Judah Folkman 1933–2008

When Bruce Zetter called me late at night on January 14 with news of Judah Folkman’s passing, my shock and grief were almost as great as when I learned, 8 years earlier, of my own father’s sudden death. I suspect many people shared my reaction, especially fellow researchers in the field of tumor angiogenesis. After all, he was widely acknowledged to be the father of the field, and a doting one at that, gently mentoring, encouraging, or guiding so many others along the way during his brilliant career. In the days following Folkman’s death, hundreds of obituaries underscored his fame and reputation. Among many others, The New York Times, Time, Newsweek, Business Week, and The Wall Street Journal pointed out his importance to the field of cancer research. Understandably, and perhaps predictably, they primarily focused on his 1971 visionary hypothesis, first published in The New England Journal of Medicine. He posited that avascular microscopic solid tumors must induce sustained formation of new blood vessels (a process termed angiogenesis) to achieve relentless growth and metastatic spread, doing so by producing a secretable circulating factor called TAF (tumor-angiogenesis factor). It should be possible, he reasoned, to develop “antiangiogenesis” drugs (for example, an anti-TAF neutralizing antibody) to induce a state of tumor dormancy and hence prolong survival of cancer patients. The aforementioned obituaries emphasized the skepticism with which the scientific community greeted these ideas and pointed out how Folkman doggedly persevered until finally he was vindicated more than 30 years later with the first clinical approval of a series of antiangiogenic drugs. The best known of these, approved in 2004, is bevacizumab (Avastin), the anti-VEGF antibody used for the treatment of certain cancers and subsequently a related anti-VEGF antibody for treating age-related macular degeneration (AMD), the most frequent cause of vision loss and blindness. Much was also made about his legendary generosity and humanity, especially with cancer patients and their families. He was a pediatric surgeon by training and was Surgeonin-Chief at Children’s Hospital in Boston for 14 years. Folkman often gave out his home phone number to patients’ families. He spent countless hours, usually late in the evening after work, providing advice— and above all hope—to people he did not even know. What these obituaries omitted, also understandably, were Folkman’s numerous other scientific contributions, which not only advanced the field of tumor angiogenesis and antiangiogenic therapy but also laid crucial foundation stones for future discoveries. I think recounting these accomplishments here is important not only for their own sake but because too many researchers—especially younger ones in the field of tumor angiogenesis—do not appreciate the full extent of what Folkman accomplished. So here is a “top ten list” of Judah Folkman’s conceptual and laboratory contributions in the field of tumor angiogenesis. First is the brilliant and prescient 1971 hypothesis based not only on his own basic tumor angiogenesis work at the time but also on the largely unsung findings made by others, sometimes years earlier, which he cited in his classic paper. Back then the idea of a noncurative therapy for cancer was heretical to most. Indeed, scientific as well as popular thinking of the era was summed up in 1972 when President Richard Nixon declared the “war on cancer” and set the goal of curing the disease within a decade. Today, the clinical goal of controlling advanced cancer in patients, rather than necessarily trying to completely eradicate it, is widely accepted. Second, also in 1971, he reported a method to isolate a fraction of ascites fluid from tumor-bearing mice, which was competent to stimulate the formation of new blood vessels. This discovery went hand-inhand with his more famous 1971 paper. Third, in experiments that remain as beautiful today as when he published them in 1972 with Michael Gimbrone, a medical student, Folkman showed that small tumor spheroids suspended in the avascular anterior chamber of the rabbit eye did not increase in size, but that they grew explosively when relocated to another area (near the iris) where they were able to rapidly induce and attract new blood vessel capillaries. This work, an example of what some might derisively call “descriptive science,” supported Judah Folkman Photo courtesy of Children’s Hospital Boston/Bachrach Studio.