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Nothing in biology makes sense except in the light of evolution.
Theodosius Dobzhansky 1973 (1)
For a man of science there is no separate science of medicine or physiology, there is only a science of life.
Claude Bernard 1865 (2)
By viewing the process of angiogenesis as an ’organizing principle’ in biology, intriguing insights into the molecular mechanisms of seemingly unrelated phenomena might be gained...
Judah Folkman 2007 (3)
MEDICINE DOES NOT END IN HOSPITALS...
When Judah Folkman died earlier this year, a generation may have passed. His was the last cohort of chief resident physicians and surgeons to make sense of medicine in the light of experimental biology. Products of the post-WWII era, when hands-on bench work was the rule in medical schools, Folkman’s generation was given further training in labs run by the Army, Navy, or the NIH. They returned to universities where scientific curiosity and laboratory experience—perhaps even discovery—were expected. It may well have been "the greatest generation" of medicine; its members presided over an era when students flocked from every corner of the globe to learn experimental medicine in America. These days, sad to say, modern "health care" (a.k.a. medicine) with its competing demands of evidence-based practice, center-based bureaucracy, drug-based clinical trials, gadget-based imagery, and "translational" research, has turned the best and brightest away from the lab bench and toward the spreadsheet.
It has occurred to me that the Folkman generation lived out in full predictions made by Claude Bernard (1813–1878) for the future of medical science in his 1865 "Introduction à l’étude de la médecine expérimentale" (2)
. At the time of its appearance, Bernard had become a Professor of Physiology at the prestigious Collège de France. In one brief decade (between 1848–1857), he had discovered the world of the internal milieu, had entered the heart of a dog by means of a catheter, and had established that blood glucose was derived from liver glycogen. He defined precisely the toxic actions of curare and carbon monoxide, discovered that pancreatic secretions broke down ingested fats, and produced experimental diabetes by puncture of the fourth ventricle in rabbits (4)
. He was also the only European of his day to take note of the physiological work of William S. Beaumont, FASEB’s forefather (2
, 5)
. Considering that he was born in Beaujolais, I’d call Claude Bernard "all of FASEB in one full bottle."
As the star of Bernard’s reputation rose, the level of his laboratory accomplishments declined. In response to fallow times, instead of falling on his sword, he fell to the pen, and his efforts were splendidly rewarded. Bernard’s "Introduction," written in clear, spare prose, became appreciated as a masterpiece of French literature and was taught in all the lycées. It was also a manifesto that transformed Western medicine from an observational into an experimental science. Medicine necessarily begins with clinics, since they determine and define the object of medicine. But for a man of science there is no separate science of medicine or physiology, there is only a science of life ... in my opinion, medicine does not end in hospitals, as is often believed, but merely begins there (6)
.
AN ORGANIZING PRINCIPLE IN BIOLOGY
Judah Folkman’s science began in hospitals, was hatched in the lab, and ended up improving human health the world over. Before he was 40, Folkman had made two major contributions to medical science; he lived to see each withstand the test of time.
His best-known work, the formulation of angiogenesis and anti-angiogenesis, has held sway in experimental biology for decades. Pub Med lists 34,109 citations since Folkman’s first paper in 1971 (7)
and "angiogenesis" has ranked among the top five key words in The FASEB Journal since we’ve kept records (8)
. In 1971, he isolated the first tumor-derived angiogenic factor and proposed that tumors require new blood vessels to grow and multiply (7)
. Tumor angiogenesis, per se, was not an entirely novel proposal. Eli Moschkowitz, of Mt. Sinai, known as the discoverer of thrombotic thrombocytopenic purpura, was the first to raise the notion of "angiogenesis" in pathology (9)
. Then, Philippe Shubik of Oxford discovered that "tumor angiogenesis" was due to a substance or substances that could pass a membrane filter to induce new blood vessels in the hamster cheek pouch model (10)
.
