Julius Axelrod (1912–2004) Tissues Enriched in Sympathetic-Nerve Endings

news and views

Obituary [3H]noradrenaline was injected into rats and cats, the radiolabel concentrated in Julius Axelrod (1912–2004) tissues enriched in sympathetic-nerve endings. But lesions of the sympathetic Julius Axelrod, known to friends and nerves abolished the accumulation. So colleagues affectionately as ‘Julie’,died on Axelrod postulated that noradrenaline, NIH 29 December 2004, following a career that the neurotransmitter used by sympathetic was highlighted by so many extraordinary nerves, is inactivated by a ‘re-uptake’ discoveries about how drugs act that his system that involves the transmitter being place among the twentieth century’s pumped back into the nerve ending that greatest biochemical pharmacologists is had released it. Adrenaline, released from secure. The research for which he shared the adrenal gland, is also taken up into the Nobel Prize in Physiology or Medicine sympathetic nerves. in 1970 was only a small, and perhaps not Neurotransmitter inactivation had even the most important, part of his opus. previously been thought to be primarily Axelrod’s life story is an inspiration enzymatic, because the first known to those who care about science but lack transmitter, acetylcholine, is inactivated elaborate academic credentials. The son by an enzyme. But it soon became evident of a poor basket-maker in New York City, that re-uptake inactivation is the rule he graduated from the City College of rather than the exception for most New York and applied to numerous medical neurotransmitters. Axelrod also found schools but was rejected by all of them. For From pharmacologist major drugs that inhibit re-uptake, and his 11 years he worked as a technician in a New to neuroscientist discovery that antidepressants work in this York City health laboratory, where he was way spawned the modern generation of assigned the task of monitoring the vitamin molecular oxygen. This is the cytochrome antidepressants, exemplified by fluoxetine content of foods. Here he honed his skills in P450 family of drug-metabolizing enzymes, (Prozac). For this research he shared the developing simple, sensitive and specific and their discovery represents a classic Nobel prize with Ulf van Euler, who methods for measuring drugs. advance in pharmacology. established that noradrenaline is a A turning point was his department’s All of these discoveries were made while neurotransmitter, and Bernard Katz, who assignment to clarify why phenacetin and Axelrod was only a technician. Responding showed that neurotransmitters are stored acetanilide — the principal ingredients, to pressure from friends, he took a year’s in synaptic vesicles in nerve endings. along with aspirin, in major headache leave of absence, enrolled at George Axelrod’s gifts as a creative scientist remedies of the day — led to dangerously Washington University and, at the age were matched by his gifts as a mentor. high levels of methaemoglobin, a product of of 42, received his PhD. With a doctorate His extraordinary discoveries emerged haemoglobin metabolism, in patients’ blood. in hand, Axelrod was made head of from a tiny laboratory of only three or four In 1946, he sought the assistance of Bernard pharmacology in the laboratory of clinical scientists. Although he carefully structured Brodie, then at the Goldwater Memorial science at the National Institute of Mental concrete projects for new students, he soon Hospital, thus commencing a career- Health. weaned them, encouraging independent transforming collaboration. With Brodie he Seymour Kety, the laboratory director, thinking by the “unconditional positive showed that acetanilide and phenacetin are was intrigued by reports that implicated regard”(to quote psychologist Carl Rogers) respectively metabolized to aniline and the abnormal metabolism of adrenaline that he lavished on every student’s efforts. p-phenetidin — the toxic culprits. Another (also known as epinephrine, a He maintained an active laboratory at the metabolite, N-acetyl-p-aminophenol or neurotransmitter) in schizophrenia. To NIH until a few years ago, and subsequently acetaminophen (paracetamol), is probably understand how adrenaline is normally visited his small office there regularly. His responsible for the analgesic effects. This metabolized, Axelrod exploited a brief wife Sally died in 1992; he is survived by his discovery, never patented, made up Axelrod’s abstract reporting that adrenaline- sons Paul and Fred and three grandchildren. first two publications, and led to the producing tumours metabolize adrenaline Like almost all of Axelrod’s trainees, marketing of this metabolite as Tylenol, to a product that is methylated on one of my entire scientific career was predicated the world’s most widely used analgesic. the two hydroxyl groups of its catechol upon the lessons learned in my two years In 1950, Axelrod moved to the newly ring. Axelrod soon discovered an enzyme (1963–65) with him. Many of us have formed National Institutes of Health (NIH) that uses S-adenosylmethionine to tried to divine Julie’s gift for recognizing in Bethesda. He continued working in methylate catechols; he dubbed it catechol- important questions that can be Brodie’s laboratory but with increasing O-methyltransferase. Using radiolabelled addressed by simple means, and for independence, elucidating the metabolism S-adenosylmethionine, Axelrod went on to devising experiments so elegantly efficient of caffeine, ephedrine and amphetamine in identify several other methyltransferases. that, with just 25 test tubes, he could animals. Although he had never worked These include the adrenal enzyme that answer four or five important scientific with enzymes, he wanted to understand in generates adrenaline from noradrenaline, questions. We all have our own ideas greater detail how drugs are metabolized, and one that forms melatonin, a substance about Julie’s magic formula, but I suspect and so incubated various subcellular unique to the pineal gland. he has taken the real answer with him to fractions with amphetamine and Kety had set up research wards to the grave. Solomon H. Snyder ephedrine. Using membrane fractions compare the metabolism of radiolabelled Solomon H. Snyder is in the Department of from the liver, he discovered a previously adrenaline in schizophrenics and normal Neuroscience, Johns Hopkins Medical School, unknown group of enzymes that require controls, and provided Axelrod with 725 North Wolfe Street, Baltimore, NADPH (the reduced form of nicotinamide samples of [3H]adrenaline for metabolic Maryland 21205, USA. adenine dinucleotide phosphate) and studies. When [3H]adrenaline or e-mail: [email protected]