I reach back to 20th century medical history for today’s blog and celebrate Sir John Robert Vane, the English pharmacologist who discovered in 1971 that aspirin works by preventing the formation of certain prostaglandins.
Prostaglandins are hormone-like lipids that play a role in the human body’s inflammatory response and in a wide range of other physiological functions, such as the dilation and constriction of blood vessels and the control of blood pressure. This is common knowledge now, but it wasn’t when John Vane (1927-2004) started out.
I thought of Sir John this week when I read that Dr. Gustav Born, a German-born colleague of Vane’s, had died in April at age 96.
Born was the son of renowned physicist and mathematician, Max Born, who received a 1954 Nobel prize for his work on quantum mechanics. Of Jewish ancestry, Max Born and his wife, Hedwig Ehrenberg Born, fled Germany with their children in 1933, eventually settling in Edinburgh. (Fun fact: Olivia Newton-John is the daughter of Max and Hedi Born’s daughter, Irene, and, therefore, the niece of Gustav Born.)
Gustav Born and John Vane met as students at Oxford University and worked together during the 1960s in the extraordinarily successful pharmacology department at the University of London’s Royal College of Surgeons. During Vane’s 18 years at the university (1955-73), he developed important bioassay techniques, focusing his research on the angiotensin-converting enzyme (ACE), which is instrumental in the control of blood pressure, and on the action of aspirin.
A bioassay is a laboratory method by which a pharmacologist or other scientist can assess the effect of a substance—its potency, for example—on living cells or tissues. Vane’s cascade bioassay technique, which I describe below, was ingenious.
The elucidation of aspirin’s mechanism of action catapulted Vane into celebrity, and, in 1973, he accepted the top research & development job at Burroughs Wellcome in Beckenham, England. A career academic, Vane rejected his Royal College colleagues’ admonitions about selling his scientific soul to commerce and, instead, brought some of the naysayers with him, setting up a prostaglandin unit that enjoyed much success.
Vane and his industry team were the first to identify a lipid mediator that became known as the prostaglandin, prostacyclin. Prostacyclin inhibits platelet aggregation, which is clumping. Vane’s research group made synthetic prostacyclin analogues, in an attempt to develop a drug that could be used in humans to stop dangerous platelet clumping. The drug, epoprostenol (Flolan®), is such an analogue, but I do not know who developed it. Vane’s initial clinical studies with prostacyclin were in peripheral vascular disease. Epoprostenol is used to treat pulmonary hypertension, also called pulmonary arterial hypertension or PAH.
Vane is more often associated with ACE inhibitors, drugs that control blood pressure by dilating blood vessels to improve blood flow. His research led to development of the first ACE inhibitor, captopril (Capozide®), and he later oversaw the development of the inhibitors, atracurium (Tracrium®), acyclovir (Zovirax®), and lamotrigine (Lamictal®).
For more on Vane’s research, see http://www.phaonlineuniv.org/Journal/Article.cfm?ItemNumber=1739.
A little background: Platelets, which are made in the bone marrow and circulated in the bloodstream, assist in forming clots to stop the bleeding of a damaged blood vessel. These irregularly shaped, disklike cytoplasmic bodies, which last about eight to 10 days, are also known as thrombocytes. A blood clot is called a thrombus.
My father first met Vane, an elegant Londoner, in the 1950s when Dad was doing pioneering work in serotonin and other neurotransmitters at the National Heart Institute in the National Institutes of Health. Albert Sjoerdsma had a Ph.D. in pharmacology, as well as a medical degree, both from the University of Chicago. As Vane wrote in tribute to my father upon the occasion of his 1989 Festschrift:
“Al had the gift to turn his prolific energy to both clinical and basic pharmacology. In the same year, he would be working on the effects of methyldopa [an antihypertensive Dad’s unit discovered] in fifty patients, the synthesis of norepinephrine in the rat heart, the collagen profile in various clinical conditions, tryptophan hydroxylation, rat brain serotonin, etc., etc.”
