Expert Views :: The Future of the Field: Beyond Endocrine Disruption? Joe Thornton “As for a future life, every man must judge for himself between conflicting vague probabilities.” -- Charles Darwin, Life and Letters Predicting the future is a dangerous and presumptuous business, so when John McLachlan asked me to initiate a session at e.hormone 2002 on the “Future of the Field,” I didn’t want to prescribe or prognosticate on the directions our research is going to take. Instead, I offered a premise about who we are and few questions to stimulate discussion on the topic, “Where are we going?” The Premise My premise is not particularly modest: I propose that our research addresses the very essence of complex life forms from the level of the eukaryotic cell to the ecosystem. The scientists and students who assembled at e.hormone 2002 do not constitute a narrow or applied specialty; rather, we address a fundamental issue in biology. We study chemically-mediated information flow within hierarchically organized forms of life – which includes everything more complex than individual prokaryotes – and its disruption by other man-made and natural chemicals. Chemically-mediated information means the transmission of information from one entity to another by the synthesis, release, and reception/transduction of specific molecules. Sometimes these information molecules travel relatively long distances, as is the case with pheromones or steroid hormones; in other cases they are locally acting, as is the case with growth factors and neurotransmitters. It is this flow of molecular information that allows a higher-level entity like an organism, a structured society, or a symbiosis to emerge as an integrated entity that is more than just a collection of its lower-level constituents. The best developed part of our field is the study of hormones and other intercellular regulators that integrate the state and activity of tissues within an individual. Signaling by these molecules makes possible the existence of organized multicelled organisms as distinct from colonial collections of cells. But the scope of our research also properly includes the study of pheromones and similar molecules that control the activity of individuals in a population, including highly structured societies like insect caste systems. In some sexually plastic fish species, for example, there is a single male in each group; if the male is removed, the largest female becomes a male in about a day. The role of each individual in society is determined by molecules secreted by other individuals. The structured society itself emerges from this tight regulation. Our field also includes molecular signals that establish and maintain tight relationships among species, like the ecologically essential symbiosis between plants and nitrogen-fixing Sinorhizobia. As Jennifer Fox and John McLachlan have shown, the mutually beneficial relationships between these two species is mediated by a plant-secreted flavonoid, which reaches a specific cytoplasmic receptor and triggers changes in gene expressionin the bacterium. Without the signal, the multi-species entities that are the base of terrestrial food webs would not exist. We can say that chemically-mediated regulation is a necessary condition of all complex life. And it’s worth remembering that these integrated systems are all products of evolution. Tight regulation of coordinated parts emerged because it conferred upon the higher-level individual and its parts characteristics that made them relatively fit in their environment compared to unintegrated assemblages of lower-level entities. The individual, then, is a historical entity which emerged through tight coordination among its parts. The Questions If the integration of living systems by molecular stimuli and their disruption by exogenous chemicals is indeed what we study, then several questions are at the core of thinking about our future. 1. What are we? Does our work really constitute a field? Do we make up a legitimate field of study with our own fundamental questions, goals, and research strategies? With a subject that is at the core of life, should we not see ourselves in such terms? Or, alternatively, are we an ad hoc group of scientists drawn from a number of other disciplines – toxicology, epidemiology, physiology, molecular biology, and so on – who cooperate because we happen to find this question about molecular stimulation and disruption interesting and important? If the answer is the latter – that we are not a field – I don’t think that should be a source of shame. Suppose that we are simply a community of individuals, each whom perceives a potentially severe threat to human health and the integrity of the environment, and we all want to apply our scientific energies to understanding and preventing it. There should be no lack of pride about that. There would also be no shame if we are a group of people who are drawn to this issue because it offers a scientific focus that lifts us out of narrow disciplinary questions and reductionist models that, while quite effective for their purposes, can be intellectually and culturally unsatisfying. 2. What are our goals? Whether we are a field or a community, what are we trying to accomplish? Is our goal to produce scientific knowledge that bears on the “Endocrine Disruption Hypothesis” – the so-called hypothesis that chemicals in the environment can disrupt molecular information systems and are causing widespread biological effects? Is our mission to evaluate that hypothesis and, if it is true, characterize the threat and produce knowledge that will help design a remedy? This would make our “field” an applied one, like conservation biology. Alternatively, our goal might be broader and our science more basic. Is our subject molecular stimulation in biological systems and the ways exogenous chemicals can disrupt it? Is that too big a mantle? What separates us, for example, from molecular endocrinologists, who would probably say they are doing the same thing? The answer might have to do with a fundamentally interedisciplinary and multi-level perspective among our group. Or perhaps we might say that molecular endocrinologists are part of our field, though unwittingly in some cases. 