Hard Days in the Trenches

^a Yale University, Department of Molecular Biophysics and Biochemistry,New Haven, Connecticut 06510, USA

	INTRODUCTION

TOP INTRODUCTION REFERENCES

 
In 1966, Jan Kott, a Pole living in exile, wrote an essay describing Hamlet as a political drama about a small country, Denmark, whose precarious existence was threatened by its two more powerful neighbors, England and Norway. While this is certainly not the only insightful reading of Hamlet, it does offer an original view echoing the author's time and place. At first it might seem inappropriate to regard contemporary biochemistry as a territory similarly threatened; however, the considerations of biochemistry are barely perceptible between the towering philosophical structures that exist in the powerful neighboring fields of physical sciences and evolutionary biology. Because of the intermediate position it occupies, in which biochemistry intermingles mathematics, physics, and chemistry with functioning of the naturally selected organism—where in effect the animate and inanimate worlds are studied jointly—one might expect that such a philosophy would be especially helpful in sorting out boundaries and strategies.

I would like to suggest that the absence of such a guiding scientific philosophy has led to lowered morale in the basic biomedical sciences, which has been described in these pages recently by Prof. Robert Pollack. Professor Pollack thoughtfully examined the effects of scientific activities on the personal and moral life in science and perceived a widespread unease, seemingly anomalous in a field that is so obviously flourishing. He noted, "Low morale is not a matter of too little money, nor of too few new ideas, but of too little kindness and decency; at the root, low morale is just a consequence, the cause of which is the fact that medical scientists busy in their labs have allowed the social and emotional foundations of their field to rot away beneath them." Regardless of how universal this disquietude may be, whether it is presently more pervasive than previously, or to what extent it is unevenly distributed across the field, Professor Pollack has revealed serious questions about morale that exist in the basic biomedical sciences. In Professor Pollack's view, the low morale arises because human values have not only been separated from scientific activities, but are in fact dehumanized by them. And one would have to be brutish indeed to disagree with his response and his call to scientists "to form themselves into proper humane communities," a cry that I endorse from my heart.

While it would be unfair to suggest that Professor Pollack recommends a governmental solution to the perceived malaise, he does blame "the absence of social structures that would validate anything about them beyond their latest papers" or "the absence of structures of kindness and decency." By placing the blame outside intrinsic scientific activities, he is shifting responsibility from the present nature of research in the basic biomedical sciences to the absence of a societal safety net that, once in place, becomes a political apparatus hardly more morally dependable than the present scientific establishment.

I propose that we look at the basic biomedical sciences directly to see how its subject matter and methodologies affect the morale of its practitioners. What is it about present scientific activity that causes the disappointing state Professor Pollack describes? Pollack offers an explanation: "So long as individual scientists believe, and behave according to the belief, that the essence of success in science is the freedom to discover the right task—experiment—and then to do it according to one's own lights, all the social structures that connect scientists to one another will be based solely on each scientist's latest piece of individual work: a Hobbesian world of each against all. Such a world is intrinsically unhappy, and profoundly unbiological as well, in the sense that no scientist's life, or work, can possibly go on indefinitely, as this sort of world demands" (emphasis added).

A lot is touched on in this paragraph—not only the explicit gentler, kinder vision of what life could be, but also the way Professor Pollack subsequently develops the consequences of his proposal for the role of science in the lives of individual scientists. I welcome many implications of this statement as developed in his article, but I disagree with the position that the present "freedom to discover the right task" causes low morale. I do not think that such freedom lowers morale, and I would dispute that an excess of individual freedom exists in the modern scene. In fact, I suggest that rather than having too much freedom of choice, biomedical scientists have afforded themselves too little. In the present structure of science, investigators are being directed towards very few, narrowly defined research areas that, for reasons discussed below, seriously limit intellectual excitement and personal satisfaction. Low morale is caused to a great extent by scientists being channeled into certain research directions that, although very popular, are seriously flawed. My alternative to these demoralizing activities is that we stoically follow scientific directions based on our internal standards. In this pursuit, a high-minded meaningfulness can be found for the individual and fruitful scientific directions can be developed. Furthermore, I will illustrate how by reprioritizing, but not abandoning, hopes for worldly success, scientists can satisfy their passionate personal dedication to scientific discovery and understanding within the professional structure of present basic biomedical science.

