Caring for patients with Parkinson disease takes up a large part of every neurologist's life. To do so effectively, the astute neurologist must have a working knowledge of catecholamine metabolism. We know that blocking the breakdown of dopamine prolongs its physiological effects, and the introduction of catechol-O-methyl transferase inhibitors (COMT) gives neurologists another approach in the fight against the disease.
In this context, accidental historians should note the death in December of Julius Axelrod, the 1970 Nobel laureate neuropharmacologist and discoverer of COMT. Dr. Axelrod was awarded the Nobel Prize for Medicine or Physiology, along with Bernard Katz of University College London and Ulf von Euler of the Karolinska Institute, for their research on synaptic transmission.
Born in Manhattan of immigrant parents from Poland, he received a master's degree at 29 from New York University, and earned his PhD from George Washington University, by which time he was already ensconced in the National Institutes of Mental Health (NIMH). In his Nobel lecture, available online at www.nobelprize.org, he tells of arriving at NIMH and looking for a suitable project. Having some experience in working on amphetamine metabolism at the National Heart Institute, he decided to investigate the metabolism of adrenaline and noradrenalin.
CLARITY OF THOUGHT
In 1955, biochemical research was conducted with test tubes, solvent extraction, paper chromatography, starch block electrophoresis, and tritium. Dr. Axelrod was a master of this type of “wet chemistry,” which depends more on clarity of thought than on overwhelming technical dexterity. He read reports on the isolation of 3-methoxy-4-hydroxymandelic acid from the urine of patients with pheochromocytoma, suggesting that catechols might be inactivated by an O-methylation. Serendipitously, Dr. G.L. Cantoni had found that S-adenosyl-methionine could act as a methyl donor in O-methylation reactions.
Dr. Axelrod did an experiment that was simple, elegant, and relevant to neurologists in 2005. He incubated rat liver with ATP (adenosine triphosphate), methionine, adrenaline, and magnesium, and measured the disappearance of the adrenaline. Sure enough, the rat liver made S-adenosyl-methionine, which then donated its methyl group to the adrenaline, which promptly disappeared. Omitting any of the reagents produced no adrenaline degradation. Dr. Axelrod had discovered COMT.
NEUROCHEMISTRY: OTHER CONTRIBUTIONS
Of course, this experiment was not Dr. Axelrod's only contribution to neurochemistry. He isolated the O-methyl metabolite and identified it as normetanephrine. He demonstrated O-methylation of noradrenalin, dopamine, and levodopa. He also participated in a series of experiments that showed that much of the noradrenaline produced in the synapse is reabsorbed by the presynaptic neuron rather than enzymatically degraded. This immediately suggested another way to increase the concentration of transmitter in the synapse.
In addition to blocking enzymatic degradation, one could also inhibit transmitter reuptake, leading to another class of drugs that neurologists use in daily practice: selective serotonin reuptake inhibitors.
Dr. Axelrod overcame several hurdles in the pursuit of his distinguished scientific career. As a young man he intended to study medicine, but was rebuffed because medical schools at the time had a quota for Jewish students. He also lost his left eye in a lab accident at a young age. He was known for his gentle, self-deprecating sense of humor. He told the story that his dentist informed him that he had won the Nobel Prize. When he asked in which field which he had won the prize, the dentist replied, “Peace.” He laughed and refused to believe that he had won for hours afterward.
Many of today's leading neuropharmacologists spent time under Dr. Axelrod's tutelage, which explains the paeans in the press. His deceptively simple way of looking at scientific problems led to elegant experiments designed to solve them, a talent that amazes accidental historians today.
A chapter about Dr. Axelrod appears in NINDS at 50 published by Demos Press.