Folkman went these observations one better. Almost immediately after he had isolated a crude "tumor angiogenesis factor" in February of 1971, he spelled out the import of his work in November (11)
. He next proposed that tumors not only provided growth substances for angiogenesis, but also that cancers were absolutely dependent on these factors to in order to survive and kill their hosts:
It seems appropriate to speculate that the inhibition of angiogenesis, i.e.,anti-angiogenesis, may provide a form of cancer therapy worthy of serious exploration (12)
Today, angiogenesis antagonists and stimulators are directed at cancer, e.g., Avastin® (bevacizumab) and at macular degeneration, e.g. Lucentis® (ranibizumab), and have undergone testing for conditions that range from coronary disease to rheumatoid arthritis and endometriosis. A generation after Folkman’s paper in The Journal of Experimental Medicine (Merci, maitre Bernard, for the name), more than 10 new cancer drugs are on the market, and more than 1.2 million patients worldwide are receiving anti-angiogenic therapy (12)
. The extension of Folkman’s concept from the treatment of cancer to the preservation of sight comes from making sense of pathology in the light of biology:
Angiogenesis—the process of new blood-vessel growth—has an essential role in development, reproduction and repair... However, pathological angiogenesis occurs not only in tumour formation, but also in a range of non-neoplastic diseases that could be classed together as ‘angiogenesis-dependent diseases’. By viewing the process of angiogenesis as an ’organizing principle’ in biology, intriguing insights into the molecular mechanisms of seemingly unrelated phenomena might be gained (3)
Folkman’s heuristic proposal, that angiogenesis is an organizing principle in biology, qualifies as a true discovery, the requirement for which was also defined by Claude Bernard:
We generally call a new fact a discovery; but I think that the idea which flows from that fact is the true discovery (14)
FROM KITCHEN TO BANQUET HALL
Bernard held an exalted view of biology—the science of life—and reassured the young investigator that there was light at the end of the laboratory tunnel:
If a comparison were required to express my idea of the science of life, I should say that it is a superb and dazzlingly lighted hall which may be reached only by passing through a long and ghastly kitchen (15)
Judah Folkman’s path to the dazzling hall was shorter than most, while the kitchens in which he labored were by no means ghastly. And while the story of angiogenesis is well appreciated, Folkman made an earlier discovery in the course of medical training that put him on the road to angiogenesis; it was based on the observations that tumors leak hormones slowly into the bloodstream. Although millions of women the world over use contraceptives based on Folkman’s discovery—the story of its application is largely unknown.
Folkman was born in Cleveland, attended Ohio State University, and as an undergraduate joined the experimental physiology laboratory of Dr. Robert Zollinger, a professor of surgery, who was no mean scientist himself. Like Bernard, he was a student of normal and abnormal pancreatic secretion: he discovered that non-beta islet cell tumors secreted gastrin, which induced intractable peptic ulcers, a condition now known as the Zollinger/Ellison syndrome (16)
. It did not escape Folkman’s notice that tumors secrete bioactive materials.
From Ohio State, Folkman was admitted to Harvard Medical School where, owing to skills developed in Zollinger’s animal laboratory, he was taken under the wing of Robert E. Gross, Chief of Surgery at Children’s Hospital. Gross’s team, interested in repairing cardiac defects in infants, soon appreciated the importance of controlling the conduction system during surgery, and Folkman was present as the first internal and external pacemakers entered the operating room.
After Harvard, he began internship and residency at Massachusetts General Hospital, but after two years was drafted by the Navy. In keeping with the fast track open to Harvard surgeons, he was assigned to the National Naval Medical Center. His first assignment there was to develop a blood substitute—"When I was drafted, I was upset at the disruption to my surgical training," he told an interviewer (13)
. Yet, his most widely applied discovery was made in Bethesda, "But it turned out to be a terrific blessing in disguise (13)
."
The "terrific blessing" turned into a matrix of scientific, social, and philanthropic interaction, featuring the National Naval Medical Center, the Dow-Corning Company, the Population Council (an independent research center working at Rockefeller University), and Wyeth Pharmaceuticals. The result: implantable contraceptives that have now been used by 15 million women in 60 countries in every corner of the globe. The development was due, in part, to the "doctor draft" of the Korean war and its aftermath as some of the draftees found their way into labs at Walter Reed, the Bethesda Naval Hospitals, and the NIH. It was the dawn of the golden age at the Bethesda campus.
