The Organ Prophet

Hannah Valantine Can Predict Heart-Transplant Rejection Before It Happens

BY BRANDON LEVY, NIMH

It was a chance encounter with a falling apple that inspired Sir Isaac Newton to develop his theory of gravity. A chance encounter inspired NIH cardiologist Hannah Valantine, too. But her encounter wasn’t with a piece of fruit. It was with a 2008 research paper published in the Proceedings of the National Academy of Sciences U.S.A. by Stanford biophysicist Stephen Quake. And the theory it inspired had to do with a new way to detect the rejection of transplanted hearts.

“I remember precisely the moment,” recalled Valantine, who at the time was director of the Heart Transplantation Research Program at the Stanford University School of Medicine (Stanford, California).

The current method for diagnosing heart-transplant rejection is invasive—and expensive—and involves taking and analyzing a biopsy of the new organ post-transplant, after the rejection process has begun. Quake’s paper, however, gave Valantine an idea for a better, noninvasive, and quicker way to detect rejection. He described a method for sequencing fragments of DNA—called cell-free DNA—from a fetus, which can also be found in the mother’s blood, for prenatal diagnosis of genetic abnormalities such as Down syndrome (Proc Natl Acad Sci USA 105:16266–16271, 2008).

“I thought, ‘Wow, the heart transplant is essentially like a fetus,’” Valantine said. She ran across the hall to Quake’s office. “This is fantastic,” she told him. “Surely it must be applicable to heart-transplant recipients.” As it turned out, Quake had been thinking the same thing. The two began working together and discovered that in heart-transplant patients, cell-free DNA from the donor heart enters the recipient’s bloodstream and can be detected months before a biopsy would show signs of rejection damage to the donated organ.

Valantine presented the fruits of their collaboration at the 2015 Anita B. Roberts Lecture in NIH’s Lipsett Amphitheater (Building 10) on April 21. She described how she and Quake sequenced the genomes of 65 heart-transplant patients and their donor hearts before surgery. Afterward, they extracted cell-free DNA from the patients’ blood and calculated how much of it was from the donor and how much from the patient. The percentage of cell-free DNA, which is elevated after the transplant, declines during the week after surgery and remains low if the organ is accepted. But when patients reject their donor heart, the percentages of donor DNA rise and remain elevated unless the rejection is treated. The findings suggest that elevated percentages of donor DNA could serve as a noninvasive tool to predict organ rejection. (Sci Transl Med 6:241ra77, 2014)

Being able to monitor donor cell-free DNA in transplant patients might allow clinicians to treat organ rejection at a very early stage. “If we can detect it earlier, we can offer therapies to prevent the progression to a later stage where there’s actually damage to the heart muscle,” Valantine explained. Earlier detection would also allow doctors to prescribe lower doses of the toxic immunosuppressive drugs that prevent rejection.

Valantine hopes a blood test that measures the amount of donor DNA in a transplant recipient’s blood might eventually eliminate the need for biopsies, which are not highly accurate. “Biopsy came into its own before we had any way of testing its validity,” she said. “It’s become the gold standard…. But I would call it a flawed gold standard.”

The next step in Valantine’s research is to reproduce the findings in a larger population. To that end, she has established a prospective, multi-center extramural-intramural research consortium—the Genome Research Alliance for Transplantation (GRAfT)—that leverages the intellectual capacity of extramural clinical centers with cutting-edge genomic approaches that are available intramurally.

The consortium includes NIH’s National Heart, Lung, and Blood Institute (NHLBI) and five local transplant centers in the Washington, D.C., metropolitan area, all of which have pre-transplant and post-transplant clinics. Valantine’s research lab, the Laboratory of Transplantation Genomics, is in the National Heart, Lung, and Blood Institute.

“I really want to do that definitive study rapidly,” said Valantine. “I think the consortium gives us the opportunity to do the necessary studies to get [the new technology] to the patients as rapidly as possible.”

The other benefit of a consortium approach is that about 40 percent of the patients enrolled in the study will be African-American, whereas most clinical studies are less diverse. Compared with Caucasians, African-Americans have poorer health outcomes including higher rates of rejection and death after organ transplants. Valantine plans to investigate whether there is a genetic basis for the racial gap in clinical outcomes.

Valantine is also interested in eliminating the barriers that prevent minorities from pursuing biomedical careers. In fact, she was recruited to NIH in 2014 to be its first chief officer for Scientific Workforce Diversity. In that role, she is leading NIH’s efforts to diversify the biomedical-research workforce by developing a vision and a comprehensive strategy to expand recruitment and retention and promote inclusiveness and equity throughout the biomedical-research enterprise. Before coming to NIH, she was the senior associate dean for Diversity and Leadership and a professor of cardiovascular medicine at the Stanford University School of Medicine.

“I got involved,” Valantine said, “because I really believe that diversity in the biomedical workforce itself will enhance the quality and outputs of science.”

Anita B. Roberts, who spent 30 years at NCI before her death in 2006, was known for her groundbreaking work on transforming growth factor–beta. The “Anita B. Roberts Lecture Series: Distinguished Women Scientists at NIH” honors the research contributions she and other female scientists have made. To watch a videocast of Hannah Valantine’s April 21, 2015, Anita Roberts lecture (“Precision Medicine in Action: Applying Genomic Tools to Improve Patient Outcomes after Organ Transplantation”), go to http://videocast.nih.gov/launch.asp?18956.

TO READ ABOUT HANNAH VALANTINE IN THE “RECENTLY TENURED” SECTION, GO TO https://irp.nih.gov/catalyst/v23i4/colleagues-recently-tenured