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Axelrod, Julius

AXELROD, JULIUS

(b. New York, New York, 30 May 1912, d. Bethesda, Maryland, 29 December 2004),pharmacology, neurochemistry neurotransmitters, metabolism.

Axelrod made fundamental contributions to understanding the mechanisms of chemical neurotransmission and drug metabolism. His discoveries contributed directly to the design of drugs to treat psychiatric disorders, to control physiological systems, and to relieve pain. He won the Nobel Prize for Physiology or Medicine in 1970 for his work on the reuptake and deactivation of neurotransmitters such as norepinephrine and serotonin.

Early Education and Training. Julius (“Julie”)

Axelrod was born and raised in a poor Jewish neighborhood on the Lower East Side of Manhattan. His parents, Isadore and Molly, immigrated to the United States from Poland. His father was a basket maker, and his mother worked in the home. Neither was functionally literate in English.

Upon graduation from Seward Park High School, Axelrod studied at New York University (NYU). He exhausted his family’s savings after one year and transferred to the tuition-free College of the City of New York. His grades in chemistry were poor, especially in qualitative analysis, the area in which he would later build his reputation. He graduated in 1933, at the height of the Great Depression, with a BS in biology. In the same year, he lost sight in his left eye in a laboratory accident. As a result, he was deferred from the World War II draft and was free to pursue his dream of becoming a doctor.

Axelrod’s applications to medical school were rejected, however, and he was hired as a laboratory technician at the Harriman Research Institute at NYU. He worked for K. G. Falk, preparing buffer solutions and assisting with research on enzymes in malignant tumors. When funding for the laboratory ran out in 1935, Axelrod turned down work with the U.S. Postal Service for a less lucrative position working for George B. Wallace, a retired pharmacology professor, in the Laboratory of Industrial Hygiene at the New York City Department of Health. Axelrod’s job was to assay the levels of vitamins in fortified food products. He had to learn the available techniques for measuring vitamins and to modify them for application to food products. This work gave him early experience as an experimentalist. The lab also exposed him to the Journal of Biological Chemistry.

While working with Wallace, Axelrod married Sally Taub, who had a degree in chemistry from Hunter College. With the birth of their sons Paul (1946) and Alfred (1949), Taub quit her job in an insurance agency to work in the home. She later earned a teaching certificate from the University of Maryland and became an elementary school teacher. Until 1949, Axelrod and his family lived within blocks of his parents and his two sisters (Gertrude and Pearl) in Brooklyn, New York.

During this period Axelrod studied chemistry in postgraduate night courses at NYU. He wrote a thesis, “The Ester-Hydrolyzing Actions of the Tissues of Polyneuritic, Normal, ‘Cured,’ and Thiamin-Fed Rats.” Rats deprived of thiamin (vitamin B1) develop polyneuritis, a general swelling of nerve tissues, which is one of the symptoms of beriberi. As part of an investigation of the mechanism producing this symptom, Axelrod ground the organs of rats, exposed them to different kinds of esters (an organic compound), and measured the ability of these tissues to hydrolyze the esters. For this research, he received his Master’s of Science degree in chemistry in 1942. He continued to work with Wallace until he was thirty-four years old.

Bernard Brodie and Non-Aspirin Pain-Relievers. In 1946, Wallace gave Axelrod a funded project to determine why protracted use of non-aspirin pain relievers (such as acetanilide, an ingredient in the then-popular pain reliever Bromoseltzer) produce an abundance of methemoglobin, the oxidized form of hemoglobin, which fails to bind oxygen. Bernard B. Brodie, a pharmacologist, invited Axelrod to perform these studies at Goldwater Memorial Hospital (Welfare Island, later Roosevelt Island, New York). Brodie was part of a research group, headed by James A. Shannon, that was charged in part with running clinical trials on anti-malarial vaccines during the Japanese embargo on quinine during World War II. Shannon recruited a number of gifted scientists for this purpose, including Robert Berliner, Robert Bowman, Thomas Kennedy, and Sidney Udenfriend, all of whom made significant contributions to biochemistry. As Axelrod later wrote, “It was in this atmosphere that, in a period of a few years, I became a researcher” (1988, p. 4).

Brodie taught Axelrod that the body metabolizes drugs and that metabolites can have both beneficial and harmful consequences. It was known at the time that the acetanilide in Bromoseltzer can be metabolized into N-acetyl-p-aminophenol and analine, and it was known that analine can produce methemoglobin. It was not known whether acetanilide metabolizes into analine in the human body. Axelrod developed a sensitive assay for analine levels in blood and urine. He and Brodie showed that analine levels rise after doses of acetanilide and that analine and methemoglobin levels are correlated. This finding led them to suggest that N-acetyl-p-aminophenol, later commonly known as acetaminophen, could replace acetanilide as a pain reliever without this potentially deadly side effect (Brodie and Axelrod, 1948). Amid worries in the 1970s that aspirin causes gastric ulcers, acetaminophen (marketed as Tylenol) became, and remained in the early 2000s, one of the best-selling pain relievers in history.

Metabolism of the Sympathomimetic Amines. In 1949, Shannon was appointed director of intramural research at the National Heart Institute (NHI), part of the National Institutes of Health (NIH) in Bethesda, Maryland. Axelrod, Brodie, and many of the other Goldwater scientists soon followed. Initially, Axelrod worked with Brodie in the Laboratory of Chemical Pharmacology, investigating analgesics and the effects of ascorbic acid (vitamin C) on drug metabolism. Again, Axelrod found himself in a stimulating environment: “Among the scientists working in Building 3 in the 1950's, more than half became members of the National Academy of Science, five became Nobel laureates, and three were appointed directors of NIH” (2003, p. 3).

By 1952, Axelrod was doing independent research in Brodie’s lab. His first project was to describe the metabolism of caffeine. This work soon broadened to include the metabolism of a class of drugs that George Barker and Henry Hallett Dale named the “sympathomimetic” amines. These drugs, which include amphetamine, ephedrine, and methamphetamine, produce effects similar to the activation of the sympathetic nervous system. The sympathetic nervous system can be activated to produce a set of coordinated responses that enable the body to deal with stresses and threats. For example, activation of the sympathetic nervous system increases blood pressure and heart rate, accelerates breathing, constricts the arteries, and dilates the pupils. Axelrod found that the sympathomimetic amines are metabolized by a variety of pathways, including conjugation (by joining with other molecules), deamination (the removal of an amino group, NH2), and hydroxylation (the addition of a radical hydroxyl group, OH). He also showed that the precise metabolic pathways vary across species (1953; 1954a).

