Judah Folkman (1933-2008): The Rabbi-like Doctor

MARK B. ABELSON, MD • ARTHUR H. NEUFELD, PHD

Success and innovation in science are guided by many things, but persistence, constant learning, and noticing what others overlook may be the most important skills of a scientist. In a 1999 interview, Judah Folkman, MD, mentioned that, as a child, every night during dinner his parents asked him and his siblings what they learned that day and showed rapt interest in what their children had to say — as if their children's new knowledge was new to them too. He was also influenced by his teachers, who often challenged their students to think of solutions outside of those provided by the textbook.¹ On trips to the hospital with his father, a rabbi, the young Judah observed that doctors had the chance to directly affect a patient's health. When he told his father, that he wanted to be a doctor, his father said, "So you can be a rabbi-like doctor." These childhood lessons of constant adaptive learning, service, and healing would guide Dr. Folkman's research and scientific explorations.

The synergy of Judah Folkman's curiosity, persistence, and intelligence was evident at an early age. As a freshman at Ohio State University, Folkman designed a mechanism to cool the liver and avoid organ damage during surgery and published his first paper.² Then, accepted to Harvard Medical School at 19, Folkman helped develop the first implantable pacemaker.³ During his surgical residency at Massachusetts General Hospital, Judah Folkman was drafted into the US Navy.

While performing biomedical research at the National Naval Medical Center in Bethesda, MD, Dr. Folkman and a colleague, Fred Becker, MD, received the assignment to investigate potential blood substitutes that could be stored for emergency use on naval ships. Dr. Folkman was experimenting with seeding rabbit thyroid gland with murine cancer cells and perfusing the gland with blood substitute, when he noted an important trend in tumor growth. He discovered that, while tumors in the gland formed in vitro, their growth was limited. In a living mouse, tumors grew vigorously when the same cancer cells were implanted. At the time, the only accepted cancer treatments involved chemotherapy and radiation — poisons that indiscriminately killed cells, cancerous and benign. What if, Dr. Folkman began to wonder, cancer could be halted simply by cutting off its blood supply?

This unorthodox hypothesis became the basis for Dr. Folkman's research career and ultimately led to a revolutionary innovation in theory: angiogenesis. In 1971, Dr. Folkman and colleagues published a paper in the New England Journal of Medicine, announcing the theory that tumor growth was dependent on blood supply and induced blood vessel formation, ie, angiogenesis.⁴

While his discovery would eventually prove ground-breaking, contemporary science was not ready for these ideas. Skepticism and resistance were waiting for Dr. Folkman at each new breakthrough. Peers categorized "angiogenesis" as a type of inflammation and believed that vessels grew out of, rather than toward, tumors, saw no credibility in his arguments that a tumor angiogenesis factor (later known as vascular endothelial growth factor [VEGF]) existed, and for years criticized his lack of scientific evidence. The National Cancer Institute turned down his application for a grant. In hindsight, Dr. Folkman commented, "If your idea succeeds, everybody says you're persistent. If it doesn't succeed, you're stubborn."⁵

Dr. Folkman and his research team persevered, convinced that the theory was correct and driven by the chance to make a difference. Interferon-alpha, the first angiogenesis inhibitor, was discovered by his postdoctoral fellow Bruce Zetter, PhD, in 1980.⁶ Further research led to the discovery of basic fibroblast growth factor as the first angiogenic molecule by Michael Klagsbrun, PhD, and Yuen Shing, PhD, working with Dr. Folkman.⁷ In 1989, the first antiangiogenic human use of interferon-alpha in treating pediatric hemangiomas proved highly successful, causing complete remission of the tumor in some patients.^8,9 Other angiogenesis inhibitors were discovered throughout the early 1990s, with the first report of a complete and sustained human cancer remission by TNP-470 in 1998.¹⁰

The discovery of VEGF opened the door to further developments. In February 2004, bevacizumab (Avastin, Genentech) was approved by the Food and Drug Administration (FDA) for the treatment of metastaticcolorectal cancer as an adjunct to standard chemotherapy. Folkman's initial simplistic view of angiogenesis has evolved into an understanding of the complex angiogenic cascade: (1) stimulation of endothelial cells; (2) activation of endothelial cells to express specific growth factors; (3) proliferation of endothelial cells; (4) recruitment of monocytes and/or leukocytes; and (5) formation of new capillaries.¹¹ Moreover, drugs in development target unique growth factors and intervene at specific phases of the cascade.

Today, the Folkman Laboratory at Boston Children's Hospital houses a diverse group of researchers investigating different aspects of angiogenesis. Folkman encouraged his colleagues to further science by thinking outside of the box, and he even kept an ongoing list of scientific questions on the chalkboard for which he challenged his researchers to find solutions.