But how have specific procedures and paradigms of basic biomedical research reduced morale in the field? And how can morale be improved? Many social factors have shaped the present state of science: financial support is not increasing as rapidly as before; in the academy and in the courts, admiration of science is being replaced by questions about science as a social construct. American prosperity, with its winner-take-all rules, is only one of the many changing social forces emphasizing success. But within a field bounded by such forces, we can still inquire as to how present scientific practices themselves are contributing to the loss of scientific pleasure. Like Professor Pollack, I do not think the low morale comes about because this is a period of Kuhnian "normal" science. Although my analysis could in part be cast into Kuhnian terms, I prefer to discuss the subject of biochemistry directly without defining its relevance to Kuhn. Basic biomedical research is not in the middle of a period of "normal science," which Kuhn saw populated with happy, puzzle-solving "nerds." Rather, this could be regarded as a time of `abnormal' science, which I will now describe.

Basic biomedical research is being distorted by widespread philosophical `reductionism', an epistemological commitment that results in meaningful experiments being replaced by narrow technical activities. Reductionism is a term with many meanings, some quite contradictory. As I interpret it, reductionism assumes that when something is divided into parts, the parts are worthy of further study be~cause they contain all of the original. The whole is merely the sum of its parts. The mistake here is not in dividing the whole into parts, because that is normal Cartesian analysis, which is the basic modern scientific method; the error is to be found in the diminished importance of the whole. The reductionist trend has replaced the necessary interplay between the parts and the whole, between methods and problems.

The reductionist influence is particularly evident in two areas of basic biomedical science. In structural biology, biomolecular structure is posited to explain molecular function; in molecular genetics, all function is considered to be reducible to the genetic material. Though biological function per se is not completely ignored in these fields, explanations of function are pursued less vigorously than are interactions between their parts. As we shall see, biological functions are being redefined in terms of their components so that, for example, biomedical questions about human disease, cell division, or classical genetics are considered to be entirely resolved and completely subsumed by molecular genetics.

Biochemistry, as all fields of biology, must reckon with its two orthogonal origins: at one end, the whole organism in its environment; at the other, the basic explanations of inanimate matter and energy in terms of physics. To include questions from both of these directions, to fuse them into an entity entitled biochemistry, requires interaction between a part and the whole that must be guarded and maintained in thought and practice. Subfields of biological research are not only located between the wholeness of the living world and the parts of inanimate sciences, but are also situated at a moving point in time, between past and future. To maintain a harmonious balance of biological function and analytic parts in a subfield, we must step back and consider the effect of these opposing extremes on methods and goals.

Let us first consider the traditional reductionism accompanying the physical theories of matter. Starting with the Ionians, successive generations of whom chose different combinations of fire, air, water, and earth as the primal particles, this kind of epistemology has moved forward to the modern physicists who proclaim that particle physics provides a similar understanding. Today when we analyze a biological process in terms of its physical composition, we break the whole process down into traditional chemical questions: 1) What is it made of? 2) What does it do? 3) Why does it do that? The rubrics under which these questions are presently answered are: 1) chemical composition and structure of components; 2) kinetics, and 3) energetics, usually thermodynamics. When answers are obtained at all of these levels, and the information is reassembled and integrated to describe the whole process, we have meaningful biochemical enquiry. However, when any one of these parts is wrenched away and studied independently of the others, when a part becomes the main subject of enquiry, then we have fallen into reductionism.

