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Perspectives in Research

doctor showing her patient a test result on a tablet at the bedside

Implementing Precision Medicine in an Academic Hospital

Precision medicine, or personalized medicine, is a growing field that uses big data to treat the individual patient. It uses tools such as DNA sequencing and bioinformatics to ask, “What are the individual characteristics of my patient?” — for example, in her genetic makeup, environment or in the mutation profile of her tumor — and then examines whether this information can be incorporated into medical decision-making. With President Obama’s 2015 Precision Medicine Initiative, the United States government has launched a multimillion-dollar investment in supporting precision medicine.

One of the leaders in this field is Dan Roden, who currently serves as the vice president for personalized medicine at Vanderbilt University. On Oct. 5, Roden gave the 2016 Sir Henry Hallett Dale Memorial Lecture at The Johns Hopkins University in a talk titled “Engineering a Healthcare System for Discovery and Implementation in Precision Medicine.”

Tailoring disease prognoses or choice of drug treatment to the individual patient is not a new concept, and Roden began by giving several examples of how patients’ genetic makeup is already being used to predict their risk of drug side effects. One such drug is procainamide, which is prescribed to treat cardiac arrhythmias. Liver enzymes modify the chemical structure of procainamide in a process called acetylation. People who have a genetic deficiency in these enzymes are called slow acetylators, whereas those with a gene that instead confers strong enzyme activity are called rapid acetylators. Since the 1970s, it has been known that slow acetylators who use procainamide have an increased risk of developing a lupuslike side effect called drug-induced lupus erythematosus. Although procainamide is not a commonly prescribed medication, knowledge of acetylation status could help doctors prescribe the right drug dose to maximize its effectiveness while minimizing the risk of side effects.

How can we broaden our efforts to find gene variants that impact disease prognosis, response to therapy or risk of adverse side effects? By combining large-scale molecular profiling and data collection with bioinformatics, Roden described ongoing projects in precision medicine aimed at discovering new associations. For example, during the check-in process at Vanderbilt outpatient clinics, patients are now given a consent form for a program called BioVU. If they choose to participate, their DNA will be extracted from any blood left over from routine blood tests that would have otherwise been discarded. The DNA is then stored in a de-identified database that can be accessed by researchers. In a related project, called eMERGE, DNA repositories like BioVU are linked with curated clinical data from the patients’ electronic health records, providing a platform for bioinformaticians to mine through the data and uncover new links among specific gene variants, diseases and therapy outcomes.

As an M.D.-Ph.D. student interested in translational medicine, I was particularly curious about tools that could guide clinicians to make better-informed medical decisions based on research findings in precision medicine. One tool is to build guidelines directly into the electronic health record, as Vanderbilt has already done for the drug clopidogrel. In 2010, the FDA added a warning to clopidogrel, a medicine used to prevent blood clots, stating that individual genetic variation alters the efficacy of the drug. Patients who have decreased activity of another liver enzyme due to variants in the CYP2C19 gene are “poor metabolizers” who cannot effectively transform clopidogrel into its active form. Alternative drugs are recommended for patients who are poor metabolizers.

By actively displaying this drug-genome interaction in the patient’s electronic health record, Vanderbilt saw dramatic changes in clinical decision-making related to clopidogrel use. Twelve months into the project, fewer poor metabolizer patients remained on clopidogrel, compared to extensive metabolizer patients (42 percent versus 92 percent), whereas intermediate metabolizers were right in the middle, at 67 percent. Unlike procainamide, clopidogrel is a widely prescribed drug that is used daily by millions of Americans.

The combination of precision medicine and the electronic health record promises to open exciting new possibilities not only to better understand the relationship between genetics and disease, but also to better treat the patient as an individual.

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nurse holds a patient's hand

Cancer Drug Shows Surprising Potential as Parkinson’s Treatment

Parkinson’s disease is a neurodegenerative condition caused by the death of dopamine-producing cells in a region of the brain called the substantia nigra, which leads to disruptions in neural circuits controlling motor function. Although the cause of this inappropriate cell death is largely unclear, one hypothesis is that it is due to the abnormal aggregation of a protein called α-synuclein in damaged neurons. Support for this theory has come from autopsies of patients showing large clumps of α-synuclein in the diseased tissue, but how or why these clumps contribute to Parkinson’s has remained largely unclear.

In a study published in the September issue of Science, researchers from the Institute for Cell Engineering at Johns Hopkins have identified a previously unrecognized role for a protein called lymphocyte-activation gene 3 (LAG3) , which may have critical implications for understanding how α-synuclein is connected to the pathogenesis of Parkinson’s disease. LAG3 is a protein better known for its role in the immune system, where its expression on the surface of immune cells prevents cytotoxic CD8+ T cells from functioning properly in a state of chronic infection or cancer.  Antibodies against LAG3 are being tested as potential cancer treatments, with the hope that by blocking the immune checkpoint receptor protein’s immunosuppressive effects, the patient’s immune system can have a chance to reactivate and more efficiently kill cancer cells.

