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COLIN MUNRO MACLEOD January 2S, 1909-February 11, 1972 BY WALSH McDERMOTT AS A BEGINNER in science, Colin Munro MacLeod was granted the most wonderful of gifts, a key role in a major discovery that greatly changed the course of biology. Great as this gift was, it came not as unalloyed treasure. On the contrary, for reasons that are not wholly clear even today, the demonstration by Avery, MacLeoct, ancT McCarty that deoxyribonucleic acid is the stuff that genes are made of was slow to receive general acceptance and has never really been saluted in appropriately formal fashion. The event was origi- nally recorcled in the now famous paper of 1944 in the Journal of Experimental Medicine, entitled: "Studies on the Chemical Nature of the Substance Inducing Transformation of Pneumococcal Types. Induction of Transformation by a Desoxyribonucleic Acid Fraction Isolated from Pneumococ- cus Type III." The title tells the story; clearly this was an historic watershed. Sir MacFarIand Burnett states that "the discovery that DNA COUi] transfer genetic information from one pneu- mococcus to another heralded the opening of the fielct of molecular biology."2 Writing in Nature in the month before MacLeod cried, H. V. Wyatt3 reports it as "generally ac- cepted" that the field of molecular biology began with the 183

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184 BIOGRAPHICAL MEMOIRS appearance of this paper. Lederberg terms the work "the most seminal discovery of twentieth-century biology." To make an important individual contribution to one of history's great scientific achievements was an act of creation of a special sort. It took place in the decade between MacLeod's twenty-fourth and thirty-fourth years. He could have rested on this achievement; he could have continued with it, thus emphasizing his role; or he could have gone on to something else. As things worked out, he followed the last-named roacI, influenced to an undeterminable extent by World War Il. But there are other forms of creation in science, and, in some of these, MacLeod also excelled. Before looking at these aspects of his life, it is worthwhile to pause a moment over the question of how he hacT been prepared so that he might make such great contributions. (Dr. Robert Austrian, in a sensitive and perceptive piece, has describer! MacLeod's early years.4) One of eight children of the union of a schoolteacher and a Scottish Presbyterian minister, the young MacLeod skipper! so many grades in school that after being accepted at McGill University he had to be "kept out" a year because he was too young. His birth on January 2S, 1909 took place in Port Hastings, Nova Scotia. In his early chil(lhoo(l, he moved with his family back and forth across Canada from Nova Scotia to Saskatchewan to Quebec. He obviously was a splendid stu- dent, for, as related by his sister, Miss Margaret MacLeod, he skipped the third, fifth, and seventh grades and graduated from secondary school (St. Francis College, Richmond, Quebec) when only fifteen years of age. His career as an educator starter! almost immectiately. While being "kept out" of school to become old enough for McGill, he was incluced to leave an office job to serve at the age of sixteen as a substitute teacher of the sixth gracle in a Richmond school. He held this job wholly on his own for the entire year. These

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COLIN MUNRO MACLEOD 185 early signs of superior intellectual capacity were not a part of the stereotype "infant prodigy." Indeecl a clear sign to the contrary was the fact that within only a few years he was on the McGill varsity hockey team then, as now, a most im- pressive athletic achievement. After two years of premedical education at McGill, he entered the Medical School and received his clegree in med- icine in 1932. In 1934, at the age of twenty-four, after two years of residency training at the Montreal General Hospital, he came to New York. Less than ten years later, he would make his own highly important individual contribution to the Avery- MacLeocl- McCarty study. The nature of the reception of this work was to test the remaining thirty years of his life, for its significance clid not receive the early attention it might be thought to have merited. Shortly before MacLeod died, this aspect of the story formed the basis of several articles in scientific and popular periodicals.5 He had the chance to see these, but sadly enough, he did not live to see the most extensive and authoritative account, published in ~ 976 by R. J. Dubos in his book, The Professor, the Institute and DNA. 6 There is no intent here to attempt to add to this literature. The chance of painting a distorted picture is too great for one who was not close to the situation at the time. Moreover, the endpoint of "acceptance" is hard to measure, for in science it floes not occur all at once like a directed plebiscite in a totali- tarian state. Some highly knowlecigeable scientists perceive the full significance of a particular discovery right away; others require longer. It is necessary, however, to cite the major events in the research itself in order to describe MacLeocl's clearly definable and individual contribution. AncI, given that contribution, some mention of what hap- pened to the recognition of the work is inescapable in telling the story of MacLeod's career in science. For it is the way the

