Folkman, Judah

Folkman, Judah
Feb. 24, 1933-Jan. 14, 2008
American surgeon

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In the early 1970s, Judah Folkman, then a relatively young surgeon at Children's Hospital, in Boston, Massachusetts, proposed a strategy for combating cancer that was radically different from treatments then in use. He hypothesized that for a tumor to grow beyond a certain small size, it would have to have its own blood supply, and that if the formation of new blood vessels-a process called angiogenesis-could be prevented, tumor growth might be controlled. Few researchers, however, thought this concept was worth investigating, and many were openly skeptical. "For 10 years there was almost nothing but criticism every time I gave a paper," Folkman told Nicholas Wade for the New York Times (December 9, 1997).

By the 1980s, however, his laboratory's accumulated evidence, as well as that of other laboratories, began to erode his critics' skepticism. And in just the past five years or so, in what may be a major development in the treatment of cancer, pharmaceutical companies have begun testing drugs that have been developed based on the very insight that Folkman had more than three decades ago. Called "angiogenesis inhibitors," these drugs combat cancer by preventing tumors from sparking the formation of their own blood vessels.

Folkman came up with his novel strategy to combat cancer unexpectedly, and indeed, accidentally, in the 1960s, when he was a young researcher in the U.S. Navy. At that time, he was conducting experiments on substances that could act as substitutes for blood in blood transfusions. These experiments were set up so that blood substitutes flowed through the blood vessels of rabbit thyroid glands that were being kept alive in a glass chamber. At one point, Folkman noticed that tumor cells implanted into the glands stopped growing when they were still quite small-smaller than a kernel of corn-and then became dormant. However, when the dormant tumor was transplanted into a living mouse, the tumor grew rapidly. This observation led Folkman to conjecture that to sustain their growth, tumors must be "angiogenesis-dependent"-dependent on the formation of their own blood vessels.

How angiogenesis might be "turned on" became the focus of Folkman's research in the late 1960s. By this time, he was surgeon-in-chief and chairman of the Department of Surgery at Children's Hospital. To provide conclusive evidence, Folkman realized, he had to purify the substances that regulated the process of angiogenesis. He was aided in his research by a $23 million grant he received from the Monsanto Company in 1974. (At the time, it was one of the biggest grants ever given by the private sector to a researcher, and some scientists criticized Folkman for crossing the line that separated academia from industry.)

In the early 1980s (by which time Folkman had stepped down as chairman of the Department of Surgery at Children's Hospital to devote himself more fully to research), Folkman's laboratory began making extraordinary discoveries. The first came when two researchers in his lab at Children's Hospital, Michael Klagsbrun and Yuen Shing, purified the first "angiogenic" substances. These substances are proteins, and they are sometimes referred to as "on switches," "inducers," or "growth factors," because they stimulate the formation of blood vessels. The process by which they do so is as follows. Once a tumor grows to approximately a million cells, the cells at the center become cut off from nearby capillaries-those super-fine blood vessels, thinner than a strand of hair, that supply cells with needed nutrients and rid those same cells of their waste products. Stranded, these center-most cells begin to die. (This explains why a tumor suspended in an artificial substance cannot grow beyond a certain size: The creation of new tumor cells is offset by the death of cells at the center.) In a living organism, on the other hand, tumors are able to circumvent the death-at-the-center syndrome by secreting certain chemicals-the so-called on switches-that stimulate nearby capillaries to grow. The new blood vessels that form also provide the route by which tumors metastasize, or spread to other organs in the body.

In the mid-1980s, Folkman made an even more crucial discovery, at least in terms of the treatment of cancer: He discovered the first "angiogenic inhibitors," platelet factor 4 and angiostatic steroids. Inhibitors are also called "off switches," because, as their name implies, their presence reverses the effect of the "on switches." A third angiogenesis inhibitor, called TNP-470, was discovered by Don Ingber, a member of Folkman's lab. In the early 1990s, Robert D'Amato, another member of the lab, discovered that the drug thalidomide could inhibit angiogenesis. (Thalidomide became notorious in the 1960s, when researchers discovered that it can cause deformities in infants born to mothers who took the drug during their pregnancies.) Both TNP-470 and thalidomide are currently in clinical trials for patients with advanced cancer.

