JOHN TYLER BONNER Depaztment of Biology, Princeton University, Princeton, New Jersey
1THINK it would be correct to say that the extent of our present knowledge of biology is to a large measure the result of the contribution of chemistry. The reverse is true as well, for certainly biology has contributed to chemistry also; there has been a mutual parasitism or dependence, that has, with time, taken on an ever in. creasing importance. The benefits of this commensal arrangement are so diverse that it is hard to compare the two, although probably the boost that chemistry imparts to biology is of greater importance than the gain chemistry derives from biology. The reason for this, and in fact the most obvious thing one can say about these two areas of natural science, is that they represent artificial subdivisions, or at least they are not subdivisions that should in any way oppose one another, for, after all, living organisms are heaps of chemical substances. There are certain important and act,ive areas of hiology today that are, a t least in their basic outlook, essentially non-chemical. The study of evolution is a good example, for the fundamental concept of natural selection is foreign to the world of simple chemical solutions. The study of evolutionary mechanisms therefore appears far removed from chemistry. However, it is not wholly removed; there are now two well-known hooks on "biochemical evolution." But these studies are only secondarily important in the study of the workings of selection, and their prime value is to show that changes can be demonstrated in chemical constitution as well as gross morphology. It is a modern revival of the classical morphology, but on the finer molecular level, and as with the older work the adaptive advantage of each change is a matter of important speculation. Another non-chemical field is animal behavior-the study of instincts, tropisms, learning, and related processes. This is one of those areas where presumably the ultimate analysis of the problem will be highly chemical and the only justification for calling it "uonchemical" a t the moment is that our ignorance of mechanism is so profound that we are miles away from the goal. Since living organisms are masses of chemicals, we ultimately look forward to an understanding of living processes in molecular terms, and when we say a subject is "strictly biological" we mean that we are especially blind as to how it works. It should be added that in recent years there has been an interest in the effectof hormones and other suhstances in the blood and the results have been sufficiently rewarding t o justify our saying that the chemical analysis of behavior has at least begun. A final example of a non-chemical area of biology ' This address was delivered at the conference on
"Science in
Perspective" held at Randolph-Macon Woman's College, Lgnehburg, Virginia, Xovember 12-14, 1957. 218
might be ecology, the study of the relationship of t,he organism and its environment. Originally, as an offshoot of the older natural history, ecology was concerned with population densities, distribution, preypredator relationships, and similar phenomena, and although these interesting studies continue today, the change has been a keen awareness of the importance of chemistry. As one case of many, the spacing of plants in a forest was for many years a matter of measurement, hut as the causative factors were sought it wae found that plants give off toxic substances in the soil that inhibit the vegetation about them, and in this way they stake out their territory. For other examples of the rise of chemistry one need only turn to the ecological studies in fresh and salt water; the slightest, alteration in t.he chemical constitution of the water may have a profound effect on the aquatic organisms. It is perhaps somewhat easier to argue for a pure chemistry for there are so many chemical substances and processes that are not found in living organisms. But then the opposite is true as well and often the pure chemist leans heavily on biological material. Take, for instance, the organic chemist who is interested in the chemical structure of terpenes. It is from the naturally occurring terpenes that he obtains his main clues as to how the substances can be put together; this is the basis for his syntheses. Organisms are packages of a vast variety of different substances and they provide endless material for the chemist. CHEMICAL STRUCTURE OF BIOLOGICAL MATERIAL
There is one aspect of the dependence between biologists and chemists that is of special interest. Being a biologist I have often wondered why first-rate organic chemists are willing to devote so much of their time to help a biologist with his problems. For instance, it is an everyday occurrence for a biologist to discover that some animal or plant produces a substarice that is of key importance in its life history. Frequently it is a hormone that has been isolated and upon injection produces some striking specific effect. The biologist will now approach the chemist and ask him to identify the chemical structure of the substance. Arrangements are made whereby the biologist supplies crude extracts and the chemist proceeds to make an analysis, often a laborious and difficult procedure, all for the purpose of supplying the biologist with a structural formula. This pattern has been repeated over and over, with great success, and I mean by success that all concerned are content. There is something clean and satisfying about finding the chemical stmcture of a compound that does important things within an organism. I n fact I suspect that sometimes the satisfaction that comes exceeds the real value of the discovery. JOURNAL OF CHEMICAL EDUCATION
What does the biologist gain? He gains information t,hat may be of theoretical interest (if the compound is related to some other known compounds) but more likely the value is practical for now he might conceivably have a bottle of the synthesized substance on a shelf and perform further experiments under controlled and known conditions. Being far more puzzled by the advantage to the chemist, I asked a few chemist friends whether they did the work to be friendly to biologists or whether they had some reason of their own. They were shocked at my question and informed me that such new materials of biological origin presented chemical problems of the first importance often involving the development of new methods of analysis. What puzzled them was why intelligent biologists were willing to spend hours of hard labor providing raw material for them when the biologists had so little to gain. So yon see it is a perfect case of symbiosis as I said before, and furthermore both sides imagine themselves t o be t.he ones to have all the advantages. RISE OF BIOCHEMISTRY