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86 BIOGRAPHICAL MEMOIRS whole story seemed to him that could have had a telling influence on his subsequent career. When he first arrived at the Rockefeller Institute, MacLeod fell under the influence or spell of 0. T. Avery, or "Fess" as he was called, who was the inspiring teacher of so many others, including Rene Dubos, Maclyn McCarty, and the late Frank Horsfal1 and Martin Henry Dawson. Some years before, as related by Dubos, an old school friend of MacL.eod's, Henry Dawson, had been asked by Avery to investigate the variations in pneumococcal colonial morphology from "rough" to "smooth" (R/S) then being studied by Griffith in England. Several years later, when ~~ 1_ 7 _1 , , ~ . ~ ~ , ~rlrIlln aemonslra~ecl Nat one pneumococcus type could be transformed in vivo into another, in effect a directed and heritable alteration, Dawson was captivated by the feat. Working with R. H. P. Sia, he was able to repeat the experi- ment and to produce the chance 8 newton ho to Han the project, which was taken up by J. S. Alloway,9 who was able to show that the substance responsible resided in a thick, syrupy preparation. The techniques used by Dawson, Sia, and Alloway were ~ _ . . ~ _ _ ~ ~ ~ _. . ~ ~ . . not at all reliable. Neither the phenomenon of transforma- tion nor the harvesting of transforming principle could be reproduced with a high degree of oredictabilitv. A ohenome- _ _ r , ,~ 1l . 1 ~ -- rip ---it --r--~--~~-~~ non ot potentially great blologlc significance had been clearly identified. Yet without methods to produce it with oredict- ability and to extract its active principle in ways permitting precise characterization, any attempts to study the matter further were bound to be marked by frustration. Neverthe- less, because of the potential significance of the phenome- non, Avery decided that the work must go on. He continued to see the first essential task to be the chemical characteriza-

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COLIN MUNRO MAt~LEOD 187 tion of the active material, but the available techniques were obviously not sufficiently reliable to permit such chemical studies. It was at this point that MacLeod entered the picture in 1935. By improving the medium and isolating a consist- ently reproducible rough strain of pneumococci, MacLeod macle it possible (with Avery's encouragement and counsel) to move the project from what was the study of a fascinating phenomenon, but one of irregular occurrence and not pos- sible to assay, to a predictable one. The critical substance could then be fully characterized in chemical terms. The subsequent phase of the study, the actual conduct of these chemical studies, became the responsibility of McCarty. Each of the six investigators who worked with Avery thus made a contribution to the solution of Griffith's mystery, but it is now fully conceded that the critical contributions were those made by MacLeod and McCarty under the continuing, brilliant intellectual stimulation, advice, anct course! of Avery himself. OcicIly enough, as Dubos has clescribed, although MacLeod and McCarty worked closely together on the proj- ect, they were not officially at the Institute at the same time, for in 1941, at age thirty-two, MacLeod became chairman of the Department of Microbiology at the New York University School of Medicine. He left the Institute as McCarty arrived. As the Medical School of NYU and the Rockefeller labora- tories are both in the micI- East Side of Manhattan, it was easy for MacLeod to travel back and forth, and he maintained a continued and wholly recognized association with the project. In large measure, however, whether it was realized or not at the time, he had made his contribution. He had taken an almost formless, erratic phenomenon and macle it into some- thing predictable and measurable. This had to be clone, and he click it. Thus, the problem had been brought to the very stage at which McCarty's own considerable biochemical ex-

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188 BIOGRAPHICAL MEMOIRS pertise was exactly what the situation called for. Two years later (November ~ 943), the paper was submitted to the Journal of Experimental Medicine. A In subsequent years, MacLeod continued to work on this problem in his laboratory at New York University, first with M. R. Krauss i~ and R. Austrian, and at a later period with E. Ottolenghi.~3 It is appropriate to postpone discussion of these subsequent phases of his scientific career in universities and government and to dwell for a moment on the story of how the finding presented by Avery anc! his two younger colleagues in the 1944 paper was received. A revolutionary concept, as pointed out by Kuhn,~4 does not usually increase knowledge by adcling on to it; it is more apt to replace it. A problem in 1944, and a far greater one today, is how one can evaluate new research with implied revolutionary finclings when, as a practical matter, one can- not employ the techniques necessary to repeat it. The scientists who read the ~ 944 paper by Avery, MacLeoct, and McCarty hacI, in theory, two choices: they couIct accept or deny the validity of the demonstration on the basis of comprehension, or they could repeat the experi- ments. To (lo the former requires an intimate knowleclge of the reliability of the techniques. At first glance that is a state- ment of the obvious something that occurs on the reading of any scientific paper. But such is really not the case. Most of the time, in biomedicine at [least, published experiments represent logical sequences in a series of experiments on the same subject. The degree of reliability of the key methods is known to be understood by those intimately engaged in the fielct, and the rest take it on faith. When this is not the case when the results clepend on a new methodif the field is reasonably in the scientific fashion of the clay, it contains other workers. These other workers soon clefine the limits of the technique. Obviously, this system depends on the jucig-

