Homecoming for a top cell biologist

For several years, the School of Medicine’s Department of Cell Biology has invited a distinguished scientist to Yale each year to deliver the George Palade Lecture, named in honor of a beloved former Yale faculty member and Nobel Prize winner whose integration of electron microscopy and biochemistry helped lay the foundation of modern cell biology.

Following Palade’s death at age 95 in 2008, the department decided to “elevate the status of the lectureship to a university-wide event, a major international lectureship renamed the George E. Palade Memorial Lectureship in Cell Biology,” says Chair James E. Rothman, Ph.D., the Fergus F. Wallace Professor of Biomedical Sciences.

In a fitting tribute, on April 4, the inaugural Palade Memorial Lecture was given before a standing-room-only crowd by world-renowned cell biologist Marilyn G. Farquhar, Ph.D., Palade’s widow and his frequent scientific collaborator, now Distinguished Professor of Molecular and Cellular Medicine at the University of California–San Diego (UCSD).

In 1973, Farquhar came to Yale with Palade and with James D. Jamieson, M.D., Ph.D. (now professor of cell biology and director of the medical school’s M.D./Ph.D. Program) to establish a new Section of Cell Biology, ultimately spending 17 years on the faculty and rising to Sterling Professor.

For Farquhar, the occasion was suffused with nostalgia, with many familiar faces dotting the capacity crowd at the medical school’s Anlyan Center auditorium. For her listeners, the lecture was a tour de force of scientific exposition by a researcher with five decades’ experience in the lab.

In a pair of classic 1957 papers that she published as a postdoctoral fellow at the University of Minnesota in collaboration with Robert A. Good, M.D., and Robert L. Vernier, M.D., Farquhar used electron microscopy to examine biopsies from children with kidney diseases and made the first descriptions of the structural abnormalities that compromise renal function in these patients.

After joining Palade’s cell biology lab at The Rockefeller University in 1959 as a postdoctoral fellow, Farquhar continued her work on kidney structure and function. In 1963 she discovered tight junctions, crucial sites of cell–cell interactions, and in her subsequent work at the University of California–San Francisco, Rockefeller, Yale, and UCSD she has made seminal contributions to our understanding of membrane trafficking, the process by which proteins and other materials are transported within and between cells. This diverse body of work has earned Farquhar many accolades, including the A.N. Richards Award from the International Society of Nephrology, the Homer W. Smith Award from the American Society of Nephrology, the E.B. Wilson Medal from the American Society for Cell Biology, and membership in the National Academy of Sciences and the American Association of Arts and Sciences.

In her April lecture at Yale, Farquhar crisply presented a new line of work centered on GIV, a protein recently discovered in her lab which appears to play a role in cancer growth and metastasis.

GIV binds to Gαi, a member of a family known as G proteins, which are usually found on cells’ outer membranes, where they act as middlemen between receptors that detect extracellular signals and effectors that induce actions inside the cell. By contrast, Farquhar’s group and others found Gαi to be abundantly expressed in the Golgi apparatus, an intracellular structure, with no associated receptor; when Gαi was localized with a red fluorescent protein, explained Farquhar, underscoring a vivid micrograph projected behind her, the Golgi “lit up like a Christmas tree.”

Further studies of this peculiar protein led to the discovery that GIV regulates and activates Gαi: when Gαi is in an active state, cells tend to migrate, whereas inactive Gαi prompts cells to divide. Because unregulated cell migration and division are hallmarks, respectively, of the metastasis and rampant proliferation seen in cancer, Farquhar’s team next explored the potential role of GIV–Gαi interactions in human cancers.

The scientists’ analysis of specimens from rapidly spreading cancers versus those from localized cancers revealed that GIV was far more abundant in the former than the latter, findings that were replicated in pancreas, colon, and breast cancers.

Taken together, the results indicate that drug compounds that target GIV and prevent activation of Gαi may slow the metastatic progression that proves lethal in many cases of cancer, a direction now being pursued by Farquhar’s trainees.

Farquhar summed up her talk with a straightforward acknowledgment of the remaining mysteries in this latest research, and with thanks to the many young scientists who have helped her probe these questions in the lab.

Then, with the wisdom gained during a life in science, she elegantly tied a bow around both sentiments. “After all, these young people all need something to do,” she said. “So we need to leave some questions on the table for them.”