So far I have talked of chemistry and biology, but the most strikimg event that has occurred in recent years is the rise of biochemistry. I t is truly a geometric rise for in the nineteenth century there were a mere handful of biochemists, but now the number is staggering and seems to continue to move upward. I n the nineteenth century "biochemistry" was not recognized as a separate discipline and often it was a chemist like Louis Pasteur who turned his attention to biology, although there are cases of physiologically minded biologists who contributed as well. I n the early part of this century the discrete subject of biochemistry arose, creating, as one might expect, considerable resentment on the part of both chemists and biologists. But the subject was so obviously a rather specialized branch of chemistry, and an equally specialized branch of biology, that while there were general complaints, the biochemist was left alone to carry out research in no man's land. Success came rapidly in the early years of biochemistry; there were many notable advances such as Warburg's studies on the mechanism of cell respiration. Biochemists became respectable solely by the magnitude of their own discoveries. With the success came ereat horde^ of young and enthusiastic scientists and the result is really an extraordinary progress, certainly without parallel in any other field of biology. The possible exception to this sweeping statement might he the progress of genetics, but as I will show presently, genetics is now inextricably wound up in biochemistry. A most striking way to see the turnover in facts and concepts in biochemistry is to look at a textbook 15 years old and compare it with a modern book. There are whole areas that did not exist then that are with us now, and we all have the easy conviction that in 15 more years we will see equally large changes. Fifteen years ago we did not know about high energy phosphate bonds, the structure (or the importance) of nucleic acids, or the chemistry of the contractile proteins of muscle. These are not trivial discoveries but major steps in our progress. There is an important human element-a matter of a t t i t u d e t h a t enters into the relation of biology and chemistry. On more than one occasion I have heard
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VOLUME 35, NO. 5, MAY, 1958
uon-chemical biologists say that since the future of biology lies in biochemistry, there is little point to their own work; they must either stop and become biochemists or go into the insurance business. I strongly disagree with this abject position. Our ignorance of biological phenomena is so large that there is ample room for significant advances on a purely biological, or nonchemical level. As an example, the major events until recently in the progress in genetics have been biological, and biological information of heredity is still eagerly sought. On the opposite extreme, and this is an old refrain, some say that living processes are so complex that any analysis on a purely chemical level is doomed for either chaos or over-simplification. This brand of defeatism is used to justify biologists being biologists and aggressively refusing to take notice of biochemistry. Like all extremes this attitude will do little more than make a few insecure biologists sleep better at night. It is trne that it has become increasingly difficult to be both an active biologist and biochemist a t the same time for the facts in both areas have become too numerous, but nevertheless this is no justification for ignoring the other area. A person with a well-rounded education has nothing but gain, and it is with this in mind that in our training programs today all biologists are given a good load of organic, physical, and biochemistry. CELLULAR CHEMISTRY
The great difficulties (and therefore the great hopes for the future) lie in certain areas of biology where we have large masses of biological information and masses of biochemical information, yet putting the two together in one picture is impossible. Cell metabolism is a good case in point. Every year new facts are added and new steps established in the chemical pathways involved in the burning of fuel in cells. I n aerobic organisms oxygen and fuels such as sugar are taken into cells and these are burned giving off carbon dioxide and water. This is the same process of combustion that occurs in a coal furnace hut the difference lies in the fact that the furnace is made of iron, while the cell is made up of the same materials it burns. This means that in living organisms the heat must remain low and be given off slowly in small amounts or else we would consume ourselves with our first mouthful. I t is now well known that the rates of the combustion reactions are controlled by enzymes which are catalysts and catalysts can either speed up or slow down chemical reactions. However, the conversion of sugar t o carbon dioxide and water is not made in one enzyme-controlled step, but many; in fact one of the ways in which the speed is controlled is by having a large number of small steps each governed by a specific enzyme. There are still many details of this elaborate process that continue to elude the biochemist, hut the major steps arewell known. One further realization that has become increasingly stressed is that the rate of combustion is also controlled by the spacing of the enzyme systems. It is an old observation that if the cells are macerated their combustion rate will go way up and it is presumed that by disturbing the spatial arrangements certain pathways have become short-circuited. I n fact it might be compared to the maze of wires in a television set which
