FEDERAL SECURITY AGENCA (LEAVE BLANK) PUBLIC HEALTH SERVICE _ - E-72 (chs) NATIONAL INSTITUTES OF HEALTH APPLICATION FOR RESEARCH GRANT MeI (3) (Supplenental) PUBLIC HEALTH SERVICE Date NATIONAL INSTITUTES OF HEALTH Rec.201f-52 June 52 Council DIVISION OF RESEARCH GRANTS Bethesda 14, Maryland Application is hereby made for a grant in the amount of $ 4860 for the period from September i 1952 through August, 51 1993 Month Day Year Month Day Yoar inclusive [not to exceed 7 year) for the purpose of conducting a research project on the following subject: TGive only brief descriptive fitlel TITLE OF ; . PROJECT Genetica eof Bacteria NAME OF PRINCIPAL INVESTIGATOR . TITLE OF PRINCIPAL INVESTIGATOR doshua Lederberg Associate Professor of Genetics ADDRESS OF PRINCIPAL INVESTIGATOR Department of Genetics University of Wieconain Madiem6 Wisconsin NAME OF FINANCIAL OFFICER TITLE OF FINANCIAL OFFICER TO WHOM CHECK SHOULD BE MAILED . Ae We Peterson Vice President, Business & Minenos ADDRESS OF FINANCIAL OFFICER Bascom Hall Undvereity of Wisconsin Madison 6, Wisconsin AGREEMENT It is understood and agreed by the applicant: (1) 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, NAME OF INSTITUTION The University ef Wieconsin wa Pc? EU EN eatin ee z ¢ . NAME AND TITLE OF OFFICIAL AUTHORIZED TO SIGN FOR INSTITUTION {Please Type! (signed) A. W. PETERSON PERSONAL SIGNATURE____. (This agreement mi carry the actual signature of the official whose wame appears on the Ilne above.) ort PA PHS-398 Form Approved Rev. 8-51 Budget Bureau No. 68-R249.4 (LEAVE BLANK) B=72 (ChS)MEI (3) These dates to be the same as those given on page 1. BUDGET PROPOSED FOR THE YEAR (Sepplementel) through NOTE: Under column entitled "OTHER" indicate funds presently available BUDGET or anticipated from other sources including own institution. REQUESTED FROM P.H.S. OTHER PERSONNEL (ltemize all 7; names of PERMANENT EQUIPMENT (itemize) CONSUMABLE SUPPLIES (itemize) TRAVEL, (State purpose} Maitions), far consultations with ether workers (including eclentifie meetings in the U.S.) OTHER EXPENSE (itemize) Kone 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 TOTAL FOR THE YEAR ESTIMATE OF FUTURE REQUIREMENTS 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. The blanks at the right provide space for requesting four additional years of support: any amounts entered should include "overhead" if such is to be requested. Do not leave any of these spaces blank—enter one of the following as applicable: The amount needed, "not applicable,” "unknown" or "none". FOR FURTHER INFORMATION: See detailed instructions accompanying application forms. PAGE 2 PHS-398 Rev. 8-51 if selected.) 360 $ A860 ) that. appearing 2 -9288) on the prinary _eonte "Bitty restate 3 ¥ restéted 4 Uaknown (LEAYE BLANK), E-72(chS) MeI (3) 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 $ 37680 Jaly 1948 1445-60-02 Geneties of Salwenella 3780 te (E-72) | : 7 11,880 | Angast 1951 CURRENT . : " . E-72 (C3) Genetics ef Bacteria 4320 Sept. 1951 ~ August 1952 , Excluding Public Health Service, but including that from own Institution, list support from other ALL OTHER SUPPORT: sources for this project. If none, so indicate. SOURCE TITLE OF PROJECT AMOUNT PERIOD OF SUPPORT CURRENT. — AEC Cytogenstic effect of radiations $ 1000 3/51. - 2/52 Chemical Corps /|Host-parasite relationships:lysogenic'y, 6000 Vn - 1/52 Institation Geneties,ef Racteria qyooo * | 7/51 ~ 6/52 * & Rockefeller| Immunogenetics of Basteria go0o 9/51 - 6/53 PENDING AEC Cytegenetie effecte of radiations gn00 3/52 - 2/53 Cheaical Corps | Lysegenieity; resombinatien in bacter., 8000( 1/52 - 9/53 Tastitation Genetics of Bacteria @000 # «=| 7/52 - 6/53 *Exnlusive of investigator's salary. Incl. current % costes RESEARCH PLAN AND SUPPORTING DATA On the continuation pages provided give detalls 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. 1, RESEARCH PLAN A. Specific Aims—Provide a concise statement of the aims of the proposed work. B. Method of Procedure—Give details of your plan of attack. C. Significance of this Research—Explain why the results of the proposed work may be important. D. Facilities Available—Describe the general facilities at your disposal. List the major items of permanent equipment. 