The two most potent inhibitors, angiostatin and endostatin, were discovered by Michael O'Reilly in the mid-1990s; he, too, is a member of Folkman's lab. These substances can arrest the growth of or shrink tumors and their metastases in mice without observable toxicity or side effects, and thus far, no tumors have developed resistance to them. (Because cancer cells divide at an astonishingly rapid rate, chances are high that some of their descendants will have mutations that make them resistant to chemotherapy and radiation therapy. However, angiogenesis inhibitors target not cancer cells but rather slower-reproducing blood-vessel cells, so the development of resistance to the drugs is less likely.) What is most exciting is that when used to treat human tumors (including those of the breast, colon, and prostate) that have been implanted in mice, these inhibitors can shrink the tumors to microscopic size and then keep them in a dormant state.

It is not yet known whether the drugs will work as well in humans as they do in mice. Angiostatin and endostatin are currently being manufactured by pharmaceutical companies and the National Cancer Institute for eventual use in clinical trials in patients with advanced cancer. Folkman has emphasized that even if the drugs are effective in humans, it may be several years before they become readily available. "I am really worried because I have been at this a long time," he told Nicholas Wade. "I have watched wonderful things in the laboratory not make it to the clinic."

In the meantime, many pharmaceutical firms and biotechnology companies are developing other angiogenesis inhibitors, and some are already in clinical trials. In the future, angiogenesis inhibitors may be used alone, in combination with chemotherapy or radiotherapy, or as a platform for vaccine therapy, immunotherapy, or gene therapy. "The importance of angiogenesis is so obvious when you think about it," Isaiah Fidler, an immunologist at the M. D. Anderson Cancer Center in Houston, Texas, told U.S. News & World Report (December 9, 1996). "The world owes Judah Folkman a debt of gratitude."

Angiogenesis inhibitors have the potential to treat diseases other than cancer as well. These include life-threatening hemangiomas; in children's hospitals throughout the world, infants with this condition who have failed to improve with conventional steroid therapy are being treated with the angiogenesis inhibitor alpha-interferon. Thalidomide is being studied in patients suffering from macular degeneration (a disorder of the retina that often leads to blindness) and in people with Crohn's disease (a chronic inflammation of the intestines). Eventually, angiogenesis inhibitors may be used to treat arthritis, psoriasis, and a wide variety of eye diseases, including neovascular glaucoma.

Folkman sometimes gives the impression that he is awed by how much has been accomplished since he began his research at Children's Hospital, where he has worked for some three decades. As he told Current Biography, "The benefits of science are so unpredictable that it could not have been foreseen when this work began that research in a children's hospital would lead to new treatments for heart disease, stroke, and cancer in adults, in addition to potential new ways to treat children with cancer."

Judah Folkman was just seven years old when he decided that he would become a doctor. He was born Moses Judah Folkman on February 24, 1933, in Cleveland, Ohio, and he became interested in medicine through his father, a rabbi who often visited patients at a local hospital. The young Folkman was sometimes permitted to join his father during these visits, as a reward for being good. Though early on he thought that he, too, would become a rabbi, the visits showed him that medicine, as well as spiritual aid, could help people.

In 1953, Folkman graduated cum laude from Ohio State University; as an undergraduate there, he had co-authored papers on a new method of hepatectomy for treating liver cancer. In 1957, he graduated magna cum laude from Harvard Medical School, in Cambridge, Massachusetts. While completing his M.D., he helped develop the first atrio-ventricular implantable pacemaker, an achievement that earned him the Boylston Medical Prize, the Soma Weiss Award, and the Borden Undergraduate Award in Medicine.

Between 1957 and 1965, Folkman did postdoctoral work at the surgery unit of Massachusetts General Hospital, in Boston. His residency was interrupted by his stint in the U.S. Navy, from 1960 to 1962. As a lieutenant at the National Naval Medical Center, in Bethesda, Maryland, he helped develop, with David Long, "artificial glands" made of silicone rubber; when implanted in the body, the "glands" slowly release drugs. The technology that made their development possible later led to the development of Norplant, an implantable contraceptive.

After his residency ended, Folkman held a variety of junior academic and hospital appointments at Harvard Medical School and Boston City Hospital. In 1967, at the age of 34, he became a professor of surgery at Harvard; since 1968, he has served as the school's Julia Dyckman Andrus professor of pediatric surgery, and since 1980, as a professor of anatomy and cellular biology. He has also served as the surgeon-in-chief and chairman of the Department of Surgery at the Children's Hospital Medical Center, in Boston, from 1967 until 1981, when he stepped down to become a senior associate in surgery and director of the Surgical Research Laboratories there.

Many scientists have expressed their deep admiration for Folkman on both a personal and a professional level. "He saw things others didn't see," Robert S. Kerbel, of the Sunnybrook Health Science Center, in Toronto, told Wade, "but on top of that, he had the persistence to stick with it and almost single-handedly has opened up this very substantial field of research."

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