Axelrod’s work on the sympathomimetic amines led him to discover and localize a new class of liver enzymes. To study amine metabolism in vitro, Axelrod exposed livers

from different species to sympathomimetic amines, measured the rate at which the drugs are metabolized, determined the metabolic end products, and inferred the pathways by which those end products are produced. His study of amphetamine metabolism was the centerpiece of this project (1954b; 1955a). When Axelrod applied amphetamine to sliced or homogenized rabbit liver, the drug was rapidly metabolized. He found that he could speed up the metabolism by adding triphosphopyridine nucleotide (TPN, later known as NADP, for nicotinamide adenine dinucleotide phosphate), which was already known to be a coenzyme in many biochemical pathways. Axelrod concluded that the metabolic pathway involves TPN as a coenzyme.

To determine which parts of liver cells metabolize the amphetamine, he centrifuged the cells, separating them into different cell fractions containing different cellular components. He then applied amphetamine and TPN to the different cell fractions. None of them metabolized the drug by itself. When he added amphetamine and TPN to

a mixture of the cytosolic fraction (the intracellular fluid) and the fraction containing microsomes, the drug rapidly disappeared, leaving ammonia and phenylacetone as end products. This reaction led him to conclude that in rabbit liver, amphetamine is deaminated by an oxidative enzyme that uses TPN as a coenzyme.

Axelrod did not know whether the necessary enzyme was in the cytosol or in the microsomes. To decide, he heated the cell fractions to denature the heat-labile enzymes. When he heated the cytosolic fraction to 55°C and then added unheated microsomes, amphetamine, and TPN, the amphetamine was metabolized. When he heated the microsomal fraction to 55°C and added unheated cytosol, amphetamine, and TPN, the amphetamine was not metabolized. The crucial enzyme, he concluded, was in the microsomes, but the cytosol must contain a necessary coenzyme; amphetamine is not metabolized by the microsomal fraction and TPN alone.

To identify the coenzyme, Axelrod exposed the microsomal fraction to amphetamine, TPN, and to three different substrates (glucose 6-phosphate, isocitric acid, and phosphogluconate). The single quality that these substrates have in common is that they all reduce TPN to TPNH (or reduced TPN, later known as NADPH). The amphetamine disappeared. Perhaps, then, the coenzyme in the cytosol is necessary to reduce TPN to TPNH. When he added TPNH to the microsomal fraction alone in the presence of oxygen, the amphetamine was again metabolized, convincing Axelrod that he had discovered an enzyme in rabbit liver that deaminates amphetamine in the presence of oxygen and TPNH. The structure of amphetamine, and the necessity of TPNH for its metabolism, suggested that this was a new kind of enzyme. Similar enzymes were subsequently discovered for the metabolism of ephedrine and other drugs as well. These findings amounted to the discovery of a new class of liver enzymes, later known as cytochrome P450 enzymes. These enzymes, which are found in all lineages of life, metabolize most organic chemicals (such as bilirubin) and many drugs and pollutants. They are also involved in the synthesis, activation, and inactivation of a number of regulatory molecules.

Axelrod’s Conversion to Neurochemistry. The work on sympathomimetic amines gave rise to an authorship dispute between Axelrod and Brodie, and Axelrod left Brodie’s lab. Despite his already substantial contributions to science and his post as a senior chemist at NIH, Axelrod recognized that his chances for advancement were limited without a PhD. He took a leave of absence to do graduate work at George Washington University. His advisor, pharmacologist George Mandel, arranged for him to submit some of his work on the sympathomimetic amines as a dissertation, “The Fate of Sympathomimetic Phenylisopropylamines.” In 1955, at the age of forty-two, Axelrod earned his PhD.

While Axelrod was working on his dissertation, Seymour Kety, scientific director of the joint intramural program of the National Institute of Mental Health (NIMH; established 1949), and Edward Evarts, director of the Laboratory of Clinical Sciences, invited Axelrod to set up a section in their laboratory. Kety became head of that laboratory in 1956. The explicit mission of the NIMH was to integrate basic and clinical research on psychiatric disorders. Although Kety allowed Axelrod considerable intellectual freedom, Axelrod felt obliged to do work relevant to mental health. His first project was to characterize the distribution and metabolism of lysergic acid diethylamide (LSD), an experimental psychiatric drug that would become widely used as a recreational drug (Axelrod et al., 1956). Axelrod did not take this drug himself.

Methyl Transferase Enzymes. Early in 1957, Axelrod attended a seminar in which Kety recounted evidence that epinephrine, a neurotransmitter and hormone (also known as adrenalin) is rapidly converted to adrenochrome when it is exposed to air. Kety also reported that ingestion of adrenochrome produces hallucinations like those experienced by people with schizophrenia, which suggested that schizophrenia might result from abnormal metabolism of epinephrine. Axelrod decided to study the metabolism of epinephrine and norepinephrine (also known as noradrenalin), using the same tools he had used to study other sympathomimetic amines.

At the time, it was widely believed that epinephrine and other catecholamines are metabolized in the body by the enzyme monoamine oxidase (MAO). This hypothesis conflicted with the fact that pharmacological inhibitors of MAO have no effect on the rapid recovery of the sympathetic nervous system from the effects of an injection of epinephrine. Axelrod surmised that a different enzyme was implicated. In March 1957, the biochemist Marvin Armstrong and Armand McMillan reported that patients with norepinephrine-producing tumors excrete large quantities of 3-methoxy-4-hydroxymandelic acid (VMA), a product that could be produced by the O-methylation (the addition of a methyl group, CH3) and deamination of epinephrine and norepinephrine. Guessing that the donor of the methyl group in the methylation reaction might be S-adenosylmethionine, Axelrod added S-adenosylmethionine and epinephrine to a rat liver homogenate. He observed that the epinephrine was rapidly metabolized and that the product was an O-methylated form of adrenaline (which he called metanephrine), indicating the presence of an O-methylating enzyme. Axelrod purified this enzyme and then demonstrated that it could O-methylate catechols but could not O-methylate monophenols. The enzyme, which he named catechol-O-methyltransferase (COMT), was soon found to be ubiquitous in the brain. (Axelrod and Tomchick, 1958). The discovery of this enzyme furthered the understanding of catecholamine metabolism, led to the development of drugs to inhibit COMT in the treatment of Parkinson’s disease with Ldopa, and led to the development of new biological markers in biopharmacological studies. Axelrod later wrote, “As a result of these findings, I then considered myself a neurochemist” (1988, p. 13).

