Paul Greengard (1925–2019) Nobel Laureate Who Traced Signals Through the Brain

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COMMENT OBITUARY Paul Greengard (1925–2019) Nobel laureate who traced signals through the brain.

aul Greengard shared the Nobel Prize with the release of neurotransmitters, with in Physiology or Medicine in 2000 for controlling the electrical potential across the discovering pathways that modulate cell membrane, or with regulating protein pro Psignalling between neurons in the brain. duction through altered DNA transcription. This fundamental advance transformed These slow, long-term changes suggested the search for new ways to treat neuro a neural basis for learning and memory, later degenerative diseases, such as Parkinson’s demonstrated by Kandel in his work on the and Alzheimer’s, a search in which he and sea slug Aplysia. Greengard’s proposal, as his group at the Rockefeller University in he wrote in his Nobel lecture, was “greeted New York City were involved right up to his initially with enormous scepticism, and at death on 13 April, at the age of 93. times downright hostility”. Greengard used his US$400,000 Nobel- One issue was that neurophysiologists prize money to found (with his wife, sculptor could not see how such slow mechanisms Ursula von Rydingsvard) an annual prize for (hundreds of milliseconds to seconds) could outstanding female biomedical scientists. mediate much faster physiological responses, Named after Greengard’s mother, who died such as identifying an image. Greengard

THE ROCKEFELLER UNIVERSITY giving birth to him, the Pearl Meister Green explained that slow synaptic transmission gard Prize has been awarded since 2004. is “the software that controls fast transmis Recipients include genetics pioneers Mary hearing an inspiring lecture by British Nobel sion”, which he dubbed “the hardware of the Lyon, Elizabeth Blackburn and Jennifer prizewinner and biophysicist Alan Hodgkin. brain”. He went on to show that molecules Doudna. With a PhD from Johns Hopkins University that participate in these second-messenger When Greengard was a young researcher in Baltimore, Maryland (he studied meta cascades (such as the dopamine-modulated in the 1950s, neuroscience was in its infancy. bolic changes accompanying degeneration protein DARPP-32) are depleted or altered Most biophysicists thought nerve impulses in frog peripheral nerves), in 1953 he went to in conditions such as schizophrenia and simply triggered the release of neurotransmit Europe. He spent several years in the United substance-use disorder. They are also impli ters such as glutamate and GABA into the tiny Kingdom and the Netherlands. His postdoc cated in the side effects of l-dopa treatment gap between cells, and that the interaction of toral work included looking at the effects of for Parkinson’s disease. these with receptors passed on the signal by drugs on neurotransmitter release in excised Greengard made his final move, to the causing rapid electrical changes across the nerves at the National Institute for Medical Rockefeller University, in 1983, and from cell membrane. Such a mechanism, however, Research in Mill Hill, London. 1995, he also headed its Fisher Center for could not account for longer-term changes Soon after returning to the United States Alzheimer’s Research. His group contin that might underlie learning and memory. in 1959 — he liked England, but not its cold ues to work on potential drug targets for During his biochemical studies, Greengard houses or bewildering choice of schools for degenerative brain diseases, depression learnt that glucose metabolism involved a his two young sons — he joined the research and schizophrenia. Greengard set up a reaction in which enzymes catalysed the arm of the drug company Geigy Research company, Intra-Cellular Therapies, that phosphorylation of proteins, tuning their Laboratories in Ardsley, New York, as direc aims to develop improved treatments based function. His hunch that a similar mecha tor of biochemistry. He later said it was on the findings of his group. Some have nism might be at work in neurons led to his easier to set up drug-development research reached phase III clinical trials, notably, discovery in the late 1960s that ‘fast’ signal programmes in a university laboratory than lumateperone for schizophrenia. transmission is underpinned by a cascade of in a drug company. In 1968, he joined Yale Throughout more than six decades as slower, intracellular changes in response to University in New Haven, Connecticut. group leader, Greengard surrounded him neurotransmitters such as dopamine. It was here he made the first breakthroughs self with young researchers, chosen for their Greengard was born in New York in 1925 that would lead to the Nobel he shared with commitment to his vision. He was meticu into a Jewish family, but was brought up a Eric Kandel and Arvid Carlsson for their lous in crediting them with discoveries made Christian by his Episcopalian stepmother. independent work on signal transduction in under his general direction. His own drive He joined the US Navy aged 17, in 1942, and the nervous system. Studying extracts of rat was relentless, and although he appreciated worked at the Massachusetts Institute of Tech brain tissue, Greengard’s group first found the world of the arts that he encountered nology in Cambridge on an airborne early- an enzyme that was sensitive to dopamine through his wife, there was really nowhere warning system against Japanese kamikaze (the depletion of which Carlsson had discov he would rather be than in the lab. aircraft. After the end of the Second World ered to be related to Parkinson’s disease). The Greengard did not learn of his mother’s War, he received a degree in mathematics and enzyme converted ATP (adenosine triphos death until he was aged 20. The absence of any physics from Hamilton College in Clinton, phate) to the second messenger cyclic AMP photo or other physical record of her exist New York. He decided against graduate work (adenosine monophosphate). ence affected him deeply. Hence the prize in in physics because the only funding available Soon afterwards, the group found the rest which her name — like his — lives on. ■ at the time was for atomic-energy projects. of the links in this and other chains that lead Turning to neuroscience, he decided to the phosphorylation of target proteins. Georgina Ferry is a science writer from to deploy both biophysics and bio Many of these targets turned out to be neuro Oxford, UK. chemistry in the study of neurons, after transmitter receptors; others were associated e-mail: [email protected]