The Enduring Legacy of David Livingston, MD

Remembering a Groundbreaking Cancer Researcher

April 29, 2022

Ovarian Cancer
Breast Cancer

By Richard Saltus

Dana-Farber's David Livingston, MD, was a titan among the giants of cancer research. When he died unexpectedly on Oct. 17, 2021, at age 80, he left a legacy of groundbreaking insights into the development of cancer, especially breast and ovarian cancers. Equally important for the future of the field, he trained scores of students and postdoctoral fellows, many of whom, inspired by his rigorous scientific methods and his passion for improving cancer treatment, are working at Dana-Farber and other prominent research centers and hospitals around the world to fulfill his vision.

In a research career spanning more than 50 years, highlights included Livingston's landmark insights into how mutations in the BRCA1 and BRCA2 genes can dramatically raise the risk of breast and ovarian cancer.

"Collectively, [Livingston's] research has revolutionized the mechanisms by which malignancies such as breast and ovarian cancer are understood, prevented, and treated," the American Association for Cancer Research said in a statement. "His laboratory also examined how defects in various tumor suppressor loci regulate cell proliferation, genome integrity, and cell survival. David Livingston was a brilliant translational researcher whose understanding of molecular biology and genetics led to enduring improvements in the research and treatment of breast and ovarian cancer."

His early work focused on how the DNA tumor virus SV40 caused cancer. His lab showed this involved inactivation of the protein encoded by the tumor suppressor gene RB1, which, when defective, can lead to retinoblastoma, a rare cancer of the eye in children. Later, Livingston also worked on the BRCA1 and BRCA2 tumor suppressor genes that contain the blueprint for BRCA proteins. The BRCA proteins are critical to repairing DNA damage, among other functions. When a mutant version is inherited, the malfunction of the DNA repair system markedly increases the lifetime risk of breast and ovarian cancer.

The roles of the mutant BRCA1 and BRCA2 proteins in causing tumors "are derived in large part from their function as mediators of the DNA repair process of homologous recombination, and David's lab was the first to make this connection," says Robert Weinberg, PhD, a pioneering cancer researcher at MIT and the Broad Institute. "He proposed that the genomic destabilization that occurs when one of these proteins is lost from the repertoire of mammary cells is a driving force of BRCA-linked tumorigenesis. At the time of his passing, David's lab was actively engaged in revealing new aspects of BRCA1 function."

A Legacy of Mentoring

Livingston was the Emil Frei III Distinguished Professor of Medicine and Genetics at Harvard Medical School (HMS) and the Charles A. Dana Chair in Human Cancer Genetics at Dana-Farber, where he had been on the faculty since 1973.

Equally important as his discoveries was the immense impact Livingston had by recruiting and training some of the brightest young scientists, many of whom have gone on to prestigious faculty positions. By one count, he mentored nearly 200 fellows and students in his laboratory. In many cases, after moving on to open their own labs, these scientists have been inspired by their work with Livingston to continue dissecting the thorny mysteries of BRCA1 and BRCA2.

His many trainees who are now faculty at Harvard Medical School and around the world will continue to build on his work and will ultimately be his enduring legacy.
Myles Brown, MD
Myles Brown, MD

"His many trainees who are now faculty at Harvard Medical School and around the world will continue to build on his work and will ultimately be his enduring legacy," says Myles Brown, MD, a breast cancer researcher who trained with Livingston and is the director of the Center for Functional Cancer Epigenetics at Dana-Farber, and the current Emil Frei III Professor of Medicine at HMS. "His trainees populate the scientific leadership of many of the world's major medical centers.

Perhaps his most famous protégé is Dana-Farber's William G. Kaelin Jr., MD, who Livingston was able to see share in the 2019 Nobel Prize for Medicine for discoveries about how the body senses and adjust to changing oxygen levels in the environment. The findings have already led to practical applications, including new drugs to treat cancer.

William Kaelin Jr., MD

Other former Livingston trainees who are HMS professors include James DeCaprio, MD, chief of the Division of Molecular and Cellular Oncology at Dana-Farber; James Griffin, MD, professor of Medicine at HMS and a leukemia expert at Dana-Farber; William Sellers, MD, former global head of oncology at the Novartis Institutes for BioMedical Research and senior advisor to the president for experimental therapeutics at Dana-Farber; Ralph Scully, MBBS, PhD, professor of Medicine at HMS and co-director of the Program in DNA Repair and Genomic Instability at the Cancer Research Institute, Beth Israel Deaconess Medical Center (BIDMC), and Daniel Tenen, MD, professor of Medicine at HMS and BIDMC.

The most recent graduate of the Livingston lab to join the Harvard faculty is Sarah Hill, MD, PhD, who now has her own laboratory at Dana-Farber studying ovarian cancer. "I owe my career to him," she says.