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COLIN MUNRO MACLEOD . . 189 mental decisions of presumed experts, but the scientific com- munity and the public are protected against prolonged error by the competitive nature of the studies in a particular field. It is one part of the familiar "marketplace of ideas." The trouble with the Avery-MacLeod-McCarty studies was that the approaches they used did not happen to be fashionable. They were not part of a race to glory, such as that described by Watson in the Double Helix.~5 Or, more accurately, the successful approaches that were used by the Rockefeller group were far out of the ken of most of those who were working actively to solve the question. Moreover, the nucleic acids were not believed to have any biologic activ- ity nor was their structure well defined. There really was no community of competing investigators fully armed with the requisite techniques ready to jump in and repeat the experi- ments. Indeed, to do this wouicI require assembling a team with the talents, experience, and expertise of Avery, MacLeod, and McCarty. What is more, it would have to be assembled from a markedly constricted biomedical research community, for by this time the U.S. involvement in World War IT had begun. Acceptance of the chemical basis of transformation might seem to have been slow, although clearly there was no set period within which it should have occurred. There is now a small body of published material on this question of accept- ance by some of the people who were close to the field at the time. Some of these comments were recorded during the period in question or a little later; others are present-day recollections of what was thought at the time. As might be expected, these reports ranged from outright acceptance of the role of DNA to a definite interest short of conviction, to, at the other extreme, a belief that the phenomenon was not mediated by nucleic acid at all, but by minute amounts of contaminating protein. Stent believed the work had little im-

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190 BIOGRAPHICAL MEMOIRS pact on genetics.l6 Lederberg strongly dissents from this . ~ . . . . point ot view anc presents important contemporary citations in support of that position. 17 Indeed, in the year following the original report, I. Howard Quellers appears to have cor- rectly perceived the whole story, as may be seen in his article in the Annual Review of Biochemistry. Dubos,~9 in his 1976 analysis of the entire record, suggests that one of the factors in the slow acceptance was the starkly noncommittal way the results were presented, which was notable even in a scientific report. In those days at the Rockefeller Institute, there was a philosophy concerning the style in which experimental re- sults should be presented. This style was largely initiated by Avery but was also adhered to with conviction by most of his younger associates, especially MacLeod. In this style, the key words were carefully chosen to convey only that which had been clearly proved and nothing more; any suggested impli- cations were rigorously excluded. Lederberg also credits this attribute, which he terms "Avery's own a-theoreticism," with helping to postpone "the conceptual synthesis that now iden- tifies 'gene' with DNA fragment."20 Whether or not acceptance was slow, it evolved steadily. For Lederberg also mentions: "In 1946, at the Cold Spring Harbor Symposium, where Tatum and I first reported on recombination in Escherichia coli, we were incessantly chal- lenged with the possibility that this was another example of transformation, a la Griffith and Avery."2i Dubos cites a summary by Andre Ewoff of a 1948 con- ference in Paris in which the genetic role of the nucleic acids is obviously accepted. But as Dubos also states: It took an experiment, outside of the Institute, with a biological system completely different from that used by Avery to win universal acceptance for the genetic role of DNA. Using coliphage marked with 32P (restricted to the DNA component of the virus) and with 35S (restricted to the protein component), Hershey and Chase at the Cold Spring Harbor Laboratory

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COLIN MUNRO MAcLEOD 191 showed in 1952 that most of the viral DNA penetrates the infected bac- terium, whereas most of the protein remains outside. This finding sug- gested that DNA, and not protein, was responsible for the directed specific synthesis of bacteriophage in infected bacteria. In reality, the interpreta- tion of this wonderful experiment was just as questionable on technical grounds as was the chemical interpretation of pneumococcal transforma- tion, but those obtained by Avery 10 years before, that the few remaining skeptics were convinced. The case for the view that DNA iS the essential and sufficient substance capable of inducing genetic transformations in bacte- ria was not won by a single, absolute demonstration, but by two indepen- dent lines of evidenced In his Nobel Prize lecture,23 Lederberg puts it in essen- tially the same way. He attributes to Avery and his colleagues the demonstration that the interpneumococcus transference of an inherited trait was through DNA, the broadening of the evidence to Hotchkiss,24 and the reinforcement of this con- clusion to Hershey and Chase,25 with their proof that the genetic element of a virus is also DNA. Eventually such situa- tions right themselves. Today if one looks in elementary texts on human genetics, the Avery- MacLeod- McCarty ~ 944 paper is cited, in effect, as the historic watershed.26 Little imagination is required for anyone who has ever been engaged in science to envision what a cleep-seatecl disap- pointment the relative lack of formal recognition of his key contribution to the DNA work could be to a scientist, especially to one who was just starting out in his career. A sense of having in some way suffered an injustice wouIcl not be at all unusual. This could well lead to bitterness, particularly as the years went on and others reaped wide professional and pub- lic recognition for studies on DNA. But MacLeod would have none of this. Not for him wouIct be the stereotype of the unhappy investigator living off scientific "might have beens." Incleed, as far as I have been able to ascertain, at no time did he ever publicly express, even by indirection, the thought that, in the DNA story, he had been slighted in any way.