Regulation of Neurotransmitters at Synapses. Between 1958 and 1961, Axelrod carried out the experiments on the inactivation of neurotransmitters that earned him the Nobel Prize. His work focused on the inactivation of epinephrine and norepinephrine at synapses in the sympathetic nervous system. At the time it was known that acetylcholine, the neurotransmitter at the neuromuscular junction, is inactivated when it is rapidly metabolized by the enzyme acetylcholinesterase. Many suspected that all neurotransmitters are deactivated through enzymatic transformation.

Two preliminary findings set the stage for Axelrod’s discoveries. First, Axelrod showed that inhibitors of COMT did not prolong the effects of norepinephrine on blood pressure, suggesting that something else must be responsible for its inactivation at sympathetic synapses. Second, Kety commissioned the New England Nuclear Corporation to manufacture tritiated epinephrine (epinephrine labeled with tritium, or [3 H]epinephrine) and norepinephrine ([3 H]norepinephrine). He used these to show that schizophrenics do not metabolize catecholamines differently from controls.

Axelrod borrowed the tritiated epinephrine and norepinephrine from Kety and developed sensitive methods for measuring their concentrations in tissues and blood. When he injected cats with large doses epinephrine or norepinephrine, he found that the drugs failed to cross the blood-brain barrier (which prevents some substances from entering the brain’s circulatory system) and that they tended to concentrate in organs richly innervated by the sympathetic nervous system (such as the heart and the salivary glands). This result suggested to Axelrod that epinephrine and norepinephrine might be taken up by sympathetic nerves. To test this hypothesis, he and Georg Hertting (a visitor in the laboratory) made unilateral lesions to the superior cervical ganglia of cats, causing the nerves innervating the eyes and the salivary glands to die. They then injected the cats with [3 H]norepinephrine. They found that the radiolabeled neurotransmitter concentrated on the intact (innervated) side and not on the lesioned side (Hertting et al., 1961a), that it is released from nerves when they are stimulated (Hertting and Axel-rod, 1961), and that drugs such as cocaine block its reup-take (Hertting et al., 1961b). Research quickly revealed that other transmitters, such as dopamine and serotonin, are also taken up into nerve terminals and that their use could also be regulated with drugs.

Axelrod’s work on the synthesis, metabolism, and regulation of drugs and neurotransmitters provided lasting insights into the mechanisms of the chemical synapse.These insights had direct implications for the use of drugs to change the activities of the central and peripheral nervous systems. By the end of the millennium, drugs that inhibit serotonin reuptake, such as fluoxetine (brand name, Prozac), were widely used to treat depression. Axelrod predicted that in the new millennium, drugs would be available to cure mental illness, eliminate prejudice, enhance intelligence, suppress unwanted memories, and make all psychedelic trips pleasant. Asked if Freud was “dead,” he replied, “Not for people who want to spend their money on psychoanalysis, but for the treatment of severe mental illness, yes, he is.”

Melatonin and the Pineal Gland. A final major component of Axelrod’s career as a neurochemist involved work on the synthesis of melatonin (5-methoxy-N-acetyltryptamine) and its regulation in the pineal gland in accordance with circadian rhythms. In 1958, Aaron Lerner isolated melatonin from the pineal gland of cows. Axelrod was attracted to melatonin because it has a methoxy group, as do many other catecholamine metabolites, and because it has a nucleus that resembles serotonin, which is structurally similar to LSD and was then believed to be involved in psychosis.

In 1958 and 1959, Axelrod and the biochemist Herbert Weissbach used radiolabeled enzymes to establish that melatonin is synthesized in the pineal gland from tryptophan and serotonin. The synthesis required the essential enzyme hydroxyindole-O-methyltransferase (HIOMT), which was soon found to be highly localized to the pineal gland in mammals.

When Richard J. Wurtman joined Axelrod’s laboratory in 1962, he reawakened Axelrod’s interest in the pineal. Wurtman had shown that rats in constant illumination enter a persistent state of estrus (commonly known as heat) and that this state can be reversed with injections of bovine pineal extract. Axelrod surmised that environmental lighting (that is, the light/dark cycle) might control HIOMT activity. In 1963, he and Wurtman found that rats raised in constant light have reduced HIOMT activity in the pineal gland relative to those raised in constant dark. Given that injections of melatonin also prevent the effects of light on the estrus cycle, Axelrod concluded that the effect of illumination on estrus is mediated by the pathway for the synthesis of melatonin. Knowing that norepinephrine-containing sympathetic nerves innervate the pineal gland, Axelrod and his colleagues killed these nerves by removing the superior cervical ganglia. The effect of light on HIOMT activity (and so melatonin synthesis) was eliminated.

In 1963, W. B. Quay showed that serotonin and melatonin levels have regular daily fluctuations; they are high during daylight and low at night. Axelrod and his postdoctoral fellow, Solomon H. Snyder, found that the circadian rhythm in serotonin and melatonin persisted even when animals were placed in continuous darkness; there is an internal clock (Axelrod, Wurtman, and Snyder, 1965). Constant illumination, however, abolished the serotonin rhythm, as did destroying the nerves that connect the brain to the superior cervical ganglia. This result indicated that the internal clock is in the brain. Subsequent work identified regions in the hypothalamus (particularly, the suprachiasmatic nucleus) as plausible locations for the biological clock. Axelrod developed a theoretical perspective according to which the pineal gland is a transducer of information about the day/light cycle into hormonal signals for the control of bodily functions.

Nobel Prize and Axelrod’s Political Turn. Axelrod shared the 1970 Nobel Prize with Bernard Katz and Ulf von Euler for “fundamental research into the nature of the chemical neurotransmission process.” He recognized that this award gave him political clout, and he used it to promote several causes. Axelrod repeatedly made and joined public statements against governmental attempts to target biomedical research funding to specific large-scale projects, such as finding a cure for cancer. In this domain, and in his laboratory, Axelrod stressed the importance of knowing what problems can and cannot be solved with the tools available at the time. He also stressed the importance of intellectual freedom in the development of science as a whole and in the development of individual scientific careers.

