The field of cancer therapy is orphaned; Judah Folkman, “the father of angiogensis”, died two days ago, at age 74, of a heart attack.
Judah, the son of a rabbi, was a visionary scientist with an uncommon compassion for his patients. I remember a presentation he gave at the American Society of Clinical Oncologists several years ago, where he was honored for his lifetime achievements. He was an absolutely mesmerizing speaker, describing his struggles in demonstrating experimentally his theories about tumor angiogenesis (don’t despair; I’ll explain in a minute). It was a triumphant speech. Judah had an unshakable conviction in his theory. He had no second thoughts about demolishing long entrenched opinions and received wisdom, doing it with grace and good humor, to boot. His detractors were not as gracious; he encountered virulent skepticism and criticism of his work, which sometimes got ugly and personal. At long last, he prevailed, and the very same people who had criticized him at every turn were in the audience, applauding. Sweet revenge, I thought. But he did not dwell on his struggles. Instead, he projected on the giant screen the picture of a baby’s head grotesquely deformed by the growth of abnormal blood vessels (infantile hemangioma). The face was grotesquely deformed, swollen with masses of blood vessels so that it was hard to make out the normal features of a face. He meticulously described the treatment with the experimental drugs that he had developed based on his theories. And then. the moment of triumph: A picture of a totally normal, beautiful baby following a few weeks of therapy. The normally reserved audience of physicians and researchers erupted in a thunderous applause. Many in the hall, and Judah, himself, had to wipe a tear of joy at this marvelous “miracle”.
Angiogenesis (angio- blood vessel; genesis—creation) is the process of creating new blood vessels, mainly small ones called capillaries. These are tiny vessels of microscopic diameter and a thin wall of one cell width. But despite, or maybe because, of their diminutive size, capillaries are of enormous importance—they deliver the oxygen and nutrients from blood to tissue. Without them—no oxygen, no nutrients, no life.
Now, here is the hooker: They supply tumor tissue just as well as normal tissue. In fact, tumors secrete several proteins in an attempt to attract new vessels toward them, chief among them is Vascular Endothelial Growth Factor, or VEGF.
Here comes Judah
Dr. Folkman made an astute observation. When he implanted tumor cells under the skin of mice, they started dividing as expected. But then, when the tumor reached a volume of about 1 mm³, growth stopped in its tracks. And there the tumor sat—no growth. But after a while, new blood vessels started growing toward the tumor, growth took off again and even metastasized to new locations. So the logic was simple: Inhibit the growth of blood vessels, and you inhibit the growth and spread of tumors. The reasons for skepticism and criticism were myriad: “everybody knows” that tumors don’t need blood supply, and how do you inhibit the “bad” blood vessels without affecting the normal ones? And so on, and so on. In fact, the critics, some of them serving on NIH grant review committees, tried to choke off his research by rejecting his grant application. Poor science, naїve, undocumented claims; these were some of the choice reasons for rejection.
Judah was undeterred by the criticisms and rejections. He received support from industry (for which he was roundly criticized by, among others, the same people who had denied him NIH support), and proceeded to do the experiments. In the end, the facts spoke for themselves, and loudly. His theory about tumor dependence of blood supply proved correct. And as common in science, his discoveries led to further discoveries: The factors that attract blood vessels toward the tumor were identified. Other factors secreted by the tumors were shown to inhibit angiogenesis, and it became clear that it is the balance between the Ying and the Yang that determines the degree of tumor angiogenesis. Judah identifies two proteins that were inhibitory of angiogenesis. These were the proteins that caused the little baby’s miraculous cure. Genentech created an antibody molecule that inhibited VEGF. The drug, called Avastin, is now a mainstay of therapy for colon cancer, lung cancer, kidney cancer, breast cancer, and… the list gets longer every time I check. Even macular degeneration is treated with anti-VEGF. Over 20 other anti-angiogenic drugs are in various stages of development.
What a legacy. Thank you, Judah, for your gift to medicine and to humanity. Your courageous, and sometimes discouragingly lonely battle has been an inspiration to every scientist.