If you’d like to understand better what Vane means about Sjoerdsma’s wide-ranging clinical research, I refer you to my book, “Starting With Serotonin: How a High-Rolling Father of Drug Discovery Repeatedly Beat The Odds.” Much of the following material is excerpted from that book. My father’s comments appear in italics and, as usual, I omit the endnotes:
[Vane and Sjoerdsma’s] admiration was mutual: Vane was an old-time pharmacologist like von Euler. He wasn’t into modern biochemistry. He discovered things using old-time pharmacologic isolated organ baths.
[Swedish physiologist and pharmacologist, Ulf Savante von Euler, was the pioneer’s pioneer in pharmacology. Among his many accomplishments, he was the first to isolate norepinephrine in animal tissue extracts, identifying it in 1946 as the adrenergic neurotransmitter, critical to the autonomic nervous system. He was a standout in prostaglandins, as you’ll read below.]
For his ground-breaking prostaglandin research, Vane used a cascade superfusion organ bioassay system that enabled him to “superfuse,” or bathe, with blood or a specially prepared physiological solution, up to six isolated smooth-muscle tissues—such as strips of rat colon, stomach, and rectum. He would inject test substances (e.g., aspirin) into the bath and obtain instantaneous and parallel assays on all of the tissues. If he were assaying prostaglandins in the multi-level setup, the tissues would respond in a characteristic manner, such as by contracting upon contact.
The cascade went through . . . leaked over from here, onto the next level, and leaked on to the next, and from that, he could draw a pattern of what the compound was.
[Chemically,] prostaglandins consist of a twenty-carbon unsaturated carboxylic acid that contains a five-membered ring. They exist in almost every human tissue and body fluid and implicate practically every biological function, playing a controlling role in the regulation of blood pressure and the transmission of nerve impulses. Aspirin prevents the formation of prostaglandins that produce fever, pain, and inflammation.
Two Columbia University gynecologists uncovered the first evidence of prostaglandin in 1930 when they observed that strips of human uterus would relax or contract when exposed to human semen. Two years later, Ulf von Euler and British physiologist, M. W. Goldblatt, independently reported smooth-muscle-contracting and vasodepressor activity in seminal fluid and accessory male genital glands, including the prostate. Von Euler named the substance causing this activity, prostaglandin.
[In 1973, when Vane went into private industry, my father was director of the newly opened Centre de Recherche Merrell International (CRMI) in Strasbourg, France. The U.S.-based drug company, Richardson-Merrell, owned the center and hired Dad as its inaugural director, giving him a “10-year-license” to “discover something.” He was assured that the businesspeople would leave him alone.]
CRMI had a prostaglandin specialist, Boris Vargaftig, who did platelet aggregation work with an aggregometer. It had long been known that aspirin prolongs a person’s bleeding time, incident to a cut or internal injury. After Vane’s discovery, researchers attributed this effect to an inhibition of prostaglandin biosynthesis, meaning aspirin stopped its formation.
The prostaglandins play a role in platelet aggregate. There are all kinds of things that will make your platelets clump in a test tube, and machines called aggregometers measured the degree of clumping.
[I have just learned this week that Gustav Born developed the aggregometer. According to an obituary about him in The Guardian, his platelet-measuring device launched a new sub-discipline of hematology referred to as platelet aggregometry, a term that Born allegedly hated.]
Boris Varfagtig was a hard-driven, well-trained pharmacologist, who published extensively, but nothing he did ever rivaled Vane for prominence.
As I remember, I thought of trying to hire Vane; instead, he tried to hire me.
In 1976, Burroughs-Wellcome’s prolific and longtime drug inventor, the legendary George H. Hitchings, was scheduled to retire. Hitchings had joined Wellcome Research Laboratories in Tuckahoe, N.Y., in 1942, as chief and sole member of its biochemistry department, and risen up the ranks until he became vice president in charge of research in 1967. He would share the 1988 Nobel prize in Physiology or Medicine with his longtime Burroughs-Wellcome collaborator, the unsung Gertrude Elion, and Sir James Black, who developed the first beta blockers, for “their discoveries of important principles for drug treatment.”
