A rabbi-like doctor
Moses Judah Folkman was born in Cleveland, Ohio, on February 24, 1933, the first child of Rabbi Jerome Folkman and Bessie Schomer Folkman. His father, the son of an immigrant from Austria and a mother from Hungary, had been ordained at the Hebrew Union College in Cincinnati in 1928; he and Bessie had been the first students ever married in the college chapel. In 1947 Rabbi Folkman became the rabbi of Temple Israel in Columbus, Ohio, the city’s oldest Jewish congregation, where he would serve longer than any rabbi before him.
Judah was expected to continue the family’s rabbinic line. From the age of seven he went with his father on Saturday visits to the hospital, where the rabbi comforted sick members of his congregation and prayed with them. The visits were meant to prepare the boy for ordination; instead they convinced him that he wanted to give patients more than spiritual comfort. He wanted to make them well. When he told his father he would become a doctor rather than a rabbi, his father answered, according to Robert Cooke’s biography Dr. Folkman’s War, “In that case, you can be a rabbi-like doctor.” Colleagues would say for the rest of his life that he had been exactly that.
A surgeon who invented things
As a boy he preferred biographies of Isaac Newton, Marie Curie and Louis Pasteur to children’s books. In high school in Columbus he experimented on small animals in the family basement, and for the Ohio Academy of Sciences competition he built a perfusion pump, driven by a small electric motor and a bicycle pump, that kept a rat’s heart beating after it had been removed. It won a prize. He graduated from Ohio State University in 1953 and from Harvard Medical School, magna cum laude, in 1957. As a student in the surgical laboratory of Robert Gross at Children’s Hospital in Boston he helped design one of the first implantable heart pacemakers.
He trained in surgery at Massachusetts General Hospital, and in 1960 he married Paula Prial. They had two daughters, Marjorie and Laura; a son, Kenneth, died in infancy of cystic fibrosis. That year Folkman was drafted into the Navy and sent to the National Naval Medical Center in Bethesda, Maryland, to work on artificial blood. While there he also discovered that drugs could seep slowly out of sealed silicone rubber tubing at a steady rate. The idea helped inspire Norplant, the implantable contraceptive developed by the Population Council, and Folkman donated his patent to the council rather than profit from it.
The tumours that would not grow
In Bethesda, Folkman was keeping rabbit glands alive outside the body by pumping a blood substitute through them, to test the substitutes. When tumour cells were implanted in the glands, the tumours grew only to a tiny size and then stopped. Transplanted back into living animals, the same tumours started growing again. The difference, Folkman realised, was blood vessels: in the isolated glands the tumours could not recruit new vessels, while in a living animal they could.
He completed his training as chief resident at Massachusetts General, and in 1967, at 34, he was appointed surgeon-in-chief of Children’s Hospital Boston. The next year he became the youngest full professor in the history of Harvard Medical School. He kept operating on children while building a laboratory to pursue his question. In 1971 he set out his hypothesis in the New England Journal of Medicine: solid tumours cannot grow beyond a tiny size without angiogenesis, the growth of new blood vessels, which they trigger by releasing a chemical signal. Block that signal, he argued, and tumours would be starved into dormancy.
Decades of doubt
The cancer establishment was deeply sceptical. Most researchers focused on killing cancer cells directly, and many regarded a surgeon’s theory about blood vessels as fanciful. His early grant applications were rejected as too visionary, journals were reluctant to publish his work, and it was hard to attract young scientists. Steven Brem, who studied under him, later said Folkman had to fight an uphill battle to prove that a surgeon could transform science.
Folkman persisted for decades. He and his colleagues developed ways to grow blood vessel cells in the laboratory and to measure new vessel growth, purified one of the first growth factors that stimulates blood vessels, and found that some substances could block the process. To fund the work he turned to industry: a ten-year agreement with Monsanto, signed in 1974, was at the time the largest arrangement of its kind ever made, and it was the first time Harvard let its faculty apply for patents on inventions from such research. Among the young scientists in his laboratory in those years was Robert Langer, who went on to become a pioneer of drug delivery.
