Homage to Judah Folkman

“The problem of understanding the phenomenon of angiogenesis, of working out its biology, of connecting it to a large family of clinical diseases once thought to be totally separate entities, seems to have been tackled in somewhat the same way that the author E.L. Doctorow describes what it is like to write a novel. ‘Writing is like driving at night,’ he said, ‘You cannot see beyond the headlights, but you can make the whole trip that way.’” —Judah Folkman, M.D. The process of new blood vessel formation—called neovascularization or angiogenesis—is used commonly by the healthy body during the menstrual cycle, in wound healing, and in other situations in which tissue repair is needed. Normally, angiogenesis is “switched on” when required, and “switched off” when its function is completed, typically a week or two later. Dr. Judah Folkman, director of the Program in Vascular Biology at Children's Hospital Boston, and professor of Pediatric Surgery and Cell Biology at Harvard Medical School, originated the groundbreaking idea that angiogenesis is also central to the development and growth of tumors. When this idea first came to light 45 years ago, there was no conceptual framework for understanding it, and few people were actively studying blood vessel formation. Today, after a long trip made in small increments, it is widely accepted that a tumor cannot grow beyond a certain size without recruiting new blood vessels to feed it—without angiogenesis. Dr. Judah Folkman (1933–2008). Born in 1933 in Cleveland, Ohio, Folkman accompanied his father, a rabbi, on visits to hospital patients. By age seven, he knew he wanted to be a doctor, rather than follow in his father's footsteps, so he could offer cures in addition to comfort. His father replied, “In that case, you can be a rabbi-like doctor,” words his son took to heart. This early calling led Folkman to Ohio State University, where, by the end of his freshman year, he was performing surgery on dogs under the mentorship of Dr. Robert Zollinger, then president of the American College of Surgeons. The young Folkman even designed a device to cool the liver during surgery without causing organ damage, and became coauthor on his first academic paper. With this experience, he was accepted into Harvard Medical School at the age of 19. While working in the surgical laboratory of Dr. Robert Gross at Children's Hospital Boston, Folkman and an MIT graduate student, Fred Vanderschmidt, created the world's first implantable heart pacemaker, which became the basis of today's commercially available pacemakers. (Following academic policy at that time, they did not seek a patent.) During his surgical residency at Massachusetts General Hospital in 1960, Folkman was drafted to a two-year term in the U.S. Navy. This turn of fate brought him to the National Naval Medical Center in Bethesda. Here, with David Long, he first reported the use of silicone rubber implantable polymers for the sustained release of drugs. This work launched the field of controlled-release technology and led to the development of Norplant. But serving in the Navy also proved serendipitous to Folkman's future career. While working on blood substitutes to stock aircraft-carrier operating rooms, he experienced his first “Aha moment.” Folkman was studying the ability of a cell-free blood substitute to keep a rabbit's thyroid gland alive in the laboratory. Out of curiosity, he seeded the gland with cancer cells from mice, and perfused the gland with the blood substitute. Tumors formed, but they all grew to the same size and then stopped. Something missing in their environment prevented them from growing any further. Yet when Folkman implanted the same cancer cells into a live mouse, tumors grew vigorously. Folkman devoted his research career to finding out why. Returning to Boston, Folkman completed his pediatric surgery residency at Massachusetts General Hospital, becoming a teacher and mentor to his colleagues. In 1967, after an appointment as assistant surgeon at Boston City Hospital, he was recruited to Children's Hospital Boston, where he was appointed surgeon-in-chief at the young age of 34. He served in that position for 14 years, then stepped down in 1981 so that he could devote his full effort to research. From that first observation at the National Naval Medical Center, Folkman and his colleagues at Children's hypothesized, and ultimately proved, that tumor growth requires a blood supply—via an increase in new capillary blood vessels. In the early days, Folkman's ideas received scant support from the scientific community. It was widely believed that tumors grew along preexisting blood vessels. In the 1970s, when Folkman's team applied for their first grant based on the hypothesis of angiogenesis and its role in tumor development and growth, reviewers at the National Cancer Institute summarily turned them down: It is common knowledge that the hypervascularity associated with tumors is due to dilation of host vessels and not new vessels and that this dilation is probably caused by the side effects of dying tumor cells. Therefore, tumor growth cannot be dependent upon blood vessel growth any more than infection is dependent upon pus. But Folkman and his team at Children's persevered in their investigations. They proved that by shutting down the blood vessels feeding cancerous tumors, the cancer itself could be shut down. Little by little, they assembled the data and proofs. In the 1980s, they began finding factors that induce angiogenesis, and more important, factors that inhibit it. Today, angiogenesis inhibition therapy is the focus of a worldwide scientific research effort and a “front-burner” priority of the National Cancer Institute. At least 50 angiogenesis inhibitors are in clinical trials around the world, and more than 1,000 laboratories in universities and industry are conducting angiogenesis research. More than 10 angiogenesis inhibitors have been approved by the Food and Drug Administration, and antiangiogenic drugs have received approvals in more than 30 other countries. More than 1.2 million patients worldwide are now receiving antiangiogenic therapy. Folkman's work has also spawned the first treatments for the blinding diseases caused by excessive blood vessel growth in the retina, such as macular degeneration and diabetic retinopathy. It was one of Folkman's most proud accomplishments that his work led to the first FDA-approved treatments of macular degeneration—a treatment that is enabling tens of thousands of people to regain their sight. In 1968, Folkman was appointed the Julia Dyckman Andrus Professor of Pediatric Surgery at Harvard Medical School, where he [was] also professor of Cell Biology. In addition to directing