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192 BIOGRAPHICAL MEMOIRS MacLeocT's seven years in Avery's "department" at the Institute were not all occupied by the work on the pneumo- coccal transforming factor. On the contrary, he was engaged in a number of other studies, as may be seen from his sixteen publications of this period, eleven of which list him as senior author. Two things are striking in looking over this list today. First, although a number of different topics appear to be involved, they almost all clear with host-parasite relations at the very time antimicrobial therapy was coming on stage, so that the influence of this intervention in the disease mecha- nism could also be embraced by the studies. Second, virtually all were concerned with pneumonia, notably pneumococcal pneumonia; there was one stucly on the so-called primary atypical pneumonias just then coming into medical recogni- tion. Given Avery's preoccupation with pneumococcus, the fact that MacLeocI, working in his laboratory, publishecl a number of studies on pneumonia may not seem too surpris- ing. What is important, however, is that this interest lecI MacLeod to highly productive studies in his subsequent career. MacLeod's start as a university professor coincicled roughly with the entrance of the United States into World War IT. Viewed in retrospect, the impact of so pervasive a force as World War lI was bound to have deep and enduring effects on a young man just emerging as a leader in science. From this time on, three characteristics were prominent. He was forever conscious that the university department he headed was in a school for the training and education of physicians, he was deeply convinced of the social value of unfettered basic scientific research, ant! he felt a responsibil- ity to contribute what he could to the shaping of public policy in that interface of government and the universities that cleveloped so rapidly in importance dating from that time. To a considerable extent, all three characteristics tendec! toward

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COLIN MUNRO MAcLEOD 209 training in science and in biomedical science. His interest, however, was in medical education in its totality; in his few years as an executive of the Commonwealth Fund, he was able to concentrate largely on this field. Among his major accomplishments was the successful effort to convince the Fund to make a substantial investment in support of the medical education of black students. Moreover, by no means opposed to the "Centers of Excellence" concept, he was nevertheless among the first to encourage the university- basect medical centers to concern themselves also with the broacT societal issues of medical care. Probably the most care- fully written of his analytic essays on the social choices before us regarding the support of medical education and its sci- ences is "The Government ancT the University," given as the ctinner address in 1966 before the Association of American Physicians.40 These three different phases of MacLeocT's scientific and professional life were largely sequential. There was his fine work in the laboratory culminating in the sharply focused scientific effort with Avery ancT McCarty that led to the iclen- tification of DNA as the material of heredity. In the second phase, there was the creativity involved in building a model basic-science department in a university. He lect in the crea- tion of an exciting teaching program. He assemblecl a group of splendid scientists, junior and senior, anct proviclecI the leadership and the environment in which they could attain their maximal potential. There was the third and longest phase in which he pioneered in an area essential to the proper life of science: science and public policy or the inter- face between science in the university and in government. The writer had the opportunity to observe him on many occasions at work in each of the institutional frameworks in which he laborecI for so long a period. It was easy to see why

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210 BIOGRAPHICAL MEMOIRS he was so much in demand. He was responsible, knowledge- able, always even-tempered, ant! quick to sense a group ten- sion that could be allayed by his quick wit. He had attributes somewhat unusual for a young person In scienceat least in biological science in those clays. He had a considerable interest in intellectual affairs outside of science as well as those of science, and he usually appeared willing, one might almost say eager, to stay up all or half the night in discussions about them. To these he brought a quick wit and great gifts as a raconteur particularly as a teller of stories in Scot's dialect. Perhaps he possessed these behavior patterns, while others of his cohort in science did not, simply because he had the physical strength others lackecI. As Robert Aus- trian has put it: One of Colin's remarkable attributes was his boundless energy. Despite the multiplicity of his responsibilities, his endless travels here and abroad, he never seemed to tire. He required less sleep than most men; and, after an animated evening of discussion with colleagues lasting into the wee hours, he could attend a meeting the next day without visible evidence of the influence of fatigue on his thinking.4t He had strong characteristics that in another person couIcl have been defects. What in someone else might have been unattractive rigidity, in him was an enviable firmness and responsible consistency. While believing deeply in the social responsibility of science ant! in the need to work out ways to apply its useful products, he was equally deeply convinced of the importance of scientific inquiry of a completely unfet- tered sort. Even in his manner there were the contradic- tions his small size, quick movements, and careful groom- ing might easily get the label of dapper but not in him. In puzzling over why these apparent paradoxes former] an im- mensely effective person, one might say that the contradic- tions were in balance, but it was something more than that, it was really a matter of a disciplined control.

