Transcript from an interview with Arvid Carlsson

Interview with Arvid Carlsson at the Nobel Foundation, Stockholm, 9 April 2008. The interviewer is Adam Smith, Editor-in-Chief of

Arvid Carlsson, welcome to Stockholm and to this interview with You were awarded the Nobel Prize in Physiology or Medicine in 2000, together with Eric Kandel and Paul Greengard for a quite generally described work concerning signal transduction in the nervous system. But in particular the Nobel committee described your contribution as being the establishment of dopamine as a central neurotransmitter and pointed to the work in which you had used dopamine replacement therapy in animal models of Parkinson’s disease to restore normal function. Which of course paved the way to the use of dopamine replacement therapy as a standard treatment for Parkinson’s disease now. And I’d like to start by looking at that work in relation to the environment at the time, because now we all accept that the brain functions through lots of chemical transmitters, but things were very different in the late 1950s when you were working on these problems. Could you talk a bit about the atmosphere surrounding chemical transmission in the brain in the 1950s?

Arvid Carlsson: What I especially remember was a meeting a few years after we had made our original observations, it was in 1960 in London. And that was a meeting where all of the big people were in the area of chemical transmission actually, the meeting was called ‘Symposium on Adrenergic Mechanisms’, and I was there, I reported on our findings and there was very little acceptance.

It is in some way strange that chemical transmission in the brain was not so much accepted, given that Dale and Loewi had been awarded the 1936 Nobel Prize for establishing chemical neurotransmission in the periphery, so it was established there but not accepted in the brain.

Arvid Carlsson: Yes. There was a fight ongoing during the 30s, 40s and 50s between what was called the ‘sparks’ and the ‘soups’. Sparks were those people who believed in electrical transmission of course, and the soup people were those believing in chemical transmission. But at that time, I think the soup people had gained ground slowly over the decades and they had more or less conquered the whole of the peripheral nervous system. But they had to stop at the level of the blood/brain barrier to get into the brain. I think most people working in this area believed that the brain was different from the peripheral nervous system. In the brain electrical transmission was at least the predominating mechanism of signalling between nerve cells.

In some ways, it’s still a little hard to understand, given that at the level of the anatomy, there were I suppose some basic similarities between what was seen in the periphery and what was seen in the brain. And as it was established in the periphery, one would’ve thought that people would be making the leap.

Arvid Carlsson: Yes, that you may think now, but in those days when the electro-microscopic pictures came, one was so impressed by the compactness in the brain. Everything was so very close, whereas in the peripheral system, the nerves were not in that very tight contact with the whatever, muscles or heart, whatever you have. I think that was one factor really that to help the spark people to keep the brain. I think that was not the only reason why there was so poor acceptance in 1960 of our findings. Another one was that we claimed that dopamine was a neurotransmitter, and all pharmacologists in those days knew dopamine is an inactive compound. Because if you test it in the peripheral system, on the heart and gut and whatever, it doesn’t do anything. In contrast, of course, to noradrenalin and adrenalin. So, dopamine was considered to be just an intermediate in the synthesis of these other compounds and having no physiological importance in itself. So that was another factor. There were several factors like that. There was also some evidence at this meeting that actually never got published. And there probably was no evidence actually, that these compounds had noradrenalin and so forth, they are not located in nerves, they are in glial cells, in the supporting tissue. There were so many arguments that were piled up one on top of the other, so everybody was impressed by all these arguments that were against the idea of dopamine being a neurotransmitter.

Because on the face of it the evidence you presented at that meeting was fairly unequivocal, you gave this precursor to dopamine and to noradrenalin to these rabbits, noradrenalin wasn’t produced but dopamine was. You found dopamine in the motor centres, the rabbits recovered. It’s a sort of open and shut case when you describe it now, but then it just wasn’t seen like that.

Arvid Carlsson: It’s very strange. It’s funny that in retrospect things look so simple. And at the time it was very complicated. It was supposed to be complicated at least.

How did you react to this big rejection?

