Number 108 January 1, 1949 THE ROCKEFELLER FOUNDATION CONFIDENTIAL MONTHLY REPORT For the Information of The Trustees Edited by George W. Gray CONTENTS Chemistry Joins Forces with Biology «© «eel Four Books in the Natural Sefences « « « « 16 Radioactivity 4n Public Hoalth Research . 19 Grants from the Foundation? $1,240,865 to California Institute of Technology CHEMISTRY JOINS FORCES WITH BIOLOGY il More than four centuries have passed since Paraeeisus of Hohenhein gave scientific medicine its charter in his celebrated hypothesis: The human body is a conglomeration of chymical matters; when these are deranged 4liness results, and naught but chymical medicines may cure the same. It has taken man a long time to learn even a small part ef these “chymical matters," for as recently as 1849 the molecular weight eof water was 560 uncertainly known that this principal ingredient of the pody's conglomeration was still being written as HO by many chemistse Indeed, the idea that each atom has a definite combining power was yet to be accepted. Today, what a change! Biochemistry 1s now the principal battleground of science's attaek on diseases The wealth of physiologically useful chemicals whose identifi- cation has come out of these studies - such compounds as the vitamins, the hermones, and the antibiotics, to name but three groups — provides powerful evidence in support of the Paraceisian doctrine and has spurred research in mundyeds of universities, medical schools, and institutes. Notable among the centers of biochemical interest is the California Institute of Technology at Pasadena. Here there is no conscious seeking for new vitamins, new hormones, new antibiotics, or any other specific nutritional or therapeutic agent. But there is being conducted a systematic search for the ways in which the body's molecules behave. And because the living process ie always associated with huge molecules comprising hundreds, thousands, and even tens of thousands of atoms in a single structure, the program at the California Institute is being focussed primarily on these giant molecules. Their attractions and repulstons, their combinations and modifications, their breakdown into smaller units and the joining of these into new patterns of molecular architecture — it is such goings-on that the Pasadena scientists are prying into with all the techniques that chemistry can bring to reinforce those of biology. Their inquiry is directed at the most fundamental of all biological processes: reproduction, nutrition, growth, and disease, each, studied at the molecular level. If man can learn how these processes operate at the molecular level, perhaps he can better control or alleviate their disorders at the body level. Such, at least, is one visitor's understanding of the purpose of the program, after spending a week in the laboratories, talking with experimenters, watching the experiments, and breathing the atmosphere of California Institute research. The Attack from Two Sides Biochemistry has two avenues of approach. One may enter it from either the biological side or the chemical, and usually the main strength of a research program comes from one or the other of these two directions, seldom from both. A remarkable aspect of the dual project at Pasadena is 4ts balance. This is not a case of a biological laboratory adding a chemical department to its facilities, nor yet that of a chemical laboratory taking an interest in biological problems. It is, rather, a joining of forces between two coordinate divisions, each of which is a leader in its field. The Division of Chemistry at the California Institute was founded by Arthur A. Noyes. He had previously served as acting president of the Massa— chusetts Institute of Technology and was the director of its Research Laboratory of Physical Chemistry when he eames to Pasadena in 1913. At first Dre Noyes served the California Institute on a half-time basis, devoting the other half of the year to the Massachusetts Institute. But in 1919 he decided to give himself wholly to the work in California and soon made it foremost in teaching and research. He was a physical chemist; his emphasis was on the inorganic aspects of the science, and aspiring chemists from all over America came to Pasadena to study the fundamentals under the master. Among these students was Linus Pauling, a recent graduate of the Oregon State Agricultural College. Perhaps Noyes saw in him the man he wanted to train as his successore At all events, the young Oregonian became a favorite pupil, spent three years of advanced study under Noyes, and was so imbued with the physical aspects of chemistry that he seriously considered specializing in atomic physics. A National Research Fellowship enabled Pauling to spend a year in Munich with one of the world's leading theoretical physicists, Arnold Sommerfeld, and these studies were continued the following year with Niels Bohr at Copenhagen and Erwin Schroedinger at Zuriche But the problems that made the strongest appeal to him were in chemistry; so Pauling remained a chemist, meanwhile continuing his investigation of the forces which operate between atoms and molecules, a study which resulted in his great book, "The Nature of the Chemical