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Home , Arvid Carlsson

NEWS FEATURE |Vol 447|24 May 2007

The molecular wake-up call It is 50 years since Arvid Carlsson showed to be a . Alison Abbott profiles a chemical and its champion.

hey were conscious but you wouldn’t know it: able to perceive the world around them but powerless to look Taround, sniff the air or to cry out. So when the young scientist injected them with a chemical called l-dopa, he witnessed what seemed to be a miracle. They stirred, opened their eyes and began roaming around as if nothing had happened. This may sound familiar from the book Awakenings1 — the true story of how, in 1963, the neurologist Oliver Sacks used l-dopa to spectacularly revive patients with sleeping sickness who had been ‘frozen’, speechless and motionless, for more than 40 years. But the unwritten and equally startling pre- quel took place in , , several years earlier. The protagonists were rab- Catatonic rabbits were revived by bits; their saviour a young Swedish phar- dopamine in a 1957 experiment led macologist called Arvid Carlsson. by Arvid Carlsson. In his experiment, Carlsson showed that dopamine — the chemical manufac- embrace new techniques and fight tured from levodopa, or l-dopa — acts as for controversial ideas, as Carlsson a neurotransmitter in the , passing in Carlsson’s home has done throughout his career, remains essen- signals between neighbouring neurons. town of , Sweden, to cel- tial to success. “He was one of my heroes when Injection of l-dopa restored the propagation ebrate the 50th anniversary of his formative I was a young neurology resident,” says William of electrical signals in the of rabbits that paper on the awakened rabbits2. Langston, head of the Parkinson’s Institute in had been rendered catatonic, allowing the ani- During the past half century, Carlsson and Sunnyvale, California. “What impressed me mals to move. But the pharmacological estab- dopamine have followed intertwined paths. was his brilliant deductive reasoning.” lishment was scornful of Carlsson’s claim. At a Researchers now understand that the way Carlsson is a polite, soft-spoken and humor- London meeting in 1960, the foremost experts dopamine works is subtle and complex, and ous gentleman with a hallmark bow tie. He in neural transmission made it clear that they its mechanisms of action are central to the grew up in a family of academics in Lund that didn’t believe him — dopamine was thought to function of many neurological and psychiatric focused on the humanities but, in what he refers be the metabolite of another neurotransmitter drugs. And Carlsson, now a sprightly 84-year- to as a minor act of rebellion, he chose science rather than one in its own right. old, still spends hours pondering the mysteries over the arts because he thought it more useful Within years the critics were silenced. of brain chemistry. But he feels marginalized in to society. He is also single-minded and uncom- Dopamine was shown to be a pivotal chemical Gothenburg and, last year, the institute estab- promising, features that no doubt contributed in the neural circuits that drive pleasure and lished in his name closed prematurely after bit- to his success as a scientist against stiff opposi- addiction, as well as in illnesses such as Parkin- ter feuds about funding. tion — and perhaps also to his later problems. son’s disease, for which l-dopa quickly became The field of biomedicine has also evolved Carlsson calls himself a lucky man, and says a first-line treatment. It remains so today. In during this time, and much has changed. “We his first stroke of luck came when he arrived 2000, Carlsson shared the in Physi- used slide rules and manual calculators back in the lab of chemist Bernard ‘Steve’ Brodie at ology and Medicine for his discovery. And next then, so statistical calculations were quite time the National Institutes of Health in Bethesda, week will gather at a meeting consuming,” Carlsson says. But a willingness to Maryland, in the summer of 1955. Brodie’s lab