Arvid Carlsson: I think rather in a kind of aggressive manner. We should really tell them; we should show them how wrong they were. And at that meeting there was a very important person I was collaborating with at that time. His name was Nils-Åke Hillarp. Hillarp, he was a histologist, histo-chemist. We agreed on our way back from that meeting that he should develop a method by means of which one could show that these amines, that were not only dopamine but also noradrenalin and serotonin, were indeed located in nerves and looking in the same way as, for example, noradrenalin does in the sympathetic nervous system. That was what we agreed upon he should do. We got funded by the Swedish Medical Research Council. He could get on leave from his teachership in Lund, at the University of Lund, and could join me. I had just moved to Gothenburg to take over the chair of pharmacology there. He could come down, we had a beautiful new lab building. We had good resources actually, and he got the grant so he could spend all his time on this. On another related topic that also helped very much. Within less than two years, we all had it. He developed that.

He had a very clever technician, George Thieme, who did the work, first on models, just putting a protein solution, albumin actually, on object glass and then putting in whatever amine they were looking at. And then exposing the thing to formaldehyde gas and then these compounds were converted into strongly fluorescent compounds, just to put into the fluorescent microscope, and you had it. Then one could just move from there, from this model to the iris, which is of course a very thin layer containing a lot of noradrenergic nerves and the omentum, then the same thing showed up. One could see the nerves, and from then one could go to the brain. Then of course you had to do more conventional histology, you know. But still, the same principle, and there it was. So that helped very much then to convince people that we were right.

I was going to say you were a young man to be so bullish after the Ciba meeting, but at the same time you were professor of pharmacology at Gothenburg, so that’s quite an established position to be in. You took that chair quite early and you had a good track record behind you, so I suppose there wasn’t much shaking you from that point of view.

Arvid Carlsson: Yes, that’s the one thing that one can say. Yes.

Then opposition melted away.

Arvid Carlsson: Yes.

One thing you stressed in your Nobel Lecture, and have stressed elsewhere, was the importance of all the people who worked around you. I think in your Nobel Lecture you name 40 different individuals at least. I wanted to ask you a little bit about mentorship, what you had gained from people that made you the confident scientist you were at that time.

Arvid Carlsson: Of course, mentorship is enormously important. It’s interesting because I don’t know how to define a good mentor because there are so many aspects. I think one very important thing is the chemistry between the two persons simply, because my first mentor, he was not considered to be a great man at all in science. He was very promising as a young scientist and then he got very early he got a professorship in pharmacology in the University of Lund. After that he didn’t publish anything. But he was a great mentor, for me and for several others. And actually there was another person who also was among his students. He became one of the pioneers in artificial kidney. And that led to the foundation of Gambro, which is a big enterprise, still ongoing. He was an interesting man from that point, he could really convey something to his students, that evidently was very important.

I suppose there are these unrecognised teachers are seeding dynasties of researchers, but because they don’t do anything particularly noteworthy themselves, nobody really talks about them.

Arvid Carlsson: That’s correct. What he could do, he could encourage people. He kept telling me: You will become a great man. And he also guided me in a nice way, such as to broaden my experience. Then of course I had other people supporting me, and very important for me was an American pharmacologist, Bernard B Brodie, when I came over to him in 1955. My thesis was in -51 and that dealt with calcium metabolism actually. When I came to Brodie’s lab in the National Institute of Health, then I got into an entirely new field in a very exciting atmosphere. That was more or less the Mecca of modern pharmacology. Brodie, he was an organic chemist, a very brave man. He stepped right into the heart of pharmacology and started to apply his organic chemistry on pharmacology and all of the pharmacologists around there, they felt he was a crazy man. But he became a great pioneer. He could modernise pharmacology. He was enormously important for me also. These were the two main mentors that I have had.

Interesting that coming from a chemical background, presumably an organic chemical background, he then had a visionary approach to pharmacology.