3. What should we be working on? As a corollary to the question about goals, what is the importance of different kinds of research in reaching them? Several issues arise here: • How important is it that our work produce knowledge that helps diagnose and remedy health and environmental threats? Is there a place for work that doesn’t directly tell us much about environmental hazards? • What is the role of research on mechanisms? Is it important for us to study molecular mechanisms of signaling and disruption for their own sake, or is mechanistic understanding a means to an end? What is the value of phenomenological work in the absence of an understanding of mechanisms? It’s worth pointing out that work on xenohormones – DES and tamoxifen, in particular -- has been invaluable in clarifying the mechanisms of action of endogenous hormones, too. • Is there value in studying the evolution of molecular information flow? Is it useful or important to know the history of the relationships between ligands and receptors and receptors and the functions they regulate? Does a phylogenetic context help us predict what species will be susceptible to disruption by what kinds of ligands? Does it help us understand why so many synthetic chemicals seem to be endocrine disrupters? • Most specifically, what are the key specific research aims for this field or community? What research is most pressing to further our evaluation of the ED hypothesis? What do we want to know soon about molecular information systems themselves and their history? 4. What is our name? Whatever our goals, what should we call this field or community? People have used several names, and all of them have, in my view, certain problems. These is a semantic question, but delving into it points to important conceptual issues that may help us define our field. Possible names include: • Endocrine disruption. The traditional name for the field, and it encompasses much of what we do. If we are interested in more than just disruption but also in the workings and organization of molecular information systems themselves, then this term is too narrow. Even if disruption is our sole subject, we are concerned with exocrine, paracrine, and autocrine disruption – disruption of root-nodule regulation by pesticides, for example, or locally-acting molecules like prostaglandin, growth factors, and neurotransmitters. Also, there is something very vague about the word “disruption”: getting run over by a taxicab disrupts a person’s endocrine system, but surely that is not what we have in mind. • Environmental signaling. The metaphor of signaling via the environment is an improvement over “endocrine disruption,” but there are some problems with the term. First, an environmental focus excludes endocrine and paracrine systems are excluded, except to the extent they are disrupted by environmental chemicals. Second, the term signaling inappropriately imparts a kind of intent to the cells or tissues involved in molecular stimulation. A signal, by definition, involves a sender, who encodes a meaning in a message, which is received and then decoded to reveal the underlying meaning. Indeed, the word signal is derived from sign; linguists define a sign as consisting of a signifier (the manifest message) and a signified (the coded meaning) Think of a soldier waving a white flag, who hopes his meaning is understood and accepted. To a point, this idea of sending a signal that is then decoded matches very nicely the nature of signal transduction via specific intracellular or membrane-bound receptors, which initiate cascades of gene expression or other biochemical changes in response. But the idea of an encoded meaning behind or within the signal is problematic. The ovary is not sending a signal to the uterus, and the uterus has no understanding of the message’s import. The ovary is not trying to tell the uterus to get ready for an egg. Ovarian cells are responding automatically to a molecular stimulus they receive from the pituitary by synthesizing and excreting steroids into the blood. The uterus will be exposed to those steroids and respond with a series of biochemical and then histological changes that provide a better milieu for the coming egg. Signaling seems to take place between tissues but is in fact an illusion created by the tight integration of stimulus and response that constitutes the organism. There is no intent, meaning, or interpretation that takes place, and there is thus no signal per se. Information is flowing through the individual, but can we really say that the gland created the information and is communicating it? Information emerges because the stimulus and response by non-autonomous tissues are specific and tightly regulated. Now perhaps this is nitpicking and the teleological metaphor is of little consequence. After all, we always think in metaphors. But metaphors tend to slide into literalism when they are used over and over again – especially to name a field. Thinking in terms of the emergence of information from evolved responses to molecular stimuli – rather than messages with m eanings per se -- also opens up interesting questions that don’t come up when we think in the teleological terms of signals. • There are other potential names. Howard Bern suggested Chemical Mediation. I’ve referred to Molecular Information and Molecular Communication in this essay. These are all more accurate, I think. But are they adequate? And are they catchy enough? As it does every year, e.hormone gave us a very good idea of where the cutting edge of the field is right now. What the future may be is a topic for discussion. Or perhaps our direction will simply emerge from what each of us does over the coming years. For those interested in the evolution and emergence of higher-level entities from collections of lower-level parts, I recommend: Leo Buss. The Evolution of Individuality. Princeton, N.J. : Princeton University Press, 1987 and John Maynard Smith and Eörs Szathmáry. The Major Transitions in Evolution. Oxford: W.H. Freeman Spektrum, 1995.