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In Memoriam |
SEEING BEYOND THE HEADLIGHTS"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.
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A "RABBI-LIKE DOCTOR" |
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 Top A "rabbi-like doctor" The "aha" momentEarly skepticismA scientific legacyFootnotes |
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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.
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THE "AHA" MOMENT |
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TopA "rabbi-like doctor"The "aha" momentEarly skepticismA scientific legacyFootnotes |
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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.
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EARLY SKEPTICISM |
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TopA "rabbi-like doctor"The "aha" momentEarly skepticismA scientific legacyFootnotes |
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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.
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A SCIENTIFIC LEGACY |
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TopA "rabbi-like doctor"The "aha" momentEarly skepticismA scientific legacyFootnotes |
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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.
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FOOTNOTES |
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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. Until perhaps the late 1990s, Judah was rowing against the current, which favored cytotoxic and tumor cell directed therapies. However, in the past decade we have seen how right he was. The wisdom of antiangiogenic therapy has now been clearly established, and he deserves all the credit for staying the course. Along the way, as testified by others in this issue, he became a mentor and teacher to literally hundreds of young researchers, medical students, and colleagues, many of whom filled the two thousand seats in Temple Israel in Boston at his funeral. More than a thousand laboratories now study angiogenesis, and perhaps a million patients have received various antiangiogenic therapies. The Nobel Prize, which he richly deserved but sadly will never receive, would have been insufficient honor and reward for this remarkable man.
But the story is not finished, as the death of Judy McGinnis testifies. I am sure that we have not fully exploited Judah Folkman's dream. We do not know how to select tumors (and patients) that will derive benefit from therapy. All tumors are angiogenic, but some respond and others don't. We have little understanding of the phenomenon of escape from antiangiogenic therapy, something that Judah Folkman doubted would happen. We now know that those patients with renal cell cancer or hepatoma, or metastatic colon cancer, who do benefit from bevacizumab (Avastin®), or sunitinib malate (Sutent®), or sorafenib, will eventually progress. And the drugs are not perfect. Virtually all patients experience side effects and are at risk for major toxicities.
Other important questions remain unanswered. Should these drugs be used in combination with cytotoxics, as is trastuzumab (Herceptin®), and/or with other targeted drugs? Should they be used continuously, even in patients whose tumors are progressing, to slow the rate of growth? Trastuzumab has become a continuous therapy in breast cancer patients with HER-2-positive disease, but we discontinue antiangiogenic therapy with the first sign of progression, despite the fact that the tumors remain angiogenic. There is so much to learn about these new drugs. Cleaner small molecule inhibitors with better toxicity profiles and without broad effects against other kinases are in trials, and may allow us to test the concept of continuous antiangiogenic therapy, and even as Judah predicted, to test the possibility that antiangiogenic drugs might prevent cancer in high-risk patients.
It has been a sad week for me and for many colleagues of Judah Folkman. It has been an equally sad week for the families of patients who died of cancer despite remarkable progress in understanding the disease. To honor their memory, and to win a safer future, we must continue Folkman's unfinished research. Judy McGinnis loved golf, but unlike many of us who play the sport, she did not believe in "Gi'me" putts. Neither does our opponent cancer. We have to finish the hole and put the ball in the cup.
The C. Everett Koop Institute at Dartmouth
Former United States Surgeon General
We lost one of our best and brightest when Judah Folkman died of an apparent heart attack in Denver Airport en route to a meeting of the Angiogenesis Foundation on January 14, 2008. He was 74.
I was asked to write this memoir because my relationship with Judah was unique—and one of the things I felt justly entitled to brag about. He had been appointed to occupy the Julia Dyckman Andrus Chair of Pediatric Surgery at Harvard. Judah was long on those characteristics that make a genius, but short on clinical experience and technical know-how in pediatric surgery. Harvard asked me to squeeze as much of the latter into a six-month tutorial that was one of the brightest lights in my teaching career. Surgeons are apt to say, "I do it because it works." Judah's response was, "Why?" "How?", and was normally followed in a day or two by a solution to the apparent dilemma.
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The first story about Judah that I think is high on the list, took its origin from the first time I operated with him. His arrival in Philadelphia, as I recall, was on a Monday. On Friday afternoon, I scheduled a bilateral operative procedure, repairing two hernias and bringing down two undescending testicles in a very small boy. Nothing else was scheduled—no reason not to give Judah all the time he needed. I explained that I would do the right side first, sharing as much knowledge as I could along the way; he would assist me. Then he would do the left side and I would assist him. I usually took seventeen minutes to do this particular operation on one side, but on this occasion I actually took twenty-five to thirty minutes because of the time expended sharing as much knowledge of the way I did that procedure as I could.