Arvid Carlsson: Yes. And I think he was not very respectful, and that, I think, is so important. That he just applied his rather conventional chemistry onto the body, looked at the body more or less as a container, where you have a water phase and a lipid phase, and here you put in a molecule and it distributes between the two phases, just like in the test tube. That was his basic concept. And then of course he had to elaborate quite a lot on that. But that became very fruitful.

It’s kind of tearing down all the belief structures that we had around the body. Amazing. You were with him for a very short time though.

Arvid Carlsson: Five months.

It’s extraordinary that he had such a strong influence. You must have been very receptive also. I imagine it was that chemistry.

Arvid Carlsson: I was really impressed by this; it was a new world for me. This was such a dynamic lab. Every day, people came from all over the world, wanted to learn the newest, the most recent discovery, that was the kind of thing. And he developed the technology that was very powerful, especially an instrument that turned out to be very important, so called, spectro-photo-fluorometer, that for a number of decades was very important for the development, also in the field of neurotransmitters.

Because you built one back in your lab immediately.

Arvid Carlsson: Oh yes, immediately. As soon as I got back to Sweden, I ordered the instrument. It was a rather expensive instrument. I didn’t have the money for it, but I just had to have it. I thought maybe if nothing else, I will pay for it myself. I’d go to the bank to borrow the money and pay for it. But fortunately, the Swedish Medical Research Council gave me the money.

The different approaches you’ve seen to mentorship that you’ve received presumably inform the way you like to mentor people. What sort of a mentor do you think you are?

Arvid Carlsson: I have heard different descriptions. I think some people have been very positive and some people have said: Look here comes the guy, he goes into Carlsson’s office and he doesn’t look very happy. Coming out of Carlsson’s office, he looks very happy. So that does one description. Others have said: Well this guy, he just gave me the problem and told him that’s for you to solve it. There were two really very different versions. But regardless of which was correct, I think so many people coming out of my lab became successful.

Most definitely did. I suppose that was partly that you chose the right people to come in. What do you look for when you select somebody to be in the lab?

Arvid Carlsson: That was rather simple in the sense that we had courses in pharmacology medical students and those who did best in the exams, they were asked to come and stay with us. But perhaps also we felt it was very important that the person should at the very outset also have to demonstrate clear motivation. If you don’t have motivation, you do need really in science, because it’s not going to be easy, that one can be sure of.

Can you have motivation without top grades, do you think, and still be successful?

Arvid Carlsson: I would guess so, yes. The correlation between how you are doing in the exams and what you are finally doing then is not terribly good. I think there is one definitely. But there is a lot else that comes in that will have to come in, in order for you to really push your way through all the difficulties.

And do you think, on the question of motivation, is it, do you think, something that you are given as a scientist and then you apply it to whatever problem comes your way or you discover? Is it innate, the motivation, or is it more that it’s driven by the question – that you can be a scientist searching for your motivation and then find it?

Arvid Carlsson: Probably the answer to that is complicated. When I’m thinking about myself, I did several things, a couple of things very different from neurotransmitter work, before and I was happy with all of them. I must say, myself, I like to have a nice problem, to solve a problem. It is not terribly important whether we are dealing with, for example, as I was working with isotopes, the metabolism of calcium labelled the rate of calcium in the body to measure and to see how the skeleton grows and how calcium is coming into the bone and getting out the region, and the whole metabolism, that was fascinating. The reason I switched to neurotransmitters was actually that the people who were at that time dominating in pharmacology in Sweden, when they looked at me and my merits for professorship, for example, they said: Well, he’s ok, but calcium metabolism is really not what a pharmacologist should be doing. I thought these are the guys that are going to be the dominating people for a while in Sweden, I think I’d better do what they say. So that’s the reason why I came over to Brodie’s lab actually.

So you have to be a motivated pragmatist as well.

Arvid Carlsson: Yes.

If we turn back to the dopamine story, it was a good 10 years between your establishing that L-dopa could reverse the effects in the animal models and the practical use of L-dopa in human populations. And we hear a lot these days about the length of time it takes to develop a drug. But those were less regulated days and why did it take so long do you think?