Proof
Vindication came in stages. In the late 1980s other laboratories, inspired by his ideas, identified more angiogenic factors, above all vascular endothelial growth factor, or VEGF, discovered by Napoleone Ferrara at Genentech. Folkman’s own team showed in the early 1990s that interferon alpha, which they had identified as an angiogenesis inhibitor, could treat haemangiomas, blood vessel tumours, in babies; these trials, published in 1992, were among the first clinical tests of the idea. Michael O’Reilly in his laboratory discovered the body’s own angiogenesis inhibitors, angiostatin and endostatin, which shrank tumours in mice, and Robert D’Amato found in 1994 that thalidomide blocks angiogenesis.
When the wife of a man dying of multiple myeloma called Folkman to ask whether his ideas might help, he persuaded the patient’s doctor to try thalidomide. That led to a clinical trial, published in the New England Journal of Medicine in 1999, in which about a third of patients whose myeloma had resisted standard treatment responded. In 2006 thalidomide received approval in the United States for newly diagnosed myeloma, and related drugs followed. In 2004 the US Food and Drug Administration approved bevacizumab (Avastin), Genentech’s antibody against VEGF, for advanced colon cancer, the first drug designed to block tumour angiogenesis; it was later approved for other cancers.
Saving sight
Angiogenesis turned out to drive far more than cancer. In wet age-related macular degeneration, a leading cause of blindness in older people, abnormal blood vessels grow under the retina and leak. Drugs that block VEGF, beginning with ranibizumab (Lucentis), a relative of Avastin, now stop that growth; injected into the eye, they help preserve vision for patients who would once have gone blind.
When Folkman died in 2008, the Associated Press reported that his research had led to ten cancer drugs then on the market, used by more than 1.2 million patients worldwide, with dozens more in development. Nature Biotechnology wrote that more than ten new cancer drugs, most notably Avastin, had been developed as a result of his discoveries. A field that had not existed when he began now spans cancer, eye disease and disorders of blood vessels.
Hope without hype
In May 1998 a front-page New York Times story about angiostatin and endostatin quoted the Nobel laureate James Watson as saying that Folkman was going to cure cancer in two years. The remark set off a frenzy of hope and a backlash among scientists. Folkman himself played it down. In Scientific American that year he wrote that angiogenesis inhibitors would not be the cure for cancer, but that they would make cancer more survivable and controllable alongside other treatments, which is what they have done.
He never lost the habits of a physician. He spent hours each day returning telephone calls from patients and researchers around the world, and the head of Children’s Hospital called him the most amazingly kind and generous man. In lectures he spoke with compassion about individual patients and ended with stories about his granddaughter, Hannah.
Faith and family
Folkman’s Jewish upbringing was the root of his career. His father, a Reform rabbi, was known in Columbus for pastoral visits to hospitals and nursing homes, for interfaith work and for helping the Jewish community become part of the wider city at a time when antisemitism was common. The family’s values, his brother David recalled, were a love of learning and the conviction that people are here to contribute to the world and to help others. Folkman took the path his father had pointed out: the healer who also comforts.
His wife Paula sang with the Tanglewood Festival Chorus. One colleague remembered seeing Folkman in the front row at a Tanglewood concert during the interval, correcting the proofs of his latest paper.
Death and legacy
Judah Folkman died of an apparent heart attack on January 14, 2008, at the Denver airport, while changing planes on his way to a scientific meeting on angiogenesis in Vancouver, where he was to give the keynote address. He was 74. He was survived by his wife, two daughters and a granddaughter. His papers are held at Harvard’s Countway Library of Medicine.
His career shows what one stubborn idea can do. For more than two decades most experts dismissed it; today the biology of new blood vessel growth is taught in every medical school, and millions of cancer and eye patients have been treated with drugs that rest on it. The rabbi’s son who chose medicine to offer cures as well as comfort gave both.
Sources & further reading
Physician-Scientist Judah Folkman, MD, Faced Years of Skepticism, The ASCO Post · Judah Folkman, 74, pioneering cancer researcher, Associated Press via Philadelphia Inquirer · In memoriam: Judah Folkman, Journal of Clinical Investigation · Rabbi Jerome Folkman, Faith Leader, Bexley Historical Society · Judah Folkman, Wikipedia · Researched from the sources above and checked against them. Spotted an error? Tell us.
A life of tikkun olam. This is part of tikkun olam, the Jewish idea of repairing the world, and every one of us can add to it.