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 ion 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 Rev. 8-51 DO NOT TYPE IN THIS SPACE — BINDING MARGIN APPLICATION FOR RESEARCH GR@§Mr (Continuation page) (LEAVE BLANK) B72 (chs) mex (3) Justification for contimation of sapport. As has been pointed out in previous applications, thie research progras is developing in a relatively new ficld. It may be many years before new thec- yetieal advances in bacterial genetics ean be translated into specific iapreve- ments in medical practise. Continued support is requested simply in order to permit the contiqued developaent of eur experimental program on a long-range basis. Some speeific problemas have been solved, at least partially, but as many others arise out of these solutions. Justification for supplessntal support. Initial requests for research support from the Public Health Service were at the rather modest level of about $4000 per annum. This grant, applied primrily to work on Salmonella transduction, was sufficient to enable ote Graduate stedent to assist in this research, and initially, to kelp provide vas of the durable apparates needed. For some years, little substantial pro- gress could be reported from this project, and there might have been som question whether even the modest investment would be recovered. During the last year, however, the plctare has changed completely to give experimental findings of considerable general interes’. Clues of similar import have developed in studies with ©. soli. Farther expansion ef our work on these wabjecte sppeara to be desirable. The supplematal grait would perait the assign- ment of a more mature research worker { a post-doctoral associate) to eollabo- vate on these problens, the details of whieh are presented in the appended progress report. Fortunately, this step would eefacide with the provision of 4nereased laboratory space by the University of Wisconsin so that facikities for an expanded staff will. be avaliable. PAGE______ PHS-398 Rev. 8-51 DO NOT TYPE IN THIS SPACE — BINDING MARGIN APPLICATION FOR RESEARCH ir (Continuation page). (LEAVE BLANK) Be72 (GhS) Mer (3) Research Plan. Thie project is already in progress, anil ite ebjectives ani are most profitably dicoussed 2a wens we Oe Se dnvertigated. These are smmarined in the appenied Progress current grant, £72-0( 5). de Specific aims. ‘These may be restated as a deeper witeretanding af the mechanians by whieh specific traits ef bacteria are regularly tranad tted fren gereretion to gewmation, ani emyeraciy the uschenions ef bacterial variation. So far, Escherishia ecld ent Selnemella typhinuriwm have been wtatied as type erganias fer the senarenee of genetic recenhinstion, ani already two contrasting mechantews have heen feusi: sexual fusion ani reduction in E. coli; another oné new wachaetem in Salmmella, traneitietion. Innctiate objectives in this long-term study are given in pert D of the Progress Rapert. 8. Bethod ef procedure. Plenee see Progress Report, perts B and D. Cs Significance ef resserch. Pleam see Pragyess Report, part Qs. The mecharions of bacterial veriation ani the charavterietics we are inveti- gating (drug-resistance; enzyne petterns; antigeic structure) ere fusienmtel te elinieal bacterislegy, chenctherapy, veesinue preparation, ani teptcal ant — i for the D. Avedlable facilities: a well squipped micpebfclegical research laboratery with chenkoal denohes, incubaters, Sorin melted ont cheien)), Gelman race PHS-398 Rev. 8-51 heaAwWe Ml AMM DO NOT TYPE IN THIS SPACE — BINDING MARGIN SPPLICA TION FOR. RESEARCH GRANT (Continuation page) (LEAVE BANS? E=72 (chs) Med (3) 2, Previous work. This has been summarized in greater detail in previous applications and progress reports. With E. coli K-12, Tatwn and Lederberg, ani Lederberg have investigated the mechanism of genetic recombination. This hae been interpreted as a con- sequence of a sexual