Arvid Carlsson: I think it was a rather trivial thing actually. When dopamine stimulates it’s through various receptors in the central nervous system. One population of receptors that are especially sensitive are those that are in the emetic zone. That means that the first thing that happens if you give the precursor to L-dopa, it’s getting into the brain, converted to dopamine, is to induce vomiting. Nausea and vomiting. And when people started to use L-dopa they started to do intravenous injection and then it’s not easy to overcome this vomiting, this emetic action. But this particular action shows a considerable development of so-called tolerance. If you go slowly, step wise, you’ll go up in dosage, you can overcome the emetic action, not altogether, but it can be handled so to speak, the emetic action. And that is what Cotzias did in 1967.

That’s George Cotzias, yes. And it was his work that formed the basis for the Awakenings book by Oliver Sacks.

Arvid Carlsson: Absolutely, yes.

You’ve actually worked on a good number of different drugs. You developed the first selective serotonin reuptake inhibitor, the SSRIs, which the most commonly known as Prozac. But you developed number one and you also developed a beta-blocker, you brought out beta-blocker number two.

Arvid Carlsson: It is correct.

Having worked in drug research as you have, do you have a feeling for how drug research has proceeded over the decades? Do you feel that we’re in a better state now than we were when you were first doing it?

Arvid Carlsson: I’m sorry to say that the field has become rather gloomy. If you look at the output of new drugs over the last 10-15 years, it has gone down dramatically. It is a very sad thing, and something one should look into very seriously I think because it’s bad for so many reasons. Of course patients need better drugs, first of all. But the pharmaceutical industry is so important also for the development of science, of biosciences, in pharmacology, physiology, biochemistry and so on. The new molecules have a tremendous triggering effect on research. So, if there are no new molecules coming, that will have an impact on a great considerable part of neuroscience and other bioscience. It’s a very serious matter and I am disappointed that people are not more concerned about the situation than they are.

When you say that drug research has an influence on the other sciences, is it that the molecules being produced by drug companies are then feeding out into the life sciences and inhabiting experiments, basically allowing you to do new things. What’s the relationship between the drug companies, who are focused very much on producing something that will have an effect in humans and life science research?

Arvid Carlsson: First of all I think the real basic thing is that new molecules with new sites of action, they are tremendous tools in the study of the physiology of the body and biochemistry, whatever. If we look back and see how different discoveries were made, even if you look at the metabolism in the muscle and whatever, there have always been drugs, most of them poisons, for that matter, to discover. If you have a poison that blocks an enzyme, then all of a sudden you discover something very important. But it’s not only a matter of poisons. The drugs are enormously powerful tools for discovering new secrets, all the secrets that still remain in our bodies. So that’s number one. But the other thing is the triggering effect that pharmaceutical companies have by establishing, at least in many cases, a very fruitful collaboration has been established between pharmaceutical industry and academia. And I have been very fortunate in that kind of collaboration. I have had so much of really positive experience by this kind of collaboration. And of course you mentioned the SSRIs, that was a collaboration with the Astra Pharmaceuticals.

Could you speak a little bit about that? How did that work?

Arvid Carlsson: The first thing, you already mentioned the beta-blockers, actually there was a very … Ivan Renström, he was a very important man. He was head of research in a small subsidiary of Astra in the Gothenburg area. They had moved from the deep south of Sweden to Gothenburg to establish a good relation to the newly formed medical school of Gothenburg, in the University of Gothenburg.When I got there in 1960, Dr Renström – he got an honorary degree later on – he got in touch with me and he asked me what I thought of what they were doing and I thought you are a very good chemist, but I think your strategy is not the best. Because what they were doing was the classical kind of approach, you have some very ingenious chemists and they come up with some very ingenious molecules. And then you have a pharmacologist who is doing his, more or less, rather trivial models, pain, threshold, convulsion threshold, motility, that kind of thing. Then from that to they tried to figure out what these molecules could be good for. I told him that’s not the best way.

