School of Medicine

Blue-Sky Research

 

Excerpts from a talk by Sir John Vane
(Nobel Laureate, Physiology / Medicine - 1982)

Academic, basic, or "blue-sky" research, holds great promise for the community and for the health of mankind. But today's urgency to show a return on investment is leading pharmaceutical companies to demand that research be project- and market-oriented, so much so that "blue-sky" research is threatened. This industry threat is very real and is spreading to governmental funding of academia because of the same short-sighted philosophy.

I will give some examples from my own experience that illustrate the way in which "blue-sky" research can lead to totally unexpected benefits for the health of mankind. The first is aspirin.

Just under 100 years ago in the German drug company Bayer, a chemist named Felix Hoffmann was asked by his father, who was taking salicylate for his rheumatism, whether anything could be done to improve its bitter taste. Felix Hoffmann then invented aspirin by adding a simple side-arm to the salicylate molecule. This was the beginning of Bayer aspirin and nowadays hundreds of thousands of tons of aspirin are used around the world for the treatment of headaches, rheumatism, fevers and so on. But nobody knew how it worked until some 25 years ago.

My laboratory was working on a group of chemical messengers formed in many parts of the body called prostaglandins. At the time, it was becoming clear that certain prostaglandins were involved in causing inflammation and fever. I was writing a review over the weekend at home when suddenly it occurred to me that maybe aspirin and similar drugs were working by preventing the body from making these prostaglandins. In the laboratory on Monday morning, I said to my colleagues, "I think I know how aspirin works!" I am not a biochemist and so I had never made enzyme preparations before. I went to the literature and found out something about the enzyme that makes prostaglandins in the body. I prepared it in a test-tube and then added different doses of aspirin and other similar substances, including morphine, as control. I found that aspirin, or an aspirin-like drug, reduced the production of prostaglandins by this enzyme according to dose.

After repeating the experiment in many different ways in different tissues, I published the results in the prestigious journal Nature in 1971 and suggested that the mechanism of action of aspirin and similar compounds was through the prevention of the formation of those substances known as prostaglandins. The idea was that prostaglandins were released in pathological excess in inflammation and if these could be removed, then you would suppress the fever, pain, and swelling of inflammation. At the same time, we knew that all aspirin-like drugs tended to irritate the stomach and possibly lead to kidney problems; therefore, I suggested that these side-effects were due to the removal of prostaglandins that were essential for the proper functioning of the stomach and the kidneys.

The theory was generally accepted and has stood the test of time. More importantly, it was the discovery of the basic mechanism of action that has led to the use of aspirin in cardiovascular disease.

We have known for some time that heart attacks and strokes are caused by the inappropriate clumping together of platelets within the circulation. Platelets are the smallest particles in the bloodstream and their only function is to stop us from bleeding to death. Normally, when we cut ourselves, armies of platelets clump together and stick to the walls of the cut, building up a dam to stem the flow of blood. The same sort of process may happen inappropriately in a coronary artery or in an artery going to the brain and cause a blockage, leading to a heart attack or stroke. After our discovery of how aspirin works, it became clear that the platelet clumping was due to the formation of a prostaglandin-like substance in the platelets. Thus, knowing the mechanism of the action, people started to test whether aspirin may prevent the inappropriate clumping of platelets which leads to heart attack and strokes.

First of all they started out with large doses, the sort of dose (6 tablets a day) that was used in rheumatoid arthritis. However, over the years, clinical trails in the thousands and thousands of people have shown that only a small dose is needed and that even baby aspirin (75 mg or 1/4 of a normal tablet) taken once a day is sufficient to prevent the platelets from sticking together. This is such a small dose that in lectures I jokingly say that we should keep an aspirin tablet in the bathroom cupboard and lick it every morning! Indeed, clinical trials worldwide have shown that taking an aspirin every day reduces the risks of heart-attack or stroke by up to 50%. So there are many thousands or even millions of people alive today because they take a daily aspirin for the prevention of heart-attacks and strokes. These people would not otherwise have been with us had I not done that crucial experiment on a Monday morning. That is directly a result of our "blue-sky" research.

My second example comes from the same family of prostaglandins. Anatomists over the generations have known that blood stays fluid in healthy arteries but clots in dead ones. This was never understood but we also knew that the very same platelets that I have been talking about do not normally stick to the inner healthy walls of arteries. In 1976, we found that this was because the inner walls of the arteries make a prostaglandin, which prevents the platelets from sticking to them. We called it prostacyclin and this work opened up an enormous field of research. We now think that platelets stick to arteries when compounds such as prostacyclin failed to be formed. However, the therapeutic importance of this finding is that prostacyclin-like substances are now being marketed for use in obstructive vascular diseases such as those that normally lead to foot or leg amputations.

