We Must Try To Bridge The Gap Between Biological And Chemical Sciences

Chemical language has great asthetic beauty and links the physical sciences to the biological sciences. Unfortunately, the full use of this language to understand life processes is hindered by a gulf that separates chemistry from biology. This gulf is not nearly as wide as that between the humanities and and sciences, on which C.P. Snow focused attention. Yet, chemistry and biology are two distinctive cultures and the rift between them Is serious, generally unappreciated, and counterproductive. It might have been expected that the traditional separation between chemistry and biology would have been bridged by the emergence and growth of biochemistry in this century. In biochemistry, one could fulfill the wish to understand the chemical basis of cellular function in fermentation and photosynthesis, in muscle contraction and digestion, and in vision and hereditary. Despite its enormous success in solving these and other problems, biochemistry has failed to fill the gulf between chemistry and biology. Instead, biochemistry itself is being pulled apart by separate drifts of the two cultures from which it was assembled. By 1950, organic chemistry had been enriched by more than a century of impressive achievements. Organic chemists had prepared and characterized the sugar and amino acid substrates and products of enzyme reactions. They belonged to a proud and venerable science. Insights into the structure and reactivity of carbon compounds had made possible the synthesis of the extraordinarily complex alkaloids and antibiotics found in nature. The problem was that organic chemists placed arbitrary boundaries on their science. Although in their pursuit of natural products, they might still eagerly seek the challenge of an Amazonian butterfly pigment, they would not accept nucleic acids, proteins, and enzymes as proper natural products. I recall in an organic chemistry textbook of 1960 a reference to the importance of proteins “as a source of amino acids for living cells.” This is like saying the importance of an automobile is as a source of its parts. When a National Academy of Sciences committee surveyed the status of chemistry in 1964, chemistry was defined as “the research activities of chemistry departments in this country.” There was little recognition of the chemical research in biochemistry and biology departments. Nucleic acids, proteins, and enzymes had been excluded from from the province of legitimate chemistry, and chemists had excluded themselves from the essence of biology. Major changes have taken place in the past 20 years. A 1985 report on the status of chemistry claims its share in the advance of genetic chemistry and takes pride in its future. Increasingly, young professors in chemistry departments are pursuing prob lems of biological significance. Yet, a recent recipient of the Nobel Prize in chemistry, when asked by a newspaper reporter whether he considered applying his novel technique to the study of enzymes, replied: “I’m not about to switch from science to religion.” Chemists were not alone in ignoring the chemistry of living things. The physicists, who during the post-World War II period turned their attention to biology, generally focused on genetics and hoped to avoid chemistry, for which they had little patience. Those who applied physical methods to determine the structure of proteins and nucleic acids expected that they could infer biological properties directly from the structures of these molecules and thereby bypass biochemistry. Many biologists were just as eager to remain clear of chemistry. Particularly so were those concerned with systematics, evolution, and behavior. Even those biologists who realized that enzymes and proteins determine the shape, function, and fate of cells and organisms shuddered at the multiplicity of enzymes and their chemical complexity. Having criticized the biologists for their lack of appreciation of chemistry and the chemists for their disinterest in biology, one might hope that the gap between them would be filled by biochemistry. Biochemistry, by using the techniques and principles of both chemistry and biology, contributed in the past decade to an extraordinary coalescence of both cultures: the development of genetic chemistry. As almost everyone is aware, recombinant DNA technology has made possible the mass production of interferons, interleukins, rare hormones, and superior vaccines. The impact on medicine and the pharmaceutical industry has been nothing short of revolutionary, and agriculture will soon follow. Even more profound than the feats of genetic engineering is what this conjunction of chemistry and biology has done to erase the sharp boundaries that had separated classical compartments within the biological and medical sciences. The basic medical sciences, which in my school days were completely discrete from one another, have now effectively been merged into a single discipline. This astonishing development, this unification, is based largely on the expression of anatomy, pathology, bacteriology, and physiology in a common tongue—the language of chemistry. Anatomy, the most descriptive of these sciences, and genetics, the most abstract, are now simply chemistry. Anatomy is studied as a continuous progression from molecules of modest size to the macromolecular assemblies, organelles, cells, and tissues that make up a functioning organism. The transformation of genetics has been even greater. A serious question only 40 years ago was whether genetic phenomena operated by known physical principles. Of course we now understand and examine genetics, heredity, and evolution in simple chemical terms. Chromosomes and genes are analyzed, synthesized, and rearranged, thanks to the successes of genetic engineering. Is is no longer a question of whether we can sequence the four billion base pairs of the human genome. Rather, “What will it cost?” and “Should we do it now?” By manipulating DNA, we modify species at will. As the effects of this more profound grasp of chromosome structure and function become manifest, the impact of this revolution in human understanding on medicine and industry will prove to be far greater even than extrapolations from the current successes of genetic engineering. Where has the development of this new branch of biochemistry, called molecular biology, fallen short? In its rapid and turbulent growth, molecular biology has washed away much of the bridge to chemistry. In the rush and excitement surrounding the new mastery over DNA, attention in biochemistry departments has been sharply shifted to major biological problems of cell growth and development and away from chemistry. Training in enzymology and its practice have been neglected: Most biochemistry and molecular biology students are introduced to enzymes as commercial reagents and treat them as if they were as faceless as buffers and salts. As long as this inattention to enzyme chemistry and basic biochemistry persists, the fundamental issues of cell growth and development will not be resolved and their application to degenerative diseases and aging will be delayed. Molecular biology falters when it ignores the chemistry of the products of the