draws the current for its effective operation at a slow steady rate, but should you stir up the insides with a hatchet there will be a sudden flash of energy utilixation and then darkness after the fuse has gone. Recently I went to a conference on cellular chemistry and the discussion was summarized by one of the speakers. He showed a photograph from Life magazine of a forlorn French postman standing over his bicycle which had been taken apart so that all the pieces were laid out in a disorganized mess before him. This, he said, is how a biochemist feels about all the reactions he discovers; the problem of putting them together in the cell seems still a Gargantuan task. There has, however, been some progress. In the first place, gross chemical studies of different cellular constituents have shown that certain enzymes lie in certain parts of the cells. Of special importance are the small bodies called mitochondria which apparently harbor some of the key enzymes. But this is morphology on an extremely crude level and there is now an avenue for a far more refined approach. This is through the use of the electron microscope. Even though this instrument has been known for some time it is not until recently that the technique of preparing very thin sections of cells has been perfected. Years ago biologists were talking about the cytoskeleton, the structure that could not be seen with the ordinary microscope, and now we can at least approach it. Although the magnification of the electron microscope is far greater than that of the hght microscope, the images are still too small t o see molecules, with the exception of especially large protein molecules. Yet there appears beautiful order and structure in cells where before none was known. The mitochondrion, for instance, is in some forms an elaborate labyrinth of plates like a condenser. And now that we can see this detail we have to label it; we have to show the chemical, the molecular constitution of the different fine structures we can observe. This is a possibility which has suddenly opened up m d now the anatomist and the chemist must unite, for the future of histochemistry should be very bright. If we look to other areas of biology, we can find cases where there is more of a blind groping. One that is of special interest t o me is chemical embryology. The problem here is that the process of development is poorly understood in biological terms and therefore it is impossible to predict wherein lies the future breakthrough. Both the experimental morphologist and his more biochemically minded counterpart are working shoulder to shoulder (which is as it should be) for the sudden insights may come from either one. Embryology is still a t the stage where it is trying everything, but the information that we have at the moment is somewhat of a rubble. We know of many enzymes and other substances that are present in eggs and developing embryos; we know how these substances become altered a t successive stages; but the meaning of these changes escapes us. It is a field beset with "working hypotheses" but no immediate prospect of any single conceptual framework. CHEMICAL CONCEPTS IN GENETICS
I suppose the situation in development would not seem so bad were it not for the extraordinary advances of genetics in the past 50 years. This is an instanre
where there has been a major breakthrough and some clear basic connecting principles. Genetics is many years ahead of embryology even though the two fields are closely allied, for what is inherited is a specific mode of development. The first step (which went unappreciated for many years) was the discovery of certaiu regulations or laws of inheritance set forth by Mendel. The next step was to understand the cellular mecbanisms whereby these laws could be explained, and through the work of Morgan and others this led ultimately t o the concept of the gene and the order of the genes upon chromosomes in cells. Once these all important concepts were established there immediately arose the matter of the chemical constitution of the gene and since then the science of genetics has (with great profit) contracted a case of creeping chemistry. Of all the problems, however, the molecular nature of the gene has been the most elusive and remains problematical. The genetic informatiou about genes is highly complex; sufficiently so to exclude any crude hypothesis such as a series of single chemical molecules beaded on a string. Again here the problem of structure and molecular configuration is thought t,o play a vital role in the biological actions of the chemical substances that somehow make up genes. More rapid progress has been made in the relation of genes to the chemical substances they affect. This new spurt stems from the discovery of Beadle and Tatum that certain molds, which synthesize many of their own vitamins and essential food substance, can give rise to mutants that are unable to perform some specific synthetic step. This has provided a system for studying the genetic control of celiular biochemical steps, and the result is that we now know many of the naturally occurring enzyme steps and the genes concerned. These investigations have been carried on in bacteria as well and we are in the midst of a period of flowering of biochemical genetics. There are still innumerable basic questions to be answered hut new discoveries are coming rapidly. In a way the developments of genetics serve as a model of how effective this fortunate symbiosis between chemistry and biology may he. If we look to the future and indulge in the easy practice of speculation, then I suppose one could say that the merger of chemistry and biology will become even closer and more intimate. Of special significance are. the problems of molecular configuration and the role of spacing or structural relations in the living activities. But predictions of a more specific nature are certainly pointless. Our erstwhile Secretary of Defense, Mr. Charles Wilson, was castigated for the remark that basic research is research where you don't know what you are doing. If his intent was derogatory (and I fear it was) then I do not agree. But as a description of the frame of mind that leads to new discoveries it is accurate. Foundations constantly ask what areas of biology are likely to lead to new important discoveries, what topics should be showered with dollars. I t is fortunate that we are all groping for new insights in all the different areas and it is impossible to say which will lead to success. I say fortunate in that everyone has a chance and as in a horse race the odds are often mistaken. But whatever the future of biology, it is absurd to imagine that chemistry will not be central; living organisms cannot crawl away from their own substance. JOURNAL OF CHEMICAL EDUCATION
