University of Vermont

Tracy's Lab Plays Critical Role in Precision Medicine Effort, Is Go-to for Genetic Specimens

Russell Tracy, Ph.D.
A clearinghouse for thousands of DNA samples for the National Institutes of Health's Exome Sequencing Project, UVM Professor Russell Tracy's lab is the nation's go-to facility for managing biological specimens for large-scale studies. (Photo: COM Design & Photography)

Precision medicine found the limelight when President Obama unveiled a $215 million initiative to target its growth as part of his 2015 State of the Union Address in January, but for researchers both nationwide and at the University of Vermont, exploring how to best tailor medicine to individual needs has been the focus of their work for years. Whether it’s referred to as precision, personalized or genomic medicine, the goal is the same: to obtain individuals’ detailed genetic information so that both risk and treatment of disease can be dealt with at the most elemental level.

“Heart attacks are common,” says Russell Tracy, UVM professor of pathology, by way of example. “But everyone is an individual. And what precision medicine means is ultimately understanding each person’s version of these things so that it’s prevention first, and then if (a heart attack) happens, therapy can be tailored in the most precise way, so that you get the best bang for the buck.”

Tracy’s lab was at the heart of the massive Exome Sequencing Project (ESP) sponsored by the National Institutes of Health’s (NIH) National Heart, Lung, and Blood Institute, serving as the clearinghouse for thousands of DNA samples, which the lab quantified and plated before sending them on to the Harvard-Massachusetts Institute of Technology Broad Institute and the University of Washington for sequencing.

“(Tracy’s) lab was the single final conduit for organizing those specimens and managing them without contamination, without specimen swaps,” says Dr. James Wilson, University of Mississippi professor of physiology, biophysics and medicine and, along with Tracy, a member of the ESP HeartGO cohort consortium. “It’s the go-to laboratory in the country for large-cohort studies for the management of biological specimens, including serum, plasma, purified DNA, frozen white blood cells and urine.”

The ESP HeartGO consortium -- the other two ESP consortia were focused on lung disorders and women’s health -- has already published multiple papers in the New England Journal of Medicine and elsewhere on findings related to a variety of genetic mutations they were able to associate with cardiovascular disease. On a continuum that ranges from exceptionally rare genetic disorders to fairly common variances, the ESP findings fall somewhere in between. And although many of the mutations are not found in a wide swath of the population, the discovery of each one is critical. Given that vascular disease and stroke kill more people worldwide than anything else -- including all cancers combined -- drilling down to the lowest possible level will have significant ramifications.

“By definition, a rare variant is a small part of the population, but if you have enough of them, then it adds up to quite a few,” says Stephen Rich, director of the Center for Public Health Genomics at the University of Virginia School of Medicine, and a member of the ESP HeartGO team. “The importance of the project is that it’s uncovering novel genes and novel pathways that become new therapeutic targets.” He cites the example of a gene that the ESP established that is associated with extraordinarily low triglyceride levels, thereby lowering the risk of heart attack; drug companies are now working to create compounds to mimic it.

A precise approach

Obama’s Precision Medicine Initiative will bring ever-needed funding to be divided among the NIH (including the National Cancer Institute), the Food and Drug Administration, and the Office of the National Coordinator for Health Information Technology. Eventually, the initiative will focus on many complex chronic diseases, but for now, the attention is on cancer -- in large part, says Tracy, because “it may be the least difficult of all the difficult things.” Unlike many chronic diseases, cancer arises out of relatively constrained origins, he explains, so the work will begin with genetic sequencing. Beyond that, researchers will look at the expression of messenger RNA, at small regulatory RNAs, at metabolism, at the proteins themselves, and so forth. Tracy’s lab is already involved in related multi-center projects with partners around the country, and in fact, the world; current projects include collaborators in Uganda, Russia, Japan, and England, among other places.

At some point in the not-so-distant future, says Tracy, all patients will be sequenced, and that information will be available to physicians for the routine treatment of disease. To the patient who is discovered to have the APOA5 gene associated with early-onset myocardial infarction (read about a recent study on this here), a doctor might point out the documented increased risk of heart attack and, based on that, make suggestions for dietary changes, exercise and quitting smoking.

“We’re entering an era where we’re going to get more and more precise -- granular -- about all these levels and layers,” says Tracy. “The first one, as the foundation, is understanding the primary sequence of the human genome in detail in a wide variety of people so we can make all the links between those variances in the genome and health and disease.”

For Tracy and his colleagues at UVM and around the country, the greatest challenge has changed from gathering data to asking the right questions. It’s a process, says Tracy, one he likens to fixing a leak under the kitchen sink -- a seemingly simple repair that then turns into five trips to the hardware store as the problem evolves.

“The quality of the question becomes paramount,” he says. “That means you have to have a big enough selection of people to ask the proper question. And as you start asking better and better questions, you realize your initial questions were naïve.” So where once 5,000 people was considered a huge study, today researchers are looking at 100,000 people at a time -- the Precision Medicine Initiative even calls for a million-person study. The Veterans’ Administration already has something of that size underway, and Tracy’s lab is a small part of it.

“It’s an unbelievably exciting time to be in biomedical science,” he says.