(LEAVE BLANK) FEDERAL. SECURITY AGENCY PUBLIC HEALTH SERVICE E-72(65) NATIONAL INSTITUTES OF HEALTH APPLI° ATION FOR RESEARCH GRANT MeI (2) PUBLIC HEALTH SERVICE Date October 28, 1952 NATIONAL INSTITUTES OF HEALTH Rec, 10-31-52 ~ — DIVISION OF RESEARCH GRANTS Feb.153 Council Bethesda 14, Maryland Application is hereby made for a grant in the amount of $ 9180. 0Cfor the period from September 4, 1953 . through Aughst 5l, 1954 Month Day ivar Month Day inclusive [not te exceed 7 year) for the purpose of conducting a research project on the following subject: {Give only brief descriptive title) TITLE OF Geasties of Salmonella and Escherichia PROJECT NAME OF PRINCIPAL, INVESTIGATOR TITLE OF PRINCIPAL INVESTIGATOR Joshua Lederberg Associate Professor of Genetics ADDRESS OF PRINCIPAL INVESTIGATOR Department of Genetics University of Wisconsin n 6, Wisconsin NAME OF FINANCIAL OFFICER TITLE OF FINANCIAL OFFICER TO WHOM CHECK SHOULD BE MAILED A. W. Petersen Vice-President, Business & Finance ADDRESS OF FINANCIAL OFFICER Bascom Hall University of Wisconsin Madison 6, Wisconsin AGREEMENT It is understood and agreed by the applicant: (I) That funds granted as a result of this request are to be expended for the purposes set forth herein; (2) that the grant may be revoked in whole or part at any time by the Surgeon General of the Public Health Service, provided that a revocation shall not include any amount obligated previous to the effective date of the revocation if such obligations were made solely for the purposes set forth in this application; (3) that all reports of original investigatons supported by any grant made as a result of this request shall acknowledge such support; (4) that if any patentable discoveries or inventions are made in the course of the work aided by any grant received as a result of this application, the applicant will, in consideration of such grant, refer to the Surgeon General of the Public Health Service, for determination, the question of whether such patentable discoveries or inven- tions shall be patented and the manner of obtaining and disposing of the proposed patents in order to protect the public interest, UNIVERSITY OF WISCONSIN NAME OF INSTITUTION NAME AND TITLE OF A. W. Peterson uo } OFFICIAL AUTHORIZED PS ow - g >, — Vs : TO SIGN FOR INSTITUTION : g Bis (Please Type} PERSONAL SIGNATURE. 7 " eo ~ {This agreement must carry the actual signature of the official whose name appears on the line above.) PAGE 1 PHS-398 Form Approved Rev. 8-51 Budget Bureau No. 68-R249.4 (LEAVE BLANK) B-72(c5) mer (2) These dates to be the same as those given on page 1, BUDGET PROPOSED FOR THE YEAR Sept. 1, 1953 through _—sA gust 31, 1954 NOTE: Under column entitled “OTHER” indicate funds presently available BUDGET or anticipated from other sources including own institution. REQUESTED | OTHER PERSONNEL [Itemize all positions by indicating type; names of professional personnel, if selected.} Principal Investigator (prorated for research only) $$ 6 OO Research Associate TT. C. Nelson, Ph. D. # 3 600 ” " EB. M, Lederberg, Ph. D. and ) Ph. Dd. ) 7 500 iesearsh Aagistan oom: MOA. 3 000 3 Research assistants, 1/2 time grad. students Te) Hourly help (dishwashers) 500 1 000 PERMANENT EQUIPMENT (itemize) CONSUMABLE SUPPLIES (itemize) _Glassware, chemicals and minor lab. apparatus 1 000 2 000 TRAVEL (State purpose) For consultations with other workers, including scientific meetings in the U. S. 200 100 OTHER EXPENSE (itemize) Publication expenses 200 200 NOTE: The administrative official signing this application may add SUBTOTAL for overhead an amount not to exceed 8 percent of the operating costs, i.e. 8 percent of the subtotal. OVERHEAD 680 TOTAL FOR THE YEAR $ 9 160 ESTIMATE OF FUTURE REQUIREMENTS $ 9 180 Estimate of future requirements applies to funds needed from the Public Health Service for the years subsequent to the period proposed at the top of this page. 9 180 The blanks at the right provide space for requesting four additional years of support; 2 any amounts entered should include "overhead" if such is to be requested. Do not 9 180 leave any of these spaces blank—enter one of the following as applicable: The amount 3 needed, "not applicable," “unknown” or “none”. FOR FURTHER INFORMATION: See detailed instructions accompanying application forms. 4 PAGE 2 PHS-398 Rev. 8-51 (LEAVE BLANK) E-72(C5) Mar (2) PUBLIC HEALTH SERVICE SUPPORT: Show previous and current Public Health Service grants supporting this project: GRANT NUMBER TITLE OF PROJECT AMOUNT PERIOD OF SUPPORT PREVIOUS . 