Hitchings reported to Vane, but, as he made clear to me, Hitchings was very independent, because Hitchings had developed most of their drugs. Vane wasn’t about to kick Hitchings around. He told me he couldn’t manage him. Hitchings was an irascible guy. I had met him years before at the lab up in Tuckahoe.
John and I got along well. I would’ve considered leaving Strasbourg and going to the Research Triangle [in North Carolina, where Burroughs-Wellcome was headquartered]. But when I visited Burroughs Wellcome, Hitchings and I didn’t get along, and I could tell very quickly that I was not the sort of person that he had in mind to replace him.
[Because of Hitchings, my family did not move to North Carolina in the 1970s when I was a student at UNC-Chapel Hill.]
John Vane shared the 1982 Nobel Prize in Physiology or Medicine with two Swedes, Sune Bergstrőm, a biochemist-physician at the Karolinska Institute, and his one-time student and fellow biochemist-M.D., Bengt I. Samuelsson, for their prostaglandin research and discoveries.
Bergstrőm crystallized the first two prostaglandins from vesicular glands of sheep. Named prostaglandin E1 (PGE1) and prostaglandin F1α, both are potent smooth-muscle stimulants; PGE1 also acts to lower blood pressure. In 1962, Bergstrőm and Samuelsson elucidated the chemical structure of these two prostaglandins and soon characterized others in this unique family of compounds. They also achieved the first prostaglandin biosynthesis.
Bergstrőm used to visit me at the NIH. I never knew Samuelsson. He was up in Sweden tracking down the individual prostaglandins. Sune would give me this story about prostaglandins, and I would think, “. . . what a deadend field that is, you know.” (laughing) That was my own feeling about it, but there was no way I could get into it. You need very specialized equipment and measurements. . . . The prostaglandins are very complicated. The only therapeutic use ever made of them has been non-steroidal anti-inflammatories, like ibuprofen [Advil, Motrin] and naproxen sodium [Aleve], and COX2 inhibitors, such as Vioxx® and Celebrex®, marketed for arthritis pain.
COX refers to cyclooxygenase, a key enzyme in the prostaglandin synthetic pathway that has two forms, designated COX1 and COX2. Developed in the 1990s, the COX2 inhibitors came under a cloud in 2004 when Merck, responding to clinical-trial evidence of an increased incidence of stroke and heart failure associated with its COX2-inhibiting drug, Vioxx, withdrew it from the market. Three years later, the pharmaceutical giant agreed to a $4.85 billion fund to settle tens of thousands of Vioxx-related lawsuits.
The pitch from industry was that the COX2 inhibitors do not cause ulcerations in the stomach, which aspirin and all the other non-steroidals do. But the thing that reared its ugly head, and was suspected from the beginning, is that the COX2 inhibitors do not block out the pro-thrombotic side of prostaglandins. [In other words, prostaglandins promote clotting, too.]
I have never understood how and why Celebrex (celecoxib) weathered the Vioxx (rofecoxib) storm and managed to remain on the market. Perhaps I’ll research that question and write a blog about it. For more scientific detail about prostaglandins, see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3081099/.
Knighted in 1984, Sir John Robert Vane left an impressive legacy of scientific inquiry and research. His intellectual spirit lives on at the William Harvey Research Institute, which he founded in 1986 after he returned to academia. He was working there up until his death from pneumonia at age 77.
The research institute, named for the 17th century English physician, anatomist, and physiologist who was the first to detail the human circulatory system, is an international powerhouse in pharmacological research. It aspires to lead world-class research in cardiovascular, inflammatory, and endocrine diseases, just as Sir John himself did.
John Vane was one of the greatest pharmacologists of the 20th century.
(I obtained the photograph of Sir John from the website of the William Harvey Research Institute, https://www.qmul.ac.uk/whri/.)