The best way of approaching this is to start out from what we know about the body. Start out from the biology and go from there to chemistry and not the other way around. And he accepted this idea, so then I gave him as an example, I said, why not look into these very interesting beta-receptors, the adrenergic beta-receptors, they had been known for a while, actually it was a pharmacologist of Swedish ancestry who discovered the alpha and beta receptors. Ahlquist, right. And then I had been to a meeting in 1958 in Bethesda, where there was the first report of a beta-blocker, DCI, dichloroisoprenaline, and I found that extremely interesting. They had tried it, that was at the Lilly company, and they were unfortunate, one of the first patients died. This probably had nothing to do with the drug.

How inconvenient of them.

Arvid Carlsson: That’s why they stopped it. But I thought this is a great thing. I told him, why not start on this because this is something new that should be, it acts on the heart, it will dampen any too strong stimulating influence on the heart that is likely to occur. If we could dampen that it could be useful for something, I told him. I cannot tell you exactly what. But why not go ahead with this. He like the idea and started on it, and it took a couple of years after we started on this and got some molecules that we learned that there was another company ahead of us. That was the ICI.

That was James Black.

Arvid Carlsson: Exactly, yes. And that was good, and it was bad. It was good from the point of view because the people up in the centre of the headquarters here outside Stockholm, at Astra, they started to understand that maybe what we’re doing is not just some academic playground business, but there could be something real in it. But we were, on the other hand, a bit disappointed, but of course at the same time encouraged. It wasn’t so bad after all what we were doing because there was a big English company doing the same thing. We felt encouraged and finally we came up with Xylocain which turned out to be very competitive. And is still actually making money for Astra Zeneca.

Really, even though it’s off patent?

Arvid Carlsson: Oh, sure yes. They were very clever; they managed to get a renewed patent. But even that one has run out. It has been going on for decades and still it’s one of their major drugs.

Do you still benefit from it?

Arvid Carlsson: No. When the first patent expired, I was out. But they’ve made a new one on the same molecule, but you know a little bit of chemistry on … But it was still the same compound but with a new patent. But I was out. Never mind. Another thing that came out of this was the beta-stimulants, that came out of the same concept, the same kind of bio-assays that we were doing, could also discover stimulants on the beta receptors. That project was considered by the management to be too much for the little Gothenburg subsidiary, so they moved that down to the subsidiary in Lund and that was another good thing coming out that was Bricanyl, also a major drug. These two drugs, Xylocain and Bricanyl, became very important for building our financial strength, for Astra. And probably created a good platform for developing Losec, which of course became an even bigger drug.

Is it now unusual to see companies look outside the walls for their inspiration in the way that Astra were doing then?

Arvid Carlsson: The development here has been very interesting. At that time the very goal-directed politics of Hässle, this subsidiary outside Gothenburg, to create a good collaboration with academia. I think that was something that Mr Östholm was really the man behind doing this, and it was not so usual at that time. But then so many things have happened, not only in Sweden, but all over the world, during the subsequent 1960s, 70s and 80s, the pharmaceutical companies became so enormously powerful, they were so successful. And they became much more financially powerful than academia. That was a switch, an imbalance between the two. The pharmaceutical industry becoming so much more powerful.

What has happened after that is a new phase where, as I said, the big pharma has become much less successful in developing new drugs. They are still successful in making money, but that’s because of the drugs that they are still selling, that they developed earlier. Now they are coming down in terms of being innovative. What has happened because of that? Well, in order to show that they have muscles, what do they do? They merge. They merge and then they look very strong and powerful. But at the same time, during the mergers, then some of the most creative people within big pharma, they move out of it, they don’t like it at all, all these mergers, they get confused. There is no peace of mind for them anymore. So that is how, at this time, the small biotech companies have developed. And now they are the ones that perhaps one should hope for.

I was going to ask you, yes, that’s the hope for drug research now. And also the hope for academic collaboration because they spring out of academia.