Interest in the structures of biomolecules has grown enormous, overwhelming kinetics and energetics and creating a division between the parts and the whole in which biological functions of biomolecules receive only as much attention as can be provided by structural information. Biochemistry has developed during the past century through the cumulative successes of explaining biological function in chemical terms. Such chemical knowledge has been obtained by analyzing the complexity of in vivo chemical reactions into the specificity of molecular recognition and the closely linked catalytic increase in reaction rates, both of which are intrinsic to biochemical function. While specificity is explained well by the chemical composition and structure of biomolecules, the act of catalysis remains generally resistant to structural explanation. Since catalysis does not yield to structural explanations, it receives scant attention at present compared to biomolecular activities that can be more readily explained from a structural basis. I suggest that interest in the protein `folding' problem does not derive from its role in explaining enzymatic function, but from its structural basis. This is not to say that tertiary enzymatic structure is not a requisite of life, but only that the present pursuit by X-ray crystallography and nuclear magnetic resonance of the `folding' problem is technique driven and has reversed the order of analytic understanding in that the parts are determining the whole—the availability of structures results in the choice of problem. In contrast to the widespread pursuit of `folding', the important questions involving rates such as enzymatic catalysis and the roles of individual enzymes in controlling the fluxes through cellular pathways are almost completely neglected.

Structural biology, though, is a small field compared to its reductionist companion molecular biology, or as it is recently called, `molecular genetics'. The reductionist aspects of molecular genetics have provoked considerable resistance, particularly from organismic biologists and from philosophers of science. Evolutionary biologists, led by Ernst Mayr, successfully resisted the claims that all of biology could be explained by being reduced to molecular and submolecular understanding. They showed there is a science of biology where understanding does not depend on reduction, and have emphasized the emergent "interaction among phenomena at all levels." Mayr's younger Harvard colleagues, Stephen Jay Gould and Richard Lewontin, have brilliantly rebuffed claims that molecular genetics explains all of biology, and have thereby protected and nurtured the intellectual vigor of modern organismic biology.

A similar criticism of molecular genetics has been made by the philosopher Philip Kitcher, who in 1984 pointed out the errors in the usual reductionist claim that "classical genetics has been reduced to molecular genetics." Without disavowing either the great advances of molecular genetics or its extensive contributions to the understanding of classical genetics, Kitcher showed that emergent properties of classical genetics could not be completely explained at the molecular level. Kitcher extended the anti-reductionist stance in defense of other traditional subfields of biology (e.g., physiology or development) by opposing the `hegemony' being consolidated by molecular genetics as early as 1984. His anti-reductionist position maintained, first, "that there are autonomous levels of biological explanations" as manifested in these traditional subfields and, second, that "understanding the phenotypic manifestations of a gene . . . require(s) constant shifting back and forth across levels," in contrast to the reductionist focus on complete genetic explanations of all fields.

Unfortunately, this analysis and other early criticisms of the reductionism of molecular genetics have had little effect. Today the claims of molecular genetics to contain the explanation of all life processes are grander than ever. These hopes find tangible support from the Human Genome Project, which is spending $3 billion to sequence the human genetic material, and from the Howard Hughes Medical Institute, which is adding its financial heft to support molecular genetics and its reductionist sibling, structural biology. To symbolize the widespread overconfidence in the unlimited powers of genetic explanation, I need only quote the colleague who explained, "We have now, in our hands, the methods of molecular genetics, which will explain everything."

Kitcher's concern that molecular genetics will establish a hegemony over traditional subfields of biology has been vindicated. Several medical schools have already discussed unifying preclinical departments on the basis that they now all use the same genetic methods and seek the same explanations. This consolidation not only would eliminate departments but, more significantly, would undercut the established emergent properties of basic biomedical sciences. The existence of these traditional disciplines—biochemistry, physiology, pharmacology, etc.—is needed to protect biomedical science from the hegemonic moves of molecular genetics. Each subfield has its own culture, embodied in concepts that are not formulated exactly as laws, but that have defined these fields through practice. As Kitcher shows, such conceptualization cannot be reduced to more basic laws of molecular genetics or molecular structure. We must not jump across fields too readily or too far because, for example, molecular disease is never explained completely by genetics, and quantum mechanics, which is the basis for much chemical understanding, has not yet been helpful for physiol~ogy. Historical selection of functions characteristic of the subfields of basic medical science has led to harmonious understanding, thereby denying that all of biology can be explained by genetics or by molecular structure.