Bond." California Institute made him a full professor in 1931, when he was only 30 years of age, and following Dre Noyes death in 1936 Pauling was appointed to succeed him as chairman of the division and director of the chemical laboratories. "T was a physical chemist," explained Dr. Pauling, "with this dominating interest in the forces which cause atoms to join into molecules and molecules to react with one another. The forces are electrical, of course, and depend on the number of protons and electrons present and the order of their arrangement in the structures. This is essentially a physical subject; or, rather, 1t belongs to that borderland where chemistry and physics merge. In these studies I naturally selected the simpler molecular structures to work with, such as the metals and inorganic compounds; but in the course of the investigation I also tested an organic substance whose molecule is large and complicated: the hemoglobin which gives the blood cells their red colore I found that in arterial blood the hemoglobin was repelled by a magnet, but in yenous blood it was attracted.e This led to a study of the chemical bond between the hemoglobin and the oxygen which it picks up in the lungs. I wanted to consult someone who had specialized on hemoglobin and found the authority in As Ee Mirsky of the Rockefeller Institute for Medical Research. Dre Mirsky came to the California Institute for a year, and we collaborated on a study which resulted in a joint paper." This paper attracted the attention of Karl Landsteiner, the dise- coverer of blood types, and Dr. Landsteiner asked Dr. Pauling if his theory of the chemical bond could throw light on a certain antibody reaction. Landsteiner's request introduced Pauling to the highly complicated specialty of immmology; the two men became close friends and frequent conferees on the subject, with Landsteiner supplying information and hypotheses from the pio- logical angle and Pauling from the chemical, "From that time on I gave a great deal of thought to the chemical aspects of immunology," said Dre Pauling, “trying to understand, in terms of the chemical pond, how an antibody neutralizes a virus or other antigen." By 1939 he had arrived at a chemical picture of the reaction and reported his results to the American Chemical Society as "A Theory of the Structure and Process of Formation of Antibodies.'! Thus, under Dr. Pauling, there was & transition. In the course of a few years the division added to its program the investigation of hemoglobin, antibodies, and other molecular giants which originate only in living systems, while still continuing the basic work in the chemistry of inorganic and simpler organic substances. The Rockefeller Foundat jer contributed to this devel~ opment through financial grants, beginning/in 1932. th additions in 1933 and 1934, it had made appropriations to the Ca “Institute for "research in pent aed pee chemistry under Dr. Linus Pauling." The shift in program was reflected in“1938 é oF when the first of five annual appropriations was voted "for the development of chemistry in relation to biological problems." Other grants were earmarked for "researches on the structure of antibodies and the nature of immunological action." Meanwhile, a transition was also taking place in the Institute's Division of Biology. This division had been organized in 1928 by Thomas Hunt Morgan, who had left the chair of experimental zoology at Columbia University to pioneer this new planting in California. Like Dr. Noyes in physical chemistry, Dre Morgan was already world-famous in genetics; and his coming to Pasadena brought several strong additions to the faculty, most of them geneti- cists, and attracted from all parts of the country students who wished to specialize in this science. The Foundation made two grants to support Dre Morgan's researches. Genetics lends itself to mathematization more easily than most bio-— logical sciences, and perhaps it is rightly called the most "physical" of the branches of biology. Certainly Morgan had a strong urge toward collaboration between biology, on the one hand, and chemistry, physics, and mathematics, on the others In the first announcement of this division he said: "A closer relation of these sciences with biology is imperative »" and during his regime interrelations with the physical sciences were cultivated. But the main effort of his division was in genetics, and particularly in classical genetics, a field in which Morgan was the acknowledged master. Classical genetics has to do with the morphology of the mechanism of heredity, the position and order of the genes in the chromosomes, and their identification as dominant or recessive in the control of inherited characteristics. After Dre Morgan's retirement in 1941, the division was administered for several years by a staff committee headed by Alfred H. Sturtevant. The serological aspects of genetics interested Dr. Sturtevant, and during this period there was increasing collaboration between the two divisionse The Toundation made several grants for joint researches by Drs. Sturtevant and Pauling. But direction of the division by a committee was only a temporary expedient while the Institute was seeking a successor to