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COLIN MUNRO MAcLEOD 2 The greatest paradox of all was in personal relations. Here he gave much of himself; he hacT a wicle circle of ex- tremely clevotect friends and was always open to their seeking of help. He gave much of himself, but he gave very little about himself. Several people who knew him well have commented that there seemed to be an extraordinarily large group of people, each one of whom consiclerec! themselves to have been a close personal frienc! of MacLeocT. Although he wouicT not talk of himself in a personal fac- tual sense, he would get into quite serious discussions about his philosophical beliefs. His view of life as I heard him ex- press it on more than one occasion was basest on the concept of immanence. He was fascinated with this iclea. Unfortu- nately for a precise discussion, the concept of immanence has several rather different meanings. My own unclerstancting from our numerous conversations is that MacLeod's imma- nence hacT the "Got! is everywhere" meaning. Certainly this fitted well with his unpretentious and utterly convincing won- derment about the effective intricacies and orderliness of living systems a characteristic not so often met with in one who also was extremely interested in disease and the human . . cone lotion. Describer! in this way, he seems like a paragon of virtues - something ~ suspect he was, but cannot testify to because of the familiar phenomenon of our relative ignorance of the "other sides" of persons we know quite well. ~ cTicT not know him in his roles as brother, husband, or father. ~ knew him as an extraordinarily capable member of the scientific commu- nity and an equally effective leader in the world of science and public policy. In short, ~ knew him in a certain environ- ment, ant! it is the particular environment that is especially concerned in these archives. In the relatively broact confines of that environment, this is the way he was to me. Tolstoy believed our method of classifying people by at-

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212 BIOGRAPHICAL MEMOIRS tributing to each some particular leading quality was all wrong. He concealed that one could say that someone is more frequently kind, wise, or energetic than the opposite, but to him: Men are like rivers. The water is alike in all of them; but every river is narrow in some places and wide in others; here swift and there sluggish, here clear and there turbid; cold in winter and warm in summer. The same may be said of men. Every man bears within himself the germs of every human quality, displaying all in turn; and a man can often seem unlike himself yet he still remains the same man.42 It is on this Tolstoyan scoreboard that the MacLeoc! career stancis so high, for almost without exception, regarcI- less of how wide or how coIc! the river, he remained the same man. NOTES 1. O. T. Avery, C. MacLeod, and M. McCarty, "Studies on the Chemical Nature of the Substance Inducing Transformation of Pneumosocial Types,"Journal of Ex- perimental Medicine, 79(1944):137-58. 2. Sir F. M. Burnet, Changing Patterns: An Atypical Biography (London: Heine- mann, 1968), p. 81. 3 . H. V. Wyatt, Nature, 23 5( 1972) :86. 4. R. Austrian, "Infectious Diseases Society of America: Colin Munro MacLeod~ 1909-1972 ," Journal of Infectious Diseases, 127( 1973) . 5. G. S. Stent, "Prematurity and Uniqueness in Scientific Discovery," Scientific American, 227(1972):8~93. 6. R. J. Dubos, The Professor, the Institute, and DNA (New York: The Rockefeller University Press, 1976). 7. F. Griffith, Journal of Hygiene, 27( 1928): 1 13. 8. M. H. Dawson and R. H. P. Sia. "In Vitro Transformation of Pneumococcal TypesIandII,"%,fournalofExperimentalMedicine,54(1931):681-99,701-10. 9. l. S. Alloway, "The Transformation in Vitro of R Pneumococci into S Forms of Different Specific Types by the Use of Filtered Pneumococcus Extracts," Journal of Experimental Medicine, 55(1932):91-99; l. S. Alloway, "Further Observations on the Use of Pneumococcus Extracts in Effecting Transformations of Type in Vitro," Journal of Experimental Medicine, 57(1933):265-78. 10. Avery, MacLeod, and McCarty, "Studies of the Chemical Nature of the Sub- stance Inducing Transformation of Pneumosocial Types."

