When the world learned of Judah Folkman's unexpected death from a heart attack in Denver last month while en route to yet another of the countless scientific conferences he attended, those who knew him mourned the loss of a great, humane man, as well as a groundbreaking scientist and visionary.
Dr. Folkman's once controversial and eventually accepted and praised assertions about the role of angiogenesis and tumor growth opened up the possibility of what some have called the fourth modality of cancer treatment—antiangiogenesis therapy that cuts off nourishment from blood vessels created by tumors to aid their growth.
When Dr. Folkman postulated his theory, which was published a decade later in 1971 in the New England Journal of Medicine, he was widely ridiculed by the medical and scientific establishment, which took little that he said or did seriously for many years to come.
Still, he persevered by shrinking tumors in mice in the lab through two natural compounds discovered in his lab—endostatin and angiostatin—and founding a field that has spawned angiogenesis research in approximately 1,000 laboratories worldwide, contributing to the development of at least 10 cancer drugs now treating more than 1.2 million patients.
His work famously received worldwide attention 10 years ago when a questionable front-page story in the Sunday New York Times quoted Nobel laureate James Watson declaring that “Judah is going to cure cancer in two years.”
Dr. Folkman, Founder and Director of the Vascular Biology Program at Children's Hospital Boston, and Andrus Professor of Pediatric Surgery and Professor of Cell Biology at Harvard Medical School, trained as a surgeon, but was at home in the laboratory and made significant contributions in cancer and ophthalmology.
Not Just Oncology
In addition to his work in oncology, he is credited with developing one of the first internal pacemakers while still a student at Harvard Medical School; helping to invent implantable controlled-release drug therapy, the basis for the contraceptive Norplant, while serving in the US Navy; and contributing to the successful treatment for age-related macular degeneration, the leading cause of blindness in older adults.
Soft-spoken and unassuming, he also mentored numerous physician researchers in oncology and other areas of medicine.
One such disciple was Roy S. Herbst, MD, PhD, Professor of Medicine, Chief of Thoracic Medical Oncology, and Co-director of the Phase I Clinical Trials Working Group at the University of Texas M. D. Anderson Cancer Center, who recently co-edited Antiangiogenic Cancer Therapy with Darren W. Davis, PhD, and James L. Abbruzzese, MD.
Initially, Dr. Herbst—as well as a number of other oncologists—was reluctant to speak publicly about his friend and mentor, but told OT, “I'm so saddened by this event that I've tried not to talk to anyone [from the media] even though I've received numerous calls, but I think that Dr. Folkman would specifically want me to comment here because he felt it was so important that oncologists think more carefully about designing trials to test this new class of agents, while working to detect cancer before it's metastatic by looking at tumor markers and angiogenic markers in the blood.
“He'd want us to think about how we might match the right inhibitor with the right tumor, and how to develop cocktails of agents—some investigational but many standardly available—and I think it's very important to make the case to do this.”
Dr. Herbst first met Dr. Folkman in the early 1990s during grand rounds at Dana-Farber Cancer Institute. “I was a first-year fellow and afterwards the other fellows and I went out to dinner with Dr. Folkman, who had been the speaker.
“I hadn't been a Harvard Medical student so I didn't know him well, but we were all so engaged by his work and his vision. The thing that caught me as an oncologist also trained as a PhD was how he really had the vision of how to translate new cancer therapies to the clinic.”
Dr. Herbst followed up by visiting Dr. Folkman, whom he said he found to be extremely warm and caring. “Here I was a first-year fellow and he sat with me and talked until the conversation ended on its own, an experience I know was common to many.
“He never rushed you, he always brought up new scientific questions. I also observed first-hand how he always found time to talk to patients, returning their calls at the end of the day no matter how busy he was.”
Dr. Herbst ended up working with Dr. Folkman in a clinical translational capacity. Over the years, the two had shared many patients who were referred to M. D. Anderson by Dr. Folkman.
“We felt like we were his arm in Houston. He was a top-notch laboratory scientist, but at the end of the day Dr. Folkman was a clinician, and he looked to his research as a way to bring new therapy and hope to patients with incurable tumors.
“Dr. Folkman was very sensitive to the fact that he himself did not treat patients any more, but he enabled all of us to do this better with his constant urging that we needed to think creatively. This vision was refreshing to patients and clinicians alike.”