Dr. Morgan, and toward the end of 1945 he was found in the person of Stanford University's professor of genetics, George W. Beadle. Beadle's history closely parallels that of Pauling. Both men were Hat@onal Research Fellows; and as Pauling came to the California Institute to study under Noyes, so Beadle came to study under Morgan. It is also significant that at the time when Pauling was turning his attention more and more to the biological molecules, Beadle was becoming enamoured of chemistry as the handmaiden of genetics. During his ten years at Stanford he devoted most of his research effort to experiments with the bread mold, Neurospora, and was able to demonstrate in this lowly fungus that the processes of mutrition (which are purely chemical) are directed by the genes. Perhaps it 4g not undue praise to say that Dr. Beadle's work with the mold did more than any other research to establish the chemical nature of genic actions Classical genetics now has a lively daughter lmown as chemical genetics, a prolific contributor of new findings to sclences This, then, was the situation in 1946. With chemical research in charge of a biologically-minded chemist, and with this chemically—minded geneticist placed in charge of biological research, the California Institute offered an unusual opportunity. ‘The Divisions of Biology and Chemistry imme- diately prepared a prospectus outlining Ya joint program of research on the fundamental problems of biology and medicine.” The program would occupy fifteen years and require a budget of $400,000 a year; and application was made to foundations for support. It was estimated that about five years would be required to bring the program to its full operating capacity, and as interim grants The Rockefeller Foundation appropriated $50,000 in 1946 and an equal amount in 1947, followed this year by a long-term appropriation of $700,000 to be paid in annual installments of $100,000. Thus, $800,000 has been committed within the last three years. The earlier contributions, begin- ning with the first grant on behalf of Dr. Pauling's work in 1932, have totaled $440,865, making a grand total of $1,240,865 given to California Institute for research in chemistry and biology. In addition, the joint program of research on the fundamental prob-— lems of biology and medicine has attracted support from other funds: $60,000 a year from the National Foundation for Infantile Paralysis, and lesser grants from the Nutrition Foundation, the Hermann Frasch Foundation, and others. As rapidly as competent scientists can be found and trained for the new posts called for by the program, the work is being expanded to the full scope envi- sioned by the prospectus. Research Manpower Of the two essentials to successful research — manpower and equip- ment - the human element of course is the more important. Wickliffe Rose used to say that his main function as an officer of the Rockefeller Boards was to discover men of superior brains and then back them up through a period suf- ficient to demonstrate their abilities. What makes the situation at the Cali- fornia Institute so challenging is the presence there of the two staffs of scientists with their already integrated teamwork of biology and chemistry. In 1946, when the joint program was projected, the staff in biology, including all workers from professors to research fellows and assistants, comprised 32 persons; and the corresponding groups in chemistry totaled 86. At present biology is employing the services of 79, and chemistry 97, a grand total of 176 for the two divisions, or an increase of 49 per cent over the status of three years ago. Not all of these staff additions were financed from the funds earmarked for the joint program; some of them represent new fellowships that have become available in the last year or two or chairs recently estab-— lished by the Institute. But all are engaged in research, and the joint program is benefiting enormously from this increases Among the recent staff additions are John G. Kirkwood in chemistry and Max Delbriick in biology. Dr. Kirkwood ig in the distinguished line of physical chemists and had held research and teaching positions at Massachu- setts Institute of Technology, University of Chicago, and Cornelle He was fodd professor of chemistry at Cornell in 1948 when called to the newly- established Arthur A. Noyes professorship of physical chemistry at the Galifornia Institute. Like Dr. Pauling, he has a predilection for the giant molecules, and recently developed a new type of electrophoresis apparatus with which to study their properties. Tests made at Pasadena within the last few months show that the Kirkwood apparatus will separate the proteins of blood plasma to a finer degree than any other device heretofore used. Dr. Delbriick 1s a physicist turned biologist. His primary training was in Germany in theoretical physics, but he became interested in bacteri- ology, and came to the United States as a Rockefeller Fellow in biologye He has made many contributions to our kmowledge of bacteriophages, the invisible viruses which prey upon bacteria. Although these viruses multiply with great rapidity when they penetrate a bacterium, and in some of the experiments seem