the Children's Hospital Boston Surgical Research Laboratories, which grew to become the Vascular Biology Program, for nearly four decades he was the scientific director of the hospital's Vascular Anomalies center. A revered figure at the hospital, Folkman's insights informed many active research efforts outside the field of Vascular Biology, and he forged new collaborations at the hospital to study disorders as wide-ranging as hydrocephalus and hemorrhages in the brains and eyes of premature infants. His presentations consistently drew standing-room-only audiences. Folkman was a member of the National Academy of Sciences, the Institute of Medicine, the National Academy of Arts and Sciences, and the American Philosophical Society, among many other honorary appointments. He was an author on some 400 papers and more than 100 book chapters and monographs. He received scores of United States awards and honors for his distinguished research, as well as numerous international awards, including Canada's Gairdner Foundation International Award, Israel's Wolf Foundation Prize in Medicine, Germany's Ernst Schering Prize, the Italian Association of Cancer Research in Rome's Gold Medal, the United Kingdom Society for Endocrinology's Dale Medal, and Switzerland's Dr. Josef Steiner Cancer Research Award. In 2006, Folkman was one of seven people appointed by President Bush to the National Cancer Advisory Board of the National Institutes of Health. Folkman's scientific accomplishments are unequalled—he founded a new field of biology and a new approach to understanding and treating cancer and other diseases. He has mentored and collaborated with hundreds of brilliant colleagues at Children's Hospital Boston and around the world. Yet, Folkman's greatest legacy may be his calling to heal, to improve care for patients, and to teach others to heal with compassion—lessons learned as the son of a rabbi in Columbus, Ohio. Folkman was married to the former Paula Prial (of Fall River, MA). He was the father of two daughters, Laura and Marjorie, and had one granddaughter, Hannah. Bruce A. Chabner, M.D. Editor-in-Chief, The Oncologist Massachusetts General Hospital, Harvard Medical School This week two of my friends died. They did not know each other, but they were intimately connected in their passion and reverence for life. One was a cancer patient, Judy McGinnis, and the other a pioneer in cancer research, Judah Folkman. Both were unforgettable people. Judy McGinnis had been our family's friend for more than 40 years, a generous and gracious woman who had an unquenchable interest in medicine and its progress. More than 30 years ago, she had worked as a laboratory assistant for Wendell Ross at Duke, and had acquired hepatitis C. Five months ago, she learned that she had hepatocellular cancer (HCC). It was inoperable. The only realistic option was sorafenib (Nexavar®), a b-raf and vascular endothelial growth factor (VEGF) receptor inhibitor that was approved for treatment of HCC in October 2007, based on an extension of survival of 5 months. Determined not to sit idly by as the tumor progressed, she chose this new drug. It was neither easy nor straightforward to obtain sorafenib, but she and her husband, Mac, negotiated the hurdles posed by the insurers and the drug distribution system. She remained on therapy for two months, experiencing fatigue and gastrointestinal symptoms, but persisting in the hope that the drug was having an effect. When evidence of tumor progression became clear, she chose hospice care, and died 5 months after diagnosis. It is impossible to determine whether she benefited from the drug, but it did give her, her family, and friends, much needed hope, and this meant a great deal to all of us at the time. The drug's antitumor effects are likely related to VEGF receptor inhibition, and thus the direct result of Judah Folkman's 40-year passion for the concept and implementation of antiangiogenic therapy. Ironically, Judah died suddenly, two days before Judy McGinnis's death. As eulogized at his funeral on January 20, 2008, Judah was a larger-than-life character, a man of incredible intelligence, conviction, and passion. I had first met him when I was a medical student at Harvard, and he was finishing his surgical training. Stories abounded among the medical students about this young man who operated by day and ran a laboratory by night, and had found the first evidence that tumors could elicit new vessel growth. Through the following years, I followed his research and often met him at the National Cancer Institute, and offered help and what limited advice I could muster regarding his efforts to develop antiangiogenic compounds. Several early attempts with steroids, with fungal products, and with peptide fragments of serum proteins showed efficacy in the lab but failed to help patients. the Judah was the which and tumor in the have he The of antiangiogenic therapy has now been and he all the for the the as by others in this he became a mentor and teacher to hundreds of young medical and many of the two in in Boston at his More than a laboratories now study angiogenesis, and a million patients have received antiangiogenic The Prize, which he but have been and for this But the is not as the of Judy McGinnis I that have not Judah Folkman's not know to tumors that from therapy. tumors are but some and others have understanding of the phenomenon of from antiangiogenic that Judah Folkman now know that patients with cancer or or who from or or sorafenib, progress. the drugs are not all patients side effects and are at for drugs be used in with as is with other they be used even in patients tumors are to the of has become a therapy in cancer patients with but antiangiogenic therapy with the first of the that the tumors is so much to about new drugs. small inhibitors with and without effects other are in and may us to the concept of antiangiogenic and even as Judah to the that antiangiogenic drugs cancer in patients. It has been a week for and for many colleagues of Judah Folkman. It has been an week for the of patients who died of cancer in understanding the their and to a Folkman's research. Judy McGinnis but many of us who the she did not in our have to the and the in the C. The C. Institute at United States General one of our and when Judah Folkman died of an heart in to a of the Foundation on January He was I was to write this my with Judah was one of the I to He had been appointed to the Julia Dyckman Andrus of Pediatric Surgery at Judah was long on that make a but on clinical and in pediatric Harvard to as much of the into a that was one of the in my career. are to it it and was followed in a day or two by a to the Dr. C. 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