1445 $378 | mly 198 1445-0 Gansties of Salmonella 3 760 1445-02 4 320 te E-72-03 Genetics of Bacteria 4 3® kagust. 1952 CURRENT E=72-C4 Genatics of Bacteria 9 160 Sept. 1952 to Angas’ 1953 ALL OTHER SUPPORT: Excluding Public Health Service, but including that from own institution, list support from other * sources for this project. If none, so indicate. SOURCE TITLE OF PROJECT AMOUNT PERIOD OF SUPPORT CURRENT A.E.C. Cytogenetic affects of radiations $ 2 162 3/52 = 2/5 Chemical Corpo | Recoubioation in bacteria & 000 52 ~ 9/53 Rockefeller Tasunogenetics of bacteria 8 000 §2 ~ 8/53 UB. of Wis. Ges tiey ef Bacteria il $00" =| 7/52 ~ 6/53 PENDING U. of Wis. Resodel. building & new lab. furnishing) 6000+ | oa. 1/53 U. of Wis. ot yet Lormmlated, but & to 53-54 Rockefeller § not ye 8 expec apply *isel. research portion, investigator's salary RESEARCH PLAN AND SUPPORTING DATA On the continuation pages provided give details of the proposed plan and other necessary data in accordance with the outline below. Number each page, the first continuation page being page 4. Additional continuation pages, if needed, may be requested from the Division of Research Grants. See detailed instructions before preparing this portion of the application. Il. RESEARCH PLAN A. Specific Aims-——Provide a concise statement of the aims of the proposed work, B. Method of Procedure---Give deteils of your plan of attack. C. Significance ef this Sesearch—Explain why the results of the proposed work may be important. D. Facilities Availabie--Describe the general facilities at your disposal. List the major items of permanent cauipment, 2. PREVIOUS WORK DONE ON THIS PROJECT Describe briefly any work you have done to date that is particularly pertinent. 3. PERSONAL PUBLICATIONS Cite your most important publications on this or closely related work. List no more than five. 4. RESULTS OBTAINED BY OTHERS Summarize pertinent results to date obtained by others on this problem, citing publications deemed pertinent. Select no more than five. 5. BIOGRAPHICAL SKETCHES Provide brief sketches for All professional personnel selected who are to be actively engaged in this project. | PAGE 3 PHS-398 Rey, 8-51 DO NOT TYPE IN THIS SPACE — BINDING MARGIN t APPLICATION FOR RESEARCH GRANT (Continuation page) (LEAVE BLANK) E-72(C5) M&I (2) 1. Research Plan A. Specific Aima. The long term chjective is a deeper uderstending of the mechanians of bacterial heredity, and their relation to the evolutionary ecology of bacteria in their natural environments. Hore immediately, two dis- tinctive mecheniems of variation, sexual recombination and genetic transduction, have been found in related becterial groups, Escherichia coli and the Salmonellas. These mechanisms are to be studied more in- tensiveiy to learn better how they work, and extensively to see the range of microorganisms to which they apply and the part they play in the evolution of new bacterial types. The problems which are being studied now, and which will engender the research topice for 1953-54, are msmarized in the appended Progress Report, including the develop- ment cf new serotypes in Salmonella, the mechaniam of flagellar phase variation, the cytological basis of sexual recombination in E. eoli and the genetic role of latent bacteriophage. Bo Method of Procedure The preceduree are inherent in the work in progress ae outlined. Co Significance of Research. The most immediate applicatione of this work concern the serological diagnosis of Salmonella types. The impor- tance ef a fuller knowledge of the biology of microbial pathogens re- quires no ye-emphasie; some of the mest potent approaches to this fun- damental knowledge are through genetics and cytology. It is indispen- sable to epidemiclogy and to the long-term success of chemotherapy in the face of the development of drug-resistance. D. Available Facilities: a well equipped microbiological research leboratory with chemical benches, incubators, refrigerator, cold room, freezer anc fume hood. The equipment includes several centrifuges (including multispeed and chemical), Coleman spectrophotometer, ana- lytical balance, shaking and pipetting machines, ultraviolet irradia~ tion equipment, eireular Warburg manometric apparatus, deFonbrune micromanivulatas, lyophil acparatus, and a well appointed setup for critical microscopy (including darkfield and phase contrast) and phote- micrography. Jt should be pointed out, however, that this type of work depends mors on personal inspiration and dexterity than on special apparatus. Fer apecial purpeses, the facilities of the Enzyme Research Institute and of other university departments have been made available and used from time to time. enor DO NOT TYPE IN THIS SPACE — BINDING MARGIN APPLICATION FOR RESEARCH GRANT (Continuation page) (LEAVE BLANK) . 