One of the real differences in operating on small children as compared to adults, is that their tissues are much more fragile; they tear easily and must be handled with special care. The best of adult surgeons remark on this phenomenon when they do an occasional baby. Well, one hour and forty-five minutes later, Judah admitted to being in a mess on his side; I agreed. We finally got everything fixed and the youngster off the table, but Judah was depressed. This was before the days of cell phones, etc., but Judah had a phone in constant connection with his office in Boston. He recorded all sorts of things, including his frustration over the difficulties of handling delicate pediatric tissues.
The next morning, Judah and I met about seven o'clock for rounds and he was his old self. "Fingernails! Fingernails!" he cried. "You have long fingernails and I have essentially none." Surgeons are often unaware that little things they do make their technique seem simple and easy. Therefore they fail to pass little tricks on to others. I had not made it as clear as I could have that the way I used my thumbnail of my left hand applying pressure to an underlying index finger helped me a lot with dissection of fragile tissues.
When Judah left me and went back to Boston, the first thing he told his resident staff was to grow a long thumbnail on their non-dominant hand. Watching Judah operate after his return to Boston showed me no deficit in his understanding of operating principles in small babies with fragile tissues.
In 1967, Judah received an appointment to the Boston City Hospital and soon after invited me to speak there emphasizing my esoteric and spectacular experience in pediatric surgery. Among the cases I chose to discuss was a child of about five to seven with a Wilms' tumor on the right side. Surgery of abdominal tumors in those days, twenty years into my forty years of experience in pediatric surgery, was very protocol-driven with reliance on meticulous surgical technique rather than chemotherapy to add to the failsafe cushion. I found the tumor in the right kidney had grown down the right renal vein, filling it and then taking a sharp ninety degree turn to the left cephelad to grow up the vena cava until it made a sharp right angle turn to enter the superior vena cava and descend into the vicinity of the right atrium. I extracted the entire tumor/thrombus still attached to the kidney by the tumor in the renal vein along with the affected kidney.
To photograph a dramatic presentation, after closing the patient's abdomen, I placed the tumor and extended thrombus on his supine body, the tip of the thrombus in the right atrial area and about twenty-four centimeters from its anchor in the right kidney. I then showed a microscopic slide of the tip of the thrombus to prove it was Wilms' tumor. As the slide was shifting to the next, Judah asked the projectionist to back the slide up and he very adroitly pointed out that the tip of the aggregated tumor cells at the very end of the thrombus was a short distance away from the next more proximal tumor cells—but between them there were two blood vessels. So, years before Judah's fame and contributions were primarily associated with angiogenesis, his mind was on the basic cellular biology that made my demonstration possible. Harvard later appointed Judah Professor of Cellular Biology.
One night a few hours before dawn, Judah called me and said that one of his children had sufficient signs and symptoms to suggest appendicitis; would I please see the youngster and take charge. It's never easy to have a doctor or his relative as a patient. When that doctor is a close friend and a colleague, it is worse. When the doctor is a protégé to whom you are trying to impart the art of pediatric surgery, believe me, it does get tougher; when the patient also has a complicating respiratory disease, it is even dicier. I prided myself as much on the management of abdominal pain in children, as I did in the handling of family members under such tension. I had been looking for just such a situation in my ongoing effort to prepare Judah as much as I could; I never thought I would have such an ideal teaching scenario, but I did not expect the Folkman family to be the cast!
I have made it seem as though the physician in charge carried a heavy burden; it is not as great as the physician relative, Judah in this case. And he came through, as you might imagine, with a heartfelt, stellar performance as a surgeon who must have said to himself, "I know as much as I'm being taught," the learning protégé, the loving father of a sick child, a respectful pupil, a supportive husband. After much fence-straddling and soul searching, the decision was made not to operate, and time proved it to be right. The thing I learned that night was that Judah Folkman was a remarkable individual. Certain circumstances forced him into a number of different roles, and he was the star in each.
Making rounds with the residents one non-operating morning in Philadelphia, I asked if anyone had noticed anything unusual about the patient's mother. Only Judah had seen what I saw: The more animated she got, the larger and deeper the hue of a red-purple blush that spread over her lower neck and upper chest. I asked Judah to take over, and he did so and magnificently. It might have been surgical, vascular, family medicine, or psychiatric rounds, or all four combined—so erudite was his presentation.
Judah could always outshine his colleagues in a noncompetitive way. After he returned to Boston from Philadelphia, I made general pediatric surgical rounds with the surgical staff at the Boston Children's Hospital. The other pediatric surgeons on the hospital staff had six to eight patients each; Judah had two. Yet, his remarks on a hernia and an appendectomy, I think it was, were truly outstanding; something for everyone and done modestly, yet with erudition.
Judah Folkman discovered that tumors require blood vessels to support continued growth, angiogenesis. A natural outgrowth of that was his work with antiangiogenesis, which not only revolutionized the treatment of cancer but also of a whole host of other major medical problems, such as diabetes, macular degeneration, coronary disease, ischemia, and wound healing. Others will have more to say about this than will I.
