The biochemically active pineal gland may be as important as any other A few years ago, when they thought about it at all, scientists were blithely dismissing the pineal gland as biologically extinct in humans. But three centuries back, the philosopher Descartes hailed it as a reservoir for vital "animal spirits," calling it the "seat of the rational soul." It turns out that, biologically, Descartes came closer to the truth. For as scientists recently heard in Chicago, the pineal gland, seated in the brain, is one of the most biochemically active and complicated organs in the body. And it may be as important as any. A crowded pineal symposium held during the 51st annual meeting of the Federation of American Societies for Experimental Biology heard that the tiny pea-shaped gland, from a research point of view, "has something in it for everybody." It holds significance for pharmacologists, biochemists, organic chemists, and neurochemists, as well as for biologists at large. This is why: • The pineal is the only gland in the body directly penetrated and thus stimulated by nerve fibers. All others are controlled by circulating hormones. • It is loaded (up to 100 micrograms per gram) with the biogenic amine serotonin. Pharmacologists are studying serotonin intensively in their research on tranquilizers, antidepressants, and hallucinogenic drugs as well as on agents for treatment of heart disease. • Its major secretory product, which scientists are just now getting around to calling a hormone, is melatonin. The level of enzyme responsible for producing melatonin (hydroxyindoleo-methyl transferase) rises during the night and falls during the day, in rats. Serotonin levels rise and fall inversely. • These rhythmical fluctuations, therefore, are directly influenced by darkness and light, via nerves that connect the pineal to the eye. • Under prolonged darkness, the reproductive activity of rat gonads diminishes. Turn on the lights and the sex glands activate. • This sex gland atrophy is directly related to high melatonin levels. When levels fall, sexuality is restored. • Finally, the pineal appears to of-
fer at least partial chemical explanation for the operation of the so-called biological clocks. Thirteen papers were read during the symposium—the first pineal parley ever held in the Western Hemisphere. Cochairmen were Dr. Julius Axelrod of the National Institutes of Health and his former colleague, Dr. Richard J. Wurtman, now at Massachusetts Institute of Technology. Both men played the major role in drawing scientific attention to the pineal in this country. In the few years of serious pineal research, Dr. Wurtman says, dividends are already appearing. "For biochemists and pharmacologists," he says, "here is the chance to study their favorite neural transmitters in one neat system. This gland has become an experimental tool to a large number of people who don't concern themselves with overall physiology." Dr. Wurtman, in an interview with C&EN, mentioned several gaps in pinealogy. No good chemical assay for melatonin in blood or urine yet exists. The only assay being used now is based on melatonin's blanching of frog skin—a crude biological determination. A more precise chemical method could nail down the relationship of melatonin secretion and thus pineal function to, say, the woman's menstrual cycle. Is the cycle controlled by the night and day rhythms? Or is it independent of pineal function? For the biochemist, pineal enzymology seems replete with opportunity to uncover neurochemical pathways. What, for example, is the connection between such neural transmitting compounds as noradrenaline and the synthesis of melatonin? What else is serotonin doing besides serving as a source of melatonin? What other compounds is the pineal producing? Dr. Wurtman thinks it manufactures dozens of others. How does melatonin biochemically interact with target tissue such as ovaries, testes, and the thyroid gland? For physiologists studying biorhythms, the pineal is a dream come true. Up to now, scientists thought the body's biological clock mechanisms
H Melatonin, N-acetyl-5-methoxytryptamine 40 C&EN MAY 1, 1967
operate independently of external influences. Now, the pineal's direct neural connection with the eyes, and the influence of light on melatonin synthesis, does havoc to that theory. Pharmacologically, the pineal also offers possibilities. As Dr. Wurtman explains it, the gland is activated by the sympathetic nervous system, under the chemical mediation of noradrenaline, the transmitter of the electrical stimulus. At night, pineal noradrenaline levels rise in the rat to 10 micrograms per gram, considered high for nerve cells or any tissue. During the day, they drop down to more normal levels of 2 to 3 micrograms per gram. If the same pattern holds for humans (and it might be just the reverse, since rats are nocturnal animals while humans usually aren't) the payoff could take the form of wiser methods of drug therapy. Dose selection, for example, is still a rather crude art, notably for drugs like dexedrine that work by influencing noradrenaline secretion. Nonadrenaline secretion is directed by the sympathetic nervous system, so therapists might eventually have to vary drug amounts according to pineal activity, or time of day. In humans, the pineal hardens just after puberty, forming a bonelike calcium phosphate matrix. This observation led scientists to regard the pineal merely as vestigial—useful as a lightsensitive "third eye" to lizards and lower vertebrate animals but decreasingly important in evolutionary ascent. However, biochemical studies of glands taken at autopsy by Dr. Wurtman, Dr. Axelrod, and others have shown that the pineal remains enzymologically active in humans right up to death. Currently, the chief chemical means of determining pineal activity is assay of the enzyme hydroxyindole-o-methyl transferase, which catalyzes the formation of melatonin from ZV-acetyl serotonin and S-adenosyl methionine. Activity of this enzyme is inhibited or enhanced by neurochemical events, undoubtedly involving noradrenaline but also including others. Biochemists are trying to work out the details, which should be available in coming months, thanks to the success in developing a way to culture whole pineal organs by Dr. Harvey Shain of Harvard Medical School, Dr. Axelrod, and Dr. Wurtman. Pineal biochemistry is still very primitive, and confusing. But this much is clear: It is a gland whose biochemistry is under direct control by light via the nervous system. It offers biochemists a tool for studying how at least one aspect of the external environment impinges on an organ and sets into motion what may be a huge variety of significant cyclical events.
