Judah Folkman

Moses Judah Folkman
Born (1933-02-24)February 24, 1933
Cleveland, Ohio
Died January 14, 2008(2008-01-14) (aged 74)
Denver, Colorado
Citizenship American
Institutions Harvard Medical School
Alma mater The Ohio State University, Harvard Medical School
Known for angiogenesis
Notable awards Charles S. Mott Prize (1997)
Massry Prize (1997)
Keio Medical Science Prize (1998)

Moses Judah Folkman (February 24, 1933 – January 14, 2008) was an American medical scientist best known for his research on tumor angiogenesis, the process by which a tumor attracts blood vessels to nourish itself and sustain its existence. He founded the field of angiogenesis research, which has led to the discovery of a number of therapies based on inhibiting or stimulating neovascularization.[1]

Early life

Born in 1933 in Cleveland, Ohio, Judah 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.[2]

Career

Folkman graduated from The Ohio State University in 1953, and then Harvard Medical School in 1957.[3] While a student at Harvard Medical School, he trained under Robert Edward Gross[4] and also worked on a prototype pacemaker, work that he never published.[5] After his graduation, he started his surgical residency at Massachusetts General Hospital. In 1960 his residency was interrupted when he was drafted in the United States Navy and did research for the Navy until 1962 at the National Naval Medical Center in Bethesda, Maryland. During that time, he studied the use of silastic for the sustained release of lipophilic drugs; the 1964 publication of that work helped inspire the technological development of the Norplant implantable contraceptive at the Population Council.[6]:117[7] The navy research was focused on developing artificial blood; in the course of testing potential products to see if they could keep alive thymus glands taken from rabbits, he noticed that tumors in the gland couldn't grow, as they did if the glands were perfused with blood. His curiosity as to why led to his work on angiogenesis.[2]

After his two years work for the navy, Folkman completed his residency at Massachusetts General Hospital. He worked as an assistant surgeon at Boston City Hospital, then trained further in pediatric surgery at Children’s Hospital of Philadelphia under C. Everett Koop.[4] In 1967 he was appointed surgeon-in-chief of Children's Hospital Boston at the age of 34. Folkman was appointed the Julia Dyckman Andrus Professor of Pediatric Surgery at Harvard Medical School in 1968, where he was also Professor of Cell Biology. He was the youngest full Professor at Harvard Medical School in history.[2] 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.[2]

Work on angiogenesis

In 1971, he reported in the New England Journal of Medicine that solid tumors are angiogenesis-dependent. He hypothesized that there was an unknown "factor" that tumors secreted to help it increase its blood supply, and that if that factor could be blocked, tumors would wither and die. Though his hypothesis was initially disregarded by most experts in the field, Folkman persisted with his research. He and collaborators, who included Bert L. Vallee, soon identified the already-known fibroblast growth factor as an angiogenic factor, but the team's work showed that there were additional, unknown factors.[1] To help accelerate the work, Folkman started collaborating with industry.[4] In 1974 Harvard University and Monsanto signed a ten-year industrial-funded research grant to support his cancer research, which at that time was the largest such arrangement ever made; medical inventions arising from that research were the first for which Harvard allowed its faculty to submit a patent application.[3][4] Robert Langer worked as a postdoc in Folkman's lab during this time, concentrating on using silastic and other materials to deliver drugs.[4]