Although he became an atheist early in life and resented the strict upbringing of his parents’ religion, he identified with Jewish culture and joined several international fights against anti-Semitism. Alexandr Solzhenitsyn won the Nobel Prize for Literature in the same year that Axelrod won his own, but Solzhenitsyn was not allowed to attend the ceremony. After returning home, Axelrod repeatedly called on the Soviet Union to free such Jewish scholars as Benjamin G. Levich, Ilye Glezer, and Andrei D. Sakharov, who were imprisoned and had been refused the right of emigration and/or imprisoned on grounds that Axelrod and many others believed to be based in an anti-Semitic Soviet policy. (These Soviet scientists came to be known as “Refuseniks.”)

Axelrod also fought political battles on behalf of Israel. In 1975, he joined an international group of scientists who threatened to resign from the International Brain Research Organization, which is affiliated with UNESCO, until UNESCO resolutions banning Israeli participation in the organization were lifted. In 1979, he was among those who advocated pulling the United States out of the World Health Organization (WHO) if the WHO failed to allow Israel a vote in its decision-making process.

Learning of these pursuits, however, should not cause one to lose sight of the fact that Axelrod was first and foremost a researcher who believed that long hours of free inquiry using the right tools with the right colleagues can result in fundamental discoveries that have the power to shape the future of humankind. Although he officially retired in 1984, he continued to work in a small lab at NIMH until he died of a heart attack in his home in Rockville, Maryland, in 2004.

BIBLIOGRAPHY

Many of Axelrod’s papers are available online at Profiles in Science at the national Library of Medicine http://profiles.nlm.nih.gov/HH/ The Julius Axelrod Papers (1910–2004) are housed at the National Library of Medicine.

WORKS BY AXELROD

With Bernard B. Brodie. “The Fate of Acetanilide in Man.” Journal of Pharmacology and Experimental Therapeutics94 (1948): 29–38.

“Studies on Sympathomimetic Amines. I. The Biotransformation and Physiological Disposition of l-ephedrine and lnorephedrine.” Journal of Pharmacology and Experimental Therapeutics 109 (1953): 62–73.

“An Enzyme for the Deamination of Sympathomimetic Amines.” Journal of Pharmacology and Experimental Therapeutics 110 (1954a): 2.

“Studies on Sympathomimetic Amines. II. The Biotransformation and Physiological Disposition of d-amphetamine and d-methamphetamine.” Journal of Pharmacology and Experimental Therapeutics 110 (1954b): 62–73.

“The Enzymatic Deamination of Amphetamine (Benzedrine).” The Journal of Biological Chemistry214 (1955): 753–763.

“The Enzymatic N-demethylation of Narcotic Drugs.” Journal of Pharmacology and Experimental Therapeutics 117 (1956): 322–330.

With Robert Tomchick. “Enzymatic O-methylation of Epinephrine and Other Catechols.” Journal of Biological Chemistry 233 (1958): 702–705.

With Georg Hertting, Irwin Kopin, and L. G. Whitby. “Lack of Uptake of Catecholamines after Chronic Denervation of Sympathetic Nerves.” Nature189 (1961): 66–68.

With Georg Hertting. “The Fate of Tritiated Noradrenalin at the Sympathetic Nerve Ending.” Nature192 (1961): 172–173.

With Georg Hertting and L. Gordon Whitby. “Effect of Drugs on the Uptake and Metabolism of3 H-norepinephrine.” Journal of Pharmacology and Experimental Therapeutics 134 (1961): 146–153.

With Richard J. Wurtman and Solomon H. Snyder. “Control of Hydroxyindole O-methyltransferase Activity in the Rat Pineal Gland by Environmental Lighting.” Journal of Biological Chemistry 240 (1965): 949–954.

“An Unexpected Life in Research.” Annual Reviews of Pharmacology 28 (1988):1–23. Axelrod’s career review.

“Journey of a Late Blooming Biochemical Neuroscientist.” Journal of Biological Chemistry278 (2003): 1–13. Axelrod’s career review, emphasizing neurochemistry.

OTHER SOURCES

Kanigel, Robert. Apprentice to Genius: The Making of a Scientific Dynasty. Baltimore, MD: Johns Hopkins University Press, 1981. Depicts Axelrod as student and mentor.

Carl F. Craver

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Axelrod, Julius

Julius Axelrod

American scientist Julius Axelrod (1912-2004) shared the 1970 Nobel Prize in Physiology or Medicine (with Ulf von Euler and Sir Bernard Katz) for his research relating to the role that neurotransmitters play in the human body's sympathetic nervous system. Specifically, Axelrod and the co-recipients received the award for their discoveries concerning “the humoral transmitters in the nerve terminals and the mechanisms for their storage, release and inactivation.”

Axelrod's research into the body's neurotransmitters has led to new discoveries in neurobiology and has enabled the development of chemical treatments for mental disease and nervous system disorders. For this reason, some people refer to him as “the father of Prozac Nation.”

Axelrod was born on May 30, 1912, in New York City, New York, to Isadore and Molly Leichtling Axelrod. His parents were Polish immigrants who came to America in the early years of the twentieth century. They settled in the Jewish section of Manhattan's Lower East Side, where Isadore Axelrod supported his family by making flower baskets for local merchants.

Axelrod attended public elementary and high schools near his tenement home. Never one to let formal schooling interfere with his “real education,” Axelrod spent many hours at the local public library. A voracious reader, he could finish several books in a single week. His literary interests were wide-ranging and included everything from contemporary pulp novels to important writers such as Upton Sinclair and Leo Tolstoy.

Obtained Master's After Medical School Rejections

After high school Axelrod spent a year at New York University, but he transferred to the tuition-free City College of New York (CCNY) when he ran out of money. He graduated from CCNY in 1933 with majors in biology and chemistry. Following college graduation, Axelrod applied to several medical schools, but was turned down. He claimed that the rejections stemmed from quotas for Jewish students. As quoted in the Washington Post, Axelrod said, “I wasn't that good a student, but if my name was Bigelow I probably would have gotten in.”

Forced to seek work, Axelrod had difficulty finding employment in New York City, as the country was in the midst of the Great Depression. However, in 1933 he secured a position as a laboratory assistant at the New York University Medical School, where he received a meager $25-per-month salary. In 1935 he became a chemist at the Laboratory of Industrial Hygiene, a nonprofit organization established by the New York City Department of Public Health to test vitamin supplements added to foods.