DNA blueprint (the en- zymes and proteins) and their products (the integrated machinery and framework of the cell). Molecular biology appears to have broken into the bank of cellular chemistry but for lack of chemical tools and training, it is still fumbling to unlock the major vaults. We now have the paradox of the two cultures, chemistry and biology, growing farther apart even as they discover more common ground. For the chemists, the chemistry of biological systems is either too mundane or too complex. As a result, they are drawn in the opposite direction, toward a deeper physical understanding of atomic and molecular behavior. With occasional gestures in the direction of biology, chemistry departments still retain the classical separations into discrete divisions of organic, physical, and inorganic-analytical chemistry. Perhaps the departments can now ignore the analysis and synthesis of proteins and nucleic acids because these procedures have become straightforward enough to be machine-programmed and operated. But the structure-function relationship of these macromolecules is another matter. Polymer chemists, for example, are frightened away not only by the size and complexity of nucleic acids and proteins but even more by their intimate association with water molecules, a habitat that introduces unacceptable complications into otherwise satisfactory calculations. Pharmaceutical chemistry was until recently the bastion of organic chemistry. Many thousands of compounds were synthesized each year in the search for alternative or superior drugs for the treatment of various diseases. After many years of this kind of effort, the likelihood of discovering winners among antibiotic, antiulcer, antihypertension, or anticancer drugs has become rather slim. At the same time, the requirements by the Federal Drug Administration for safety and efficacy have become increasingly rigid. The development of a new drug through the many required trials to the point of FDA approval now costs over $100 million dollars and takes from eight to 10 years. Two major pharmaceutical companies have both spent more than $200 million annually for 10 years without a significant new drug to show for it. No wonder that the research orientation and the leadership in the pharmaceutical industry have been shifting from chemistry to biology. With the dramatic entry of genetic engineering, there is the prospect that these techniques of molecular biology can be used to prepare natural hormones, interferons, interleukins, and other body substances in quantity and to use them to correct imbalances and deficiencies of these substances in disease states. Furthermore, the techniques of genetic chemistry make it possible to probe basic body mechanisms and understand metabolic traffic well enough to use these agents to enhance well-being. The executives of the pharmaceutical industry generally trained in business and law, often see more clearly than the scientists they employ the urgent need to merge the cultures of chemistry and biology. Biology, previously a loose confederation of botany, zoology, genetics, and museum departments, is now coalescing because of its use of chemical techniques and language. Evolutionary biology, organismal behavior, and cellular physiology are finding common explanations in the genes and proteins that can be traced through evolution to their current locations and functions. Biologists now obtain commercial kits with which they measure and use enzymes and analyze and manipulate genes. This enables them to set their sights on important problems beyond the current reaches of chemistry. For example, popular interest now centers on understanding the growth and developemnt of cells and tissues. Many laboratories are preoccupied with the origins of cancer and hope that studies of cancer processes will also provide insights into the normal patterns of growth and development. Enormous efforts are devoted to AIDS, both to the virus itself and on how it undermines the immune system. In these research studies, the effects of manipulating the cell’s genome and the actions of viruses and various agents are almost always monitored with intact cells and organisms. Rarely is an attempt made to examine a stage in an overall process in a cell-free system. This reliance in current biological research on intact cells and organisms to fathom their chemical operations is a modern example of the “vitalism” that befell Pasteur a century ago and that has permeated the attitudes of every generation of biologists before and since. In these research studies, the effects of manipulating the cell’s genome and the actions of viruses and various agents are almost always monitored with intact cells and organisms. Rarely is an attempt made to examine a stage in an overall process in a cell-free system. This reliance in current biological research on intact cells and organisms to fathom their chemical operations is a modern example of the “vitalism” that befell Pasteur a century ago and that has permeated the attitudes of every generation of biologists before and since. The reductionist approach that I am espousing has had major success in this century in explaining body metabolism and how it is affected by inborn errors, drugs, and disease. Can we come as close to understanding the mind and human behavior as we have to comprehending metabolism? The first and most formidable hurdle is acceptance without reservation that the form and function of the brain and nervous system are simply chemistry. I am astonished that otherwise intelligent and informed people, including physicians, are reluctant to believe that mind, as part of life, is matter and only matter. Perhaps the repeated failures of science to analyze social, economic, and political systems have perpetuated the notion that individual human behavior cannot be explained by chemistry and the physical laws that govern all matter in the universe. Brain chemistry may be novel and very complex, but it is expressed in the familiar elements of carbon, nitrogen, oxygen, and hydrogen and of phosphorus and sulfur that constitute the rest of the body. Brain cells have the same DNA all cells do; the basic enzyme patterns are those found here in the body. Hormones once thought unique to the brain are now known to to be produced in the gut, ovary, and other tissues and even in plants or protozoa. In brief, my plea is for a major focus of research on brain chemistry, in animals and humans, normal and sick. With the application of simple biochemical techniques, we will be able to map and assay a number of specific brain functions. Further advances will come rapidly when additional chemical techniques are developed to explore the nervous system. In the next decades we will see astonishing revelations about memory, learning, personality; sleep, and the control of mental illness. Arthur Kornberg of Stanford University received the Nobel Prize in Physiology or Medicine in 1959, sharing it with Severo Ochoa. The preceding article is adapted with permission from Biochemistry, 26 (22), 6888-91,3 November1987. Copyright 1987 American Chemical Society.

We Must Try To Bridge The Gap Between Biological And Chemical Sciences

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