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Judah Folkman
Dr. Judah Folkman (1933-2008), the "father of angiogenesis," was the Director of the Vascular Biology Program at Children's Hospital, Boston, and Andrus Professor of Pediatric Surgery, and Professor of Cell Biology at Harvard Medical School.
Moses Judah Folkman (better known as Judah Folkman) was born in Cleveland, Ohio in 1933 and spent part of his youth in Grand Rapids, Michigan. He was the son of a rabbi and used to visit hospitalized congregants with his father. By age 10, he knew that he wanted to become a doctor in order to help find cures for illness as well as to provide comfort for the sick. When Judah told his father that he would become a physician instead of a rabbi, his father responded, “then you will become a rabbi-like doctor.” Judah Folkman took this very much to heart.
On the occasion of Judah's bar mitzvah in February 1946, his grandfather, Ben Folkman, wanted to give Judah a special gift. Instead of the usual grandparent-gift of a gold watch, he offered to buy Judah a brand new, open-top, olive drab Jeep from a government surplus depot. In Michigan, the driving age was 14 and one could get a learner’s permit at 13 (probably a carryover from the pre-war days when Michigan was a heavily agricultural state, and kids were needed to drive tractors). His brother David and sister Joy thought how “swell” or “hotsy-totsy” it would be to have Judah drop them off at school in the Jeep. Judah, however, had another idea. Since about age 7 or 8, he had been using a Gilbert toy microscope to carry out research projects he learned from biology books in the local library. Twelve-year-old Judah thanked his grandfather very much for his unbelievably surprising and generous offer of a Jeep, but went on to say, “But Grandpa, if it’s OK, I would much prefer to have a 1,000-power, 3-objective Spencer microscope, so I can study with a powerful, precision instrument.” The microscope and Jeep both cost about $250 in 1946 prices. David and Joy were stunned. David recalls them thinking, "How could our brother do such a dumb thing! Who would ever turn down a Jeep for a microscope? We imagined something was truly wrong with Judah’s priorities." Of course, Grandpa Folkman was delighted with this request and delivered on the special gift, the Spencer microscope.
During his high school years, Judah set up a perfusion system in his basement, which kept a rat heart beating for days after its removal from the rat. His scientific talent led to his admission at age 15 to nearby Ohio State University, where he worked part-time all four years in the surgical laboratory of Dr. Robert Zollinger.
In 1953, Judah Folkman entered Harvard Medical School at age 19. He worked in the laboratory of Dr. Robert Gross, then Surgeon-in-Chief at Children’s Hospital. As a student, Folkman invented the first implantable heart pacemaker. He graduated medical school in 1957 with many academic prizes. Folkman served his residency at the Massachusetts General Hospital, where he was introduced to pediatric surgery.
During his residency, he was drafted into the Navy, and spent two years at the National Naval Medical Center in Bethesda, Maryland. Folkman did research on artificial blood substitutes, and he invented the first implantable device for sustained drug-release that was later known as Norplant. (He donated the device patent-free to the World Population Council for use as a contraceptive.) It was also during his naval service that Folkman noticed that tiny tumor fragments remained alive but would not grow beyond about one millimeter when they were implanted in an isolated, perfused thyroid. This led him to consider that tumors somehow stimulated the growth of new blood vessels in order to provide themselves with the necessary oxygen and nutrients required for their expansion and proliferation. The process--known as tumor angiogenesis--was the reason cancer spread, Folkman said, and its inhibition may be a way to hold cancer in check. His theory was initially met with skepticism
Folkman returned to Boston in 1962 and continued his training at MGH. In 1965, he became an Assistant Professor of Surgery on the Harvard Surgical Service at Boston City Hospital. In his tiny lab in the basement of the Sears Surgical Building, he took up the study of tumor blood vessels that would ultimately open up the new field of vascular biology. At the unprecedented age of 34, he was appointed Surgeon-in-Chief at Children’s Hospital. Before assuming the post, Folkman decided to get further training in pediatric surgery under Dr. C. Everett Koop at the Children’s Hospital of Philadelphia. In 1967, he returned to Boston to become Surgeon-in-Chief at Children's Hospital and one of the youngest full professors in Harvard Medical School history.
