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DNA sequencing to guide research, care

Program anticipates participation by many patients who can learn their own cancer and heart risks and help uncover broader trends

At the official launch of Generations on September 4, (l-r): Richard Lisitano and Marna Borgstrom of Yale New Haven Health (YNHH), Dean Robert Alpern, Keith Churchwell of YNHH, Michael Murray, and Brian Smith. Generations is one of the largest DNA sequencing projects of its kind in the United States and hopes to enroll more than 100,000 volunteer participants.
Photo by Robert A. Lisak
The official launch of Generations
At the official launch of Generations on September 4, (l-r): Richard Lisitano and Marna Borgstrom of Yale New Haven Health (YNHH), Dean Robert Alpern, Keith Churchwell of YNHH, Michael Murray, and Brian Smith. Generations is one of the largest DNA sequencing projects of its kind in the United States and hopes to enroll more than 100,000 volunteer participants.

At a ceremony at Yale Center for Clinical Investigation on September 4, Yale School of Medicine and Yale New Haven Health System officially launched Generations, one of the largest DNA sequencing projects of its kind in the United States. The aim is to enroll more than 100,000 patients in and near Connecticut, whose DNA will then be analyzed by Yale scientists to develop useful data for predicting, preventing, and treating what may eventually be hundreds of gene-related conditions.

Its architects envision Generations as a benefit to both the clinic and the laboratory. Its most immediate application may be for the actual volunteers who donate blood samples for analysis. If their genetic information suggests elevated risk for specific conditions related to cardiac disease or cancer—conditions that are considered “actionable” by the medical community—health professionals at Generations will inform them. “What we can do right now is we can give back to 2% to 3% of people information that they wouldn’t otherwise know about serious life-threatening risks that they can do something about. That’s revolutionary,” says Michael F. Murray, MD, professor of genetics and director of clinical operations for Yale’s Center for Genomic Health, who is in charge of Generations.

Murray was recruited to Yale after building a similar program at Geisinger Health System in Danville, Pennsylvania. He says genomic information collected there indicating elevated breast cancer risk was revealing. “We have very clear examples of some patients who had cancer detected at a very early stage, and cured, and will never have to suffer with the disease. That’s life changing for them.”

Changing the lives of people with conditions unrelated to cancer or heart disease will take longer. For instance, since effective therapies do not yet exist for Alzheimer’s, volunteer donors will get no information on their risk for that. “We can’t currently intervene on Alzheimer’s,” says Murray. “There is no treatment or prevention for it.” Generations will only inform volunteer donors of their genetic risk when research makes a condition treatable. For this year’s donors, that could mean being notified years from now. “There are 20,000 genes,” says Murray. We’re giving back information on between 10 and 100 genes. That leaves more than 99% that we’re not attending to because we don’t know what to do yet about conditions they might cause.”

Murray says Yale’s location will produce a scientifically meaningful cohort of participants. “Connecticut is the fourth closest match to the U.S. population in the census data for ethnicity and race,” he notes. “This is a great place to pilot genomic medicine.” That, he says, will allow Generations to make great strides in a field where existing data tend to be skewed. “The datasets are very biased toward Europeans. We know that could mean missed opportunities when you try to apply that information to somebody from a different part of the world.”

As patterns related to specific diseases and demographic groups are found, Yale practitioners will then put their findings into practice for patients of Yale Medicine and the Yale New Haven Health System. “We learn from every patient whom we treat within the health center,” says Brian R. Smith, MD, professor and chair of laboratory medicine, deputy dean for scientific affairs, co-director of the Yale Center for Clinical Investigation, and co-principal investigator of the Yale Clinical and Translational Science Award Program. “As a consequence of that, we do a better job with the next patient we treat, and on and on.”

One exciting thing to learn will be why certain people who carry a disease-causing gene mutation do not become ill. “I think a big question is why some people with the same mutation get a disease and others don’t,” says Antonio Giraldez, PhD, chair and Fergus F. Wallace Professor of Genetics, who says evaluating healthy people will be as important as analyzing those who have symptoms. “If you only study the people who have the disease, you cannot discover what protects you.”

Clinical trials and other patient studies will also be more efficient to construct because potential participants are already in the database.

Daniel L. Jacoby, MD, associate professor of internal medicine (cardiovascular medicine) and director of the comprehensive heart failure and cardiomyopathy programs, treats patients with cardiac amyloidosis, which occurs when deposits of an abnormal protein called amyloid take the place of normal heart muscle and affect heart function. Jacoby, Edward J. Miller, MD, PhD, associate professor of medicine and radiology, and Nikolaus Papoutsidakis MD, PhD, instructor of medicine (cardiology), are also investigating how the condition progresses. They anticipate that data from Generations will be a foundation for that work.

Jacoby notes that the condition, which disproportionately affects African Americans, is often misdiagnosed as hypertensive heart disease and treated as such. “The usual medications that are used to treat heart failure don’t actually work in cardiac amyloidosis,” he says. “Beta blockers and ACE inhibitors can make things worse.”

Jacoby expects the Generations information to be life-enhancing, by minimizing misdiagnoses and symptoms that go untreated while steering treatment in the right direction. “If you’re 25 years old and you go into the Generations Project and you find out you have the associated mutation, a couple of things are going to happen. One is you’re going to know, and we’ll keep close tabs. If something starts to come up, we can begin treatment right away. Second, there’s a fair chance that one of your parents will have the gene, and, in fact, have some clinical problems related to it that they may not previously have been aware of. And they’ll be able to get treatment.”

“I think genetic discovery within the next five to 10 years will become as routine as a blood test at birth” Giraldez says. He predicts that childhood maladies could also become a prime focus. “That might be ADHD, autism, or other genetic conditions, which present more suddenly and can have irreversible effects if not treated promptly. It is hard for a family to learn that, but it’s also hard when you have to jump from doctor to doctor for a diagnosis or when some kids might not be easily diagnosed.”

Genomic analysis may also help clinicians customize medication regimens. Rebecca Pulk, PharmD, clinical coordinator for pharmacogenomics at Yale New Haven Health, looks forward to providing actionable results that can improve care. “Genes linked to metabolic and transporter pathways have known population based variations that affect medications,” she explains. “An example finding would be the DPYD gene which codes for the enzyme dihydropyrimidine dehydrogenase. Fluorouracil, a chemotherapy used in GI and breast malignancies, relies entirely on this enzyme for clearance. Patients receiving fluorouracil who genetically do not produce functional versions of this enzyme are at risk of life-threatening bone marrow toxicity. Through identification of those at risk for toxicity, lower doses or alternative treatments can be used.”

Generations builds on a heritage of genetics-related firsts at Yale School of Medicine. Robert J. Alpern, MD, dean and Ensign Professor of Medicine, notes that “Yale actually had the foresight decades and decades ago to form the first department of genetics in the country.” Now, he says, “we have the ability to tie it all together, and really participate in what is going to be a revolution in health care, and we’re really looking forward to being a part of it.”

In the words of Antonio Giraldez, who led the recruitment of Michael Murray to Yale, “When we look back at this in 10 or 20 years, it will have been transformative.”