Sometimes great discoveries emerge slowly, after decades of trials and errors. At other times, ingenious ideas seem to strike from out of the blue. Such was the case with the Nobel Prize-winning findings by Sir John Vane, who—over the course of a weekend—cracked a 70-year-old mystery about how aspirin relieves pain and inflammation.
Vane’s discovery was the “tipping point,” the culmination of knowledge and technique that led to an immediate explosion in the field of pharmacology, as well as to some of the most exciting medical research going on today. It also proved the value of serendipity and “blue sky” thinking in biomedical research.
“He had an uncanny nose for going after the right kind of scientific problem,” says Philip Needleman, Ph.D., who helped pioneer the current generation of pain relievers. Needleman was one of the first Americans to study under Vane, who died in 2004.
Vane’s entry into science began humbly enough. Born in 1927, the son of businessman who ran a small company making portable buildings, Vane grew up on the outskirts of Birmingham, England. Even in his early childhood he was intrigued by experimentation, and at the age of 12 his parents gave him a junior chemistry set for Christmas.
The gift was not without its costs in terms of a learning curve. One of Vane’s early experiments (involving a makeshift Bunsen burner attached to his mother’s gas stove) exploded, splattering hydrogen sulfide all over the kitchen walls. Shortly thereafter, his father built a shed in the back yard—a suitable distance from the house and complete with gas and water—for young John to use as a laboratory.
Vane eventually went on to the University of Birmingham where he developed an extreme distaste for chemistry. By the time he graduated he realized that it was scientific discovery through experimentation that thrilled him, not academic exercises in theory. As a result he jumped when an opportunity arose for him to study pharmacology at Oxford—even though he had absolutely no biological training at the time. He was hungry to return to the laboratory bench.
As a doctoral student at Oxford in the 1950s, Vane learned to use bioassays, which detect and measure the natural sensitivity of pieces of tissue to hormones and other biologically active compounds. At that time, the instruments for bioassay were highly complicated and answers to research questions came only after weeks of laborious tests.
Vane, who in those early days was studying the biological activity of snake venom, quickly grew impatient with the cumbersome biomedical technology necessary for his research. He was determined to find a way to reach answers more quickly, in particular, to find an easier method for examining unstable compounds.
In 1956, after moving into a junior faculty position in Experimental Pharmacology at the University of London’s Royal College of Surgeons, he developed a groundbreaking technique, the “cascade superfusion bioassay,” which allowed him to investigate the release of hormones and other substances in the bloodstream in “real time.”
Says Needleman, currently associate dean for special research projects at Washington University Medical School in St. Louis: “Vane’s methodology was a perfection of existing biological bioassay methods and was so spectacular that it allowed us to ask biological questions with some specificity and get instant gratification. It required the interplay of using different responding tissues that could recognize different body chemicals, and play them off against known bioactive compounds.”
“At the time, this was a revolutionary technique of enormous sensitivity and versatility,” explains Rod Flower, Ph.D., a former protégé and longtime colleague of Vane’s, and professor of biochemical pharmacology at the William Harvey Research Institute in London. “John had used this idea to measure the release and disappearance of hormones in the circulation and also to measure the release of substances from other perfused organs, such as the perfused lung.”
From the moment of its invention, Vane thoroughly enjoyed the quick reward his bioassay provided. In fact, many times his lab members could find out the results of their endeavors in a single day. Flower recalls that at one point Vane installed a closed circuit television camera in the lab with the lens aimed at the chart recorder, and he would watch the monitor from his office. As the pen moved over the chart and the tissue began to contract, Vane would phone from his command center and reel off instructions to the people working in the lab—such as the next best dose try on that tissue sample.
Flower recalls, “As young technicians and graduate students we used to ape around behind the camera, suddenly switching to a more serious demeanor as we moved into its perceived field of view.”
About this time, investigators in London and elsewhere were making significant strides into understanding prostaglandin biology.