Arvid Carlsson: Yes, that’s correct. And the academic, I think for real innovation you need the academic atmosphere. These biotech companies, they have come out of academia and they still have quite a bit of academic atmosphere, so there is a good atmosphere for innovation. But of course, what will happen next, we don’t know. I mean what will happen to all these small biotech companies? We don’t know. I would guess that many of them will not be able to survive. And perhaps others will be bought by the big pharma and if that’s good or bad, I cannot tell.

I must at least force you to have a perspective, because you of course started your own small drug company, working on this idea of dopamine stabilisers, which seem on the face of it to make sense, that rather than turning everything off or turning everything on, you might try and go for some kind of middle ground in brain chemistry. If that’s not too simplistic a description.

Arvid Carlsson: No, I think it’s simple and that’s one of its problems. If you come up with something that’s simple, people will not be impressed. It’s so simple but it’s at the same time so obvious. That is where we have to go. The brain doesn’t like to be pushed hard in either direction, neither up or down. But if anything is up, of course, one should bring it down, if it’s too much. If it’s too little, it has to be brought up. But you have to be very careful not to overdo it. You have to move towards something that’s a reasonable base line. Therefore you must have stabilisers. Of course the simplest principle of stabiliser is of course the partial agonist concept. So that was the one we started on.

This is something that occupies a receptor but only produces a partial response.

Arvid Carlsson: That’s correct. And therefore, if it occupies it can, if there is no endogenous agonist, or very little agonist, then it serves as an agonist. But if you have a lot of the endogenous agonist and it occupies, then it will become an antagonist. It’s a mixed agonist/antagonist.

It can play either role depending on the circumstance.

Arvid Carlsson: That’s correct. And it will bring things towards something more or less normal. So that we were working on for several years and we had lots of problems making people understand that this was worthwhile. We took one molecule to testing, and minus triple P we called it, and it turned out to do exactly what we predicted. In psychoses where dopamine is high, you had an antipsychotic action, and in Parkinson’s where dopamine is low, it had an anti-Parkinson effect, that was shown. But it was not a good drug perhaps because in the long run, if we extend it, the treatment of schizophrenia over several weeks, the effect was there after one week, but then it sort of faded away. And we think we understand why. It’s simply that there is too much of agonist in it and that the brain will respond to that by reducing sensitivity. We predicted this can be done, it’s a good principle, but we have to change the so-called intrinsic activity.

Not too many people thought that was a great idea. But there was one Japanese pharmacologist, Dr Kikuchi, he started all that. He built further on our concept, and out came Abilify, which is doing very well as an antipsychotic agent and also in mania. W had proof of concept and I am very pleased for that. But now we have a new generation of stabilisers, they are different because they are not partial agonists. A partial agonist, as you said, it will bind to the same site as the endogenous agonist and do these things that we said. But in this case, the new compounds that we have, they also bind to the receptor, the dopamine D2 receptor, but on a different site, a so-called allosteric site. That makes the whole thing so much more exciting because it opens up from a medicinal chemistry point of view, so much new opportunities. Because now you’re not only working on one site, you work on two sites, so that opens up so much opportunity for medicinal chemistry. I think this stabilising concept will become a very powerful concept in the not too distant future.

It cries out for a much more detailed understanding of the systems one’s affecting. It cries out for more detail in understanding the circuitry of the brain in this case.

Arvid Carlsson: Absolutely. Also in understanding the receptor. Still there is too much of the simplistic idea that if you have identified a receptor in terms of chemistry, you have the sequence of amino acids, then you have it, they say. That’s not true, because the bodies are enormously clever. If you have a receptor sitting on one site, the brain on this side can make it do a little bit different from in another site. So that will lead to different response also to exogenous molecules. So therefore, even if you have one single receptor molecule which looks exactly the same when you have taken it out and done all the cloning and all that, when it sits in the body it’s not one thing, it’s many different things and you cannot extrapolate from the test tube as much as you think.