to do this by a kind of sexual reproduction, in other respects they appear as inert as any chemical. Indeed, each virus seems to be made up of but a few giant molecules. The viruses thus occupy a Dorderland between the living and the non-living, between biology and chemistry, and study of them constitutes an important part of the joint program. Dr. Delbriick joined the California Institute faculty in 1947, coming from Vanderbilt University- Other members of the combined staffs could be cited with equally interesting detail. There is Laszlo Zechmeister, formerly of the University of Pecs, Hungary, who came to the California Institute as professor of organic chemistry in 1940. Dr. Zechmeister is an authority in chromatography, an amazing technique for separating carotenoids and other organic pigments out of mixtures - and his specialty is contributing directly to the joint research programe Another worker is Dan H. Campbell, an immmochemist, brought here 4n 1942 with the assistance of a grant from the Foundation. Dr. Campbell has been collaborating with Dr. Pauling in an effort to synthesize antibodies ty direct chemical means - a daring project which if successful may revolu- tionize the control of infectious disease. 10 Research Equipment The laboratories and other campus buildings of the California Insti- tute are in the Meditermnem style of architecture, low structures arranged in pleasing quadrangles, with connecting colonnades. Chemistry is housed in the Gates and Crellin laboratories, which in effect are one large building in the form of a Ue Biology has its headquarters in an adjoining edifice imown as the William G. Kerckhoff Laboratories. The juxtaposition of the two buildings has proved to be of great convenience to the growing collaboration between the chemists and biologists, and symbolizes the partnership in research. In addition to its main facilities in Kerckhoff, biology has several smaller establishments off the campus. Across the street are three labor- atories of plant physiology, ons of them just being completed at a cost of $400,000, a gift from the Barhart Foundation of Detroit. Half a mile away 4g another center of botanical research, the Orlando Road Greenhouses; and five miles distant is Arcadia Farm, ten acres devoted to the study of genetics in come Fifty miles southeast, at Gorona del Mar on the Pacific shore, is the marine laboratory. This is both a center for research and a means of supplying marine animals for experiments in biology and chemistry on the campuse Last summer still another unit was completed, a large animal house which adjoins a section of Kerckhoff on the north. This animal house was built entirely underground, cost $150,000, and embodies all current conven- fences for breeding, housing, and caring for experimental animalse It is indispensable to the joint piology—chemistry program. With this combination of laboratories and auxiliary facilities, the division of biology is really superbly equipped. There is plenty of working il space, but of course as the research program expands to its full scope this will become crowded and additional quarters will be needed. The laboratories of the division of chemistry, with its larger staff, are already seriously crowded; and plans have been drawn for a new building to be erected on the campus in the vacant area north of Kerekhoff and west of Crellin and Gates. This new laboratory, designed in the same architectural style as the older buildings, will be used for the joint chemistry-biology programe It is planned to connect with both Kerekhoff and Crellin and will increase the research quarters of the two divisions vy 75 per cent. The estimated cost of the proposed building is $2,000,000, and there are good prospects that a sufficiently large fraction of the necessary funds will be obtained to permit construction to begin this coming yeare Research Objectives "We are seeking to uncover basic phenomena and learn the principles which govern them, rather than to solve specific practical problems," explain— ed Dre Beadle. "The action of genes in controlling inheritance, the action of antibodies in neutralizing the destructive effects of bacteria, viruses, and other antigens, the action of hormones jn promoting or retarding growth — these are examples of basic phenomena, processes that are fundamental to life. If we wuderstood the basic processes, if we knew precisely what is happening fm each in terms of molecular action, we believe the solution of the prac- #ical problems would follow almost inevitably." And so the biology-chemistry team at the California Institute is 4nterested in genes, antibodies, viruses, hormones, biological pigments, and melated structures. How does each behave biologically, and how can this Yehavior be accounted for chemically? 