ theory that there was a genetic component to obesity was met with skepticism from her scientific peers, who suggested she focus on “real science” because “people just need to eat less.”  It was the late 1990s, and obesity was widely viewed as a problem of personal responsibility rather than one with complex biological roots.

“My dream was to actually figure out the genetics to obesity and obesity-related diseases, and it wasn’t clear that was ever going to happen,” said Speliotes. “It certainly wasn’t encouraged when I started.”

Undeterred, she continued her training, completing a residency and fellowship in gastroenterology, as well as postdoctoral research in human genetics under the mentorship of Joel Hirschhorn, a leader in the field and recently a recipient of two Doris Duke Innovations in Clinical Research Awards. Along the way Speliotes became enamored with clinical research.

Speliotes’ hunch about the genetics of obesity led her to study non-alcoholic fatty liver disease (NAFLD), the leading cause of cirrhosis not related to alcohol consumption. Nearly 25 percent of the U.S. population has NAFLD, which typically occurs in overweight or obese individuals.[2] Her work on NAFLD resulted in dozens of research papers published in prestigious scientific journals, such as PLoS Genetics, and was compelling enough to earn her a career development award from the National Institutes of Health (NIH) in 2008. After years of training, she was on her way to establishing herself as an independent clinical researcher.

Genetic variants increase obesity riskDespite the momentum, Speliotes faced challenges common to emerging physician scientists today. The Great Recession resulted in a stagnant budget at the NIH that has yet to recover. As the main source of medical research funding in the United States, this means fewer grants remain available for fledgling investigators as they reach a critical point in their careers.

With her own NIH grant winding down, Speliotes looked for other funding opportunities that would provide her with the “protected time” she needed in order to conduct research. Protected time is carved out from the routine clinical duties a physician scientist might otherwise be doing and is generally funded through grants. It is an important commodity that is essential, though not guaranteed, to even the most promising young researchers.

In 2012, Speliotes, now an assistant professor of medicine at the University of Michigan, received a Doris Duke Clinical Scientist Development Award (CSDA). The CSDA supports emerging physician scientists by providing them with the protected time they need to pursue their research as they transition to independence.

“Once you start doing more and more clinic, you just have less and less time for research, and then that kind of snowballs upon itself, and then you can’t write the grants to get the grants. So having Doris Duke bridge that gap and say, ‘Well, no–we want this person protected a little longer’ really made a huge difference,” she said.

With the CSDA, Speliotes has delved further into the investigation of the genetic causes of NAFLD and obesity. She is analyzing over 20,000 NALFD patient DNA samples in an effort to characterize the genetic predisposition to developing the disease.

Her work has also led to explorations into the genetics of body mass index (BMI), a common measure of obesity that was the subject of the recent Nature paper. In that study, Speliotes and an international consortium of investigators looked at the genomes of nearly 340,000 individuals. They identified 97 areas on the genome that affect obesity, 56 of which were new discoveries. The findings revealed several genetic changes that associate with increased BMI and obesity, in addition to all the other factors already in the mix, such as diet and exercise. 

“A lot of the genes and regions that we’re hitting were not connected to obesity before, so this is really novel information that can now be used to redefine disease and rethink the biology and pathophysiology of it,” said Speliotes.

The most intriguing finding was that groups of regions of the genome associated with BMI are involved in brain processes including appetite regulation and energy expenditure. “It’s really some of the strongest scientific data that there’s a neuronal predisposition in humans to becoming obese or not,” she said.

Given the complex genetic origins of obesity and NAFLD uncovered by this work, a one-size-fits-all treatment approach is unlikely to be successful. Therefore, the ultimate goal of this research is precision medicine (sometimes referred to as personalized medicine), where treatment is based on the individual’s specific genetic variations. In fact, Speliotes' latest findings on obesity underscore the importance of her previous research on NAFLD, which established the existence of “subtype” diseases that contribute to the need for precision medicine.

Dr. Speliotes in the lab.Speliotes is invigorated by these recent discoveries, which would not have been possible without the protected time for her research or the diverse consortium of investigators she works with. “The  field of human genetics,” she said, “has been helped by different investigators looking at different traits and learning from each other. It has been an honor and privilege to be part of that community.” 

But, the challenges to the broader field of clinical research remain. She noted that she is one of the few
practicing physician scientists in the consortium that conducted the recent BMI research. In addition, there is an ever-present tension between time spent in the lab versus seeing patients, which often boils down to finances. Research progress is incremental and breakthroughs rarely occur overnight.

“Science takes a lot more time; it’s much harder,” she said. “The best discoveries won’t be happening on a
daily basis, whereas on a daily basis you can show what you did as a physician: You saw X numbers of patients, you brought in X numbers of dollars. So when you look at it from a business standpoint, your productivity is more easily measured on the physician side than on the research side.” 

Despite the challenges, Speliotes remains committed to her research and to her patients: “My goal is to discover something new–to contribute something new to my field that is meaningful, that actually changes my field. That’s a rewarding life.”

[1] Garrison HH, Deschamps AM: NIH research funding and early career physician scientists: continuing challenges in the 21st century, FASEB Journal, 28:1049-58, 2014.