That’s an important caveat. Just to draw you back to the start of that question on dopamine stabilisers, you started your own company to develop these but then that was bought up. We were discussing the advantages or disadvantages of small biotech’s being eaten up. Do you think that in your company’s case it was a good thing that it’s been taken over by a larger company? Or is it too early to say yet?

Arvid Carlsson: That’s correct. Because sooner or later, a small biotech company, if it is successful, it cannot take the molecule all the way to the market. Sooner or later, a big company will have to come in. In this case with Carlsson Research, actually before it was sold, it was a Japanese company. And again, it was another one, so I’m impressed by Japanese companies because there was a Japanese company, there were a number of European and American companies that looked into the stabiliser concept, and they stayed away from it. But he comes now, what is now called Astellas, there was a merger before that, but let’s forget about the name. They thought this was something worthwhile working on. They got the licence from Carlsson Research, and they are now developing this compound. But there was one indication that was still left, kept by Carlsson Research, that was Huntington’s disease. Because Carlsson Research felt a small company could very well make enough profit from … Even if it’s a very small population, if it’s a great drug in the disorder, and it seems to be. The first drug that is doing anything that’s worthwhile, that this drug is doing in Huntington’s. Therefore when Carlsson Research was sold to NeuroSearch in Denmark, now NeuroSearch is developing Huntington’s for this compound, the same molecule for Huntington’s and it’s now, this year I’m sure it will start phase 3, so maybe in a couple of years it will be on the market.

That’s exciting.

Arvid Carlsson: You can see, I cannot say, was this good or was it bad? But my conclusion out of this, because some money got freed, so to speak, for me to work on during the purchase. Because I had, and some foundation also got money out of this, because there was a foundation that had shares, and therefore got money. There is now money to do research on and development. So therefore, Carlsson Research when it was sold, it changed it’s name to NeuroSearch Sweden AB. But now I have restarted Carlsson Research, and I’m going on. There is still a very interesting molecule that was the first one of its kind, with this new kind of stabilising properties, that I have managed to get released and we have under control now. The new Carlsson Research will work on this molecule.

And is there a specific disease target for new Carlsson Research?

Arvid Carlsson: The same as the ACR16 that Astellas and NeuroSearch has. We also have data on schizophrenia, we have data on Parkinson’s disease with L-dopa induced dyskinesia, we have Huntington’s. But this is just the beginning because you see if you have something that can stabilise neuro circuitry by stabilising dopamine receptors, you will have a list, you know. It will take a long time to really get an overview of the usefulness of such a drug, but I am sure it’s going to be tremendously useful for this principle.

I’d like to turn to the topic of pharmacology in general. It’s quite unusual for a pharmacologist in the latter part of the 20th century and the 21th century to get a Nobel Prize in Physiology or Medicine, pharmacology is a discipline which perhaps has seen a downturn in interest. Yet, I imagine you’d agree that it’s of fundamental importance for it to continue as a strong discipline on its own. How do you think the status of pharmacology is looking at the moment?

Arvid Carlsson: It doesn’t look too good. It’s not just pharmacology, it’s also physiology actually. The integrated aspects of body functions and the outlook of this part of science into the clinical applications. This is not being very much favoured at this time because of the staggering discoveries in genes and molecular biology, everybody’s moving in that direction. And that is away from integrative aspects of physiology and pharmacology. Therefore there is really not enough training of new people in this field, that’s for both integrated physiology and integrated pharmacology. This is something that you will get into if you are trying to really develop anything in physiology and pharmacology, on the basis of animal work, you will have to go into the integrative aspects. It’s not enough to have a molecule or a cell because the most difficult thing is things to go into, the most complex thing that we have in our bodies is how all these different cells and organs, how they are operating together and how it is controlled from the brain and the endocrine system and all that. This aspect is now not being considered enough, and there isn’t enough people being trained for this very important aspect. You have to get through in order really to get the final answer of what is important for the human being. You must go through this part of the integrative aspects of physiology and pharmacology. And that is going to become a great problem, I think.