process, occurring at a frequency too small to be detec- table by direct microscopic stuly (about 1 per million vegetative celis). Because of the low frequency, selective methods are required to detect the recombinants. For this purpose, nutritional mutants have been particularly useful, but alternative techniques using inhibitors are also availabie. the best evidence for the sexual basis of recombination hae been the isolation ef diploid hybrid oslls which later segregate the parental mariers. The in- terpregation of these celle as heterozygotes has been verified by single cell pedigree stulies (Zelle and Lederberg) . In the emriier work, stulies wre confined te derivatives of strain K-12. Subsequently, a screening method was developed that has permitted about three percent of E. coli iselates fras various sources to be characterized as interfertile. Previous work with Salmonella has been confined to a nutritional survey. 3. Personal publications. 1947 Gene recombination in the bacterium Escherichia coli. d. Bact. 53: §75-684 (with £. 1. Tatum) 147 Gene recombination and linked segregation in &. coli. Genetics 32: 505-525 1950 ‘The selection of genetic recenbinetions with bacterial growth inhibitors. Je Bact. BD: 211-215 1951 Single cell isolations of dipleid heterozygous E. coli. J. Bact. 61: 351-955. (with ¥. R. Zelle) 1951 Prevalence of E. coli straine exhibiting genetic recombination. Selence 114: 68-@ 4h. Results obtained by others. The basic experinental findings of this work have been confirmed in several laboratories. Additional contributions may also be cited as follows: a. Confirmation that the agent of recombination in E. coli is not filtrabis. b. and c. Further linkage studies and application to drug-resistance ad. Kinetic studies on the frequency of recombination e. Stinvlation of recombination by pre-trestnents with UV. a. Davis, Bed. 1950 Nonfiltrability of the agents of genetic recombination in E. coli. de Bacte 60: 507-508 b. Newcombe and Nyholm 1950 ‘The inheritance ef streptomycin resistance ani dependence in crosses of E. coli. Geretics 35: 603-611 PAGE____ PHS-398 Rev. 8-51 DO NOT TYPE IN THIS SPACE — BINDING MARGIN PHS-398 Rey. 8-51 APPLICATION FOR RESEARCH GRAS (Continuation page) (LEAVE BLANK) Ee72 (C8) Mer (3) @. Cavalli, Lob. ant Maccasare, Gele 1950 Chlerenycetin resistence in Ee coli, a case af quentitatéve inheritance in bacteria. Nature 166:991-2. 4. Relem, T.0. i} Kinetics ef gonetia recesbination in E. coli. Genetica 56: 1755 @. Olavk, JoBe et al. 2950 The wtinulation of gene recombination in Eo coli Jo Saute 3: 375-379 See also “Papers in micrsbial genetics: bacteria and becterial virwes" selected by J. Lederberg. University of Wiscensin Prees, Madiean, 2991. 5. Biographies! sketches. Principal. Investigator: Lederberg, Joshua. b. Mentelair, N.J., 1925. B.A. Célusbia 1944. Medical School, Colusbia 1%4~-46; Ph. D. (microbiology) Yale 1947. Fellow, Jane Coffin Childs Fuad fer Medical Researek, 1%5-46. University of Wisconsin: Asst. Professor ef Geneties 1947-1950; Aesoe. Prof. 1950-——~——. University of California, Berkeley: Visiting Agscc. Prof. Bacteriology 1950. Affiliated Personnel (Salaries from other son-institutional sources): Lederberg, Esther M. (nec Zimmer) b. New York City, 1922. B.A. Banter 1942. M.A. Stanford 1%6 . Ph. D. Wisconsia 1950. Scholar, 4..Y.Bot.Gerd. 1943-42. Res. Asst. (Carnegis) at NIH. L942-43. Junior Biologist (P-1) N.I.H. 1943-44. P.H.3. Predostoral Research Fellow, N.C.I., 19M7-49. University by Wisconsin: University Fellow 1949-50; Project Assoeiate Skaar, Palmer David. ». Mishawaka, Ind., 1923. B.A. Indians 1947. Ph.D. Indians 1952(peddiag). University of Wiscensia: Project Associate 1951--——. Prospective candidate for project-associateship on thie program: Melson, Thomas Clifford. b. Colusbns,0., 1925. B.S. Queens College, N.Y. 1946 Colusbia M.A. 1946 Ph.D. 1951 Columbia. Lecturer in Biophysics, 1947-1949. Goaney Research Fellow, California Institute of Tech- nology, 1950-51. Assistant Professor of Biology, Vanderbilt U., 1951--. Publications: see section 4d above. PAGE____.