12 Chemical behavior is related directly to the molecular structure of the reacting substances; therefore one of the principal objectives of the joint research program is chemical analysis. What are the building blocks that enter into the construction of genes and the other entities? How are these building blocks put together, in what order of arrangement, and what are the resulting size and shape of the structure? "Science is still far from completely analyzing these biological agents," said Dr. Beadle, "but the investigations tend to show that the mole- cular form known as protein is the key structure. Apparently most of the bodies that we are studying in our program are either simple proteins or conjugated proteins." Simple proteins are "simple" only by contrast with the vaster architecture of the conjugated molecules. Actually, a simple protein will consist of hundreds, sometimes thousands, of atoms. When placed beside familiar inorganic molecules, such as those of water, sulfuric acid, ammonia, and table salt, even the smallest protein molecule is like a whale among minnowss But a protein is simple in this respect: when it is broken down it does not separate into its hundreds or thousands of individual atoms, but divides into characteristic groups of atoms which the chemists know as amino acids. It is as though when a house was demolished, it broke up into base- ment, rooms, and attic, rather than into individual bricks and boards» Twenty-three different amino acids have been found in proteins, and tne possible combinations that may be formed from these twenty-three building blocks run into countless millions. It is no wonder that proteins occur in the wide variety which makes one man's meat another man's poisone But a mumber of the most familiar and wholesome substances of the body's equipment 13 are simple proteins? pepsin and many of the other digestive enzymes, insulin and many of the hormones, albumin, fibrinogen, and many other components of the blood plasma. The conjugated proteins represent a further step in structure. After a simple protein molecule has been built by the joining together of molecules of different amino acids, it may hook on to a pigment and form a conjugated protein such as the hemoglobin of the blood. Or, 4% may attach ltself to a complicated chain of sugar molecules known as a polysaccharide and form a conjugated protein of another type, such as the mucin of salivae Another possibility is the joining of a protein with a vitamin ~ the enzyme carboxylase is of this type. Finally, proteins may be linked with nucleic acids to form nucleoproteins — and here we reach the ultimate of giantism among moleculese Tor if a simple protein is pictured as & whale among the minnows, @ nucleoprotein may be likened to a leviathan with form so tre- mendous that it might swallow the whale. Nucleic acid alone is a large structure - gome of its molecules contain 160,000 atoms — and when units of this size combine with units the size of proteins, the combination is truly enormouse Some of the viruses which Wendell M. Stanley isolated in his studies at the Rockefeller Institute were identified as nucleoproteins and weighed up to g,000,000 times the weight of hydrogene Such structures comprise nearly @ million atoms. It is believed that both viruses and genes are nucleoproteins, while the antibodies are thought to be simple proteins consisting of chains of amino-acid residues folded together in a certain way» According to Dre Pauling's theory, these folded chains of interlinked amino-acid residues (polypeptides, they are called) are afloat in the bloodstream; and whenever 14 they encounter the bacterium, virus, or other odd body against which they serve to protect the organism, the mutual attractions between the two cause the chain to approach and attach itself to the intruder. The action of the chemical bond thus brings the antibody to overlay an area of the surface of the foreign body with a shield or encrustation which blocks the latter's activity. This explanation is necessarily brief and oversimplified, but perhaps it suggests the action by which an antibody neutralizes a microbe. "The genes, we believe, exercise an overruling control on all these activities," said Dre Beadle. "They do this, we think, by serving as the master patterms for the many proteins which function in the processes of lifes Thus, there is probably a gene which serves as the template for the body's manufacture of insulin, another which provides the mold for pepsin, and so for albumin, fibrinogen, the polypeptide chain that forms antibodies, and all the rest. There are several thousand genes distributed among the 48 chromosomes of the human body cell, a number sufficient to provide templates for the thousands of big molecules required for health. Diabetes, on this theory, is a consequence of a missing or defective gene, leaving its victim unable to manufacture insulin. Similarly, the bleeders or hemophiliacs lack the nozmal gene for manufacturing a gamma globulin which is an essential com- ponent of the blood-clotting equipment. Our experiments with the bread mold, Neurospora, have demonstrated this genic control of the biochemical processes in numerous instancese We found, for example, that after exposure to ultra- violet radiation, the Neurospora lost its ability to make certain vitamins. The genes which controlled this manufacture had been destroyed, and there- after the Neurospora languished unless these vitamins were supplied in its food. Similarly, Sterling Emerson of our laboratory found that a minute 15 change in its genes caused the Neurospora to accept as food a compound that before the