It’s funny because there’s a huge emphasis these days on interdisciplinary research, there’s lots of encouragement for that. But yes, there isn’t an encouragement to study things as a whole.

Arvid Carlsson: That’s correct. The cell by itself of course is enormously fascinating, so people are just focusing on the cell. They are so fascinated by the cell, but the cell is just one step, then you have to go into how all these cells are operating together. That’s even more intriguing I think and even more important to understand. Everything is important of course. All the steps are important for the full understanding.

Last question on this theme, is there anything you think that could be immediately done to correct the deficit?

Arvid Carlsson: Of course there have been certain efforts in this direction and there have been great decisions made and once you’ve put in the funding for this bio kind of thing. But it’s very hard to do any … Things are evolving on its own, even if you have ideas of what should be changed and so on, it’s very hard to have an impact on how people think and what priorities they have. I think their priorities are not optimal and there will be a change of course, the pendulum will swing back, but it will take some time still and it will be a tough thing to regain what has been lost.

For a last theme, I’d just like to dwell on the Nobel Prize a little bit. In your case the award came approximately 40 years after the discovery, and I was wondering whether you felt that that was a good thing or a less good thing that it took so long to come?

Arvid Carlsson: I think I can have two comments. One is that for Einstein it took 20 years, for me it took 40 years, which means that my problem was twice as complicated as his. That’s number one. Number two, the reason why it took such a long time was that dopamine started out as really something that nobody thought could simply be of any importance. Over the decades people had started to realise, look here comes dopamine, it’s involved in everything. Therefore, the stock of dopamine has grown over the decades. Finally, so many people understood dopamine is terribly important. Of course, in addition to that, it was so … I think in perspective, it became clear that the whole concept of chemical transmission in the brain depended very much on this early work on dopamine. Dopamine was really the molecule that paved the way for the concept of chemical transmission in the brain. That also became clearer as time went by.

On that sort of theme, it strikes one that you could perhaps have been included in the Nobel Prize in 1986, although it went to three people. It went to Black, Elion and Hitchings for their development of drug treatments. But you also had developed novel drug treatments based on very novel mechanisms, so you could’ve perhaps been part of that prize. If you had been, it would’ve made you a Nobel Laureate 14 years earlier than you were. What sort of effect do you think that might’ve had?

Arvid Carlsson: That’s very hard to tell. It’s always hard to tell if that had not happened or if that had happened, what could have been the impact? I’m not sure it would have been terribly important for my research. Because I know there are people who are, so to say, in the Nobel Prize career, and where they think, in their choice or in their research, which one to take, which is best for me as a candidate for the Nobel Prize. I have never had any thinking like that. What I found that is the most exciting from the research point of view, I have chosen that. As we already talked about, I stepped away from dopamine because I got so excited again by serotonin actually, which was what I started with in Brodie’s lab, by the way. Whatever I find the most exciting thing that has been my priority. Therefore, I don’t think it would have made any difference if I had received the prize so much earlier. I doubt it really. Because I had reasonably good funding until my retirement. Then at the time of retirement, that’s a big problem in Sweden, as a retired person, because then you are pushed off. I was fortunate even from that point of view because I got a very good research collaboration agreement with Upjohn, the American Upjohn company. So that could help me to go on with my research.

It seems one would use the word retirement quite lightly in your case.

Arvid Carlsson: Yes, nobody has given me any thanks for my retirement. I sometimes think why didn’t I get any thanks? That’s because I didn’t stop, you know, it’s my fault that I was never thanked.

Yes, so the 1986 or 2000 question really isn’t relevant because it didn’t really make much of a hiccup in your productivity.

Arvid Carlsson: No. I can tell you I was asked to give a statement as an expert about these candidates. I’m not supposed to tell people, but it’s such a long time ago.

They’re interesting people too, so that’s good. On that note, I think we’ve probably explored many of the interesting things we could. We could talk for much longer, but for the moment, thank you very much indeed Arvid Carlsson for speaking to us.

Arvid Carlsson: And thank you for your kind interest.

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