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It is off-putting, to say the least, to see your work criticized in the newspapers or in scientific journals, but for Judah Folkman, this has become the norm. He talked to Nature about how his theories and findings have been challenged ever since he began research, and the reasons why he continues in the face of continual confrontation. Judah Folkman

The latest attacks on the work for which The pattern was repeated with tors.” This is precisely what has happened Judah Folkman is famed—tumor destruc- Folkman’s FGF-pellet rabbit cornea model, to the field of research. tion through angiogenesis inhibition— a test for angiogenic activity. “At first no- Folkman joined Children’s Hospital, affili- came in the form of two papers and an one could do it, it was a skill problem, they ated with Harvard Medical School, as accompanying Editorial published this kept puncturing the cornea. Then we Surgeon-in-Chief in 1967. He ran a small April in Molecular Therapy. The articles trained people in the lab. Now it’s widely lab with a couple of post-docs. “That was question the effectiveness of systemic gene used to test new inhibitors and stimula- when the field of angiogenesis research therapy with as an anticancer tors.” started and it was easy to work at your own treatment in a mouse model of transduced But his endostatin work has taken the pace. There were only 3 papers per year for hematopoietic stem cells. “Unfulfilled most knocks. Within months the New York 10 years in the 70s there are now 40 a promise of endostatin…” begins the title of Times article heralding the compound’s week.” one paper. ability to shrink tumors in mice, labs The surge in interest in the field per- Folkman has endured years of skepti- around the world were crying foul—they suaded Folkman to stop seeing patients in cism about his work—an entire career’s couldn’t replicate the finding. Only after a 1982 and concentrate full-time on labora- worth. Although the broader community team of investigators from the National tory research. As an MD, his scientific http://www.nature.com/naturemedicine only really became aware of the contro- Cancer Institute achieved success working knowledge has been gained on-the-job. “I versy over his finding that endostatin, an side-by-side with scientists in Folkman’s know the basic science training really anti-angiogenesis molecule, can destroy lab did the tide of opinion begin to change. helps, but there are as many major discov- tumors after a headlining New York Times “One of the problems was room tempera- eries from PhDs alone and MDs alone, as article five years ago, Folkman had his dis- ture was too low elsewhere. Tumors don’t MD/PhD’s. The way I work now is to learn believers back in the 1960s. There were, he grow when mice are chilly because the ves- things such as new molecular techniques remembers, “wall-to-wall critics.” sels vasocontrict, it cuts off the blood sup- from the PhDs in the lab. It’s like a perma- The dogma back then was that tumors ply and drugs don’t circulate.” nent sabbatical.” do not need a new blood supply since they “It’s difficult in the lab when your results Having opted for a career in science grow on existing vessels, and that redness can’t be reproduced. People get upset,” rather than medicine, Folkman believes re- associated with tumors was inflammation says Folkman. “If you’re a search is not for those with from dying tumor cells, not vascular tissue. PhD scientist, then you feel fragile egos or faint heart. And there were no appropriate in vitro as- the implication is that “It’s mostly failure. With

© Group 2002 Nature Publishing says to work with. Folkman recalls: you’ve done something clinical work, you select the “Endothelial cells that line blood vessels fraudulent. But to a sur- ones you can treat; you had never been grown outside the body geon, if somebody can’t re- don’t operate on inoperable and the belief was that they couldn’t be produce your work they’re patients. You have enor- grown because they live in blood. How probably not skilled mous success and positive would you see them through the blood? enough. If I operate and feedback. It’s very satisfy- When you have very bright people they have 99% success and my ing.” can think of many brilliant reasons why colleagues only get 50%, Why then, does he en- things won’t work.” that’s their problem.” dure not only the failure of Yet in 1972 he, simultaneously with Eric Recently, Folkman has research, but direct criti- Jaffe at Cornell University, grew endothe- been investigating the sys- cism of his efforts? His an- A career of endurance lial cells in culture. “Nobody believed ei- temic gene therapy ap- swer is two-fold. Many ther of us. The reaction was as if you proach. His group brilliant minds have joined published a head transplant today—laugh- published a PNAS paper a year before the the field that he started. “Peter Carmeliet’s ter!” Molecular Therapy papers also reporting no whole career and Rakesh Jain’s have been The same doubt shrouded his 1984 pu- effect with systemic gene therapy. The rea- in angiogenesis. If it hadn’t been fruitful rification of basic , son, he believes, is that efficacy follows a for all these other scientists that are mak- or FGF, when his peers were convinced bell-shaped curve. At 700 ng/ml blood or ing discoveries that we wish we had made that there could not be a protein that stim- higher receptors are turned off and there is then maybe I wouldn’t have been able to ulates endothelial cells. For a while, the re- no angiogenesis. Too low concentrations carry on.” And most importantly, there are combinant form couldn’t be made, and don’t work either. But at 30–40 ng/ml the several hundred patients in clinical tri- lack of interest in the US spawned his col- there is systemic tumor inhibition. He is als of angiogenesis inhibitors, whose qual- laboration with Takeda Chemical still working on this theory. ity of life has been improved and Industries in Japan, which eventually suc- “You never receive apologies from the prolonged. This is what toughens Folkman ceeded in mass producing the highly po- critics. If I did, I would send a bouquet,” he against the critics. tent, angiogenic molecule. says. “Instead, the critics become competi- Karen Birmingham, London

1052 NATURE MEDICINE • VOLUME 8 • NUMBER 10 • OCTOBER 2002