Folkman’s Legacy of Bold and Creative Thinking Endures

Andrew D. Smith
Published Online: Wednesday, March 19, 2014
Judah Folkman, MD

Judah Folkman, MD

Asked why Judah Folkman, MD, ranks among the greatest modernday medical pioneers, Robert S. Langer, ScD, recalled the time he told Folkman the gist of a new paper involving ultrasound. Folkman asked why heat from the ultrasound wouldn’t cause harm, and Langer explained how endothermic reactions could be used to keep things cool. Folkman pondered the technique and then, off the top of his head, began imagining how it could improve everything from cast design to hurricane management.

“Each idea was totally unorthodox and yet fully plausible. It was truly amazing,” said Langer, then a postdoc in Folkman’s lab, and now an MIT Institute professor who operates a storied biomedical engineering lab at the school. “More amazing, however, is the fact that I tell this particular story not because it was a creative apex for Judah, but because it was just a typical conversation that I happen to remember. He was just that creative. He was constantly pushing himself and others, consciously, to invent bold ideas— ideas that could change the world.”

During the course of a 74-year life cut short by his sudden death in 2008, Folkman changed the world repeatedly with bold ideas that ranged from implantable pacemakers and subcutaneous birth control to an entirely new field of medical study: how diseases like cancer recruit blood vessels from the body via angiogenesis.

A Gift for Creative Thinking

Many strengths fueled Folkman’s success. Colleagues from Harvard University—a school that has produced or employed 144 Nobel Prize winners over the years—say they’ve never encountered a smarter person. Langer—a scientist who has authored more than 1200 papers, won more than 800 patents, and launched more than two dozen companies—says he’s never met a harder worker or a more persistent experimenter.

But none of Folkman’s strengths stood out more than a consciously cultivated gift for creative thinking, one that repeatedly allowed him to see possibilities that others missed. The idea of fighting cancer by starving tumors of blood first occurred to Folkman in 1963, when he and Frederick F. Becker, MD, were comparing possible substitutes for blood transfusions. During those experiments, the two young doctors injected adult mouse melanoma cells into isolated, perfused thyroid glands taken from dogs, and noticed that while tumors did form, they never developed blood vessels or grew beyond 2 mm in diameter.

Other researchers had already made similar observations, but Folkman’s efforts to understand his findings led him to complete a few more experiments and then to hypothesize, in a 1971 paper in The New England Journal of Medicine, several very new ideas:
  • Tumors cannot grow dangerously large unless they develop vascular networks.
  • Tumors can’t build their own vascular networks, so they must trick their hosts into building such networks through angiogenesis.
  • An angiogenesis inhibitor could therefore treat cancer effectively.
The article drew such negative response that it quickly made Folkman a pariah. Most top cancer researchers at the time thought tumor vasculature to be a mere response to inflammation rather than a necessary precondition for tumor growth. Even researchers who found Folkman’s angiogenesis hypothesis theoretically possible attacked it as irresponsibly speculative.

Despite the criticism, Folkman decided to pursue the angiogenesis hypothesis, alone if necessary, until he confirmed or disproved it. “It is tempting to say that Judah just ignored his critics at this point, but it’s dead wrong,” said Donald E. Ingber, MD, PhD, another Folkman protégé who now runs a major research institute, Harvard’s Wyss Institute for Biologically Inspired Engineering.

“He considered every single critique and would have dropped the hypothesis had the critics advanced a valid argument based on experiments for doing so,” said Ingber. “But they didn’t, and Judah had the courage to proceed.”

Young Brilliant Mind

The years of (relative) isolation that followed this fateful decision marked a sharp departure from all that had come before. Folkman’s father, a rabbi who regularly visited hospitals to comfort ailing congregants, made a habit of taking his 7-year-old son along. The plan was to nudge young Folkman toward a yeshiva (a Jewish educational institution), but the trips sparked a passionate interest in physical, not spiritual, health, and the boy decided on medicine.

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