On August 30, 1938, Axelrod married Sally Taub. The couple eventually had two sons, Paul Mark and Alfred Nathan. While supporting his family, Axelrod took courses at New York University toward his master's degree in chemistry, which he received in 1941. During this period, Axelrod lost the sight in one eye in a laboratory accident (a bottle of ammonia had exploded). For the rest of his life, he would wear a dark covering over the damaged eye. At first, he wore an eyepatch. Later he opted for a darkened eyeglass lens.

Research Assignment Led to Important Collaboration

Axelrod enjoyed working at the Laboratory of Industrial Hygiene, where he found the work interesting and the pay sufficient. But in 1946 his career received a boost when he was given the chance to do some substantial scientific research. The laboratory received a grant to determine why some people who took large quantities of acetanilide, a non-aspirin pain-relieving drug, developed methemoglobinemia, a blood disorder characterized by the body's inability to recycle hemoglobin (the oxygen-carrying molecule found in red blood cells) after it had been damaged. In severe cases of methemoglobinemia, the hemoglobin cannot carry oxygen to body tissues.

Inexperienced in such complex research, Axelrod consulted Dr. Bernard B. “Steve” Brodie of Goldwater Memorial Hospital of New York, who was a well known drug researcher. Brodie found the problem so fascinating that he decided to collaborate with Axelrod to determine a solution. In addition, through his relationship with Brodie, Axelrod became part of the New York University research staff.

Joined National Institutes of Health

Working together, Axelrod and Brodie made a significant contribution to the knowledge of the chemistry of analgesic medications. They learned that the human body either metabolizes acetanilide into a substance with an analgesic, or pain relieving, effect, or into another substance that causes methemoglobinemia. Therefore, they recommended that the analgesic substance be directly administered without acetanilde.

In 1949 Axelrod and Brodie, along with several other researchers from Goldwater Memorial Hospital, received an invitation to join the National Heart Institute of the National Institutes of Health in Bethesda, Maryland. (The National Heart Institute later became the National Heart, Lung and Blood Institute.) At the institute, Axelrod conducted research on the physiology of caffeine absorption and drugs called sympathomimetic amines, which mimic actions of the sympathetic nervous system that prepare the body for strenuous activity. In addition, he studied several compounds including amphetamine, mescaline, and ephedrine. He then discovered a new enzyme group that enabled these compounds to metabolize in the body.

Obtained Doctoral Degree

Convinced that he needed to obtain a doctorate to advance in the National Institutes of Health, Axelrod sought an advanced degree in the mid-1950s. Taking a year's sabbatical from work, he prepared for comprehensive examinations at George Washington University in the District of Columbia. To meet his thesis requirements, he submitted the research from work he had already accomplished. In 1955 he received a Ph.D. in pharmacology. The degree did indeed provide new opportunities, and Axelrod did not return to the National Heart Institute. Rather, he joined the National Institute for Mental Health, which was another branch of the National Institutes of Health, where he was offered the chance to create a new pharmacology section within the Laboratory of Clinical Sciences. He became chief of the section, a position he held until he retired in 1984.

During this period, Axelrod's research included studies involving metabolism of lysergic acid diethylamide (commonly known as LSD) and the human body's pineal gland. In the course of his research, Axelrod determined that melatonin was the pineal gland's key hormone. In addition, working with collaborators, Axelrod determined the mechanism for glucocorticoid formation and demonstrated that congenital non-haemolytic jaundice is caused by a defect in glucocorticoid synthesis.

Focused on Neurotransmitters

In 1957 Axelrod began an area of research work that would culminate in a Nobel Prize. Working with colleagues and students, he focused on neurotransmitters, which are chemicals that transmit signals from one ending to another. Specifically, he studied how neurotransmitters worked inside the human body. During related research conducted the previous decade, Swedish scientist Ulf von Euler discovered that noradrenaline served as the neurostransmitter for the body's sympathetic nervous system. Now, in his own research, Axelrod looked at how the rapid deactivation of noradrenaline cleared the way for later nerve signal transmissions. This, he determined, happened in two ways: through the enzyme catechol-O-methyltransferase (which Axlerod discovered and named), which was essential to metabolism and, in turn, noradrenaline deactivation; and through the reabsorption and storage of noradrenaline by the nerves for later reuse. Axelrod's discoveries had significant impact. He was able to show that psychoactive drugs, such as antidepressants and amphetamines, achieved their effects by hindering the normal deactivation or reabsorption of noradrenaline and other neurotransmitters. This inhibition extended the impact the drugs had on the nervous system or the brain.

Axelrod's research would lead to numerous new discoveries in the emerging field of neurobiology and chemical treatment for mental disease and nervous system disorders. For instance, his work helped lead to selective serotonin reuptake inhibitors, which are antidepressant medications used to treat depression and anxiety. Perhaps the bestknown selective serotonin reuptake inhibitor is Prozac.

Received Share of Nobel Prize

In 1970 Axelrod shared the Nobel Prize in Physiology or Medicine with Ulf von Euler and Sir Bernard Katz of the United Kingdom. Axelrod and the co-recipients were awarded specifically for their discoveries concerning “the humoral transmitters in the nerve terminals and the mechanisms for their storage, release and inactivation.”

During his banquet speech, included on the Web site Nobelprize.org, Axelrod said, “This award comes at a time when our young and many of our most influential people believe that basic research is irrelevant or is put to evil uses. The selection of chemical neurotransmission for a Nobel Prize this year, makes our work highly visible to the general public and gives us an opportunity to show how misinformed and mistaken they are. I think we can easily demonstrate that although our work is of a fundamental nature, it also gives us insight in explaining such illnesses as mental depression, Parkinson's disease, hypertension and drug abuse. It can also lead the way to the treatment of these terrible afflictions.”

After he was honored, Axelrod made a point of crediting von Euler for initiating the early work that eventually led to their recognition by the Nobel committee.

Axelrod has been described as a soft-spoken individual with a wry and often self-deprecating sense of humor. Also, with his highly visible darkened lens, he had a distinctive physical presence. “I used to wear a black patch over my eye when I was young. It was very dashing, like Brenda Starr's husband,” he quipped to the Washington Post, with characteristic wit.

Noted neuroscientist Solomon H. Snyder was quoted in The Lancet as saying, “[Axelrod's] successes never went to his head. He still worked in the lab with his own two hands even when he'd won the Nobel Prize. He said he got his best ideas when he was washing glassware.”

