May 12, 1947. Dr. R.G. Meader, Jane Coffin Chikds Memorial Pund, 333 Cedar Street, New Haven, Connecticut. Dear Dr. Meader- In confoxmance with our conversation last week, I am inoorporating into this letter a prospeotus of my plans for 1947-48, which I should appreciate your sending to the Board of Scientific Advisers. I an ap- pending also a preliminary summary of the work that I have done thusfar. Preliminary Progress Report in spite of the fact that bacteria provide unexampled material material for the study of genetio ohanges (mutation studies), geneticists have been understandably loath to homologize the results of researches on this group of organiems with those on other plants and animals, largely beeause it has been thought that a formal genetio analysis by hybridization methods was impossible. The research pexformed in this laboratory with Prof. E.L. Tatum, under the auspioes of the Childs Fund has elicited evidence that there is indeed a sexual phase in Some strains of the bacterium Escherichia coli, and that the inheri- tance of several mutant biochemical characters obeys Mendelian laws. There is now no reason therefore why mutations in bacteria should not be classified along with mutations in other orgenisms. The purely genetical investigations have shown that there is probably only a single linkage group (or chromosome) in this bacteriun. Advantage 1s being taken of the opportunity afforded by this material to study the inheritance of resistance to bacteriophages and to deleterious chemical substances; the analysis is not yet complete but the data are adequate to show that there is a relatively simple mutational basis for the development of resistance to these agents. Materials are also beigg accumulated which promis# to lead to an interesting study of the process of mutation, which 1 hope to engage in next year. For example a system has been found in which mutations both to and away from a functioning condition of a gene can be readily enumerated. In another system, divers strains have been found in which the rates of mutation of & gene are widely different. A third aspect of these investigations has concerned the study of other organisms to determine whether a sexual phase can be detected in them. This attempt has so far been fruitless, but the investiga- tion is still incomplete. In addition to those publications of which reprints are already on file, this research has led to the following publications, either in press or in an advanced stage of preparation: 1. Lederberg,J. The Nutrition of Salmonella _ Arch. Bioch. in press. 2. Lederberg,J. and E.L. Tatum, Nével Genotypes in mixed cultures of biochemical mutants of e coll Gold Spring Harbor Symposium, 19496, in press. 3, Tatum, E,L, and J. Lederberg, Gene Recombination in the bacterium Escherichia coli. Joury.Bact. in press. 4. Lederberg,d. Problems in Bacterial Genetics in manuscript 5. Lederberg,J. and E,L.Tatum, The segregation of genetic fac-~ tors in Egcherichia coll. in ravas manuscript. Research Plans The research program which I have in mind is perhaps already implicit. Dr. Ryan and I have long planned to use biochemical mutants of bacteria for an intensive study of the mutation process; this will be particularly relevant now that genetic analysis isSpossible. This program includes comparisons of the effects of radiations, temperature, carcinogenic and other chemical mitagens primarily on £ the reverse-mutation of biochBilical deficiency mutations to the normal functhoning state, but in a few instances, also in the mutational loss of function. The implications of ‘reverse~-mutations' for cancer have already been mentioned in a note entitled "A nutritional concept of cancer", but these investigations mist be regarded as valuable in themshlves as attempts to ivprove our knowledge of the gene. Bacteria are unprecedentedly suitable for this type of research. The discovery of genetically conditioned differences in mutability may open up an additional avenue of researsh. For the support of the program just summarizeda of research and medical studies, I do hereby appeal to the Board for 4 renewal of the fellowship grant, for the present enjoyment of which I am most grateful. Yours sincerely, Joshua Lederberg. Plans for 1947-1948 By Septmmber 1947, all the requirements for the degree pf Ph.D. at Yale U,iversity shall have been completed, my preparation for this degree having consisted almost entirely of the research which has been sponsored by the Childs Fund. At that time, I pro- pese to return to the College of Physicians and Surgeons, Columbia University, to resume and complete studies leading to the degree of H.D. My place in the third-year class has been assured. There has been almost complete unanimity among the people whom I have consulted regarding these plans advising that the complett@on of these studies would be an exceddingly valuable preparation for later research in the medical sciences, particularly ink such & field as cancer where there must be a close collaboratgon between blological and clinical studies. On the basis of my previous experiences,however, I can assure the Board that I will also be able to continue to pursue researches in the directions that were begun under the ourrent fellowspip grant. I can anticippte that I shall be able to devote approximately one-third of my attentiona to this purpose. During my first two years, I was able to do even more, but the inoreasing burdens of the later clinical years must be taken into account. The fundamental methods and techniques and materials that will be used have been developed already here, so that I shall be able to spend what time I have on their ayplication. My wife is trained in this field and wili be able to assist me, although she expeots to be pursuing her own studies at Columbia. The space and major facilities for the proposed work have been promised to me in the laboratory of Dr. F.d-Ryan of the department of Zoology, Columbia University, with whom I have had the pleasure ofncollaborating in the past.