East Houston Street
Julius Axelrod was born on May 30, 1912, in a cold-water flat at 415 East Houston Street on Manhattan’s Lower East Side. His parents, Isadore and Molly (née Leichtling), had emigrated from Polish Galicia and met in New York. His father made baskets and sold them to grocers in lower Manhattan from a horse and wagon; on Saturdays young Julie, as everyone called him, was allowed to ride along and sometimes take the reins.
The family was not religious, but it belonged wholeheartedly to the East European Jewish immigrant culture of the Lower East Side. Julie spoke Yiddish and went to religious school every afternoon after the public school day ended. He attended Seward Park High School, later better known for show business graduates such as Walter Matthau and Zero Mostel than for scholarship, and he always said that his real education came from devouring books at the nearby Hamilton Fish Park Library.
Shut out of medicine
Axelrod began college at New York University but ran out of money and in 1930 moved to the tuition-free City College of New York, travelling an hour each way by subway and working to support himself. He graduated in 1933 with a degree in biology and applied to several medical schools. None accepted him, in part, his biographer Solomon Snyder wrote, because of the Jewish quotas that many schools imposed at the time.
It was the depth of the Depression, and he was lucky to find work as a laboratory assistant at New York University for $25 a month. When that funding ran out in 1935 he joined the Laboratory of Industrial Hygiene, a nonprofit unit set up by the New York health department, testing the vitamins added to foods. He stayed there for eleven years, earning a master’s degree from NYU at night. By his early thirties he seemed destined for a modest career as a technician.
The painkiller in the medicine cabinet
In 1946 his laboratory was asked to find out why the most popular non-aspirin painkillers of the day, acetanilide and phenacetin, were causing methemoglobinemia, a dangerous condition in which the blood cannot carry oxygen properly. Axelrod was sent to consult Bernard Brodie at Goldwater Memorial Hospital, an authority on how the body processes drugs. The two talked for hours, and Axelrod was invited to work in Brodie’s laboratory.
He developed a sensitive test and showed that a small part of acetanilide is turned into aniline, which caused the blood damage, while most of it becomes another compound, N-acetyl-p-aminophenol. That compound, he found, relieved pain without harming the blood. His first scientific paper suggested it might have a distinct advantage as a painkiller. The compound is acetaminophen, also called paracetamol and later marketed as Tylenol and now one of the most widely used medicines in the world. Neither Axelrod nor Brodie received any royalties; it never occurred to either of them to patent the discovery. He and Brodie went on to show that phenacetin, an ingredient of APC, for years the most popular headache remedy in the United States, works the same way: the body turns it into the same safe painkilling compound.
A technician at the NIH
In 1949 Brodie moved to the new National Heart Institute in Bethesda, Maryland, part of the National Institutes of Health, and brought Axelrod with him. Still officially a technician without a doctorate, Axelrod studied how the body handles caffeine, amphetamine, ephedrine and other drugs, and in 1953 he discovered that enzymes in the liver’s microsomes, today known as the cytochrome P450 system, break down a vast range of medicines. The discovery became a foundation of modern pharmacology, explaining how drugs are cleared from the body and how they interact.
He was past 40 and supporting a wife and two young sons when friends urged him to get a PhD. George Washington University agreed to accept his published papers as a thesis, and after a single year of coursework he received his doctorate in 1955, at the age of 42. That year he became head of the Section on Pharmacology in the Laboratory of Clinical Science at the National Institute of Mental Health, a section that at first consisted of himself alone.
How nerves talk
Nerve cells communicate by releasing chemical messengers, neurotransmitters, across the tiny gap between one cell and the next. Scientists assumed that once a messenger had done its job, enzymes destroyed it. Axelrod discovered one such enzyme, catechol-O-methyltransferase (COMT), in 1957, and the urine test that grew out of this work became the standard way to diagnose pheochromocytoma, an adrenal tumour that causes dangerous high blood pressure. But blocking the enzymes did not stop the messengers’ effects, so something else had to be ending them.