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COLIN MUNRO MAtLEOD 213 11. C. M. MacLeod and M. R. Krauss, "Stepwise Intra-Type Transformation of Pneumococcus from R to S by Way of a Various Intermediate in Capsular Polysac- charide Production," Journal of Experimental Medicine, 86(1947):439-53; C. M. MacLeod and M. R. Krauss, "Transformation Reactions with Two Non-Allelic R Mutants of the Same Strain of Pneumococcus Type VIII," Journal of Experimental Medicine, 103( 1956):623-38. 12. R. Austrian and C. M. MacLeod, "Acquisition of M Protein by Pneumococci through Transformation Reactions," journal of Experimental Medicine, 89(1949): 45 1-60. 13. E. Ottolenghi and C. M. MacLeod, "Genetic Transformation among Living Pneumococci in the Mouse,"Proceedings of the NationalAcademy of Sciences of the United States of America, 50(1963) :4 17. 14. T. S. Kuhn, The Structure of Scientific Revolutions, 2d ed. (Chicago: University of Chicago Press, 1970), pp. 93-94. 15. J. D. Watson, The Double Helix (New York: Atheneum, 1968). 16. Stent, "Prematurity and Uniqueness in Scientific Discovery." 17. I. Lederberg, "Reply to H. V. Wyatt," Nature, 239, no. 5369(1972):234. 18. J. Howard Mueller, "The Chemistry and Metabolism of Bacteria," Annual Review of Biochemistry, 14: 733-47. 19. Dubos, The Professor, the Institute, and DNA. 20. Lederberg, "Reply to H. V. Wyatt." 21. Ibid. 22. Dubos, The Professor, the Institute, and DNA, p. 148. 23. j. Lederberg. 1959 Nobel Prize Acceptance Lecture, Royal Caroline Medico- Surgical Institute, Stockholm, 29 May 1959. 24. R. D. Hotchkiss, "The Genetic Chemistry of the Pneumococcal Transforma- tions." Harvey Lecture, 24 January 1954. 25. A. D. Hershey and M. Chase, "Independent Function of Viral Proteins and Nucleic Acid in Growth of Bacteriophage,'' Journal of General Physiology, 36( 195 1):39. 26. Textbook, Elementary, An Introduction to Human Genetics, ed. H. Eldon Sutton (New York: Holt, Rinehart and Winston, 1965), p. 70. 27. A syndrome principally produced by mycoplasma. 28. C. M. MacLeod, "Primary Atypical Pneumonia," Medical (clinics of North America, 27(1943):67~86. 29. C. M. MacLeod, R. G. Hodges, M. Heidelberger, and W. G. Bernhard, "Pre- vention of Pneumococcal Pneumonia by Immunization with Specific Capsular Poly- saccharides,"Journal of Experimental Medicine, 82(1945):445-65. 30. R. Austrian, R. M. Douglas, G. Schiffman, et al., "Prevention of Pneumo- coccal Pneumonia by Vaccination," Transactions of the Association of American Physi- cians, 89(1976):184. 31. C. M. MacLeod, "Chemotherapy of Pneumococcic Pneumonia," Journal of the American Medical Association, 1 13( 1940): 1405. 32. MacLeod and Krauss, "Stepwise Intra-Type Transformation of Pneumococ- cus from R to S by Way of a Various Intermediate in Capsular Polysaccharide Production"; "Transformation Reactions with Two Non-Allelic R Mutants of the Same Strain of Pneumococcus Type VIII." 33. Austrian and MacLeod. "Acquisition of M Protein by Pneumococci through Transformation Reactions."

