Academic journal article Proceedings of the American Philosophical Society

The Audacity Principle in Science1

Academic journal article Proceedings of the American Philosophical Society

The Audacity Principle in Science1

Article excerpt

DEDICATED TO JULIUS AXELROD a humble, gentle scientist who nonetheless epitomized the Audacity Principle in Science. He died 29 December 2004.

MY MENTOR, Julius Axelrod, often commented, "Ninetynine percent of the discoveries are made by one percent of the scientists." This may sound like an exaggeration. However, a brief examination of the major advances in any branch of science reveals the truth of this dictum. Axelrod himself is a prime example. In the field of molecular pharmacology, many of the key advances are attributable to his own efforts. He elucidated the metabolism of the major psychoactive drugs, in the process laying the groundwork for the emergence of acetominophen (Tylenol) as a major analgesic and then uncovering the family of drug-metabolizing enzymes, now known as the P450 enzymes. He accomplished most of this while working as a laboratory technician without a Ph.D. Following receipt of his doctorate at age forty-two, Axelrod proceeded to revolutionize neurotransmitter research. Consider the catecholamine neurotransmitters such as norepinephrine and dopamine. After norepinephrine was established as the neurotransmitter of sympathetic nerves in the late 1940s, advances were relatively modest. The enzymatic processes leading to its biosynthesis from the dietary amino acid tyrosine were gradually elucidated by multiple investigators over a period of several decades. Classical pharmacologie studies comparing the effects of different drugs on sympathetic neurotransmission had led to an appreciation that there were at least two subtypes of receptors for norepinephrine, designated alpha and beta, which subsequently led to important new drugs. Then, in roughly half a decade, Axelrod had a series of insights that drastically altered our thinking about norepinephrine and, indeed, all neurotransmitters. In 1957 he discovered catechol-O-methyltransferase, a key enzyme in metabolizing the catecholamines. This led him to question the prevailing assumption that the only other known enzyme that metabolizes catecholamines, monoamine oxidase, accounts for inactivation of norepinephrine after it is released by sympathetic nerves. Inactivating neurotransmitters is of crucial importance, for it serves to remove them from the vicinity of receptors on adjacent neurons so that successive nerve impulses will be effective. In the early 1960s the only neurotransmitter known besides norepinephrine was acetylcholine, discovered in the late 1920s. It was well established that the actions of acetylcholine are terminated by enzymatic degradation via an enzyme called acetylcholinesterase. Drugs that inhibit this enzyme potentiate the actions of acetylcholine at synapses, sites where nerves communicate with each other. Such acetylcholinesterase inhibitors provide important therapy for diseases such as myasthenia gravis that are characterized by muscle weakness because of deficient neurotransmission at acetylcholine synapses.

Because of the well-established role of acetylcholinesterase in inactivating acetylcholine, it was accepted wisdom that enzymes would inactivate norepinephrine at its synapses. But no one had directly evaluated whether monoamine oxidase was in fact responsible for norepinephrine inactivation. To compare the roles of catechol-O-methyltransferase and acetylcholinesterase, Axelrod utilized drugs that inhibit the two enzymes and was surprised to find that neither enzyme could explain synaptic inactivation. About this time, radioactive forms of norepinephrine became available. Instead of pursuing convoluted biochemical experiments with the radiolabeled molecule, Axelrod simply injected it into rats. He was amazed to find that organs enriched in sympathetic nerves, such as the heart, enormously concentrated the radioactive norepinephrine. When sympathetic nerves were severed, these organs no longer took up the neurotransmitter, indicating that it was the sympathetic nerve endings that had been concentrating norepinephrine. …

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