Later Research

In his post-Nobel years, Axelrod continued with his biochemical and pharmacological research, in particular the study of hormones. Beyond his work on neurotransmitters, Axelrod also developed new experimental techniques that found wide application among his colleagues. In addition, he became well known and respected for the training and assistance he graciously provided to visiting researchers and postdoctoral students. It has been estimated that during his career he mentored about 70 younger scientists. Michael J. Brownstein, who did postdoctoral research in Axelrod's laboratory in the 1970s, told The Lancet, “He just loved to talk about science and think about science …. He had a special ability to see through biological phenomena when the rest of us couldn't.”

Even though Axelrod formally retired from the National Institute of Mental Health in 1984, he continued with his own research, despit failing health late in his life. Ironically, in 1993, when Axelrod was 80 years old, his life was saved through one of his own past scientific discoveries. He had suffered a massive heart attack and required immediate triple coronary-artery bypass surgery. But his blood pressure had fallen so low that the cardiologists at Georgetown University Medical Center, where he was being treated, feared that he could not survive such an operation. However, the physicians injected a synthetic form of noradrenaline to stimulate the contractions of his heart and raise his blood pressure to an acceptable level. Axelrod not only survived, but was able to go back to work in two months.

He continued to work regularly at his office at the National Institutes of Health until his death on December 29, 2004. Axelrod reportedly died in his sleep at his home in Rockville, Maryland. He was 92 years old. His wife of 53 years, Sally Taub Axelrod, had passed away 12 years earlier.

During his career he received numerous honors and awards. Along with his Nobel award, only a few of these included the National Science Foundation Travel Award (1958), The Gairdner Foundation Award (1967) and the Distinguished Achievement Award from George Washington University. He was a member of several distinguished scientific societies, and served on the editorial boards and committees of important scientific and medical journals, including Journal of Pharmacology and Experimental Therapeutics, Journal of Medicinal Chemistry, Life Sciences, Circulation Research, Journal of Neurobiology, Pharmacological Research Communications, Journal of Neurochemistry, and International Journal of Psychobiology.

Books

Notable Scientists: From 1900 to Present, Gale Group, 2001.

Periodicals

The Lancet, January 29, 2005. Washington Post, December 30, 2004.

Online

“Julius Axelrod: The Nobel Prize in Physiology or Medicine,” Nobelprize.org, http://www.nobelprize.org/cgi-bin/print?from=%2Fnobel_prizes%2Fmedicine%2Flaureates%2F1970%2Faxelrod-bio.html (November 10, 2007).

“Julius Axelrod: The Nobel Prize in Physiology or Medicine - Banquet Speech,” Nobelprize.org, http://www.nobelprize.org/nobel_prizes/medicine/laureates/1970/axelrod-speech.html (November 10, 2007).

“The Nobel Prize in Physiology or Medicine 1970,” Nobelprize.org, http://nobelprize.org/nobel_prizes/medicine/laureates/1970/press.html (November 10, 2007).

World of Health Online, http://www.galenet.galegroup.com/servlet/BioRC (November 10, 2007).

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Axelrod, Julius

Julius Axelrod (ăk´səlrŏd), 1912–2004, American biochemist whose work was influential in the development of pharmaceuticals, b. New York City, grad. City College, N.Y. (B.S. 1933), New York Univ. (M.S. 1941), George Washington Univ. (Ph.D. 1955). Axelrod spent much of his career at the National Institutes of Health (1949–84), where from 1955 to 1984 he was chief of the Section on Pharmacology, Laboratory of Science, at the National Institute of Mental Health. Along with Bernard Katz and Ulf von Euler, Axelrod was awarded the 1970 Nobel Prize in physiology or medicine for work on neurotransmitters. During the late 1950s and early 1960s Axelrod's investigations into the role of norepinephrine in brain chemistry led to an understanding of how neurotransmitters work and how their levels are regulated. This research made possible the development of the antidepressants and antianxiety drugs known as selective serotonin reuptake inhibitors (SSRIs). In the 1940s Axelrod helped identify the analgesic properties of acetaminophen, and in the 1960s he explained the nature of melatonin and the role of it and the pineal gland played in regulating biological rhythms (see rhythm, biological).

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Axelrod, Julius

AXELROD, JULIUS

AXELROD, JULIUS (1912– ), U.S. biochemist, pharmacologist, and Nobel Prize laureate. Born in New York City, the son of Polish immigrants, he obtained his B.Sc. in 1933 from New York's City College, his M.A. in 1941 from New York University, and his Ph.D. in 1955 from George Washington University. In 1949 he joined the staff of the National Heart Institute, Bethesda, Maryland, and in 1954 he was invited to establish a pharmacology section and was appointed chief of the section, Laboratory of Clinical Science, National Institute of Mental Health (nimh). In 1957 he began his most famous research project which focused on the activity of neurotransmitter hormones. Axelrod specialized in the field of biochemical mechanisms, drug and hormone actions, and glandular research. His achievement was based on Euler's discovery of noradrenaline (norepinephrine), a chemical substance that transmits nerve impulses. Axelrod identified the mechanisms that regulate the formation of noradrenaline in nerve cells as well as the mechanisms in its inactivation. He discovered the enzyme that neutralizes noradrenaline by an enzyme, and named it catechol-o-methyl transferase. The enzyme was shown to be useful in dealing with the effects of certain psychotropic drugs and in research on hypertension and schizophrenia. Axelrod's work enabled researchers during the 1970s to develop a new class of antidepressant medication such as Prozac. Over the next 30 years, until his retirement in 1984, he worked on many research projects in pharmacology. He shared the 1970 Nobel Prize for physiology and medicine with the British biophysicist Sir Bernard *Katz and the Swedish physiologist Ulf von Euler. Axelrod remained an active scientist and researcher and distinguished lecturer throughout the 1970s. He was the recipient of many awards and a member of many editorials boards and committees of scientific journals. In 1984 he formally retired from nimh and was named Scientist Emeritus of the National Institute of Health in 1996.

[Gali Rotstein (2nd ed.)]

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Axelrod, Julius

Axelrod, Julius

(b. 30 May 1912 in New York City; d. 29 December 2004 in Rockville, Maryland), pharmacologist, biochemist, and Nobel Prize winner whose discoveries contributed to the understanding of the biochemistry of the sleep-wake cycle, led to the development of such antidepressant drugs as Prozac, and elucidated the metabolism of nonaspirin analgesics, enabling development of the drug Tylenol.