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214 BIOGRAPHICAL MEMOIRS 34. MacLeod, Hodges, Heidelberger, and Bernhard, "Prevention of Pneumo- coccal Pneumonia by Immunization with Specific Capsular Polysaccharides; M. Hei- delberger, C. M. MacLeod, S. J. Kaiser, and B. Robinson, "Antibody Formation in Volunteers Following Injection of Pneumococci of Their Type-Specific Polysaccha- rides,"Journal of Experimental Medicine, 83(1946):303-20; R. G. Hodges and C. M. MacLeod, "Epidemic Pneumococcal Pneumonia. I. Description of the Epidemic," American journal of Hygiene, 44(1946):183-92; R. G. Hodges and C. M. MacLeod, "Epidemic Pneumococcal Pneumonia. II. The Influence of Population Characteris- tics and Environment," American f ournal of Hygiene, 44( 1946): 193-206; R. G. Hodges, C. M. MacLeod, and W. G. Bernhard, "Epidemic Pneumococcal Pneumo- nia. III. Pneumococcal Carrier Studies,"American journal of Hygiene, 44(1946):207- 30; R. G. Hodges and C. M. MacLeod, "Epidemic Pneumococcal Pneumonia. IV. The Relationship of Nonbacterial Respiratory Disease to Pneumococcal Pneumo- nia," American journal of Hygiene, 44(1946):231-36; R. G. Hodges and C. M. MacLeod," Epidemic Pneumococcal Pneumonia. V. Final Consideration of the Fac- tors Underlying the Epidemic," American journal of Hygiene, 44(1946):237-43; M. Heidelberger, C. M. MacLeod, R. C. Hodges, W. G. Bernhard, and M. M. DiLapi, "Antibody Formation in Men Following Injection of 4 Type-Specific Polysaccharides of Pneumococcus," journal of Experimental Medicine, 85(1947):227-30; M. Heidel- berger, C. M. MacLeod, and M. M. DiLapi, "The Human Antibody Response to Simultaneous Injection of 6 Specific Polysaccharides of Pneumococcus," journal of Experimental Medicine, 88(1948):369-72; C. M. MacLeod, M. Heidelberger, and M. M. DiLapi, "Antigenic Potency in Man of the Specific Polysaccharides of Types I and V Pneumococcus and Their Products of Alkaline Degradation," journal of Immunology, 66(1951):14~49; C. M. MacLeod, M. Heidelberger, H. Markowitz, and M. M. DiLapi, "Absence of a Prosthetic Group in Type-Specific Polysaccharides of Pneumococcus," Journal of Experimental Medicine, 94(1951):359-62. 35. Austrian, Douglas, Schiffman, et. al., "Prevention of Pneumosocial Pneumo- nia by Vaccination." 36. In November 1978, both Heidelberger and Austrian received Lasker Awards for Heidelberger's work with carbohydrate Polysaccharides and Austrian's clinical studies establishing the effectiveness of the vaccine. 37. The other members were R. I. Dubos, J. Kidd, M. McCarty, W. McDermott, A. M. Pappenheimer, and L. Thomas. 38. E. J. Van Syke, Science, 104(1946):559. 39. D. R. Nalin, R. A. Cash, R. Islam, M. Molla, and R. A. Phillips. "Oral Mainte- nance Therapy for Cholera in Adults." Lancet, ii( 1968):37~73. 40. Transactions of the Association of American Physicians, 99. 41. Austrian, "Colin Munro MacLeod." 42. L. Tolstoy. Resurrection. (New York: The New American Library, Signet Classic), p. 191.

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COLIN MUNRO MAT LEOD BIBLIOGRAPHY 1933 215 With H. S. Carter. Meningitis due to haemophilic organisms. Lan- cet, ii:412- 13. 1937 With L. E. Farr. Relation of carrier state to pneumococcal peri- tonitis in young children with nephrotic syndrome. Proc. Soc. Exp. Biol. Med., 37:556-58. 1938 With R. I. Dubos. Effect of tissue enzyme upon pneumococci. I. Exp. Med., 67:799-808. With F. L. Horsfall, Jr., and K. Goodner. Antipneumococcus rabbit serum as therapeutic agent in lobar pneumonia; additional observations in pneumococcus pneumonias of 9 different types. N.Y. State I. Med., 38:245-55. With C. L. Hoagland and P. B. Beeson. Use of skin test with type- specific polysaccharides in control of serum dosage in pneumo- coccal pneumonia. I. Clin. Invest., 1 7: 739-44. 1939 (A 1 Treatment of pneumonia with antipneumococcal rabbit serum. Bull. N.Y. Acad. Med., 15: 11 ~24. Metabolism of "sulfapyridine-fast" and parent strains of pneumo- coccus type I. Proc. Soc. Exp. Biol. Med., 41:21~18. With G. Daddi. "Sulfapyredine-fast" strain of pneumococcus type I. Proc. Soc. Exp. Biol. Med., 41 :69-71. 1940 With G. S. Mirick and E. C. Curnen. Toxicity for dogs of bacteri- cidal substance derived from soil bacillus. Proc. Soc. Exp. Biol. Med., 43:461-63. With L. A. Erf. Increased urobilinogen excretion and acute hemo- lytic anemia in patients treated with sulfapyridine. J. Clin. Invest. 19:451-58. Inhibition of bacteriostatic drugs by substances of animal and bac- terial origin. J. Exp. Med., 72:217-32.

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216 BIOGRAPHICAL MEMOIRS With L. E. Farr and others. Hypoaminoacidemia in patients with pneumococcal pneumonia. Proc. Soc. Exp. Biol. Med., 44: 29~92. 1941 With O. T. Avery. Occurrence during acute infections of protein not normally present in blood; isolation and properties of re- active protein. J. Exp. Med., 73: 183-90. Occurrence during acute infections of protein not normally present in blood; immunological properties of C-reactive protein and its differentiation from normal blood proteins. T Exp. Med., 73: 191-200. With G. S. Mirick. Bacteriological diagnoses of pneumonia in rela- tion to chemotherapy. Am. J. Public Health, 31:3~38. 1942 With E. C. Curnen. Effect of sulfapyridine upon development of immunity to pneumococcus in rabbits. J. Exp. Med., 75:17-92. Quantitative determination of bacteriostatic effect of sulfonamide drugs on pneumococci. I. Bacteriol., 44:277-87. Primary atypical pneumonia, Med. Clin. North Am. 27:67~86. Introduction to conference on sulfonamides. Ann. N.Y. Acad. Sci. 44:447. 1944 Primary atypical pneumonia, etiology unknown; report on cultures of hemophilic organisms sent from Camp Clarborne. Am. I. Hyg., 39:301. 1945 With E. R. Stone. Differences in the nature of antibacterial action of the sulfonamides and penicillin and their relations to therapy. In: The Bulletin, pp. 375-88. New York: Charles C. Morchand. 1946 Infection due to hemolytic streptococci. Lek. Listy, 1:473-75.

