Professor Julius Axelrod, the Nobel laureate who has died aged 92, made fundamental discoveries about the function and metabolism of adrenalin and other hormones in the brain, and was one of the creators of the new pharmacology. He was known affectionately throughout the world's laboratories as "Julie".
His highly specific biochemical approach to the structure, metabolism and effects of drugs, once revolutionary but now fundamental to research and clinical strategy, had its roots in the urgent need, during the second world war, to find why the anti-malarial drug mepacrine (atabrine in the US) had failed to protect allied forces in the Pacific.
Recommended doses produced side effects, yet poor control of infection. A group set up at the Goldwater Memorial Hospital, New York, under JA "Jim" Shannon, an Irish-American physiologist who was later to inspire and shape the development of the United States Institutes of Health (NIH), proved that the problem happened because little of the drug actually reached the bloodstream. They modified the regimen, and it worked.
A key member of the group was the Liverpool-born US pharmacologist Bernard Brodie, whom Axelrod joined in 1946, and to whose influence he was to owe much of his development and success.
Axelrod was plucked from scientific obscurity in the New York industrial hygiene laboratory, where he had been working on the development of standard vitamin analyses. His boss, Dr George Wallace, had recognised that Axelrod, a super-technician, possessed abilities essential to the emerging requirements of pharmacology.
Wallace saw that, if fused with a broader knowledge of physiology, Axelrod's originality and biochemical insight would enable him to develop sensitive new techniques needed to track drugs with great precision. This was to be the exacting research of the future.
Axelrod's first task under Brodie was more down to earth. It was to find out why some over-the-counter headache remedies could sometimes produce side effects that included the blockage of oxygen uptake by red blood cells (methaemo globinemia). Brodie predicted that a common major ingredient, acetanilide, might be partly broken down into aniline by the body, and would have this effect. The difficulty lay in proving that this was what happened.
Axelrod quickly refined measurement techniques for aniline and other breakdown products that allowed him to unravel the major metabolic pathways, and thus prove Brodie's prediction. He took a dose of aniline to show that it did block oxygen uptake in humans, went rather blue and advised others not to try it. Hints of his future were evident when his joint technical paper, instead of focusing on aspects of laboratory techniques in the study, took them as a basis for broad general principles for new and sensitive measurement techniques, with exacting guidelines for their reliable application.
This was real science but, as Robert Kanigel emphasises in Apprentice To Genius (1986) - a book tracing the geneaology of modern US pharmacology - Axelrod was not yet a fully-fledged research scientist.
He had a master's in chemistry but no doctorate; under Brodie's direction, he was no more than a gifted technician. Although Axelrod was a fount of research ideas, and worked for years with Brodie unravelling the brain metabolism of ephidrine and amphetamine, Brodie's ideas remained dominant.
In 1954, Axelrod, after bargaining with George Washington University, which wanted him to do a minimum three years of course work, took a year off to get his doctorate. His thesis synthesised and reinterpreted his many original findings on enzymes in brain metabolism - the foundations of a new frontier of research. Legend has it that, at his viva voce exam, his peers were at first disbelieving and then amazed to find themselves quietly outgunned by him.
The true measure of his stature is that, the very same year, he began a pioneering investigation of the brain metabolism of LSD. This, plus the doctorate, his profound knowledge of biochemistry, and good fortune, let him jump almost immediately into his own research programme at the new Institute of Mental Health, part of the rapidly growing and reorganised NIH.
As a section leader, rejecting promotion to stay in research, he dived into aspects of brain function and malfunction that lay at the limits of biochemical detection. As a by product, he created "Julie's laboratory"; its vigour, freedom and creative enthusiasm made it a pharmacological draw for generations of post-doctoral students worldwide.
Within 10 years, Axelrod had unravelled the brain metabolism of adrenaline and noradrenaline, identified and isolated key enzymes, shown how drugs affected the brain's metabolic balance and hence its function, investigated L-dopa and dopamine, and confirmed important aspects of the cyclic biochemistry of neurotransmitters.
In 1970 he shared the Nobel prize in physiology, not with Brodie - whom many felt deserved part of the award - but with the Swedish physiologist Ulf von Euler and Sir Bernard Katz (obituary April 24 2003).
Axelrod maintained his research drive until his retirement in 1984, when he became a guest researcher at the NIH laboratory of cell biology. His interests expanded to the function of the membrane in cell signalling, and the biochemistry and metabolism of the pineal gland - the brain's "third eye." His eagerness to comb the literature and find crucial gaps, his rapid grasp and ability to produce a stream of research ideas, remained until his last years. "In science," he said, "the accepted interpretations are usually wrong. Find and fill an important gap and you may change the whole picture."
Axelrod did exactly that. He had been born and brought up in New York's tough and poor lower East Side. His Galician Jewish parents - his father had been a basket-maker - arrived in the US in 1906. As a boy growing up in the family's cold-water walk-up apartment, he learned to avoid other immigrant areas where he was likely to be beaten up.
In his early teens, he was good but not outstanding at school, and rejected the religious training that his family hoped he might take. He decided to study medicine as a route to research. Even when very young, he spent his spare time in the local library. He recalled the poverty: "But I never felt deprived or anything like that. We were happy." He went to Seward high school (whose other graduates include Tony Curtis, Walter Matthau and Zero Mostel), and then to New York city college, now a powerful university, which was a free-tuition haven and academic crucible for generations of bright immigrants.
Armed with a first in chemistry and biology, he tried for medical school; however as a Jew, moreover without money and with uncertain grades in Latin and mathematics, he was rejected. That left him suddenly jobless in the social and economic disaster of the great depression.
Beginning in 1933 as an unpaid volunteer at the Harriman laboratory, Axelrod graduated to a paid job as a bacteriology department laboratory assistant. In 1934, an exploding ammonia bottle blinded him in one eye - and a piratical black patch became part of his personality. In 1935, the Harriman laboratory closed.
Axelrod found a better job as a chemist, analysing and developing more reliable tests for vitamin concentrations, at New York's new public industrial hygiene laboratory, which had been set up to check, among other things, that commercial labels told the truth.
This was a solid living in a lean world and, disbarred from military service by his eyesight, Axelrod worked there contentedly for a decade and might easily have stayed there for the rest of his life. He married Sally Taub in 1938, and became a family man with an occasionally creative technical job.
Locked into this routine, he still dreamed of real research, but the goal seemed distant. On Lincoln's birthday in 1946, when he first walked into the Goldwater to join Brodie, it felt like leaping on an intellectual roller-coaster. Many would have hesitated. The quiet, gentle Axelrod easily made the jump that transformed him into a scientific giant.
He remained unchanged despite the many awards. His postgraduates loved him because only two things were of supreme importance to Axelrod: his science and his two families, those in the laboratory and those at home. He loved them both.
His wife died in 1992. He is survived by two sons and three grandchildren.
· Julius Axelrod, scientist, born May 30 1912; died December 29 2004. This obituary has been revised and updated since the writer's own death in 1998.
