Expert Views ::
Chemical Mediation in Living Systems: Reflections from Fifty Years of Research and Teaching

Howard A. Bern

About sixty-five years ago at UCLA, Professor Bennet Mills Allen first taught me the elements of endocrinology. Allen along with Karl Gudernatsch and Philip E. Smith pioneered research in developmental endocrinology, and unknowingly comparative endocrinology, when they demonstrated thyroid control of frog tadpole metamorphosis and, later, pituitary control of thyroid function.

About 54 years ago, when I arrived at Berkeley, I began to teach endocrinology, cribbing some of the material from my then 10-year-old lecture notes from Allen's course. Some of this material is probably still being taught unsuspectingly at Berkeley by my colleague and successor Tyrone Hayes who took his first endocrinology course from me when he was a graduate student.

The initial endocrinology that I taught was general endocrinology, mostly mammalian, using C. Donnell Turner's splendid General Endocrinology as a text. I soon recognized, as Turner had partially, the ubiquity of endocrine and paraendocrine phenomena in the animal, plant and microbial worlds, and from that point on I taught the biology of chemical mediation. I was impressed by efforts such as Lucas's emphasis on chemical ecology and the role of chemical agents in determining the inclusion and exclusion of species from the biotic community environment (Lucas particularly referred to planktonic masses) by the release of chemical agents, then (and now) largely undefined.

I felt somewhat unique in my stance, but became increasingly convinced that chemical mediation was in fact an essential characteristic of living systems – of life. Finally a major confirming event occurred. A few years ago Professor Arnold De Loof of the University of Leeuwen (Louvain) in Belgium, whom I knew as an outstanding insect peptide molecular endocrinologist, was asked to write an essay on the 50th anniversary of the publication of Erwin Schroedinger's "What is Life?" Schroedinger was a physicist, a Nobel Laureate, who can justifiably be considered the father of molecular biology. In his tribute, De Loof makes the claim that THE characteristic of life is communication, largely chemical but also bioelectrical. I felt vindicated in my longtime conviction. De Loof went on to write a book in Flemish (a subspecies of Dutch), called Wat is Leven. To make your (and my) comprehension easier, there has just appeared an English version: Communication, Life, Mega-evolution; the title now clearly indicates the emphasis on COMMUNICATION. A sine qua non for communication, as De Loof early recognized, is compartmentalization. Agents communicate between compartments, be they subcellular, cellular, tissue, organ (this is the subject of endocrinology proper),organismal, speciational, populational, community (organized into ecosystems).

For an agent to act, according to present doctrine, there must be a receptor, and the characterization and measurement of receptors has become a career for many biologists. But the receptor issue has become an article of faith, when it is essential to recognize the possibility of other modes of action. As an example, let me refer to the action of sex hormones on neonatal mice, which Dr. Takasugi earlier discussed. During reproductive tract development, natural animal estrogens, phytoestrogens, synthetic estrogens (such as diethylstilbestrol--DES), antiestrogens (such as tamoxiphen and clomiphene), androgens both aromatizable and nonaromatizable, the inactive stereoisomer of an androgen, progestins, and 17alpha-estradiol, all have the same effect and produce the same histopathological changes. Agents may act differently during development from their actions in adult stages. And receptors as we ordinarily view them may not be centrally involved.

What then is a possible mode of action in such situations? When I first taught students about chemical mediation, the mechanism of hormone action was being actively debated. Claude Villee at Harvard was strongly advocating a hormonal action directly upon enzymes. This proposal was doomed by the discovery of receptors, both cytosolic and membrane. However, a consideration of latter-day information on how chemical mediators may act raises again the reality of action by enzyme activation or inhibition. Isn't this what the action of nitric oxide is all about? An effect on a metalloprotein enzyme (Fe-containing) guanylate cyclase resulting in the generation of cGMP. Plant hormones such as ethylene also act on metalloprotein enzymes (Zn- or Cu-containing). I recognize the semantic issue – the enzyme can be called ipso facto a receptor. However, I urge my colleagues who are working on endocrine disruptors to be cautious in assuming that estrogenic pollutants, for example, are necessarily acting through the established estrogen receptors, or through other recognized receptors, wherever they may be located.

One last point that I would like to deal with refers back to the ecological effects of external metabolites, to use the title of Lucas's 1940 article. I think that Lou Guillette presented a cleverly conceived system approach to endocrine disruptors about 3 years back. Inasmuch as he is chairing Session VI on ecosystem perturbation, my few comments here may prove redundant. The workshop on ecosystem communication scheduled for this evening further indicates that this approach may not need my particular provocation. Nevertheless, I suggest that we may be on the threshold of a needed ecosystem approach to the understanding of environmental endocrine disruption. We need to become concerned with more than the individual organism – the single species — but also with the interactions among organisms affected by a particular agent. How do affected organisms affect one another: vertebrate and invertebrate, animals and plants, fungi and microorganisms? This is chemical communication (as Arnold De Loof and I conceive of it) on the ecological level, and I think that biologists will have to rise to the challenge and the complexity that it poses.

As a brief indication of what I mean, consider the implications of the recent paper by Fox et al. (one of the "als" being John McLachlan himself) in Nature, which indicates the effect of endocrine disruptors on nitrogen fixation by bacteria living on the roots of leguminous plants. It does not require much imagination to visualize the negative ecological, the disruptive community effects of interference with the metabolism of these vital bacteria.

In conclusion, I hope that I have acquainted you with my views on the ubiquitousness of chemical communication and with my biases in regard the multivalency of how endocrine disruptors, along with other chemical mediators, may act. Finally because of the ubiquity of chemical communication as a necessary feature, maybe THE necessary feature, of life, why we must think in macroenvironmental terms as well as in microenvironmental terms.