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COLIN MUNRO MAc;LEOD 1947 217 With M. Heidelberger, R. C. Hodges, W. Bernhard, and M. M. DiLapi. Antibody formation in men following injection of 4 type-specific polysaccharides of pneumococcus. J. Exp. Med., 85:227-30. With H. Chasis, J. A. Zapp, J. H. Bannon, J. L. Whittenberger, J. Helm, and }. I. Doheney. Chlorine accident in Brooklyn. Occup. Med., 4: 152-76. Studies on sensitization of animals with simple chemical com- pounds, antibodies inducing immediate-type skin reactions. I. Exp. Med., 86:489-514. With A. S. Roe. Natural antibodies to pneumococcus in man. Tr. Old. T., 60:22-27. 1948 With M. Heidelberger and M. M. DiLapi. Human antibody re- sponse to simultaneous injection of 6 specific polysaccharides of pneumonococcus. I. Exp. Med., 88: 369-72. 1949 With others. Antibody response of rabbits to single injection of type I pneumococci. I. Immunol., 61: 179-83. With R. Austrian. Type-specific protein from pneumococcus. J. Exp. Med., 89:439-50. Acquisition of M protein by pneumococci through transformation reactions. i. Exp. Med., 89:451-60. 1950 With M. Heidelberger, H. Markowitz, and A. S. Roe. Improved methods for preparation of specific polysaccharides of pneumo- coccus. }. Exp. Med., 91:341-49. With M. R. Krauss. Relation of virulence of pneumococcal strains for mice to quantity of capsular polysaccharide formed in vitro. J. Exp. Med., 92:1-9. With G. H. Stollerman and A. W. Bernheimer. Association of lipo- proteins with inhibition of streptolysin S by serum. I. Clin. In- vest., 29: 1636-45;

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218 B I OGRAPH I CAL M E M OI RS 1951 With M. Heidelberger and M. M. DiLapi. Antigenic potency in man of specific polysaccharides of types I and V pneumococcus and their products of alkaline degradation. I. Immunol., 66: 14~49. With M. Heidelberger, H. Markowitz, and M. DiLapi. Absence of prosthetic group in type-specific polysaccharide of pneumo- coccus. I. Exp. Med., 94:359-62. 1 953 With M. R. Krauss. Control by factors distinct from S transforming principle of amount of capsular polysaccharide produced by type III pneumococci. I. Exp. Med., 97:767-71. With B. A. D. Stocker and M. R. Krauss. Quantitative experiments on pneumococcal transformation. }. Pathol. Bacteriol., 66:330. 1 956 With M. R. Krauss. Transformation reactions with two non-allelic R mutants of the same strain of pneumococcus type VIII. i. Exp. Med., 103: 623-38. 1957 Experimental problems concerning the role of deoxyribonucleic acid in growth of bacteriophage T2 (discussion), Spec. Publ. N.Y. Acad. Sci., 5:262. With R. M. Bracco, M. R. Krauss, and A. S. Roe. Transformation reactions between pneumococcus and three strains of strepto- cocci. I. Exp. Med., 106:247. Obituary Notice, Oswald Theodore Avery, 1877-1955. J. Gen. Microbiol., 1 7:539. 1 959 With S. Jackson and M. Krauss. Determination of type in capsu- lated transformants of pneumococcus by the genome of non- capsulated donor and recipient strains. I. Exp. Med., 109:429. 1 963 With M. R. Krauss. Intraspecies and interspecies transformation reactions in pneumococcus and streptococcus. J. Gen. Physiol., 46:1141.

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COLIN MUNRO MAcLEOD 219 With E. Ottolenghi. Genetic transformation among living pneumo- cocci in the mouse. Proc. Natl. Acad. Sci. USA, 50:417. 1969 Prevention of pneumococcal pneumonia by immunization with specific capsular polysaccharides. In: Topics in Microbiology, ed. S. Mudd. p. 165. Philadelphia: W. B. Saunders.