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pioneered studies with , one of the But when Carlsson examined dominated the brain itself. “It’s very first drugs to be introduced for the selec- the revived rabbits’ brains hard to imagine now, but when tive treatment of schizophrenia, and hence one after injecting l-dopa he saw I was an undergraduate stu- of the hottest molecules for pharmacologists of a lot of dopamine and very dent at Cambridge [in the late the day. Reserpine injections made rabbits cata- little noradrenaline. At this 1950s] we were taught categori- tonic, but how the drug worked was a mystery. point it dawned on him that cally that there was no chemi- dopamine could be a neuro- cal transmission in the brain Direct measures transmitter in its own right, a — that it was just an electrical At the time, pharmacologists typically tested memory that still summons machine,” recalls pharmacolo- the potency of with assays astonishment to his face. gist Leslie Iversen, professor of their biological activity — for example, Within months his gradu- emeritus at the University of applying them to a piece of animal gut under ate students Åke Bertler and Oxford, UK. tension in an organ bath to see how much Evald Rosengren had found In this setting, Carlsson’s they could contract or relax the muscle. Bro- that dopamine is normally ideas went down like a stone. die’s team instead developed the spectrophoto- concentrated in areas of the The meeting unceremoniously fluorimeter, a machine able to measure how brain known to be involved “I won the Nobel Prize rejected his interpretation of much neurotransmitter was synthesized from in movement, such as the 40 years after my his data and, to his mortifica- 3 fluorescently tagged precursors. This allowed . Knowing that discovery. Einstein tion, the single comment in the the researchers to measure the precise level of high doses of reserpine cause discussions praising his work a compound extracted from tissue rather than side effects that are similar won one some 20 was excluded from the sympo- an indirect measure of its activity, and later to some of the movement years after his. So I sium book. “The Ciba meeting became a standard instrument in biological difficulties experienced by guess my work was might have been the oppor- labs. When Carlsson returned to Lund after his patients with Parkinson’s dis- tunity to tell the world how five-month visit to Brodie’s lab, the first thing ease, Carlsson proposed that twice as complicated.” things really were, but there he did was order a spectrophotofluorimeter. “I this disease might be caused — Arvid Carlsson was uniform hostility from the didn’t want to be confined by the indirectness by a lack of dopamine. community,” says Iversen. of bioassays,” he says. Carlsson stuck to his guns, Carlsson’s work with this device showed Sparking opposition and data began to amass to a point that made that reserpine completely drains the stores of In late 1958, Carlsson travelled across the denial impossible. Later in 1960, for example, several neurotransmitters in the brain. Loss of Atlantic to explain his ideas to a symposium in the Austrian pharmacologist Oleh Hornykie- one of these was causing the rabbits to become Bethesda. There, his story was well-received. wicz published studies on postmortem brains catatonic — the question was, which one? “But this was not the case when I presented my from patients with Parkinson’s disease, show- Carlsson reasoned that he could answer this results at the Ciba meeting in London,” says ing the absence of dopamine in the basal gan- question by adding back the missing neurotrans- Carlsson, who is still clearly a bit hurt. glia4. And a few years later, Annica Dahlström mitter to rabbits that had been frozen with reser- The prestigious 1960 Ciba Symposium on and Kjell Fuxe at the Karolinska Institute in pine — the crucial awakening experiment. The Adrenergic Mechanism attracted all the key Stockholm, Sweden, showed that in the healthy blood–brain barrier prevents the neurotrans- European players in the field. At the time, a brain neurons in this region contain high levels mitters noradrenaline and serotonin from pass- vigorous debate was going on between the of dopamine5. ing into the brain from the blood, so Carlsson ‘soups’ — who thought that nerve transmission In 1961, neurologist Walter Birkmayer, work- instead injected precursors of these molecules occurred through chemicals — and the ‘sparks’, ing together with Hornykiewicz, injected the that can enter the brain and are then metabolized who argued that it was all electrical. The soups first Parkinson’s patients with l-dopa to dramatic into the relevant neurotransmitter. One of these had more or less won their case for neurotrans- effect, allowing previously immobile patients to precursors was l-dopa, which is converted into mission outside the brain but, owing to lack move freely6. Carlsson recalls the penchant of his dopamine and then, in turn, into noradrenaline. of experimental evidence, the sparks’ view still collaborator Tor Magnusson for testing drugs openly on himself — something that would be Arvid Carlsson regarded with horror today. Expecting to see collects his some kind of neurological effects, Magnusson Nobel prize in hooked himself up to intravenous dopamine, 2000, more but, says Carlsson, “all we saw was emesis!” than 40 years Many other aspects of practising science were after showing different then. Fax and e-mail did not exist, and dopamine to be a all papers were read in the library rather than on neurotransmitter. a computer. “We certainly wore white lab coats and we addressed secretaries and assistants more formally as Miss,” Carlsson says. Over the next few years, clinicians learnt to start patients on low doses of l-dopa to avoid side effects such as nausea and vomiting. They also noticed other intrinsic imperfections of the drug. After a few years of therapy, its effects temporarily, and unpredictably, switch off in

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Degeneration of Until this time, Carlsson and dopamine had the nerve cells that both followed stellar trajectories. But after the secrete dopamine Nobel prize, Carlsson’s luck began to falter (red) leads to — and the uncompromising side of his nature, Parkinson’s disease. which had served him so well in his scientific career, failed to help. Just a few months before winning the Nobel, Carlsson was voted off his own company’s board of directors. And in the next few years, plans for his namesake institute also went awry.

