P&S Journal: Winter 1997, Vol.17, No.1
Alumni Profile - Patricia Donahoe: Surgeon-Scientist Takes Knowledge to the Cutting Edge
By Peter Wortsman
Up at 5:30 a.m. to check the progress of her eight research projects running concurrently in the lab before scrubbing in on a difficult neonatal diaphragmatic hernia operation and later returning to the lab to huddle with colleagues in preparation for an upcoming NIH site visit, Patricia Donahoe'64 is understandably peaked by the time she sits down to an afternoon interview. She will be at it a good many hours more before calling it a day.
Patricia K. Donahoe'64
Her voice is weary and a bit subdued. Her eyes dart about nervously. Her fingers, clearly unaccustomed to idleness, wander between a pair of glasses and a mug of coffee appropriately labeled WORKAHOLIC. These, if not the primary tools of her trade, are the fulcrum and fuel that keep her mind and body running through the grueling 18-plus hours of a typical working day.
There is, however, nothing typical about the Marshall K. Bartlett Professor of Surgery at Harvard Medical School and chief of pediatric surgery at Massachusetts General Hospital. She specializes in complex and delicate procedures, including the surgical correction of a large number of congenital abnormalities, many of which are now discovered in utero. She has, moreover, attracted national attention with her ongoing research and study of muellerian inhibiting substance, a rare embryo protein she and her colleagues have been able to clone and purify in enhanced amounts from a cell line altered to express the protein, which she hopes will prove a viable treatment for ovarian cancer. And while the scramble for research funding is an ongoing concern, Dr. Donahoe continues to delight in the adventure of the quest. Having honed her dexterity and resilience early in life on the basketball court and lacrosse field, she concentrates on every step of the search, ever mindful of the goal.
A Unique Path to Pediatric Surgery
A lifelong fascination with "the gorgeous anatomy of the human body" is rooted in her firsthand experience of the body's abilities under stress. Co-captain of all women's sports at Braintree High School in Brookline, Mass., and destined according to the yearbook to become the "first coach of the girls' Boston Celtics," she went on to pursue a B.S. degree at the Sargent College of Physical Education at Boston University. It was here that she discovered the lure of science and "began to think more seriously about what I should do besides knocking around a basketball." Impressed by her intellectual promise, Dean George Mackechnie steered her toward medicine.
Dr. Donahoe accepts P&S Alumni Gold
Medal for Distinguished Achievements in Medicine
Following a brief tenure as instructor of physical education at Indiana University, where she simultaneously fulfilled her pre-med requirements in organic chemistry, physiology, and mathematics, she was accepted to all the medical schools to which she applied and opted for P&S. Athletics gave her a unique perspective that later would serve her well in surgery.
Her medical school experience, she recalls, was "among the happiest periods in my life. It was like dying and going to heaven." The intellectual ferment she found at P&S, epitomized by such outstanding faculty as her mentor David Seegal, then the chief of medicine at Goldwater Hospital and a revered teacher of physical diagnosis, fired her imagination. While attempting to understand congenital anomalies in cardiac defects, she and classmates Will Andrew'64 and Bill Friend'64 developed an early pacemaker, for which she received a Borden Undergraduate Research Award at graduation in 1964, the first of many encomia to come. It was, however, the surgical aspect of the research project, not the technology, that thrilled her. Impressed by the skill of such outstanding surgeons as Drs. Thomas Santulli, Cushman Haagensen, and Carl Feind'50, among others, she decided to pursue surgery.
"People thought I was crazy," she recalls of her resolve to enter a field by and large off limits to women. "But I was pretty naive back then," she chuckles. "I had spent a lot of time trying to find something I liked better, but I just loved surgery. Surgery, we used to say, is medicine plus: You could think like a doctor and fix like a surgeon."
The dexterity and eye-hand coordination came easily to her, as did the sense of geometric depth. Gender-based exclusion proved a more daunting, albeit surmountable, hurdle. Not a single woman had ever been accepted into a general surgical residency program in the Boston area, where she and her husband Jack Donahoe returned following his assignment to a high level position with the Ford Motor Co. Nevertheless, Dr. Donahoe applied and bucked the odds in 1969, the first woman ever appointed a surgical resident at the Tufts-New England Medical Center. She subsequently returned to research, pursuing a fellowship in basic science under Judah Folkman at the Children's Hospital Medical Center and a clinical fellowship the following year under the master surgeon W. Hardy Hendren at Massachusetts General.
Scientist-surgeon Donahoe combines
theory and practice
In addition to her considerable responsibilities on the professional plane, she and her husband decided it was time to have children. "That was a bit of a juggle," she smiles with a sigh, hinting at the complexities of combining career and family. "My daughters are professionals today, but they're taking time off to have children," a choice not available to her but which she wholeheartedly supports, encouraging maternity leaves and family time in her lab and on her surgical service, since "the brain does not turn off or dissolve away with motherhood."
Attracted by the "tremendous variety of surgical challenge and the chance to work with kids," she decided to further specialize in pediatric surgery. Molecular biology, she explains, "has provided us with the tools to unravel mysteries of developmental biology in ways that couldn't possibly be done before." What particularly appealed to her was the prospect of technical correction of anomalies in conjunction with an enhanced understanding of their pathophysiology, just the right mix of surgery and science. A year as senior registrar at the Alder Hey Children's Hospital and Neonatal Surgical Unit in Liverpool, England, exposed her to pioneering procedures in the field. Upon her return in 1973, she joined the surgical staff at Massachusetts General and the Department of Surgery at Harvard. She was named full professor there in 1986, the first woman ever to hold that title. Since 1973, she also has been principal investigator and director of the hospital's Pediatric Surgical Research Laboratory.