In 1971 Folkman published his first paper on his angiogenesis theory in the New England Journal of Medicine. In it, he proposed that tumors could not grow beyond a certain size without a dedicated blood supply. He postulated that they secreted a protein to stimulate the ingrowth of capillaries, and that this process, angiogenesis, transformed a tumor composed of mutated but harmless cells into a potentially lethal neoplasm. Since physiological processes most often have checks and balances, he further proposed that naturally occurring substances that inhibited angiogenesis kept some tumors dormant despite their malignant potential.
In the 1970s, Folkman studied the molecular basis of tumor angiogenesis. He developed assays and tools to study angiogenesis in vivo and in vitro. These assays remain in use today. They include long-term culture of capillary endothelial cells, the chick chorioallantoic membrane and corneal pocket bioassays, and the sustained-release polymers required to deliver angiogenic regulators to be tested.
In 1982, Dr. Folkman stepped down from his position as Surgeon-in-Chief at Children's Hospital in order to devote himself to full-time research. Although he saw patients after 1982, he returned to the operating room only for rare consulting situations.
In the early 1980s, his lab purified the first angiogenic stimulator, basic
fibroblast growth factor (bFGF), which ushered in an era of discovery, validation, and refinement that established angiogenesis as the defining process in a tumor's ability to grow and metastasize. Folkman's lab and others went on to identify more than 30 endogenous angiogenesis inhibitors, including angiostatin and endostatin, and over a dozen stimulators. They also began to map multiple pathways through which pathological angiogenesis occurred. Drugs based on this work have since been used to treat many forms of cancer and the wet form of age-related macular degeneration.
In 1989, Folkman proposed the concept of the "angiogenic switch," the point in a tumor's development when the balance of stimulators and inhibitors is altered in favor of angiogenesis stimulation, triggering the transition to the angiogenic phenotype. He theorized that blocking the switch would keep cancer from developing. The key would be to identify biomarkers of the switch, then "treat the biomarker" with nontoxic angiogenesis inhibitors, akin to using statins in response to high cholesterol levels. He began clinical trials to evaluate the efficacy of biomarkers in detecting recurrent cancer before the tumors could be imaged or palpated, a first step toward his vision of "cancer without disease."
Folkman thought that angiogenesis was an organizing principle of biology and pathological angiogenesis was a common factor in many different diseases. He maintained that angiogenesis was necessary to support the growth of any mass--e.g., arthrosclerotic plaque, adipose tissue, or a malignancy-- and that it characterized conditions ranging from retinopathies to endometriosis. Consequently, Folkman suggested that angiogenesis-based biomarkers could be used to monitor the progression or regression of a number of these diseases. Furthermore, drugs developed for one angiogenesis-dependent disorder could potentially treat another. He envisioned a time when a single, broad-spectrum angiogenesis inhibitor or a combination of antiangiogenic drugs would be used to treat a wide range of conditions.
Judah Folkman authored about 400 peer-reviewed papers and more than 100
book chapters and monographs. He was elected to the National Academy of Sciences, the American Academy of Arts and Sciences, the American Philosophical Society, the Institute of Medicine, and the President's Cancer Advisory Board.
By the time of his death in 2008, the Children's Hospital Boston research lab that he founded in 1967 with just one assistant had grown into the Vascular Biology Program, which employed 125 scientists. More than 1000 labs around the world are now pursuing angiogenesis research.
[Paraphrased from Michael Klagsbrun and Marsha A. Moses, "Obituary: Judah Folkman, M.D., February 24, 1933 - 14 January 2008," Cancer Cell, 13 February 2008; and from a "Faculty of Medicine--Memorial Minute" on Judah Folkman published in the Harvard Gazette, 28 May 2009. Other sources include Paula Folkman, Judah Folkman's wife, and David Folkman, his brother. For a more detailed biography, plus a short video of Dr. Folkman speaking about his work, visit the Harvard Gazette's website.]