This work has been so monumental that it has threatened to eclipse his many contributions to pediatric surgery, in addition to the pediatric applications of antiangiogenesis.
But no scientific discovery can eclipse Judah Folkman the man: creative and innovative pediatric surgeon, healer in the broadest sense of the word, compassionate physician. Our condolences go to all whose lives he touched—and he never touched them lightly. Meanwhile, we cherish every memory of our loyal colleague and friend.
National Cancer Institute
Four times a year, the National Cancer Advisory Board (NCAB) comes to Bethesda, MD, to give counsel to the National Cancer Institute. In long days that are as much a marathon as a meeting, this group of 23 distinguished scientists and cancer advocates challenges us to do better, both in our science and in the ways we communicate our science. The meetings are always lively and sometimes contentious, but also invaluable.
In July 2006, President Bush, at my suggestion, appointed Judah Folkman to a six-year term on the NCAB. Judah, as anyone who knew him for even a minute quickly recognized, was a quiet man who neither sought nor felt comfortable in the spotlight. But when Judah would seek the chair's recognition to address the NCAB, the room would immediately go silent. Already a legend among his peers, Judah's soft voice commanded attention and respect. Everyone knew that this distinguished, quiet man spoke only when there was truly something to say. We knew that his words would provide unique insights; they would provide a key factual detail gleaned from his thorough knowledge of the subject at hand, along with a vision for the most appropriate direction.
Judah first entered my life when he unexpectedly popped through the door of my laboratory at the University of Michigan, in the Department of Microbiology. A surgeon who, like myself, had roots in Ohio, he was simply curious about what a fellow surgeon was up to in the laboratory. We were friends ever after.
Judah was an admired clinician scientist who didn't know how to say "no," whether in service to the NCI, the National Institutes of Health, or to those who are his living legacy: the legion of students and fellows Judah trained and guided. Many of those men and women are, today, scientific leaders of global renown.
In the later years of his outstanding career, when even his skeptics became his advocates, Judah was also called upon, each day, to answer a long list of calls and E-mails from cancer patients: men and women who were desperate to grasp hope, through the novel therapies Judah was responsible for developing. He never failed to answer every query.
In what is now a poignant memory, just a week before his passing, Judah attended NCI's annual retreat for its intramural scientists. He came, he said, to spend time with our young principal investigators, who were yet another group of bright people Judah could sit with "discussing science." I watched, with a smile, as he spent hours walking from poster to poster.
Judah loved science. But there was another light in his life: his granddaughter, Hannah. It was quite common, in recent years, for Judah to conclude seminars with a picture and his latest story about Hannah. These endings became a chronology of Hannah's joy in discovering science. Whether it was a day in her grandfather's lab or taking his latest book to her school, she was, for her grandfather, the personification of the excitement of scientific awakening. She was the one topic, other than the unexpected discovery at the bench, that made Judah's eyes sparkle with excitement and pride. I know that she—and all of Judah's family—will feel his loss in ways we, his colleagues, simply can't, despite the moist eyes when it dawns on us yet again that we won't see him at the next meeting.
Newsweek writer Claudia Kalb, who co-authored a cover story about Judah and his research, wrote a remembrance of this great man. She recalled his perseverance, his humility, and the creative spark of a brilliant scientific mind now silenced. "You have to think ahead," Judah told her. "Science goes where you imagine it."
It was a very special privilege to have known this giant of medicine and science. I know that each of us, as time goes on, will trade stories about Judah. We will remember his gifts, through the recounting of a story, a little vignette, or a favorite quote—even as we try to accept the fact that his life was much too short.
Vice-chairman, Netherlands Organization of Health Research and Development
The Hague;
Honorary Chairman, VUmc Cancer Center
Amsterdam, The Netherlands
Year after year he spoke for us at the EORTC/NCI New Drug Meeting in Amsterdam. He never missed a meeting, nor did any attendees miss his lectures, despite the pouring rain and dark grey skies. They all came to listen and were enthralled by his serene manner of speaking, conveying to them all his knowledge and experience. It was standing room only in a setting of intense stillness, and at the end of his lecture their appreciation of him ended with a standing ovation. This applause always reminded me of the one Rubinstein received after his last performance in the Concert Hall in Amsterdam. After his lecture he was always surrounded by a multitude of oncologists with their individual questions. Many had to wait for a long time before getting a chance to get his opinion on their patients; still he always stayed and discussed until everyone had their chance to address him.
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Judah and I met in the eighties and have been friends ever since. We often had what I call our Sunday conversations where we exchanged new findings and thoughts. It was a mutual creative link which allowed us to brainstorm in an undisturbed session. He was a coach and father to not only the scientists in his lab at Children's, but to an entire population of future angiogenesis scientists. One of his students I am proud to mention, Henk Verheul, has just been appointed chief of the Department of Medical Oncology at the Free University, in Amsterdam. This is also a continuation of Judah's legacy.
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