Art on the molecular level

For Simon Campbell, the British scientist who created Viagra, the pharmaceutical industry has grown too much to be able to bring together the fundamental elements for discovering new drugs: “high-level science, art and personal focus”

By Fábio de Castro

Agência FAPESP – Recent technology has opened the door to millions of new compounds through synthesis, but this will not reverse the pharmaceutical industry’s stagnation. What leads to the discovery of new drugs is a combination of high-level science and “art”, meaning “high doses of personalized, authorial creativity.”

This is the opinion of British scientist Simon Fraser Campbell, whose curriculum vitae boasts such discoveries as Viagra—the well-known erectile dysfunction drug—and Norvasc, the fourth most-sold drug in the world, used for angina and high blood pressure.

Campbell took part in the São Paulo School of Advanced Sciences on Natural Products, Medicinal Chemistry and Organic Synthesis, held at the Universidade Estadual de Campinas (Unicamp) in August,  as part of the São Paulo School of Advanced Sciences (ESPCA), a FAPESP funded program.

A graduate of the University of Birmingham in England, Campbell was a visiting professor at the Universidade de São Paulo (USP) from 1962 to 1972. Later, he worked at Pfizer, where he retired in 1998 as vice-president of R&D. Former president of Great Britain’s Royal Society of Chemistry, the scientist is co-author of over 120 publications and patents.

Read excerpts from the interview that Campbell granted Agência FAPESP below:

Agência FAPESP – In your opinion, does the discovery of new medications have elements of a creative process analogous to art?
Simon Campbell – Yes. As you can see by the title of my lecture at ESPCA in Chemistry was “Science, art and the discovery of drugs—a personal perspective.” First off, I speak to the role of science, because in order to discover new drugs, we must practice the best science possible, the best quality. And I speak about art because oftentimes we don’t know what the molecular structure of our target is and in order to imagine it, we need to use our creativity. We don’t know what the drug is interacting with, so this requires a large dose of imagination.

Agência FAPESP – Does the personal perspective refer to your experience with the discoveries of Viagra and Norvasc?
Campbell – Yes, in the sense that the discovery of drugs is in the hands of individuals. That means it depends on people, not machines, and not exhaustive tests with thousands of compounds. The personal touch is the most important. The discovery of new drugs is something that is strongly connected to high level science and art (because we need imagination and innovation) aside from a personal touch.

Agência FAPESP – Investments on the part of the pharmaceutical industry are increasing all the time, with fewer and fewer results. What is wrong with the paradigm of new drug discovery?
Campbell – The problems are diverse. In the first place, in recent years we have seen a number of pharmaceutical companies go through mergers and acquisitions, and I believe that they have gotten too big. When a pharmaceutical company’s research team has thousands of scientists, it doesn’t work. I think the companies are too large to be managed, and especially too large to be innovative.

Agência FAPESP – This seems to be related to your view of personal perspective.
Campbell – Yes, because the personal character disappears. I like groups where I can talk with people. I like to be able to cross the hall and knock on a colleague’s door if I have a question. Research teams thousands strong spread across the globe aren’t appealing to me. It may seem trivial, but this changes the work dynamic quite a bit and makes all the difference. But there are also scientific reasons for the stagnation in discoveries.

Agência FAPESP – Of what sort?
Campbell – There are some 23,000 genes in the body and the drugs we have today only have 300 of these genes or proteins as targets. That leaves a gap of over 22,000. But how do we pick them? One of the problems we have is that we aren’t very good at validating the targets. We aren’t working hard enough at being able to say, “This target is relevant to a human disease.” That’s a problem. The next problem is that sometimes we make compounds that are simply ineffective. So we have to make better compounds. And finally, we don’t know which patient will respond to them.

Agência FAPESP – What do you mean? We don’t know how each patient will react to each drug?
Campbell – Right. We need to greatly improve our knowledge about the genetic basis of an illness so we can then choose the patient, and the therapy. This is working quite well with cancer. With cancer, we can identify certain patients or groups about whom we can say, “This will probably work, but not that.” We can’t do that with asthma or high blood pressure. We don’t have the knowledge. So it’s necessary to validate the target, have the best quality of compounds and know how to identify the patient that will respond. I don’t think we pay much attention to these three factors and I believe it’s probably the reason there have been so few new drugs in recent years.

Agência FAPESP – What would be the way to get around these problems?
Campbell – I think the way is to establish institutions for drug discoveries. I don’t mean simply going to the Chemistry departments at universities and saying, “Discover medicines!” You have to create institutions with experienced researchers, 300 or 400 at the most. Hire professionals and create institutions exclusively for the purpose of discovering new drugs.

Agência FAPESP – Multidisciplinary institutions?
Campbell – People well-trained in Chemistry, Biology...yes, multidisciplinary institutions that allow everyone to work together toward the goal of finding new drugs. It’s a proposal we are presenting to the government in the United Kingdom. I still don’t know if they will be receptive or not, but that is our plan. And I think Brazil has a huge opportunity to establish new institutions or strengthen the drug research institutions that already exist.

Agência FAPESP – New technology has made it possible to do thousands of screenings. But how do we process all those data? How can all this information be applied to biological systems?
Campbell – I think that the synthesis of compounds has reached its definitive level, just like screenings did. But basically, the discovery of new drugs doesn’t have anything to do with numbers. It’s imagination; it’s art. You have to think. Just performing millions of screenings and millions of syntheses of compounds won’t lead to a drug. My analogy is automotive production: a factory can produce millions and millions of cars, but if it wants to win the Formula 1, it has to have the best technology, it has to have an Ayrton Senna to drive the car and it needs an excellent team in the pit. To me, the discovery of drugs resembles a Formula 1 race. Making millions of cars won’t do any good—if you want to win the race, you have to have a car with cutting-edge technology, the best pilot and a good team.

Agência FAPESP – Do you also need luck? 
Campbell – Look, we always have a goal. We always start with a hypothesis. When we started with Viagra, we wanted to try to inhibit an enzyme that we thought was involved with cardiovascular diseases. We had no structure. We imagined what the enzyme must look like, with molecules specifically designed for the task. We realized that the compound had no cardiovascular activity whatsoever. Then, we performed a final test on male volunteer subjects with the maximum dosage for ten days, and saw two or three erections. After that, we started to think about how the compound worked. At the same time, the commercial team alerted us that erectile dysfunction was a critical medical problem. There was great concern and high demand. We saw we had found something important. Of course, we were lucky. But I think we created our own luck. We created the fertile ground so that it could appear.