My third example shows how a new important kind of drug can come through serendipity, international collaboration, and of course, "blue-sky" research.

In the mid-1960s when I was working at the Royal College of Surgeons in England, I had an application for a post-doc position from a Brazilian scientist named Sergio Ferreira. For his PhD, he had worked on the venom of a particularly nasty Brazilian snake called Bothrops Jararaca. He had shown that extracts of this venom contained small peptides that potentiated the action of a pain-producing substance in the venom called bradykinin, probably by enzyme inhibition.

He came to my laboratory carrying some of his venom extracts in his pocket. I suggested to Sergio that we should study his snake venom extract on the renin-angiotensin system, so called because an enzyme known as renin is released from the kidney into the bloodstream and thus leading to the formation of a very strong pressor substance called angiotensin. However, he had other plans. He wanted to continue his work on bradykinin, and being a forceful personality, he convinced me to let him do that.We worked together on bradykinin for two years, and only at the end of that period did I persuade another colleague, Mick Bakhle, to test the snake venom on the renin-angiotensin system. It turned out to be a potent inhibitor of a key enzyme- angiotensin converting enzyme (ACE) in that system.

At the time I was consulting with Squibb in New Jersey. Nobody knew whether angiotensin was important in high blood-pressure even though it was suspected. I suggested to Squibb that this inhibition of ACE by the snake venom peptide would test the concept as to whether angiotensin was involved in high blood-pressure or not. Scientists at Squibb were enthusiastic and started a programme to isolate the active venom peptide. The marketing people were unenthusiastic because they could not see a market for an anti-hypertensive compound that had to be injected, as a peptide would.

I visited Squibb three times a year and each time found that I had to re-infuse enthusiasm into the programme. It was almost dropped because of marketing pressure. Eventually, they made a kilogram of the peptide from the snake venom, which was shown in New York by John Laragh to reduce a high blood pressure. Thus, the concept had been proven. Now if only a similar compound absorbed by mouth could be found, there would be great therapeutic potential.

Having introduced the programme to Squibb and kept it alive for several years, I then joined Burroughs Wellcome, a competing pharmaceutical company, as the R & D Director, thus allowing me to no longer consult with Squibb. Nevertheless, a few years later their own scientists had discovered an orally-active ACE inhibitor, which they took to the market calling it Captopril or Capoten. Merck also found an ACE inhibitor around two or three years later, which they called Enalopril or Innovace. I have a paternal pride in the fact that these two compounds alone now have $20 billion worth of sales per annum around the world. That would not have happened without the "blue-sky" research on the snake venom which started in Brazil and then went on in my laboratories in London. There were so many extraordinary coincidences that were needed in order for that process to fructify, including Ferreira's choice to visit my laboratory rather than Oxford.

With these examples, I hope that I have begun to convince you that breakthroughs in medical science must come from "blue-sky" research. Without it, and without public support for it, society would be poorer as would our health. And taken in perspective, "blue-sky" research is not all that costly compared with the development process following it. Of course, the whole process of drug discovery takes many years and the work of many hundreds of people - a whole sort of inverted pyramid of costs balancing on the much less costly, but inescapable, "blue-sky" research. Without this fundamental research, important drugs such as antibiotics, the betablockers, the H2 antagonists, and the calcium channel blockers would not now exist.

An especially fertile area for basic or "blue-sky" research is, of course, the brain. This has been left last by scientists because of the enormous technical difficulties of studying the brain. The kind of exploration of how nerves work and how brain cells communicate with each other is being studied by Dr. Bazan's Neuroscience Center and is vital for our future understanding of how the brain works. Without it ,we shall not find effective cures for strokes and neurological diseases, such as Alzheimer's, as well as problems, such as schizophrenia, epilepsy, and depression that are so empirically treated by present-day drugs.

Over the last 40 years or so, I have visited many laboratories around the world. Here in New Orleans, you have excellent universities and the LSU Neuroscience Center, which is led by the enthusiasm and energy of Nicolas Bazan. It is a real centre of excellence and is recognized as such around the world.

About Sir John Vane, FFS (1927 - 2004):

• Nobel Prize in Physiology / Medicine (1982).

• Director of Research and Development at the Wellcome Foundation.

• Founder, Chairman and Director General, The William Harvey Research Foundation (London).

• Fellow of the Royal Society.

• Knighted in 1984