Born on the Lower East Side of Manhattan, Axelrod was the son of Isadore Axelrod, who made a living making and selling baskets, and Molly (Liechtling) Axelrod. Axel-rod’s parents were immigrants from Galicia, a part of what was later Poland and Ukraine. His father and mother met and married after arriving in America. Axelrod, who also had two sisters, attended public schools, although he attributed his important early education (his “real education”) to his reading at the public library a block from his home. He had high aspirations to attend competitive high schools in the city. However, his performance did not merit admission (he attended Seward Park High School instead), nor did he later earn scholarships or admission to the most prestigious colleges.

After attending New York University for a year, he left for lack of sufficient funds and transferred to the tuition-free City College of New York, which he described as the “proletarian Harvard.” He majored in biology and chemistry, although his best grades were in history, philosophy, and literature. With his characteristic persistent ambition, he had hoped to attend medical school upon graduation. However, he failed to gain admission despite his many applications, due in part to his own performance and in part, he believed, to quotas imposed at that time on admission of Jewish students to medical schools.

Axelrod graduated with a BS in biology and chemistry in 1933, when the country was in the depths of the Depression with more than 20 percent unemployment, yet he managed to find a job for very low pay in a research laboratory affiliated with New York University. After two years he was hired as a chemist in the Laboratory of Industrial Hygiene of the New York City Department of Public Health. An important part of his work there was developing methods of measuring vitamins, which had only shortly before been introduced as food additives, in various types of food.

On 30 August 1938 Axelrod married Sally Taub, a graduate of Hunter College who became an elementary school teacher, and they had two sons. In the same year as his marriage, Axelrod lost an eye in a laboratory accident, which led to his wearing an eye patch for many years and to his being deferred from military service during World War II. Attending classes at night while working as a chemist, Axelrod earned an MS in chemistry from New York University in 1941.

An invitation in 1946 from Dr. Bernard “Steve” Brodie of the Goldwater Memorial Hospital to work with him on a research project changed the course of Axelrod’s career. Brodie, who became an important mentor to Axelrod, was attempting to learn why nonaspirin analgesics (pain-killers), sold under various names (the most common of which was Bromo Seltzer), caused a side effect in which hemoglobin in the blood was chemically modified to hinder its capacity to carry oxygen. Through an ingenious series of experiments, Axelrod and Brodie demonstrated that the main ingredient in the analgesic, acetanilide, was metabolized in the body into different chemicals, one of which caused the detrimental side effect on hemoglobin and another of which generated the desired painkilling effect. The desired substance, acetaminophen, was subsequently developed by Johnson & Johnson as the drug Tylenol.

In 1949 Axelrod moved to the National Heart Institute, a division of the National Institutes of Health (NIH), in Bethesda, Maryland, to work as a research chemist. Despite great recent success, Axelrod recognized that not having a doctorate limited his career. He decided to take leave for a year to earn the degree at George Washington University. Upon completing a PhD in pharmacology in 1955, the research for which was essentially a continuation of work in which he was already involved, he was invited to set up a section in pharmacology at the National Institutes of Mental Health (NIMH), where he remained until he retired in 1984.

Axelrod’s major scientific advances fall into three phases, of which the discovery concerning acetaminophen was the first. The second phase, although it was in some ways a continuation of earlier research, was conducted during the late 1950s at the NIMH and involved the “sympathomimetic amines.” The drugs in this group—among which are caffeine, benzedrine, mescaline, codeine, and ephedrine—mimic the effects of chemical neurotransmitters in parts of the nervous system. The first research topic in Axelrod’s new laboratory at the NIMH was lysergic acid diethylamide (LSD), which was at that time used experimentally by psychiatrists as a treatment for certain severe mental disorders. LSD subsequently became a popular drug of the counterculture in the 1960s. Although Axelrod never promoted its use, in response to a reporter’s question whether he had used the drug himself, he said, “I used to do that. I met with an accident... and ever since stopped using myself as a guinea pig.”

The set of experiments that led to his winning the Nobel Prize in 1970, shared with Sir Bernard Katz of Great Britain and Ulf von Euler of Sweden, involved the fate of the naturally occurring neurotransmitters that are released at nerve cell endings and that transfer impulses across the junction to other nerve cells. At that time it was believed that neurotransmitters were chemically degraded after release. Axelrod and his coworkers found that nerve endings actually reclaim the neurotransmitters (“reuptake”) and that different drugs can facilitate or block this process, leading to various effects on the nervous system. This work and subsequent discoveries led to the development of a group of antidepressant drugs, called “selective serotonin reuptake inhibitors,” among which are Prozac, Zoloft, and Paxil. In addition to the selective reuptake inhibitors, the work of Axelrod and his close collaborators—including many prestigious researchers—led to elucidating the mechanism of action of several psychoactive drugs, including cocaine and the amphetamines.

In the third major phase of his work Axelrod was attracted in the late 1950s to the pineal gland, a tiny mass of tissue embedded deep inside the brain. The role of the pineal, referred to as the “third eye” because of its sensitivity to light, was relatively unknown, but in 1958 its effect on pigment synthesis in tadpoles was shown to be associated with the release of a hormone called melatonin. Axelrod and his collaborators discovered that melatonin is synthesized in the pineal glands of mammals from the neurotransmitter serotonin, that melatonin and serotonin act to synchronize the “biological clock,” and that these hormones are released from the pineal gland in response to environmental light conditions. Both melatonin and serotonin are known to affect the sleep-wake cycle, and they have effects on the timing of reproductive functions of some mammals. This line of research was one of Axelrod’s main preoccupations during the later years of his career.

Axelrod’s impact in the scientific community was greatly extended through his role as a mentor to young investigators and as a collaborator with peers. He hosted more than fifty postdoctoral fellows and visiting scientists in his laboratory, over half of whom came from abroad. Axelrod strongly believed that creating a rich intellectual community of researchers was key to making major advances in science.

After receiving the Nobel Prize in 1970, Axelrod took up a number of social and political causes, including leading a protest with some of his NIMH colleagues against President Richard Nixon’s proposal to establish an agency with the specific goal of finding cures for cancer. He and many others felt that an agency with such a narrowly defined mission would divert funding from basic research, in which so much of the foundation for major discoveries is developed. During the 1970s Axelrod joined protests against the former Soviet Union’s treatment of dissident scientists, including the nuclear physicist Andrei Sakharov, and in 1974 he publicly protested the United Nations’ threat to impose sanctions against Israel.