20 Previous Work. (has been largely summarized in reference 1 below) The mechaniam of recombination of genetic factors in E. soli Ke l2, first discsyerad by Tatum and Lederberg in 1947, haa been the aubfect of the larger part ef previous research. It haa been concluded that sone sort of sexual precese is involved, although the cytological aspects are still undemonctrated. The main evidence for this cenelu- sion comes from the genetic analysis and the production ef persistent diploid hybrids, and from the obligatory association of intact celle with the ability to exchange genetic factors. Throughout thie peried, Salmonella typhimurium was studied from a similar viewpoint, beginning with a nutritional survey of the Salmonella group. Frem 1948-52, Mr. No Zinder was assceiated with thie program as a graduate student, cul- minating in his dissertation fer the Ph.D. (Wisconsin, 1952). (Dro Zin- der'a interest in the program will continwe under hie appointment at the Rockefelier Inetitute). The transduction of genetic factere in Salmonella was discovered and developed during 1951-1952. 3. Personal publications. 1947 The nutrition of Salmonella. Areh. Biochem. 13: 287-290 1751 Recombination analysis of bacterial heredity. Celd Spr. Harb. Sympo 16:413-445 (with Eo Mo Lederberg, No D. Zinder and Eo Ro Lively3 reviews earlier studies) 1952 Genetic sxehange in Salmonella. Jo Bact. 64: (Nev. '52) (with No Do Zinder) 1952 Sex compatibility in Escherichia coli. Genetics 37:720~730 (with Lo Lo Cavalli and E. My Lederberg) 1953 Genetic studies of lysogenicity in Escherichia coli. Genetics 36: (Jan. "53, with Eo M. Lederberg) 4. Resulte chtained by others. The basic experimental findings of the work with E. cold hawe been cenfirmed and extended by several ether laboratories aa indicated in the following titles. Cavalli, Lolo 1952 Geneties analysis of drug-resistance. World Health Org. Bult. 63 185-206 [Istituto Sieroterapieo Milanese |] Hayes, Wm. 1953 Observations on a transmissible agent determining sexual differentiation in Bacterium coli. J. Gen. Microbiol. In Press. [Postgr. Med. Sehoel Lendon] Rothfels, K. 1952 Gena linearity and negative interference in crosses of Escherichia coli. Genetics 37:297~311 (University of Toronte] Nelson, T.C. 1951 Kinetics of genetic recombination in Escherichia coli. Genetiss 36: 162-175 [Columbia University] a PHS-398 Rev. 8-51 DO NOT TYPE IN THIS SPACE — BINDING MARGIN PHS-398 Rev. 8-51 APPLICATION FOR RESEARCH GRANT (Continuation page) (LEAVE, BLANK) R=72(C5) M&I (2) Newcombe, 8.B, and Nyholm, M.H. 1950 Amomalous segregation in eresses of Escherichia coli. Amer. Nat. 84: 457-465 {Natl. Rea, Counsil Canada) 5. Biographical sketchee. Prineipel Davestigator: Lederberg, Jeshva. b. Montelair, NoJo, 1925. BoA. Columtdea 1944. Medical Sehool, Columbia 1944-46; Ph. Do (microbiology) Yale 1947. Fellow, Jane Coffin Childs Fund fer Medical Research, 1945-46; Publie Haalth Service Fellow 1947 (resigned). University of WISCONSIN: Asst. Prof. Genetics, 1947-50; asses. Prof. 1950---. University of California, Berkeley: Visiting Assoc. Pref. Bact. 1950. Affiliated Persomel (PHS funds): Nelsen, Thomas Clifford. b. Columbua,0., 1925. B.S. Queens College N.¥. 1946, Mo Ao 1946. PhoD. ( z001 ogy—bi ophysi om) Columbia 1951. Columbia Uo: Lecturer in Blophysice 1947-49. Califernia Inst. Tech.: Goaney Research Fellow 1950-51. Vanderbilt U. Asset. Praf. Biology, 1951-52. University ef WISCONSIN: Project Associate 1952---. Affiliated Persormmel (other funds): Lederberg, Eether M. (mee Zimmer) b. N.¥.City, 1922. Bodo Hunter 1942. Mofo StenPard 1946. Ph.D. Wiecensin (Genetics and bacteriol ) 50. Seholer NoY. Bot. Gard. 194)~42. NoloHos Rea. Assto (carnesie’ 1942-45, Jp. BMolegist 1945-44. University of WISCONSIN: PHS Pre- doctoral Research Fellow, NCI, 1947-49. University Fellow, 1949-50. Preject Agsoeiate 1950--—. Skaar, Po Dawid Ba Mishawaka, Ind os 1923. Bodo Indiana 1947. PhoDo (zeolegy) Twiiane 1952. University of WISCONSIN: Project Assoc. 1951-—~o Stecker, Bo AoDo So MoDo( Weatminster ) Dipt. Bact. ( Londen). Srp Lecturer, University of Lemion, Lenden Schoel of Hygiene and Trop. Med. Commonwealth Fund travelling Fellow, 1952. Spicer, 0.0. MoBo Diplo Bact. ( London) Scientiet, Standards Laboratory, Central Public Health Laboratory, Public Health Laboratory Service, Londen, Eng. Fallow, World Health Organization, 1952 pace