Prostaglandins are lipid molecules found in virtually all tissues and organs, which have powerful physiological effects. Often produced in response to trauma, stress or disease, these so-called mediators can affect smooth muscle activity, for example, in blood vessel walls and the uterus, and they play a role in a host of other metabolic processes.
Scientists at the time knew that prostaglandins were useful in obstetrics for both inducing and terminating pregnancies, and that the compounds could inhibit ulcer formation in the stomach and cause fever and inflammation in animals. Some of the most interesting prostaglandins were notoriously difficult to study, however, because they are potent for only a few seconds before they are rendered inactive and excreted. Even after four decades of research, the specifics of prostaglandin activity had yet to be worked out.
By the mid-1960s, some of those questions were being answered. Sune Bergstrom of the Karolinska Institute in Stockholm had purified the first prostaglandins and determined their structure, and his student Bengt Samuelsson was examining the various components within this newly discovered biological system.
One weekend in 1971, Vane had a remarkable idea. He knew that aspirin, by then the world’s most commonly prescribed drug, reduced pain and relieved fever and inflammation—although no one understood exactly how. Vane hypothesized that aspirin might work by inhibiting the generation of prostaglandins—and he realized he could easily test his theory by using his cascade superfusion assay.
“It was a brilliant experiment. It immediately gave us a conceptual framework by which to evaluate the role of prostaglandins in inflammation,” says John Oates, M.D., an internationally known prostaglandin researcher at Vanderbilt University Medical Center. “We could use his assay as a tool for identifying prostaglandin activity in any number of processes,” Oates says. “It linked prostaglandins to fever and analgesia.”
Also, Vane’s work laid the cornerstone for three decades’ worth of new directions in research, including the current focus on the role of cyclooxygenase (COX) enzymes. Today researchers are looking at evidence that such nonsteroidal anti-inflammatory drugs (NSAIDs) as aspirin, Advil and Motrin that block COX activity might reduce the risk for some kinds of cancers and for Alzheimer’s and other diseases. “None of this would have made sense without Vane’s early experiments on prostaglandins,” Oates says.
A year after his findings were published, Vane left academia for industry, accepting a position at the British pharmaceutical company, the Wellcome Foundation, and bringing a number of outstanding colleagues with him. Needless to say, Vane caught tremendous flak from his academic colleagues for his decision, but he remained undeterred.
During his 13 years at Wellcome, Vane was in on the development of many new products, including prostacyclin, a prostaglandin derivative important in cardiovascular medicine because of its action in dilating constricted blood vessels and inhibiting platelet aggregation, or blood clots. Vane engineered a collaboration between Wellcome and its competitor Upjohn to introduce prostacyclin into the medical marketplace.
Needleman says, “He was driven. And it was quite natural for anyone working in prostaglandins, whose research was strong enough, to be in direct competition with John Vane. A lot of people melted.”
To many of his colleagues and students, however, Vane’s competitive spirit and verve was invigorating. “John had a lively, productive lab,” Oates says. “He drew around him a remarkably talented and energetic group of fellows.”
When dealing with young investigators, Vane gladly shared his scientific credo: “Always do the simple experiment first!” Flower says, “He was a master of the clever, low-tech, high-thought experiment that involved nothing more complicated than a small strip of artery or similar tissue moving a lever or transducer.”
Needleman adds, “John Vane was like a symphony conductor. He was a great scientific strategist. The week I spent with him in 1972, I learned the bioassay methods very quickly, then we spent day and night talking about strategy.”
While Vane was fiercely loyal to those who worked for and with him, he was never one to suffer fools gladly. With a big booming voice and all the confidence of a British aristocrat (although he was raised in decidedly middle class family), Vane could command attention long before he became renowned for his research.
Needleman recalls one international pharmacology meeting in Switzerland in 1969. In keeping with the free-spirit attitudes of that era, the meeting organizers planned to allow a free-flow of ideas in the large amphitheater—an open, unstructured discussion among the hundreds of attendees.