Dr. Folkman's research reaches beyond oncology to applications in other fields and is notably present in the applications of angiogenesis research in blinding ophthalmic diseases caused by excessive blood vessel growth in the retina, including diabetic retinopathy (DR) and wet age-related macular degeneration (AMD). When Anthony Adamis, MD, a young ophthalmologist interested in diabetic retinopathy, attended a lecture by Dr. Folkman at the Schepens Eye Research Institute in 1989, he realized, "It was just a marriage that was so appropriate … the eye and blood vessels. Vascularization and angiogenesis. The main reason people go blind."

Dr. Adamis earned a spot in Dr. Folkman's laboratory and Dr. Folkman advised him that, to continue learning all that there was to know about angiogenesis, he "needed to eat, sleep, drink, and dream angiogenesis."⁵ Dr Adamis' research exposed links between angiogenesis and DR and the important role of VEGF in the process. Bevacizumab is currently in phase 3 clinical trials for the treatment of DR. Dr. Adamis also played an integral role in development of a drug approved for treating wet AMD, pegaptanib sodium (Macugen, OSI/Pfizer).

Another ophthalmologist interested in Dr. Folkman's work, Robert D'Amato, MD, joined the team of researchers in the Folkman Lab in 1992 and focused on the potential to use antiangiogenesis treatments for AMD. Dr. D'Amato was able to show that oral doses of thalidomide could block the growth of new blood vessels in rabbit eyes.¹²

In December 2004, pegaptanib became the first FDA-approved anti-VEGF angiogenesis inhibitor for wet AMD. Pegaptanib is a selective antagonist to the VEGF isoform 165 and blocks VEGF actions to prevent the growth of abnormal new vessels and leakage of fluid and blood in the retina. Off-label use of bevacizumab has proved effective in wet AMD treatment, as well as a fragment of bevacizumab — known as ranibizumab (Lucentis, Genentech) — which is FDA-approved for treatment of wet AMD. Ranibizumab inhibits VEGF activity by competitively binding with VEGF and is injected intravitreously. Monthly injections of ranibizumab have shown dramatic success in recovering or stabilizing vision.¹³ With these therapies, Dr. Folkman's angiogenesis research led to the reality of preventing vision loss in people with macular degeneration.

While the scientific community suffered a great loss with Dr. Judah Folkman's passing in January, his discoveries, innovation, and passion for the field will certainly not be forgotten. At least 10 angiogenesis inhibitors have been FDA-approved for various diseases, with at least 50 angiogenesis inhibitors in clinical trials worldwide and more than 1000 laboratories conducting angiogenesis research. It is clear that the extent of Dr. Folkman's discoveries will continue to be expanded for many years to come. In a 2006 interview with the Harvard Medical Bulletin, Dr. Folkman commented:

"When Verdi was in his 70s, people asked him what his best opera was, and he answered, 'I haven't written it yet.' When he was close to 80, he wrote Falstaff. For me, the ideas keep coming, and maybe because of experience, they're better and better. As long as these kinds of ideas are coming and we're working on them, I should keep on going."¹⁴

As a scientist, philosopher, educator, and colleague, Dr. Judah Folkman will be deeply missed. RP

REFERENCES

1. Judah Folkman interview. Academy of Achievement Web site. http://www.achievement.org/autodoc/page/fol0int-1. Updated November 2007. Accessed January 25, 2008.
2. Burch BH, Traphagen DW, Folkman MJ, et al. Temporary aortic occlusion in abdominal surgery. Surgery. 1954;35:684.
3. Folkman J, Edmunds LH Jr. Endocrine pacemaker for complete heart block. Circ Res. 1962;10:632-641.
4. Folkman J. Tumor angiogenesis: therapeutic implications. N Eng J Med. 1971;285:1182-1186.
5. Cooke R. Dr Folkman's War: Angiogenesis and the Struggle to Defeat Cancer. New York, NY: Random House; 2001.
6. Birmingham K. Judah Folkman. Nat Med. 2002;8:1052.
7. Shing Y, Klagsburn M, Folkman J. A new method for purifying heparin-binding growth factors. Ann N Y Acad Sci. 1989;556:166-172.
8. Folkman J. From the lab to the clinic: one investigator's journey. J Law Med Ethics. 2002;30:361-366.
9. White CW, Sondheimer HM, Crouch EC, et al. Treatment of pulmonary hemangiomatosis with recombinant interferon alfa-2a. N Eng J Med. 1989;320:1197-1200.
10. Kudelka AP, Verschraegen CF, Loyer E. Complete remission of metastatic cervical cancer with the angiogenesis inhibitor TNP-470. N Eng J Med. 1998;338:991-992.
11. Augustin HG. Antiangiogenic tumour therapy: will it work? Trends Pharm Sci. 1998;19:216-222.
12. D'Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci. 1994;91:4082-4085.
13. Folkman J. Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discovery. 2007;6:273-286.
14. McCaffrey P. The thin red line. Harvard Med Alumni Bull. 2006;80.