Difference of opinion The Arvid Carlsson Institute was launched in November 2004 with SKr630 million (US$92 million) funding over five years — a tribute from Gothenburg University and the regional authorities to the city’s only Nobel prizewinner. Its original mission was to promote health care and research in the region, and Carlsson was named honorary chairman of its developmental council. But disagreements some patients. In severe cases, patients can transmission in particular brain areas. began almost immediately about how the suddenly become frozen and be stuck, immo- Too little dopamine in one area produces Par- money should be divided up. Carlsson wanted bile, for minutes or hours. kinson’s, too much dopamine in others can cause a significant proportion to support his field of Neurologists were also starting to learn that psychoses. Over recent decades the importance , but others argued it should dopamine is involved in much more than the and complexity of the dopamine system have go to neuronal stem-cell research. Scientists control of movement. They noticed that high mushroomed in scientists’ eyes. Dopamine decline to discuss details of the arguments, but doses of l-dopa cause some of the symptoms of acts on many types of receptor, at varying levels the hostilities became so bitter that the institute psychoses such as schizophrenia, and that the and in different brain areas, and in concert with was dissolved in April 2006. Carlsson’s daugh- antipsychotic drugs used to treat schizophrenia other neurotransmitters. ter Maria, who is also a neuropharmacologist, can cause the same movement problems that Another of Carlsson’s legacies receives a small proportion of are indicative of dopamine deficiency in Par- has been the development of “When I was an the funds — too small in the kinson’s. This led to the idea that schizophrenia dopamine stabilizers. These are opinion of her father, “given could be related to a disturbance of dopamine dopamine-like molecules that undergraduate that the research was stated to neurotransmission in areas of the brain other have been chemically modified student we were be done to honour my contri- than those involved in movement. so that they activate dopamine taught that there butions to science”. receptors to only a certain Carlsson’s contributions to The molecular multitasker degree, effectively constraining was no chemical science continue. He is closely Carlsson reasoned that antipsychotic drugs the level of dopaminergic acti- transmission in the involved in his daughter’s work could be blocking dopamine receptors, and vation in the brain to within the brain.” and they sometimes publish that neurons might be spitting out more and healthy range. The theory is that together, although he wishes he more dopamine to try to compensate for the a stabilizer could compensate for — Leslie Iversen could still work in the lab. He blockage. He was right. This type of feedback lack of dopamine in Parkinson’s also jets around the world to control of neuronal activity is now a well without causing overactivation; or block the meetings. Much in neuroscience has changed understood, and critical, phenomenon in overactivity in schizophrenia without too much during Carlsson’s time, but he believes at least neuro transmission. And this way of thinking depletion. Several companies have dopamine one thing has remained constant. “When I won Carlsson many fervent admirers. He is stablizers in development, and one, aripiprazole, started my career, the most important genera- “just about the most creative, intuitive scien- has been approved by the US Food and Drug tor of science was the human mind,” he says. tist I’ve met”, says Solomon Snyder of the Johns Administration for use as an antipsychotic for “This has probably not changed much during Hopkins University in Baltimore, Maryland, schizophrenia and bipolar disorder. the past half-century.” ■ who discovered opiate receptors in the brain. When Carlsson reluctantly retired aged Alison Abbott is Nature’s senior European Another side effect of l-dopa treatment is 66 — then the law in Sweden — he kept his correspondent. that patients may develop an irrational ten- research going by forming a company called A. dency to gamble. It is now well known that the Carlsson Research where, among other things, 1. Sacks, O. Awakenings (E. P. Dutton, 1973). neural pathways controlling behaviours such as he developed a dopamine stablizer. Then, in 2. Carlsson, A., Lindqvist, M. & Magnusson, T. Nature 180, motivation and feelings of reward pivot around 2000, Carlsson’s work on dopamine and its 1200 (1957). 3. Bertler, Å. & Rosengren, E. Experientia 15, 10–12 (1959). dopamine. These pathways drive pursuit of food control of movement was recognized with a 4. Ehringer, H. & Hornykiewicz, O. Klin. Wochenschr. 38, and sex — and are hijacked by addictive drugs share of a Nobel prize. “I won it 40 years after 1236–1239 (1960). and addictive behaviours such as gambling. In my discovery,” he jokes. “Einstein won his some 5. Dahlström, A. & Fuxe, K. Acta Physiol. Scand. 62 (Suppl.), 232 (1964). the 1960s, Carlsson was among the first to spot 20 years after his discovery. So I guess my work 6. Birkmayer, W. & Hornykiewicz, O. Wien. Klin. Wochenschr. that drugs of abuse work by boosting dopamine was twice as complicated as Einstein’s.” 73, 787–788 (1961).

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