Using radioactively labelled adrenaline and noradrenaline, Axelrod and his colleagues traced where the messengers went. They found that noradrenaline is soaked back up into the very nerve endings that released it, stored and used again. Reuptake, not destruction, is the main way the signal is switched off, and it is now recognised as the most common way that chemical signalling between nerves is ended. Axelrod then showed that cocaine, amphetamine and the tricyclic antidepressants all block this reuptake. With his postdoctoral fellows Jacques Glowinski and Leslie Iversen he showed that the ability of antidepressants to block noradrenaline uptake in the brain matched their power as medicines.
From reuptake to Prozac
The idea that mood medicines work by blocking the reuptake of brain messengers became the guiding principle of drug development in psychiatry. In the decades that followed, companies designed drugs to block the reuptake of serotonin selectively, the SSRIs such as fluoxetine (Prozac), and later drugs that block both serotonin and noradrenaline. These medicines are now taken by many millions of people for depression and anxiety. His reuptake work also explained how cocaine and amphetamines act on nerve endings.
Axelrod went on to open another field. When melatonin was identified as the hormone of the pineal gland, he found the enzyme that makes it, and with Richard Wurtman showed how light controls melatonin production, laying groundwork for the modern science of sleep and circadian rhythms.
Nobel Prize
In 1970 Axelrod shared the Nobel Prize in Physiology or Medicine with Bernard Katz and Ulf von Euler for their discoveries concerning the chemical transmitters in nerve terminals and how they are stored, released and inactivated. His share recognised the discovery of reuptake. He was the former technician without a medical degree, rejected by every medical school he applied to, who had become one of the leading pharmacologists in the world.
He used the platform the prize gave him. He joined fellow laureates Marshall Nirenberg and Christian Anfinsen in organising a petition by scientists who feared that President Nixon’s new campaign against cancer would starve other areas of medical research, and he lent his name to protests against the imprisonment of scientists in the Soviet Union.
Jewish identity and character
Axelrod became an atheist early in life and resented the strictness of his parents’ religion, but he identified with Jewish culture and joined several international campaigns against antisemitism. When he died, his funeral was held within two days, in keeping with Jewish tradition, and, in keeping with his own dislike of fuss and religious dogma, without a rabbi or eulogies; a few old friends, including a high school classmate, shared memories instead.
He was quiet and self-effacing, and his students remembered his sheer joy in research. After the Nobel Prize he told one audience that speaking invitations seemed to be a conspiracy to get him out of the lab, and that he found it hard to believe he was paid for doing something so much fun. He worked at the bench every morning, wrote papers by hand with his students in the afternoon, and liked simple experiments: he once compared his approach to a single line by Picasso, which takes a lot of time and thought. He trained a remarkable roster of scientists, among them Solomon Snyder, Irwin Kopin, Richard Wurtman and Leslie Iversen.
He disliked pretension in all its forms. He distrusted elaborate statistics, saying that if the difference between two groups was so small that a statistical test was needed to prove it, it might not be a very important difference. He wrote in simple declarative sentences and objected when scientists wrote that laboratory rats had been sacrificed: there were no altars in his laboratory, he said. Looking back, he insisted that original research did not require a great brain, only motivation, judgement, imagination, determination and a little luck.
Last years and legacy
Axelrod married Sally Taub, who had grown up on the same Lower East Side streets, in 1938. She taught second grade for many years and died in 1992. They had two sons. He kept an office at the NIH until the end, going in several times a week to read the literature and talk with colleagues, and he died at his home in Rockville, Maryland, on December 29, 2004, aged 92.
Few scientists have left so many traces in everyday medicine. The acetaminophen in household medicine cabinets, the understanding of how the liver clears drugs, the diagnostic test for an adrenal tumour, and the antidepressants that help millions of people all lead back to the basket maker’s son whom medical schools turned away.
Sources & further reading
Julius Axelrod, Biographical Memoir by Solomon H. Snyder, National Academy of Sciences · Julius Axelrod, Biographical, NobelPrize.org · Julius Axelrod dies, The Scientist · Julius Axelrod, Wikipedia · Researched from the sources above and checked against them. Spotted an error? Tell us.
A life of tikkun olam. This is part of tikkun olam, the Jewish idea of repairing the world, and every one of us can add to it.