Unfortunately, this was a disastrous idea. “It was bedlam,” Needleman recalls. “Everyone was talking at once, nobody had the floor. Suddenly John Vane stood up and in this wonderful English baritone announced, ‘I have a question!’ Everyone stopped talking to hear his question. Vane asked, ‘WOULD YOU PLEASE PAUSE LONG ENOUGH SO THAT I CAN LEAVE THIS MEETING?’”
At that point, Vane turned on his heels and headed for the exit. The others in the audience applauded and followed him out the door.
In 1982, Vane, Bengt and Samuelsson shared the Nobel Prize for medicine for their discoveries in prostaglandin synthesis. Oates finagled his schedule and attended the ceremony in Stockholm, Sweden, with a group of his international associates, cheering on their Nobel Prize-winning prostaglandin cronies. It was, he says, one heck of a party.
In 1986, Vane retired from the business world and devoted his energies towards preserving and advancing scientific research. He recruited some of his old lab buddies to form The William Harvey Research Institute, an organization designed to bridge the gap between academics and industry.
In 1990, Flower, who had spent several years as chairman of Pharmacology at the University of Bath, joined the Institute, this time on equal footing with his beloved mentor as a member of the board of directors. The purpose of the institute, an affiliate of the United Kingdom’s Association of Medical Research Charities, has been to encourage creative approaches to basic research, present new data and foster collegiality among medical scientists.
For all of his accomplishments, Vane’s greatest legacy may be the people he trained.
Flower worked on understanding the biology of such autoimmune inflammatory diseases as rheumatoid arthritis and asthma. Sergio Ferreira, Ph.D., professor of Medical Biochemistry at the Federal University of Rio de Janeiro, is internationally renowned for his contributions to the collection of ACE inhibitor drugs for lowering blood pressure. John Hughes, Ph.D., shared the prestigious Lasker Award in 1978 for the discovery of endogenous opioid peptides involved in the body’s regulation of pain.
Salvador Moncada, Ph.D., currently director of the Wolfson Institute for Biomedical Research of the University College London, pioneered research into nitric oxide, now considered a “super-molecule” because of the role it plays in the immune and nervous systems, in inflammation and in programmed cell death (apoptosis).
Needleman went on to hold executive positions in the pharmaceutical giants, Pharmacia, Monsanto and Searle, and was involved in the development of such drugs as the COX-2 inhibitors Celebrex, Bextra and Dynastat, and Inspra, a blood pressure drug that blocks the actions of the hormone aldosterone.
Needleman says, “The years I scientifically jousted with John Vane more than prepared me for a career in industry where I would be dealing with CEOs, boards of directors and industry analysts. To survive a scientific interaction with John Vane you had to be at the top of your game. He was a great influence.”
Throughout his career, Vane was, first and foremost, an activist for scientific freedom.
Recalling his days in training, Flower says, “John’s attitude to drug discovery was that if you gave bright scientists (creative freedom) then they would come up with the goods sooner or later. We had few formal departmental meetings or departmental seminars, and yet somehow we seemed to know more about what we were individually doing, and what our colleagues out there were doing, than at any other time.
“Despite these factors, which no doubt would horrify a head of department today, the department was undoubtedly the friendliest, the fairest, and the safest I have ever worked in.”
Vane echoed this point of view in his speech at the 1982 Nobel banquet—expressing ideas that still resonate 22 years later: “The medicines of today,” he said, “are based upon thousands of years of knowledge accumulated from folklore, serendipity and scientific discovery. The new medicines of tomorrow will be based on the discoveries that are being made now, arising from basic research in laboratories around the world …
“In many countries now, research in universities is under severe financial restraint. This is a shortsighted policy. Ways have to be found to maintain university research untrammeled by requirements of forecasting application or usefulness. Those who wish to study the sex-life of butterflies, or the activities associated with snake venom or seminal fluid should be encouraged to do so. It is such improbable beginnings that lead by convoluted pathways to new concepts and then, perhaps some 20 years later, to new types of drugs.”