A Prospective Cure for Ovarian Cancer at the Pathway of Maleness
W hile in England, at a lecture at the Royal Liverpool Medical Society, Dr. Donahoe first heard of the work of French developmental endocrinologist Alfred Jost, who discovered muellerian inhibiting substance (MIS), a hormone secreted in the embryo of the male that leads to the regression of the muellerian duct, the female reproductive tract present in all embryos. Already interested in the study of growth regulators and specifically growth inhibitors, Dr. Donahoe felt an immediate surge of excitement. "I was seated in the back of the room," she recalls, "and the lights went on in my mind, the bells clanged, and the whistles blew. 'That's it!' I said." Here was a fetal inhibitor that could be studied in vitro in an assay.
"The leap of faith," she explained, "was that the receptors for these fetal inhibitors would be recapitulated in tumors that emanated from the source that responded to the inhibitor in fetal life." And, just possibly, "you could treat the adult ovarian tumors with the same growth factors or growth inhibitors that influence embryonic development."
Undaunted by her lack of previous in-depth training in biochemistry and molecular biology, Dr. Donahoe boldly forged ahead, learning as she went. In research, she says, "you've got to accept a chronic amateurism to pursue a problem to its solution. There are always new unknowns. And though you never really come to the conclusive answer," she laughs, "you've got to really love the adventure of the search."
She heeded the advice of Nobel laureate John Enders, who isolated the polio virus in the very same lab (now Dr. Judah Folkman's) in which she did her research fellowship and who one day came by to visit and told her: "There are two ways you can do research. One is to learn a skill and be better at it than anybody else in the world and look for problems to solve with that skill. The other way is to follow your nose." For more than two decades now, Dr. Donahoe has been pursuing the latter course with great success.
The practice of surgery gives her a certain sense of fearlessness in addressing problems in the lab. Or, as she puts it: "We all put our shoes on and tie our laces the same way, don't we?" As to the interplay of her dual roles, she firmly believes that "the research makes me a better surgeon and the surgery a better investigator, because I'm constantly looking for what a discovery might mean for my patient."
Originally working with the minuscule amount of MIS secreted from the testes of newborn calves, she and Richard L. Cate at Biogen, the Boston-based biotechnology company, soon realized that the natural source of the hormone would never suffice. In Dr. Donahoe's words, "there aren't enough bulls in the world to treat one patient." Working in collaboration, Drs. Donahoe and Cate made headlines in 1986 when they successfully grew the precious substance in the ovarian cells of a genetically engineered Chinese hamster.
Financial considerations eventually compelled Biogen to pull out of the project. Dr. Donahoe admits to a "clash of cultures" between the short-term goals of a company responsible to its shareholders and the slow painstaking nature of biomedical research. Thanks to the ongoing support of the NIH and the NCI, her research continues. In its new Protein Production Facility, NCI is making MIS to support a long-awaited clinical trial testing the safety and early efficacy of MIS in treating ovarian cancer.
Another major area of ongoing interest is lung development in the fetus, a research complement to her work in the OR treating diaphragmatic hernia.
Adamant about the team nature of research, Dr. Donahoe readily shares all credit with her colleagues. "There are many captains in this team. I think I'm just the coordinator."
Relishing her role as a teacher, she takes a long view of the search for knowledge and the rewards and disappointments of scientific investigation. "Substantive accomplishments," she says, "often come from the people that you influence. And if you influence them in the right way you can accomplish far more than if you did it yourself."
Recognized as a surgeon's surgeon and a world-class research scientist, she was saluted by Ms. magazine in 1987 as one of the Women of the Year. The co-author of a textbook on the clinical management of intersex abnormalities, 38 book chapters, and 168 peer-reviewed papers, her work has attracted major research funding from the NIH and the National Cancer Society. She serves on the scientific advisory council of the Sophia Foundation in Rotterdam, Holland, the MIT Corporation Visiting Committee, and the Board of Scientific Consultants to the Memorial Sloan-Kettering Cancer Center in New York. In 1987 she was elected a fellow of the American Academy of Arts and Sciences and in 1991 a fellow of the Institute of Medicine of the National Academy of Science. Her long list of honors includes Boston University's 1984 Alumni Award for Distinguished Public Service; the 1990 Ortho 21st Century Women's Awards-Science Award; and the P&S Alumni Association's 1995 Gold Medal for Distinguished Achievements in Medicine.
Such honors notwithstanding, Dr. Donahoe is a tough taskmaster on herself. In a feature profile in the Boston Globe in 1993, she was quoted as saying, "I am taking up space in a hospital and I have to know why I'm here." Nurturing the talent in her lab, she looks to her junior colleagues for inspiration and support. "On days when I'm not feeling particularly productive," she smiles, "I look around me at the wonderful young colleagues in the pediatric surgical services and in the lab and realize that we must be doing something right."
With women comprising half the current class of surgical residents at MGH, Dr. Donahoe is gratified at the way things have changed. "There's a much more humanizing influence by virtue of women being in the field."
In the little time left from her 80-hour work week, she enjoys moments of leisure with her husband and children, now grown with families of their own. Perhaps less nimble than she once was, the lacrosse stick may have been shelved but the ball has merely been conceptualized, internalized. Now it's a molecule, an idea knocked around, a new procedure attempted, while she remains ever mindful of a more elusive goal--"my grail," she calls it, as she walks around the laboratory and asks her colleagues in jest, "Have you cured cancer yet?"