‘Always Gave Credit to His Two Generations of Trainees’
When Dr. Herbst was training at Dana-Farber, his fellowship program was headed by its current Director, Robert J. Mayer, MD, Professor of Medicine at Harvard Medical School, Vice Chair for Academic Affairs at Dana-Farber's Department of Medical Oncology and Director of its Center for Gastrointestinal Oncology, and a member of OT's Editorial Board.
Dr. Mayer had last spoken with his longtime friend and colleague, Dr. Folkman, at a dinner-lecture in Boston several weeks before his death.
“Judah always gave credit to the two generations of trainees he had from many parts of the world. His laboratory conference room was a trophy case because of all the awards he'd received when he traveled to see his former trainees when he would go to give a talk.
“Furthermore, he would never say no if you had a symposium, and his coming would foster the attendance or importance of that particular meeting. He would show up and wouldn't do it with a flourish, but would just quietly come in and sit through the lecture or dinner and make small talk and help anyone who was there.
“One of the frustrations we all felt was that the world didn't really think his work was proven because Judah still paid for his own plane fare every time he visited Stockholm and he never received the ultimate prize that would have indicated the scientific and medical community actually embraced this concept, but he embraced it, and never lost sight of it.”
Dr. Mayer recalled that when the Avastin colon cancer trial data was presented at ASCO a few years ago, he saw Dr. Folkman come in and sit down and listen to the paper, before quietly leaving to take a plane home without saying anything or attending the press conference.
“He didn't make waves, he just did his thing. He was also an amazing mentor, and there were a number of these apocryphal stories about talks he gave about how to get post-mortem permission from religious orthodox families, whether they were Jewish, Muslim, or any other faith.”
‘Practical Clinical Tips’
“Another was that if you were home and the nurse called you in the middle of the night to ask what to do with a patient, and if you were half awake and didn't want to just blurt something out, you would ask some inane question to get the nurse to look it up so you could stall for time. These were some practical clinical tips, but of course you were getting them from this internationally reputed scientist.”
Dr. Mayer also explained how a Harvard-trained surgeon without any pediatric experience could become head of the surgical service at Children's Hospital Boston.
Moses Judah Folkman, the son of a rabbi, was born in Cleveland, graduated from Ohio State University, and went to Harvard Medical School before becoming a resident at Mass General, where he was chief resident of adult surgery.
His first academic job was as part of the Harvard service of what was then the Boston City Hospital, a municipal facility shared by Harvard, Boston University, and Tufts medical schools.
“He was an incredible clinician and surgeon, and was invited to become chair of the Department of Surgery at Children's even though he had no pediatric training.”
Dr. Mayer said that this was the way Harvard did things and still does them, by taking somebody who the school thinks is the best and the brightest and not bothering with clinical credentials, but instead figuring that the person will just learn.
Trained under C. Everett Koop
Dr. Folkman was sent for six months as a “quasi-chief resident” to Children's Hospital of Philadelphia, where he learned pediatric surgery under future US Surgeon General C. Everett Koop, MD, before returning to take over the pediatric surgical chair in Boston.
“He also was running this laboratory and was interested in neo-vascularization and vascular medicine, initially studying the cornea because it is an avascular organ or tissue in humans and mammals,” said Dr. Mayer.
“And then as years went by he came up with this very novel concept about neo-vascularization in tumors, that if you could block the neo-vascularization you could selectively destroy the tumor.”
‘Antithesis of Being Imperious’
“Judah had no experience or formal training in oncology, pediatric or adult, but was a charismatic and persuasive person and also had this personality that was the antithesis of being imperious—he was soft spoken, he was constructive, he was available, and he never talked down to people,” Dr. Mayer recalled.
“He always made you feel that what you were saying was incredibly intelligent, he never forgot who people were, and in response people went out of their way to do whatever they could to help Judah.”
Dr. Folkman is survived by his wife Paula; two daughters, Marjorie Folkman and Laura Folkman Steuer; his brother, David, and sister, Joy Folkman Moss; and a granddaughter.
Children's Hospital Boston has established a fund to benefit the Folkman Angiogenesis Research Institute in his memory. Further information is available from the Children's Hospital Trust, 1 Autumn Street #731, Boston, MA 02215, 617-355-6890