Obituary

M. Judah Folkman (1933–2008)

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Scientist, surgeon and creator of the field of angiogenesis research.

Credit: K. JOHNSON

Judah Folkman often said “Science goes where you imagine it.” Few imagined more boldly or pushed science further than he did. As director of the Vascular Biology Program and a former surgeon-in-chief at the Children's Hospital Boston in Massachusetts, Folkman brought both a scientist's and a surgeon's perspectives to finding solutions to medical problems. His research observation that some tumours grow whereas others remain dormant, fused with his clinical experience in removing hot, bloody malignancies, produced a profound insight — that the recruitment of a dedicated blood supply, a process known as angiogenesis, is essential to tumour growth.

Folkman's single-mindedness in demonstrating this principle redefined our understanding of cancer biology. Furthermore, it established angiogenesis as a fundamental biological process operating in health, embryonic development and many diseases besides cancer — macular degeneration, heart disease, diabetic retinopathy, endometriosis and obesity among them. Peter Carmeliet has predicted that treatments to stimulate or repress angiogenesis will eventually benefit half a billion people worldwide (P. Carmeliet Nature 438, 932–936; 2005). Today, thousands of researchers around the world, many trained in Folkman's lab, are working to make this promise a reality. But when Folkman embarked on the scientific odyssey that would establish the field of angiogenesis, he sailed alone.

Folkman was born in 1933, in Cleveland, Ohio, and was educated at Ohio State University and Harvard Medical School. He followed this with a surgical residency at Massachusetts General Hospital. His angiogenesis hypothesis had its roots in the late 1960s. On leave from his surgical residency to complete two years of military service at the National Naval Medical Center in Bethesda, Maryland, he was developing blood substitutes and testing them by perfusing rabbit thyroid glands in the lab. Out of curiosity, he seeded the glands with mouse tumour cells. The tumours grew to about 1 millimetre, then stopped. Yet, in vivo, the same cells formed large, lethal cancers.

After completing his surgical training and establishing his lab at the Children's Hospital, Folkman pursued the puzzle of dormant versus active tumours. Watching thread-like capillaries grow straight towards dormant tumours, he concluded that the tumours secreted an angiogenesis stimulator. Because not all tumours become vascularized, however, he further proposed a corollary process of angiogenesis inhibition. Blocking angiogenesis, he argued, would provide a new approach to controlling certain cancers.

Folkman published his ideas about angiogenesis in 1971 (J. Folkman N. Engl. J. Med. 285, 1182–1186; 1971). This landmark paper initially met with scepticism. Undaunted, he and his small research group developed the cell-culture methods, bioassays and drug-delivery systems they needed to validate the theory. Notably, the technology for slow-release, drug-delivery polymers emerged from this work.

It took a decade for Folkman's lab to isolate the first angiogenesis stimulator — basic fibroblast growth factor (bFGF) — and yet another for it to identify the inhibitors angiostatin and endostatin. These breakthroughs launched an era of discovery and validation, during which Folkman's group and others uncovered additional pro- and antiangiogenic factors, began mapping the molecular pathways of pathological angiogenesis, and started to develop antiangiogenic drugs. Today, more than 50 angiogenesis inhibitors are approved or in clinical trials around the globe. Although most target cancer, drugs to treat a condition called wet age-related macular degeneration have had the most stunning success so far, reversing blindness in many patients.

Folkman never stopped pushing his own imagination or the bounds of scientific understanding. In 2004, he proposed that we may someday control cancer by “treating a biomarker” with angiogenesis inhibitors (J. Folkman & R. Kalluri Nature 427, 787; 2004), just as we treat heart disease by prescribing statins in response to high cholesterol levels. Folkman foresaw biomarkers for the 'angiogenic switch', the point at which the balance of angiogenesis stimulators and inhibitors shifts in favour of stimulation, generating the web of blood vessels that turns cancer into a killer. The switch happens years before a tumour can be imaged or felt. Folkman speculated that if cancer were detected this early and treated with low-toxicity antiangiogenic drugs, it would remain dormant. Patients would have cancer but not disease.

At the time of his sudden death on 14 January, Folkman had been testing this theory in patients at risk of recurrent cancer, using biomarkers for early angiogenesis developed in his Vascular Biology Program. He had also begun to view angiogenesis as an organizing principle of biology, essential for the growth of any mass from a cancerous tumour to an atherosclerotic plaque. He had proposed that angiogenesis biomarkers could potentially detect a range of blood-vessel-dependent diseases, and that one day a single, broad-spectrum angiogenesis inhibitor or a combination of antiangiogenic drugs might be used to treat them all. This was another bold theory, one left for others to pursue.

Folkman's contributions to vision and cardiovascular research, as well as to cancer biology, were widely recognized. Apart from being elected to the National Academy of Sciences and Institute of Medicine, and appointed to the President's Cancer Advisory Board, he received more than 150 awards and prizes, including scientific honours from 11 nations. But neither the awards nor accounts of his scientific accomplishments capture what those who knew him valued most in Folkman — his humanity and generosity. He was legendary for sharing unpublished data, and masterly at balancing guidance and creative freedom to nurture young investigators' careers.

Nowhere was Folkman's compassion and generosity more evident, however, than with patients. He would leave the office late in the evening, a briefcase slung over each shoulder, a notebook of to-do's in his breast pocket, wheeling his laptop behind him. After dinner with his wife of 47 years, Paula, he would retire to his study, take out the notebook, and begin calling patients who had left messages that day. Most were people he had never met, desperate for hope and advice. He called them all.

Folkman never used his first name, Moses, but he shared much in common with his Biblical namesake. He was a teacher, leader and iconoclast. Although he did not live to see the full promise of antiangiogenic therapy realized, he trained and inspired many who will carry forward his dream.

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Klagsbrun, M., Moses, M. M. Judah Folkman (1933–2008). Nature 451, 781 (2008) doi:10.1038/451781a

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