change had acted as @ poisone Indeed, after mutation, the Neurospora would not grow uniess fed a sulfonamide which previously had blocked growth and caused death.” The strongest impression that one brings back from a visit to the Caltech team is the magnitude of the task of analyzing these invisible moleculese As a step toward understanding the proteins, the group is working first on the amino acids, trying to map precisely the structure of these protein puilding-blocks. Robert B. Corey of the chemistry staff spent a year and a half analyzing the configuration of glycine, the simplest of the amino ecids. He bombarded it with x-rays, and measured the angles at which the rays bounded. off the molecule. In this way he not only determined the position of each carbon atom, each oxygen, and each hydrogen in the glycine, but actually measured the distances between the atoms. After completing this job, Dre Gorey went on to alanine, which is larger and more complicated. The experi- ence he had gained on glycine stood him in good stead, and he required only @ year to work out the exact pattern of alanine. He has now taken up a still more complicated amino acid, threonine, and this winter is deep in a study of 4te In this way, the group plans to move from the amino acids to more compli- eated structures, with the hope that eventually they may be able to dissect gome of the proteins, perhaps even nucleoproteins, into their integral parts. 16 TOUR BOOKS IN THE NATURAL SCIENCES Among the books in the natural sciences which were published during 1948, four may be listed as of special interest because of the relationship of the authors and their subjects to projects fostered by the Toundation. Mathematical Biophysics, by Wicholas Rashevsky. The University of Chicago Press, Chicago, 1948, pp. 669, $6. This is a revision and extension of a briefer book pub—- lished in 1938 with the assistance of a grant from the Founda- tion. Dr. Rashevsky is professor of mathematical biophysics in the University of Chicago. His special field of research has been the attempt to interpret biological processes such as cell division, growth, nutrition, and communication in terms of physical phenomena. His treatment includes a physico- mathematical theory of the operation of the central nervous system. Gybernetics, by Norbert Wiener. The Technology Press, John Wiley and Sons, New York, 1948, pp. 194, $3. Another book which undertakes to interpret biological processes in terms of physical phenomena is this new work by Dr. Wiener, professor of mathematics in Massachusetts Institute of Technology. Professor Wiener dedicates the book to Arturo Rosenblueth, physiologist of the Mexican National Institute of Cardiology, and there is a strict appropriateness in this dedication, for Cybernetics treats of a problem on which the mathematician and the physiologist have been collaborating for @ number of years, and since early 1946 with the help of a grant from the Foundation. The problem is that of nervous control, how the brain communicates with the muscles and directs their action. As the book discloses, the brain does this in ways quite parallel to those used by dial telephones, thermostat regulators, electronic calculators, and other automatic machines. "In their more elaborate forms," says Professor Wiener, "modern computing machines are capable of memory, association, choice, and many other brain functions. Indeed, the experts have gone so far in the elaboration of such machines that we can say the human brain behaves very much like the machines. ‘The construction of more complex mechanisms actually is bringing us closer to an understanding of how the brain itself operates." The word 17 cybernetics was coined from the Greek "kybernetes," meaning steersman, and Wiener uses it as the name for the new science "communication and control in the animal and the machine.” His book is heavily loaded with mathematical equations and other technicalities, and ts hardly a manual for the layman, but a very readable interpretation was written by Wiener for the "Scientific American" and appeared in its November number. Submicroscopic Morphology of Protoplasm and Its Derivatives, by Albert Frey-Wyssling. Elsevier Publishing Company, Amsterdam, 2nd edition, 1948, pp. 268, $6. Professor Frey-Wyssling was a fellow of the International Education Board in 1925-26, and in recent years his work at the Bidgenbssische Technische Hochschule in Zurich has received sup- port from the Foundation. He and a small group of associates in Zurich are specialists in the study of structures beyond the reach of the optical microscope ~ such as the minute morphology of chromosomes, slime molds, cellulose, and silke The present work is a new edition, in an English translation, of a work that has long been standard in this difficult field. Radioactive Indicators, Their Applications in Biochemistry, Animal Physiology, and Pathology, by George Hevesy. Interscience Publishers, Ince, London, 1948, pp. 556, $10. Professor Hevesy was among the first, perhaps the very first, to use radioactive elements as tracers in biochemical researche As early as 1923 he published an article under the title, "The Absorption and Translocation of Lead by Plants: