Arvid Carlsson:
"The Nobel Prize did change my life!"

Nobel Prize winner Arvid Carlsson is not yet thinking of taking it easy.

At the verge of his 80th birthday he is still running his company in Gothenburg in southern Sweden, making the most of the money and respect the award brought along to develop and research drugs to help people with mental and neurological disorders.

An interview with a man ECNP can be proud to have recently voted honorary member.

1. When you started out as a scientist, was there a specific disorder you wanted to help cure?

"No, everything that has happened to me has been a coincidence. Even getting into neuropsychopharmacology in the first place. When I started to study medicine in 1941, I more or less had made up my mind to become a scientist.

My first course was in anatomy; after my exams I was offered a position as an amanuensis. So I started out in anatomy until the professor of pharmacology came along. He asked me to be his amanuensis and it sounded more fun than anatomy. So that is why I became a pharmacologist. The professor gave me a topic related to the central nervous system (CNS) as it dealt with drugs capable of awakening people who had taken an overdose of a hypnotic. These central analeptics are not much used now. My colleague Folke Serin, who is still a very good friend, and I published a paper in 1950 on our discovery that the effect of the drugs depended on the time of day. The drugs hit the rodents the hardest at night when they were the most active. The funny thing was that many decades later a research paper by the American Space Programme credited our study to be the first of this kind. I, then, temporarily abandoned CNS for something entirely different. Again, it was my professor who talked me into doing research on calcium tablets, using radioactive tracers that had just become available. This study ended up as my doctoral thesis that dealt with calcium metabolism, using radioactive calcium to find out how the formation of bone takes place."

2. It must be very exciting to take part in the discovery of something major as you experienced later on in your career?

"It is indeed very exciting. What happened a few years after defending my doctoral thesis was that I applied for a professorship but ended as number 2.Actually my friend Folke Serin got the position, which is quite right as he is my senior by five years. The reason, however, that I was turned down was that they were not impressed with my research and advised me to leave the focus of calcium metabolism if I wanted to remain a pharmacologist. So I did and that led me to many more exciting experiences, starting in the Laboratory of Chemical Pharmacology of the National Heart Institute in Maryland, in the United States.

When I went there in 1955, Bernard Brodie (1907-1989) was head of the laboratory. I was welcome to work at Brodie´s lab if I did not mind not getting paid because he had no money… Still, this was the best career move ever as I got to be in the forefront of major developments! Bernard Brodie was a real character! He was nicknamed Steve after Steve Brodie, a famous sensation seeker in the States. Bernard himself was also a bit of a sensation seeker; he had been a fairly successful boxer before he got into organic chemistry in which he reached great success. He was one of the pioneers in biochemical pharmacology, especially in the area of drug metabolism.

This was the fifties: the time of discovering antipsychotic agents. Brodie had just experienced a tremendous breakthrough by using a new instrument: the spectrophotofluorimeter. This instrument made it possible for the first time to measure very low levels of drugs, metabolites and endogenous compounds such as serotonin that had been discovered in the brain shortly before. So they had measured serotonin after administering reserpine and the level of serotonin was down to almost zero.

3. Do you work together with patients' organizations at all?

"When I started the work on the effect of reserpine the focus was entirely on mental functions. It just so happened that we stumbled on dopamine and then we had the whole story about Parkinson's disease. In 1967 George Cotzias (United States) demonstrated how to use levodopa (L-DOPA) to bring about the dramatic improvements. Around that time I attended a meeting in Canada where his documentary was shown. I rushed back to Sweden and persuaded clinicians here to start working on this as well, which they did the same year.

I still remember the patients in their wheelchairs and thinking to myself: I do not think this is going to work. But it did! After they had had their L-DOPA, they got up and actually started to walk. It was exactly like Oliver Sacks' description a few years later in Awakenings. It was very dramatic and also meant my first contact with people suffering from Parkinson's disease. As my field of research is preclinical I do not have much to do with patients' organizations. But I do maintain close contact with some organizations. For example, about once a year I give a presentation for the Swedish Parkinson's Disease Association. Last May I was also asked to talk to the European Committee in Brussels about Parkinson's disease."

4. What did you think of Oliver Sacks' Awakenings?

"What happened with L-DOPA was Awakenings like in the rabbits. In the movie, many of the humans after the initial awakenings relapse again. It is a great tragedy that that happened. It really is very sad, especially because when these patients came back to life, they started off at the age they were when they fell asleep: in their twenties. Oliver Sacks' patients did not actually have Parkinson's disease but rather a very severe form of Parkinsonism developed after sleepy-sickness they contracted during the great epidemic after World War I, much more severe. In both cases you have a degeneration of dopamine but the loss is so much greater with the sleepy-sickness. So therefore in many of the patients L-DOPA could not work very well. Fortunately, with Parkinson's disease the activity remains for several years, sometimes for as long as 20 years or more. But sooner or later many patients still run into problems with L-DOPA."

5. Could the relapse of the patients ever be prevented?

"It is not at all impossible that a drug will be developed to prevent or cure this. But it will not happen in the next ten years or so. There is also the problem of the cause; the genetic factor seems to be relatively weak. So one has to look for environmental factors; lately there have been some quite interesting developments. In the United States, an environmental poison called rotenon has been tested in rats and these rats have shown a degeneration of dopamine. Imagine the importance of actually identifying compounds causing Parkinson's disease and then getting rid of them! There are other exciting areas of research. For example, there is the idea that the disease is caused by the failure of our own antioxidants. The research of stem cells is another very exciting area. It is my guess that this will ultimately lead to success but unfortunately not in the near future…"

6. What do you think are your most important research contributions to science?

"I would put the discovery of dopamine and its role for normal brain functions as a winner, no doubt about it. A good second place would go to the research into the role of dopamine in mental disorders in schizophrenia, followed by the third: the mode of action of antipsychotic drugs. Fourth prize would go to the studies of the antidepressant zimelidine, a predecessor of prozac and other socalled SSRIs."

7. The discovery of dopamine was also the main reason for the Nobel Committee to present you with the 2000 Nobel Prize for Medicine or Physiology. What did this mean for you?

"It did not entirely come as a surprise as I knew I had been on the short list for a long time. Actually, I was starting to think they had forgotten about me. I think there are several aspects to the reason why it took so long.
The first has to do with the reluctance of pharmacologists to recognize that dopamine is not merely a precursor of noradrenaline. We had a lot of resistance to deal with.
Secondly, maybe the generation shift in the Nobel Committee had something to do with it as the new generation clearly has a different perspective than the former. This is not so unusual; it took Albert Einstein 20 years to be presented with the Nobel Prize as the chair thought he was "…merely writing formulas". As soon as the chair stepped down, the prize went to Einstein.
A third aspect might be that many in the 2000 Nobel Prize Committee knew me and have worked with me at the Karolinska Institute in Stockholm. I received the prize together with Paul Greengard, who I have known for many years, and with Eric Kandel. Both are from the United States. Although I somewhat expected to receive the prize, I was certainly not ready for the awe surrounding it. I have been presented with so many prizes before and one of them, the Japan Prize, was more than the award money of the Nobel Prize and I also got to sit next to the empress of Japan at the banquet. And yet… when I was presented with the Nobel Prize it was so much more visible. The media make such a fuss about it! For this reason getting the Nobel Prize did change my life; October 9, 2000 was an important date for the Arvid Carlsson Company especially. In 1998, at the beginning, we had no funding, but we managed to sell a piece of the cake - 60 million Swedish Krona - to a pension fund. This was actually before October 9. But a lot of problems remained. Accommodation was starting to become an extremely difficult issue until October 9. After that we could choose from three different offers…"

8. Could you elaborate on the activities of Carlsson Research Company?

"We have chemists synthesizing molecules and pharmacologists testing these molecules. The idea of the Carlsson Research Company is to develop new molecules and to characterize them pharmacologically. The next step is to develop drugs, taking them through all the required toxic testing such as to show them suitable and safe for human beings. First testing them on volunteers and then on patients who we hope will benefit from them. We are on our way now. Our first drug has gone through all the animal work and phase 1 tests on healthy human volunteers for safety purposes. Studies on treating patients suffering from Parkinson's disease with L-DOPA nduced dyskenisia have been initiated and show promise. Not only people with Parkinson's disease participate in the now on-going studies but also people suffering from schizophrenia and other disorders."

9. What are your expectations of the development of neuropsychopharmacology in general?

"I think there will be a shift away from purely molecular aspects of chemical transmission to include neurocircuits of intact systems on both the microscopic and the macroscopic level. It is very important to grasp a number of tissue patterns using modern computer techniques. I believe that we will awake from treating the brain as a chemical factory and look at it more as a extremely complicated survival machine. This is not to say that modern techniques are not very useful, but it is even better to work together with both the new imaging techniques and advanced computerdependent statistics involving pattern recognition. Those studies will probably prove extremely useful and very much help to bridge the gap between animal and human observations. The future looks very bright indeed. I am positive that lots of important things will happen and that many people suffering from mental and neurological disorders shall benefit greatly from these developments!"