Folkman's Legacy of Bold and Creative Thinking Endures

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.

By the time Folkman entered high school, he had set up a medical research lab in the basement of his family’s house. His most impressive experiment: removing the heart of an anesthetized rat and keeping it beating for several days in a perfusion system of his own design. Officials from the local high school, not surprisingly, decided shortly thereafter to send the precocious 15-year-old directly to Ohio State University, where he spent four years studying under the world-famous surgeon Robert M. Zollinger, MD, before enrolling, at age 19, in Harvard Medical School. Folkman’s years at Harvard Medical School saw him invent and install the world’s first implantable pacemaker. (The school somehow permitted that radical experiment but lost out on a fortune when it nixed another of the young student’s innovative ideas: patenting the design.)

After graduation, during a two-year stint in the Navy, Folkman and a colleague discovered that silicone rubber could be made to release chemicals at a predictable rate, and Folkman turned that insight into the world’s first implantable birth control device. (This time, he willingly gave away the patent rights, to the World Population Council.)

In 1967, just two years after Folkman completed his residency at Massachusetts General Hospital as chief resident, colleagues at Harvard named him chief of surgery at Children’s Hospital in Boston. He was 35.

Folkman somehow met all of the resulting commitments of that job—he was famous for returning every patient call—while he built and ran the laboratory that would test his controversial ideas about angiogenesis.

Passing Down the “Intellectual Adventure”

He also managed to squeeze in a happy family life. In the obituaries that followed Folkman’s death, his widow, Paula, described their marriage as a 48-year-long romance.

His two daughters described life with Folkman as an “intellectual adventure,” filled with impromptu brain games such as inventing new uses for common items.

It was the same sort of game that Folkman played in his conversations with Langer and with everyone else he knew well. He had learned it from his father, who played it with him at the dinner table and helped build a mind that saw what others could not.

Partnering With Corporate America to Further Research

Folkman’s many commitments naturally left him very short of time, but over the next decade, he was often shorter of the money he needed to do his research. Grant committees frequently declined to finance experiments that challenged their beliefs so directly. Folkman responded by challenging himself much as he would challenge his daughters—to devise creative funding ideas. His brain responded with a concept that would change academic research forever: corporate financing.

In 1974, he accepted a $23 million grant from Monsanto Corporation.

Academics denounced Folkman for selling out, but Harvard Medical School’s president supported him, and corporate funding has since become an invaluable component of scholarly research. Throughout the early 1970s, Folkman attracted enough money and talent to produce a steady stream of published findings.

His team found several angiogenesis “factors,” compounds secreted by tumors that induce blood vessels from the host to rapidly extend into the cancer.

Moreover, team members also demonstrated the existence of at least one angiogenesis inhibitor with an elegant experiment that showed how growing blood vessels avoid cartilage. The team struggled to isolate any of the antiangiogenic compounds from the cartilage, however, so Folkman challenged his brain again, this time for ideas that would strengthen his team. His brain responded with another worldchanging idea: bringing other types of scientists into medical research.

In 1974, Folkman hired Langer, who had just earned his doctorate in chemical engineering from MIT, and Langer proceeded to help the team take a big step toward isolating the angiogenesis inhibitor in cartilage. Science published the paper in 1976, the same year that Nature published an article by Folkman and Langer that is now credited with helping create the field of controlled-release drug delivery. The inhibitor was not purified or identified until 1990, when the findings were published again in Science, by Langer and his postdoctoral fellow at the time, Marsha A. Moses, PhD.

Between 1980 and 1996, Folkman and his team found 12 angiogenesis inhibitors, and went on to show that several of them produced incredible benefits in cancerous mice. When one of those compounds excelled in animal studies and another seemed promising in early human trials, mainstream publications such as The New York Times speculated that Folkman’s once-derided work would soon cure cancer.

The Angiogenesis Inhibitor Success Story

Skeptics enjoyed a brief resurgence when the compound stalled in clinical trials, but the tide by then had definitively turned. Other labs around the world had begun their own investigations into angiogenesis. In 2004, 33 years after Folkman predicted that angiogenesis inhibitors would one day become a mainstream cancer treatment, the FDA approved Avastin (bevacizumab) for use in patients with advanced colon cancer. Just four years later, there were 10 angiogenesis inhibitors approved in the United States and hundreds of labs were looking for more.

DR FOLKMAN’S SELECTED PUBLICATIONS:

• Folkman J. Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov. 2007; 6(4):273-286.
• Naumov GN, Akslen LA, Folkman J. Role of angiogenesis in human tumor dormancy: animal models of the angiogenic switch [published online August 15, 2006]. Cell Cycle. 2006;5(16):1779-1787.
• O’Reilly MS, Boehm T, Shing Y, et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell. 1997;88(2): 277-285.
• D’Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci USA. 1994;91(9):4082-4085.
• O’Reilly MS, Holmgren L, Shing Y, et al. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastasis by a Lewis lung carcinoma. Cell. 1994;79(2):315-328.
• Weidner N, Folkman J, Pozza F, et al. Tumor angiogenesis: a new significant and independent prognostic indicator in early-stage breast cancer. J Natl Cancer Inst. 1992;84(24):1875-1887.
• Langer R, Conn H, Vacanti J, Haudenschild C, Folkman J. Control of tumor growth in animals by infusion of an angiogenesis inhibitor. Proc Natl Acad Sci USA. 1980;77(7):4331-4335.
• Gimbrone MA, Leapman SB, Cotran RS, Folkman J. Tumor angiogenesis: iris neovascularization at a distance from experimental intraocular tumors. J Natl Cancer Inst. 1973;50(1):219-228.
• Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285(21):1182-1186.
• Folkman MJ, Long DM Jr, Becker FF. Growth and metastasis of tumor in organ culture. Cancer. 1963;16:453-467.

With so many scientists now taking up the task of discovering individual inhibitors and turning them into drugs for mature tumors, Folkman focused more of his attention on the role angiogenesis plays in the earliest stages of cancer and in a range of other diseases.

His publications on angiogenesis and macular degeneration led to tests that proved angiogenesis inhibitors can restore vision lost to abnormal ocular neovascularization or exudative age-related macular degeneration, a condition that afflicts roughly 3% of Americans.

His publications on angiogenesis in other diseases may one day lead to new treatments for both the many diseases characterized by too much angiogenesis (psoriasis, rheumatoid arthritis, and more than 70 others) and several other ailments characterized by too little (stroke, coronary artery disease, chronic wounds).

A Passion That Will Live On

“He was still doing world-changing work—and was still consumed with the passion for discovery—on the day that he died,” said Moses, another of the protégés who came to Folkman as a postdoctoral researcher and rose to international fame. Moses is director of the Vascular Biology Program founded by Folkman at Children’s Hospital Boston.

“He was also mentoring an incredible number of researchers from around the world who had, by that time, taken up the field he created. Much of that time went to veterans of his program who had gone on to run their own labs, but Folkman also mentored countless people who had no ties to him whatsoever,” she said.

“Some people would probably say that Dr Folkman was helping his competition, but such an idea was absolutely foreign to him,” said Moses.

“His only goal was pushing the science forward in order to improve the lives of the patients that he cared so much about. This is exactly what he did—and to an extent that very few others ever imagined. He truly was an amazing man, and we were honored to have known and worked with him.”