In neurons, LAG3 plays a much different role, and instead recognizes and interacts with certain materials outside the cell, resulting in their uptake and import. In searching for an answer as to how α-synuclein enters neurons, the researchers found that not only was LAG3 able to import the pathological protein aggregates, but it was also necessary to transport them between cells. They followed up by deleting the LAG3 gene in mice and found that when they injected them with α-synuclein, they developed symptoms of Parkinson’s much more slowly than control mice.

This research is a critical step toward understanding the underlying causes of Parkinson’s disease, since until now, the role of abnormal α-synuclein spread was mostly based on observation and theory, with little mechanistic detail. Now, with the discovery of the role of LAG3, a new door in Parkinson’s research has been opened — with the exciting possibility that a drug already in the pipeline for cancer treatment could potentially benefit the nearly 10 million Parkinson’s disease patients worldwide as well.

Sources

  1. Goedert M, Masuda-Suzukake M, Falcon B. Like prions: the propagation of aggregated tau and alpha-synuclein in neurodegeneration. Brain. 2016 Sep 21.
  2. Mao X, Ou MT, Karuppagounder SS, Kam TI, et al. Pathological alpha-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science. 2016 Sep 30; 353(6307).
  3. Nguyen LT, Ohashi PS. Clinical blockade of PD1 and LAG3 – potential mechanisms of action. Nat Rev Immunol. 2015 Jan; 15(1): 45-56.
  4. ClinicalTrials.gov
  5. Braak H, Sandmann-Keil D, Gai W, Braak E. Extensive axonal Lewy neurites in Parkinson’s disease: a novel pathological feature revealed by alpha-synuclein immunocytochemistry. Neurosci Lett. 1999 Apr 9; 265(1): 67-9.
  6. Statistics on Parkinson’s. Parkinson’s Disease Foundation. 2016.

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salmon, avocado, flax seed and other examples of fatty acids

Omega-3 Fatty Acids May Lower the Risk of Fatal Heart Attacks by More Than 10 Percent

The human body synthesizes most of the fats it needs. However, there are certain fats — called essential fatty acids — which are required for its function and that the body is unable to make from scratch. Humans instead must depend on food consumption for these fatty acids, which are called essential fatty acids and include omega-3s. Omega-3 fatty acids are a type of fatty acid with a specific chemical structure and consist mainly of eicosapentaenoic acid and docosahexaenoic acid — found in seafood, such as tuna and salmon — and α-linoleic acid — found in several kinds of nuts.

Omega-3s play an important role in brain function and normal development, and deficiencies have been linked to poor memory, disorders of the liver and kidneys, impaired immune function, depression and fatigue. Consumption of omega-3 fatty acids has been associated with a reduced risk of developing atherosclerosis, heart disease, stroke, Alzheimer’s disease, dementia, asthma and joint pain. However, while several studies have reported significant benefits associated with omega-3 consumption, others’ results were inconclusive. Explanations for these inconsistencies include small sample sizes, as well as self-reported consumption of omega-3s via questionnaires and surveys from study participants, which are not necessarily reliable methods of measuring intake.

This is where the Fatty Acids and Outcomes Research Consortium (FORCE), led by Dariush Mozaffarian at Tufts University, comes into play. In a recent study published in JAMA Internal Medicine, the consortium provided the largest data set to date assessing the purported benefits of omega-3 consumption. The authors pooled data from 19 groups with over 45,000 participants from 16 different countries. Instead of relying on self-reported estimates or questionnaires to measure intake, the researchers used direct blood and tissue measurements of omega-3 fatty acids to provide an unbiased analysis of the heart-healthy benefits of omega-3s.

Did you know: 1 in 4 deaths in the U.S. is a result of heart disease?The study, which is the most comprehensive of its kind thus far, found that participants with higher circulating blood levels of omega-3 fatty acids had, on average, a nearly 10 percent lower risk of a fatal heart attack, as compared to participants whose levels were lower by one standard deviation. The authors also found that the higher the omega-3 levels, the lower the risk of heart disease, with participants with the highest blood level of omega-3s having the greatest reduction in risk, of more than 25 percent. These effects held true irrespective of age, sex and race, suggesting that anyone can enjoy the benefits of adding omega-3s to their diet.

Given that one in four of all deaths in the United States is due to heart disease, a 25 percent reduction in risk could translate to significant numbers. However, the authors caution that because their study focused only on the consumption of omega-3s from natural plant and seafood sources, their results do not make claims that fish oil supplements will have the same beneficial effect. FORCE will also provide future opportunities to study the relationship between fatty acid biomarkers and other health outcomes besides heart health. Now that the link between omega-3 consumption and prevention of fatal heart disease has been more firmly established, the authors are beginning to look into other measurements of health in the hopes of better understanding the relationship between omega-3s and the risk of developing diseases such as diabetes, obesity and various types of cancers.

Source: Del Gobbo, L.C.; and Mozaffarian, D., et al. ω-3 Polyunsaturated fatty acid biomarkers and coronary heart disease. Pooling project of 19 cohort studies. JAMA Intern Med. 2016;176(8);1-13. doi: 10.1001/jamainternmed.2016.2925. Published online June 27, 2016.

Read More »Omega-3 Fatty Acids May Lower the Risk of Fatal Heart Attacks by More Than 10 Percent