In the mid to late 1980s, two other angiogenic factors were identified by other labs that had been inspired by his work: angiogenin and VEGF.[4] With the factors identified, drug discovery could begin. When the Monsanto agreement (which yielded no products for Monsanto) ended, Folkman started receiving research funding from Takeda and then from a startup company, Entremed, that put half its venture capital funding into research in the Folkman lab.[4] Donald E. Ingber soon discovered that a fungus, Aspergillus fumigatus, secreted a chemical, fumagillin, that inhibited angiogenesis. Takeda performed medicinal chemistry to optimize it, leading to development of TNP-470.[4] Folkman's team later tested it in adults with hemangiomas; they also used interferon alpha, an already approved drug that they had already shown to be an angiogenesis inhibitor, to treat infants with hemangiomas in some of the first clinical trials of angiogenesis inhibitors which were published in 1992.[8] In these trials they also studied the levels of fibroblast growth factor in the urine of the trial subjects and published that work in 1994; these were some of the first explorations of the of biomarkers in clinical trials as surrogate endpoints.[4][9] In 1991 Michael O"Reilly, working in the Folkman lab with Entremed funding, discovered the first endogenous angiogenesis inhibitor, angiostatin and then another, endostatin. Entremed began developing them and soon struck a collaboration with Bristol-Myers, which caught national interest and spurred further investment in angiogenesis inhibitors by other pharma companies.[4][10]

In 1993 he surprised the scientific world by hypothesizing that angiogenesis is as important in blood cancers as it is in solid tumors,[11] and the next year he published work showing that a biomarker of angiogenesis was higher in all people with cancer, but especially high in people with blood cancers, and other evidence of the role of angiogenesis in blood cancers emerged as well.[11] Meanwhile, a member of his lab, Robert D'Amato, was looking for angiogenesis inhibitors, and discovered that thalidomide inhibited angiogenesis in 1994.[12][13] Around that time, the wife of a man who was dying of multiple myeloma and whom standard treatments had failed, called Folkman asking him about his anti-angiogenesis ideas.[8] Folkman convinced the patient's doctor to try thalidomide, and that doctor ended up conducting a clinical trial of thalidomide for people with multiple myeloma in which about a third of the subjects responded to the treatment.[8] The results of that trial were published in the New England Journal of Medicine in 1999.[8][14]

In 2004, the first angiogenesis inhibitor, bevacizumab (Avastin), was approved by the FDA, as a treatment for colon cancer. It is a recombinant humanized monoclonal antibody that was discovered and developed by Napoleone Ferrara. a scientist at Genentech.[15][16] Avastin and a similar drug, Lucentis, were also later approved for treating macular degeneration.[2] After further work was done by Celgene and others, in 2006 the U.S. Food and Drug Administration granted accelerated approval for thalidomide in combination with dexamethasone for the treatment of newly diagnosed multiple myeloma patients.[8][17]

Controversy

Dr. Folkman's approach generated a lot of controversy, and not only as his views contradicted the established knowledge based on how cancers started and were treated. In addition, he was a clinician and not a traditional researcher. His efforts to start a debate based on his observations while removing cancers from patients, were met with a dismissive attitude and open criticism. He was also subject to many attacks because of his deal with a corporation (Mosanto) to fund his research (after he couldn't get a traditional research grant), which is now described as "having paved the way". The challenges he experienced are well described in the "Surgeons Scientist" chapter of the book co-written by Senator McCain and Mark Slater.

Awards

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 others. He was the author of some 400 papers and more than 100 book chapters and monographs and received scores of United States awards and honors for his research as well as numerous international awards, including the George Ledlie Prize from Harvard, Canada's Gairdner Foundation International Award, Israel's Wolf Prize, Germany's Ernst Schering Prize, the United Kingdom Society for Endocrinology's Dale Medal in 2000,[18] Prince of Asturias Award and Switzerland's Dr. Josef Steiner Cancer Research Award.[19] In 2006, Folkman was one of seven people appointed by President Bush to the National Cancer Advisory Board of the National Institutes of Health.

For his discoveries which originated the concept and developed the field of angiogenesis research, Folkman was awarded the Wolf Prize in Medicine in 1992.

He was awarded the Massry Prize from the Keck School of Medicine, University of Southern California in 1997.