THE ENDOCRINE PACEMAKER
At the National Naval Medical Center, Folkman and Edmunds tried to form an "Endocrine Pacemaker for Complete Heart Block" (17)
by implanting raw suspensions of cardiac stimulants such as triiodothyronine directly into dog hearts. They were out to relieve heart block biologically by implanting tissue extracts or pure hormones instead of the electrical devices Folkman had studied at Harvard. Looking for ways to mimic the geometry of real endocrine glands, and to avoid grinding up T3 tablets before they were injected into the dog’s heart, Folkman and David Long sought to shield the active hormone with a number of synthetic and natural polymers, among them the biocompatible polymer Silastic® from Dow-Corning. To label the injection site, they enclosed a lipophilic dye, Trypan blue. To their surprise, when they opened the chest a few days later, they found that the Silastic® implants were absolutely pale: the dye had slowly leaked out.
It turned out that other drugs, dyes, and anesthetics could also be delivered in this fashion: Zollinger’s student had finally found a way to leach bioactive substances into the circulation (18)
. Years later, the concept was patented and assigned to Dow-Corning (Midland, Michigan). Sheldon Segal, then responsible for research at the Rockefeller Foundation’s Population Council, described the next steps:
I learned about the diffusion of vital dye from Silastic® in 1966 while hosting a Dow-Corning representative (Silas Brady) in the Rockefeller University faculty dining room overlooking the East River. He told me that Judah, also making use of the bio-compatibility feature, had coated experimental pacers, to prevent fibrosis when implanted in heart muscle but, alas, discovered to his surprise that the dye had diffused out of the Silastic®. That was Judah’s Eureka! moment. Mine was when I heard the story from Silas (19)
Segal’s moment was also Folkman’s: they had developed the endocrine pacemaker. Segal expanded on that moment by testing the release rate of steroid hormones from Silastic®. He found that synthetic progestins could be used in a system small enough to be a biocompatible subdermal contraceptive implant and could have a long-acting lifespan (18)
. After acquiring access to an appropriate contraceptive progestin (levonorgestrel) from Wyeth, Segal explained the Council’s work to Folkman who immediately agreed to waive royalty rights for any product that might come out of the Council’s work and supported its cause with Dow-Corning. Ultimately, the Council received the waivers necessary to justify the major investment that would be required. Since its first launch in Europe in 1983, the growth in popularity of Norplant®, or an authorized version has been steady—from 5 million worldwide users in 1990, to 10 million in 2001, and 15 million by the end of 2006. An additional 3 million women use a later version (Jadelle®) (19)
.
BACK TO THE LAB
These days, smart, well-motivated young docs in training are persuaded by their local sachems to join "Centers of Excellence in Health Care Delivery" or large multi-centric "wellness" surveys. We could do worse than to ask the best and brightest of these to spend some time in labs like those of Bethesda Naval, Walter Reed, or the NIH—or simply, to get back to the nearest bench in a good lab. It would benefit not only experimental medicine and biology, but also, as the career of Judah Folkman shows, humankind.
Claude Bernard would be on board:
I tell those whose path leads them toward theory or toward pure science, never to lose sight of the medical problem, which is to preserve health and cure disease. I tell those whose career, on the contrary, guides them toward practice, never to forget that if theory is meant to enlighten practice, practice in turn should be of use to science... Experimental scientific medicine will thus become the achievement of us all; and every one of us will make his own useful contribution (20)
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FOOTNOTES
The opinions expressed in editorials, essays, letters to the editor, and other articles comprising the Up Front section are those of the authors and do not necessarily reflect the opinions of FASEB or its constituent societies. The FASEB Journal welcomes all points of view and many voices. We look forward to hearing these in the form of op-ed pieces and/or letters from its readers addressed to journals@faseb.org
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