Robert Langer gives more than a hundred talks each year. He begins each in much the same way, by acknowledging his debt to his mentor, the late Judah Folkman. After one lecture, he was approached by an elderly man who said he had once met Folkman’s father, a rabbi, and his 9-year-old son. “He told me 9-year-old Judah Folkman was the smartest person he’d ever met,” said Langer.
Legends of famous people often recount how the seeds of greatness were sown early in life. Langer told his own version during a day-and-a-half scientific symposium, “A Celebration of the Life and Work of Judah Folkman.” Organized by Marsha Moses and Donald Ingber, the event—held on Dec. 5 and 6 and preceded by a morning of reminiscences by Folkman’s colleagues and wife, Paula—drew hundreds of scientists from around the world, most of them Folkman’s former students, postdocs, colleagues, and patients. It could have been an opportunity for exuberant mythmaking about an indisputably great scientist, so towering and revered that many of his closest colleagues called him “Dr. Folkman.” And there was plenty of lionizing and lamenting at the loss of such a valued colleague and mentor, as speakers described Folkman’s enormous influence on their professional and, in many cases, personal lives and on the lives of his patients.
But there was also something unorthodox about the proceedings, which is what Folkman, an iconoclast, might have wanted. If there is one storyline that has prevailed, not just in the public imagination but also in the minds of scientists, it is how Folkman spent the better part of his career hatching and then struggling to gain acceptance for his theory of tumor angiogenesis—that for cancer cells to take root and grow they must put out a nourishing growth of blood vessels.
With talks by former students and fellows covering a dizzying array of Folkman-inspired topics—from hemangiomas and other vascular deformities to neurosurgery, transplantation biology, drug delivery and design, chemotherapy dosing regimens, parenteral nutrition–associated liver disease, biomarkers for cancer and other diseases, and mechanical forces in biology—the overall effect of the symposium was to splinter, if not shatter, that storyline.
Though angiogenesis—in cancer and other areas—was the centerpiece of his work, and of the symposium, Folkman had time in his 100 plus–hour workweek to come up with other innovative, occasionally outlandish, hypotheses, many of which turned out to be correct. Observing that tumor cells phagocytose dying cancer cells, he suggested that they were taking up the dead cells’ genes to enhance their genomic instability and ability to progress. He and Lars Holmgren would go on to show that tumor DNA could be taken up by host endothelial cells and that the cells could cause explosive blood vessel growth when injected into mice. “No one would really expect that except for one person, Judah Folkman,” said Holmgren, professor of tumor biology at the Karolinska Institute.
Folkman’s fundamental perception—that blood vessels do not merely connect isolated organs and tissues but instead make up a dynamic, interactive, pulsatile system, constantly shaping and reshaping themselves and the tissues they feed, exerting chemical and physical forces—would lead to another hypothesis: that cells, in particular cancer cells, live in a messy, high-pressure world; they are stretched, pulled, and jostled and can be stimulated to grow or die by these mechanical forces—a theory that would attract the young Ingber.
“I didn’t come to work for Judah Folkman because of angiogenesis. I never heard of angiogenesis,” said Ingber, the Judah Folkman professor of vascular biology in the Department of Pathology at Children’s Hospital Boston, who has spent the past 30 years exploring the effects of mechanical force in many areas of biology.
Remarkably, Folkman had his insight into angiogenesis at a time when endothelial cells were barely known to most biologists. “When I began in the late 1960s as a medical student, the word endothelial didn’t exist as a title in the card catalog at Countway,” said Michael Gimbrone, the Ramzi S. Cotran professor of pathology at HMS and Brigham and Women’s Hospital. There were no media for culturing endothelial cells. Gimbrone, Folkman’s first postdoc, would collect discarded umbilical cords from Brigham and Women’s Hospital and run them back to Folkman’s lab in Enders Hall. Eventually, they hit on a method for growing the cells. “I get a rush even now just thinking about it,” said Gimbrone.
The speakers recounted many goose bump moments. For Langer, Institute Professor at MIT, one occurred when he and Folkman, after many attempts, developed a polymer microsphere capable of delivering relatively bulky angiogenesis-inhibiting molecules into the eyes of mice—a feat many believed impossible because polymers were thought to distribute only very small molecules. “The only problem Dr. Folkman and I had was we really didn’t know that,” said Langer.
For Michael O’Reilly, associate professor of radiation oncology and cancer biology at the University of Texas M.D. Anderson Cancer Center, it occurred when he isolated from 200 liters of extraordinarily pungent mouse urine the angiogenesis inhibitor angiostatin and showed that it could stop tumors from metastasizing, confirming Folkman’s hypothesis. For Moses, HMS professor of surgery at Children’s, it was her demonstration that human urine held matrix metalloproteinases (MMPs), telltale cancer-related molecules, a discovery inspired by Folkman’s long-held belief that cancer would someday be detected before tumors were actually visible.
In a twist on the age-old narrative of early brilliance, some speakers traced Folkman’s greatness as a scientist to his ability to retain certain characteristics of a young child. Patricia Donahoe, the Marshall K. Bartlett professor of surgery at Massachusetts General Hospital, recited a poem she wrote that began, “A boy filled with wonder/Remains so as a man.” Steven Fishman said he once told a reporter that Folkman reminded him of his then 5-year-old child. “He would draw conclusions from observations unencumbered by prior knowledge. He would spontaneously make bold statements with seemingly no evidence,” said Fishman, HMS associate professor of surgery at Children’s. “Dr. Folkman could make the big leap. He would then go back to design hypotheses to test it. Those that were correct would launch many a career and improve many lives.”
It is a central aspect of the Folkman legend that he sowed many seeds of his own. In fact, Robert D’Amato compared him to Johnny Appleseed, “who didn’t get credit for all the apples he planted around Ohio and that people are still picking.” One of Folkman’s biggest groves was the famous white board on the 12th floor of the Karp building, where he wrote down all of the central questions in a given year. “People would come look at the 12th floor board and say to him, ‘Don’t you worry that people will steal your ideas?’” said D’Amato, HMS associate professor of ophthalmology at Children’s. “He said, ‘I hope they do.’”