Death

Folkman died of a heart attack in Denver on January 14, 2008 at the age of 74 en route to deliver the 2008 Keynote Address at the Keystone Symposium (Molecular Mechanisms of Angiogenesis in Development and Disease) in Vancouver, British Columbia.[20]

He was survived by his wife, Paula, whom he met and married while doing his surgical residency,[4] two daughters, and a granddaughter.[20]

References

  1. 1 2 Cao, Yihai; Langer, Robert (9 Sep 2008). "A review of Judah Folkman's remarkable achievements in biomedicine". Proc Natl Acad Sci U S A 105 (36): 13203–13205. doi:10.1073/pnas.0806582105. PMC 2533169. PMID 18772371.
  2. 1 2 3 4 5 Children's Hospital Boston Remembering Judah Folkman: Biography
  3. 1 2 Harvard Medical School Bio at Harvard Medical School
  4. 1 2 3 4 5 6 7 8 9 10 11 Patricia K Donahoe. Judah Folkman: 1933–2008. A Biographical Memoir National Academy of Sciences, 2014
  5. ↑ Academy of Achievement. Jun 17, 2010 Judah Folkman Biography, Foundations for Cancer Therapy
  6. ↑ Laura J. Frost and Michael R. Reich Access: How Do Good Health Technologies Get to Poor People in Poor Countries? Bibliomotion, Inc., 2014. ISBN 9781629560304
  7. ↑ Judah Folkman and David M. Long. The Use of Silicone Rubber as a Carrier for Prolonged Drug Therapy. J Surg Res. 1964 Mar;4:139-42. PMID 14130164
  8. 1 2 3 4 5 Bielenberg DR, D'Amore PA. Judah Folkman's contribution to the inhibition of angiogenesis. Lymphat Res Biol. 2008;6(3-4):203-7. PMID 19093793
  9. ↑ Nguyen M, Watanabe H, Budson AE, Richie JP, Hayes DF, Folkman J (March 1994). "Elevated levels of an angiogenic peptide, basic fibroblast growth factor, in the urine of patients with a wide spectrum of cancers". J. Natl. Cancer Inst. 86 (5): 356–61. doi:10.1093/jnci/86.5.356. PMID 7508518.
  10. ↑ John Crewdson for the Chicago Tribune. April 11, 1999 Crucial Test For Cancer Drug
  11. 1 2 Folkman J. Angiogenesis-dependent diseases. Semin Oncol. 2001 Dec;28(6):536-42. Review. PMID 11740806
  12. ↑ D'Amato RJ, Loughnan MS, Flynn E, Folkman J (1994). "Thalidomide is an inhibitor of angiogenesis". Proceedings of the National Academy of Sciences of the United States of America 91 (9): 4082–4085. Bibcode:1994PNAS...91.4082D. doi:10.1073/pnas.91.9.4082. PMC 43727. PMID 7513432.
  13. ↑ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2268723/
  14. ↑ Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, Munshi N, Anaissie E, Wilson C, Dhodapkar M, Zeddis J, Barlogie B (November 1999). "Antitumor activity of thalidomide in refractory multiple myeloma". N. Engl. J. Med. 341 (21): 1565–71. doi:10.1056/NEJM199911183412102. PMID 10564685.
  15. ↑ Andrew Pollack for the New York Times. February 27, 2004 F.D.A. Approves Cancer Drug From Genentech
  16. ↑ Ribatti D (2008). "Napoleone Ferrara and the saga of vascular endothelial growth factor". Endothelium 15 (1): 1–8. doi:10.1080/10623320802092377. PMID 18568940.
  17. ↑ "FDA Approval for Thalidomide". National Cancer Institute. Retrieved 8 January 2012.
  18. ↑ Society for Endocrinology Medal Winners
  19. ↑ The Dr. Josef Steiner Cancer Research Foundation
  20. 1 2 Pollack, Andrew (January 16, 2008). "Judah Folkman, Researcher, Died at 74 on January 15, 2008". The New York Times. Retrieved 11 April 2010.

Further reading

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