Professor Pollack describes the limited chances that students have of finding a successful career and deplores the absence of advice that offers kindly consulting and realistic projections. Although these types of support, if available, would create a more open, decent atmosphere, the facts are that the paths to success are perfectly obvious to the students I have met, and speak louder than words. Get with the program! Students look at the support, honors, prizes, and rewards lavished on X-ray crystallographers and molecular geneticists and they want to be there. By working within these fashionable fields, scientific creativity, adapted to a flourishing technology, can still exist and be recognized. Outside of these fashionable directions, however, although survival is possible, recognition is extremely difficult.

Let me close with an illustration of the kind of limited success possible lying outside these reductionist directions by describing how an individualistic scientific vision is restoring the harmony between the whole and the parts of biochemistry. Henrik Kacser, a physical chemist turned microbiologist at the University of Edinburgh in the early 1970s, invented the field of metabolic control analysis (MCA), which he continued to develop until his death in 1995. This subject relates the activities of enzymes in a pathway to the control of flux and the concentration of intermediates. While developing the field, he often pointed out how it provided the understanding necessary to predict and explain the consequences of altered gene expression on pathway rates and the physiology of the organism. Without this understanding, he showed, we cannot predict or understand consequences for the organism of controlling enzyme number through genetics or of changing enzyme activities through structural modifications. MCA thereby addressed a classical problem of biochemistry: how does the activity of an enzyme molecule relate to its functioning in a pathway? MCA describes the causal connections between the pathway function that represents the biological whole being studied as well as properties of the constitutive enzymes that are its parts. In its specific identification of a biological function (the control of pathway flux) and its constitutive parts (enzymes in the pathway), MCA explores the fruitful relationship between the whole and its parts that has been defined by 100 years of biochemistry. At the same time, MCA offers a way out of the present reductionist jungle, overgrown as it is with numerous dead-end genes and their gene products and with numerous enzyme structures in search of functional tasks. It provides methods for understanding the results of genetic engineering; it relates gene product to function.

MCA has the additional advantage, in my opinion, of being defiantly unfashionable, of reclaiming from the refuse heaps of history such subjects as enzyme kinetics, intermediary metabolism, and systemic physiology—a veritable gang of outcasts. With the use of these concepts, MCA has been able to show how the techniques of gene expression and biomolecular structure can be used to explain genuine biological function such as the control and regulation of biochemical fluxes. Kacser was the ultimate outsider in recent biochemistry, an outsider who was further handicapped by originality. After 25 years of important contributions, there are still no discussions of MCA in biochemistry textbooks, whose multicolored pictures of enzyme structures become more beautiful with each new edition. Kacser was not elected a Fellow of the Royal Society, which, like the U.S. National Academy of Sciences, is overflowing with molecular biologists and crystallographers. Acceptance of his studies grew steadily during his lifetime, supported now by a recent textbook lucidly presenting MCA (1).

I do not suggest that MCA is the cure for all problems in biochemistry, but show only how biochemical function can be brought into harmony with biochemical techniques. This example also demonstrates that basic biomedical science has sufficient resources and intellectual openness to support novel directions; they are not completely denied to the young investigator. However, individuals choosing such an unfashionable direction must have the passionate vision enabling them to bear considerable neglect and be able to settle for less recognition. Young biochemists have low morale not because their chances to flourish are not described clearly and honestly by caring elders, but because the opportunities available require that their passions be subordinated to fashionable directions that emphasize technical activities at the expense of biological goals.

	FOOTNOTES

 
¹ Responses to Shulman's article are invited. Both the original letters and Shulman's responses will be published in future editions of the Journal.

² Abbreviation: MCA, metabolic control analysis.

	REFERENCES

TOP INTRODUCTION REFERENCES

 

1. Fell, David (1997) Frontiers in Metabolism 2: Understanding the Control of Metabolism (Snell, K., series ed) Portland Press, London.