Sarah Hill, MD, PhD

Hill began working with Livingston in 2001, when she was an 18-year-old freshman at Harvard College assigned to Livingston as a mentee. She was quickly impressed and asked if she could do her undergraduate thesis research in his lab. She did, and with his support subsequently went to Oxford University as a Rhodes Scholar before returning to enter the MD-PhD program at Harvard, where she completed her PhD in Livingston's lab studying BRCA1. After her MD-PhD training with Livingston, she completed a short residency; and then, again with his support, earned an NIH Director's Early Independence DP5 award and a coveted Harvard faculty appointment with her own lab. Thanks to Livingston's influence, Hill's lab is studying, among other things, how BRCA mutations cause ovarian cancer.

The proteins made using the instructions in the BRCA genes are part of a protein complex that repairs DNA when both DNA strands in a cell are broken. Mutant BRCA proteins are impaired in their ability to repair this damage, thus raising the risk of a cell becoming cancerous. "But we still don't entirely understand how loss of BRCA1 function leads to cancer," notes Hill.

Fostering Collaboration

Livingston was born in Cambridge, Mass., and educated at Exeter, Harvard University, and Tufts University School of Medicine, after which he completed training in internal medicine at the Peter Bent Brigham Hospital. His postdoctoral training was at the National Institutes of Health and HMS, before being recruited to Dana-Farber.

After the isolation of the breast cancer susceptibility gene BRCA1 in 1994, there was uncertainty about where in the cell the BRCA1 protein carried out its functions. "David's group was one of the first to make monoclonal antibodies that answered the question of where the BRCA1 protein was localized, and the Livingston group determined in a landmark paper that it is located in the cell's nucleus," Hill explains. As a result, "you could finally ask: What does BRCA1 do? The antibodies used in those experiments were so critical, and people are still using them constantly."

Brown says that Livingston's work identifying the role of BRCA1/2 in DNA damage repair "was the fundamental discovery that resulted in the development of PARP inhibitors that are used to treat breast and ovarian cancers from people with BRCA1/2 mutations."

Judy Garber, MD, MPH, was one of the principal investigators of the OlympiA trial that recently reported a disease-free survival benefit for BRCA1/2-mutant breast cancer treated with the PARP inhibitor olaparib, says Brown. Garber, who leads Dana-Farber's Cancer Genetics and Prevention program, wasn't one of Livingston's trainees, but she was a very close collaborator over the years and worked to translate Livingston's work to the clinic.

David Livingston, MD, reviewing study slides in his office.

After Livingston's death, many leading scientific journals published obituaries or appreciations penned by his colleagues and former trainees. Kaelin, for example, wrote a long, personal essay in the journal Cell. "David methodically sculpted me into a scientist (and talked me out of quitting at least six times while I was in his laboratory, when the work seemed too frustrating and hard), and his mentorship and advocacy for me continued almost until the very day that he died," wrote Kaelin. "My eventually winning the Nobel Prize says more about David than it does about me."

Invariably, the memorial essays described Livingston's groundbreaking efforts to foster collaboration among scientists, from his larger institutional accomplishments to the informal retreats at the Livingston family farm for the purpose of open sharing of unpublished research findings — and always accompanied by memorable meals and stories served up by the prominent scientists at the retreats.

"David was instrumental in bringing people together in the fight against cancer, and he led the effort to establish the Dana-Farber/Harvard Cancer Center (DF/HCC)," wrote Brown and DeCaprio in an obituary in Nature. "In doing so, he brought together a prestigious yet somewhat reluctant group of leaders and investigators from seven Harvard institutions and served as its deputy director from 1999 to 2019."

Brown and DeCaprio also noted that Livingston was instrumental in forming an academic-industry partnership between Dana-Farber and Sandoz (now Novartis) in the early 1990s that has continued ever since. "David's vision played a key role in the development of several Food and Drug Administration-approved targeted cancer therapies," they said.

More recently, Livingston worked with Tyler Jacks, PhD, at MIT to develop the Bridge Project, a collaboration between DF/HCC and the Koch Institute for Integrative Research at MIT. Bridging the Charles River geographically and different disciplines metaphorically, it brings together cancer researchers and bioengineers from MIT with clinical oncologists from Harvard's hospital consortium to address pressing problems in cancer care.

Sarah Hill, who says she talked to Livingston the Friday before the weekend on which he died, said she is still deeply saddened by his passing, but continues to be inspired by his zeal for research and ambition to improve treatments for breast and ovarian cancer — and possibly to prevent them.

"He used to say to us, there are women in the hospital here who are so sick and losing their hair — we have to do something better for this disease," says Hill. "I think he would have found ways to detect cancers early and how to prevent them. Making sure David's legacy is honored is a huge thing for everyone who worked with him."

David Livingston made it possible for us to dream big about the future of Dana-Farber, because that was how he saw it, and his unflagging enthusiasm and love for the institution and everyone in it lifted our hearts and spirits every day.
Laurie H. Glimcher, MD
Laurie H. Glimcher, MD

That is also true for Dana-Farber President and CEO Laurie H. Glimcher, MD, who, although she was not one his trainees, expressed the feelings of many when she said, "We have lost not just a source of comfort but a source of inspiration. David Livingston made it possible for us to dream big about the future of Dana-Farber, because that was how he saw it, and his unflagging enthusiasm and love for the institution and everyone in it lifted our hearts and spirits every day. Surely, there is no better way to honor his memory than to do what he spent his life doing."