Physician-Scientist Judah Folkman, MD, Faced Years of Skepticism Before His Theory of Angiogenesis Was Proven


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Even as a student, I really had those moments of feeling that this man [Judah Folkman] was going to transform medicine.

—Steven Brem, MD, former student of Dr. Folkman

That Moses Judah Folkman would buck tradition, breaking his family’s long line of rabbinical succession and pursuing a career in science and medicine instead, was evident from the time he was a young child. Born in Cleveland on February 24, 1933, the first child of Rabbi Jerome and Bessie Folkman, young Judah eschewed more conventional children’s books in favor of biographies of Isaac Newton, Madame Marie Curie, and Louis Pasteur.

Early Life

At age 7, Judah began accompanying his father on his Saturday hospital visits, where Rabbi Folkman comforted ailing members of his congregation and offered prayers. Meant to prepare Judah for his eventual rabbinic ordination, the visits convinced Judah that he wanted to offer patients more than spiritual solace alone. He wanted to help make them physically well. According to Dr. Folkman’s War: Angiogenesis and the Struggle to Defeat Cancer, by Robert Cooke,1 when Judah told his father of his intention to become a doctor instead of a rabbi, his father replied, “In that case, you can be a rabbi-like doctor.”

By the time Judah was in high school, he was conducting experiments on small animals in his basement. For his entry in the Ohio Academy of Sciences competition, he devised a perfusion system powered by a small electric motor and a bicycle pump to keep the heart of a rat beating after being surgically removed. (Dr. Folkman would later jury-rig other devices, including a renal dialysis system for a patient with acute renal failure, saving the patient’s life.)

The experiment garnered Judah a prize in the competition and also put him on the path to Harvard Medical School at age 19, and a stint in the surgical laboratory of Dr. Robert Gross, then Surgeon-in-Chief at Children’s Hospital in Boston. There, he invented the first implantable heart pacemaker.

After graduating magna cum laude from Harvard in 1957, Dr. Folkman became a surgical resident at Massachusetts General Hospital. In 1960 he married Paula Prial and soon they had two daughters, Marjorie and Laura. A third child, Kenneth, died in infancy from cystic fibrosis.

Birth of a New Field

Soon after beginning his year as Senior Assistant Resident at Massachusetts General Hospital, Dr. Folkman was drafted into the navy and sent to do research at the National Naval Medical Center in Bethesda, Maryland. While conducting laboratory experiments on rabbits and mice implanted with cancer cells, Dr. Folkman noticed their tumors stopped growing when they were removed from the animals’ bodies but started growing again when the cells where implanted in another animal. The discovery led to his theory that tumors needed new blood vessels to provide them with the necessary oxygen and nutrients to keep them proliferating in a process known as “tumor angiogenesis.”

During his time in Bethesda, Dr. Folkman also invented an implantable device for timed drug release (later developed as a means of administering the contraceptive levonorgestrel [Norplant]) and donated the patent to the World Population Council.

In 1962, Dr. Folkman returned to Mass General to complete his surgical training and later became Chief Resident. Five years later, Dr. Folkman was named Surgeon-in-Chief of Children’s Hospital and continued his research efforts on tumor angiogenesis, although his hypothesis that malignant tumors must have a mechanism to induce the formation of blood vessels was met with growing skepticism—and even ridicule—from researchers steeped in methods that directly kill cancer cells. This skepticism affected his ability to obtain grants from the National Institutes of Health, his chances of being published in medical journals, and his capacity to attract young scientists to work in his lab.

“I always viewed Dr. Folkman as an uplifting, inspiring, and genuinely enthusiastic person, but his first grants were rejected as being too visionary, and he fought an uphill battle to prove that a surgeon could transform science. He had to overcome the tunnel vision of that time,” said Steven Brem, MD, Co-Director, Penn Brain Tumor Center; Chief, Neurosurgical Oncology, Department of Neurosurgery at the Hospital of the University of Pennsylvania; and a student of Dr. Folkman’s at Harvard Medical School.

Dr. Folkman’s belief in angiogenesis as a cancer-cell proliferator was finally vindicated in the late 1980s when a scientist from the biotechnology company Genentech discovered vascular endothelial growth factor (VEGF), a protein that stimulates the formation of new blood vessels. In 2004, Genentech’s drug bevacizumab (Avastin), developed to block VEGF, was approved by the FDA for use in combination with standard chemotherapy drugs in the treatment of metastatic colon cancer, and later, for non–small cell lung cancer and renal cell carcinoma. Bevacizumab was also subsequently approved as a single agent in the treatment of glioblastoma as well as in macular degeneration.

Fulfilling a Father’s Wish

A 1998 front-page article in The New York Times heralding Dr. Folkman’s laboratory work,2 including the discovery of endostatin and angiostatin as potential cancer fighters, ushered in an era of new hope about an end to cancer. The piece quoted Dr. James Watson, a Nobel laureate for the discovery of the structure of DNA, saying, “Judah is going to cure cancer in 2 years.” But Dr. Folkman refuted that claim in an issue of Scientific American later that year.3

“I don’t think angiogenesis inhibitors will be the cure for cancer,” he said. “But I do think that they will make cancer more survivable and controllable, especially in conjunction with radiation, chemotherapy, and other treatments.”

Today, there are a dozen antiangiogenic drugs approved in oncology, including thalidomide (Thalomid), lenalidomide (Revlimid), sunitinib (Sutent), temsirolimus (Torisel), and everolimus (Afinitor), with more on the way.

On January 14, 2008, Judah Folkman died of an apparent heart attack while waiting to change planes at a Denver airport on his way to a medical conference in Vancouver, British Columbia.

“Dr. Folkman was like no other,” said Dr. Brem. “He was very inspiring and always full of enthusiasm. He could look 30 years or more into the future. His work preceded all of the translational research we have today in cancer and ophthalmology as well as other vascular diseases. He understood the importance of experiments, of logical thinking. Even as a student, I really had those moments of feeling that this man [Judah Folkman] was going to transform medicine.”

Dr. Folkman’s contributions to cancer research, and his career as a relentless scientist, caring physician, and gifted teacher, show beyond doubt that he lived up to his father’s admonition to become “a rabbi-like doctor.” ■ 

References

1. Cooke R: Dr. Folkman’s War: Angiogenesis and the Struggle to Defeat Cancer. New York, Random House, 2001.

2. Kolata G: Hope in the lab—a special report: A cautious awe greets drugs that eradicate tumors in mice. The New York Times. May 3, 1998.

3. Ezzell C: Starving tumors of their lifeblood. Scientific American. October 1998.



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