Axelrod also felt a responsibility to communicate science to the general public. In 1974 he published a widely regarded article in Scientific American that facilitated a broad understanding of neurotransmitters, and he earlier coauthored an article, published in the same journal, on the pineal gland. Although he retired from his position at the NIMH in 1984, he continued involvement in research for several years until his death in 2004. He earned many honors, including the Gairdner Award (1967), which many consider to be a harbinger of the Nobel Prize.

Axelrod made extraordinary contributions to the field of psychopharmacology and to the understanding of the biochemistry of the nervous system. His discoveries, as well as those of his close collaborators, laid the foundation for the broad array of psychoactive drugs later used to treat various disorders. His career did not follow the pattern of most highly successful scientists. There was no early demonstration of academic brilliance or evident promise of scientific excellence. However, his persistence and success as a researcher led to an outstanding array of career achievements. In the concluding sentence of a 1988 autobiographical essay, he quoted F. Scott Fitzgerald as having said that there are no second acts in American lives. Describing himself as a contradiction of this, Axelrod wrote: “After a mediocre first act, my second was a smash. So far the third act has not been so bad.” This is an accurate portrayal of his remarkable career.

The Julius Axelrod Papers, an extensive array of published and personal materials, are housed at the U.S. National Library of Medicine at the National Institutes of Health in Bethesda. An autobiographical essay, which contains some personal history but is primarily a summary of Axelrod’s scientific work, is in Annual Review of Pharmacology and Toxicology 28 (1988): 1–23. Robert Kanigel, Apprentice to Genius: The Making of a Scientific Dynasty (1986), contains an account of a group of scientists, including Axelrod as a central participant, who made major discoveries in the area of psychopharmacology. An obituary is in the Washington Post (30 Dec. 2004).

W. Hubert Keen

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Axelrod, Julius

Julius Axelrod

Born May 30, 1912, in New York, NY; died December 29, 2004, in Rockville, MD. Biochemist. American biochemist Julius Axelrod conducted important research in brain chemistry that spurred the development of an entirely new class of drugs. Prozac and Paxil, the brand names of more-effective depression-treating drugs that came onto the market in the late 1980s and early '90s, were the direct result of Axelrod's discoveries about certain hormones and their actions in the part of the brain that regulates moods. For this work, he was a co-recipient of the 1970 Nobel Prize.

Axelrod was born in 1912, six years after his Polish-born parents came to America and settled on Manhattan's Lower East Side. He planned to become a doctor, and graduated from Seward Park High School on Grand Street just as the Great Depression was beginning. After one year at New York University, he transferred to the City College of New York, which offered free tuition to all city residents. After earning his undergraduate degree in 1933, he was rejected by the admissions boards of several medical schools, possibly because he was Jewish; it was an era when most medical schools accepted only a limited number of Jewish enrollees every year. Instead he took a job at a lab at the New York University Medical School, and in 1935 was hired by the New York City Department of Health to test vitamin-fortified foods. There, in 1938, Axelrod lost an eye in a laboratory accident when a bottle of ammonia exploded. For the remainder of his life he wore eyeglasses with a darkened lens over the left side.

Though his impaired vision made Axelrod ineligible to serve in the U.S. military during World War II, it did not deter his scientific ambitions in the least. He worked full time, but took night classes and earned a master's degree in chemistry from New York University. His thesis on cancer tissue enzymes impressed Dr. Bernard Brodie, who would become an important mentor to him. In 1945 Axelrod was invited to join Brodie in his research lab at Goldwater Memorial Hospital on New York City's Roosevelt Island. When Brodie moved to the National Heart Institute, part of the federally funded National Institutes of Health (NIH), in 1949, the junior scientist followed him there. Urged by his colleagues, Axelrod began work on his doctorate, and earned it in 1955, when he was in his early 40s, from George Washington University. That same year he was invited to establish a pharmacology section at the NIH's Laboratory of Clinical Science within the National Institute of Mental Health.

Some of Axelrod's earliest research work dealt with pain-relieving medications, specifically the discovery of acetaminophen as a headache reliever. The drug was later made available without a prescription under the brand name Tylenol. Around 1957, he began the work that would later earn him the Nobel Prize. His research involved catecholamines, the hormone chemicals in the brain that are stored in nerve endings. They serve as neurotransmitters, or chemical messengers between nerve cells. Axel-rod looked at noradrenaline, one of these catechola-mine neurotransmitters. The common scientific perception was that noradrenaline was dissolved by enzymes once it was no longer active, but Axelrod's work showed that noradrenaline was instead recycled, or reuptaken, by the nerve cells. His discovery led to the engineering of a new type of drugs that worked to block that reuptake process, particularly for serotonin, a mood-regulating neurotransmitter. These new anti-depressant medications, known as "selective serotonin reuptake inhibitors" (SSRIs), first became available in 1987 with the introduction of Prozac by prescription. Prozac and its SSRI siblings, including Zoloft and Paxil, began to be used by millions and would make a profound difference in the treatment of depression and substance abuse.

For his discovery, Axelrod shared the 1970 Nobel Prize in physiology or medicine with two other scientists also working in the field, Sir Bernard Katz, an Australian at University College of London, and Ulf von Euler of Sweden's Karlinska Institute. Axelrod also did important early work on melatonin, a hormone secreted by the pineal gland that regulates sleep cycles. He officially retired in 1984, but still came into the lab three times a week. In 1996 he was named an emeritus scientist at the NIH. He suffered from heart trouble in his later years, and died in his sleep at the age of 92 on December 29, 2004, at his home in Rockville, Maryland. He was married to Sally Taub, an elementary-school teacher, in 1938, but widowed in 1992. He is survived by two sons and three grandchildren. Respected by his colleagues and popular with his graduate assistants, Axelrod was known for his modesty. He learned of his Nobel Prize win from his dentist, after forgetting to listen to the radio that morning, and when President Richard M. Nixon made a congratulatory telephone call, Axelrod used the opportunity to challenge the Nixon Administration's planned budgetary revisions in scientific funding, which had caused some consternation at the NIH. The Nobel prizewinner later said that his achievements would have been impossible for the generation of scientists who followed him, when earning a doctorate at the age of 41 would put one far behind in the professional race. "There's not room in the field of research for people like me," he asserted, according to Jon Thurber's Los Angeles Times obituary, quoting an earlier interview, "who matured slowly." Sources: Chicago Tribune, December 30, 2004, sec. 3, p. 8; Los Angeles Times, January 2, 2005, p. B14; New York Times, December 31, 2004, p. A22; Times (London), January 4, 2005, p. 46.

CarolBrennan

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