Cold Spring Harbor Symposia on Quantitative Biology

COLD SPRING HARBOR SYMPOSIA ON QUANTITATIVE BIOLOGY

VOLUME XXXI COLD SPRING HARBOR SYMPOSIA ON QUANTITATIVE BIOLOG Y

Founded in 1933 by REGINALD G. HARRIS Director of the Biological Laboratory 1924 to 1936

The Symposia were organized and managed by Dr. Harris until his death. Their continued use- fulness is a tribute to the soundness of his vision

The Symposium Volumes are published by the Cold Spring Harbor Laboratory of Quantitative Biology Cold Spring Harbor, L.I., New York COLD SPRING HARBOR SYMPOSIA ON QUANTITATIVE BIOLOGY

VOLUME XXXI

The Genetic Code

COLD SPRING HARBOR LABORATORY OF QUANTITATIVE BIOLOGY COLD SPRING HARBOR, L.I., NEW YORK 1966 COPYRIGHT 9 1967 BY

THE COLD SPRING HARBOR

LABORATORY OF QUANTITATIVE BIOLOGY

Library of Congress Catalog Number: 34-8174

Printed in the U.S.A.

The Symposium Volumes are published by the Cold Spring Harbor Laboratory of Quantitative Biology. Cold Spring Harbor, New York, and may be purchased directly or through booksellers. Price of Volume 31--$15.00 (inc. postage). Price subject to change without notice. FOREWORD

In 1961, the genetic code was shown to be made up of three-letter words and the word UUU was found to code for phenylalanine. Five years have passed, and the code is now known, to all intents in its entirety. The effort that has gone into this decipherment, the strange sense of urgency, and the remarkable variety of approaches that have together led to the solution, must be without parallel in the history of biology. It seemed, therefore, to be the right moment to hold a meeting and draw together, once and for all, the many contributions to this solution. I am happy to acknowledge the help of our advisors in preparing the program. In particular, I wish to thank Drs. Francis Crick, Marshall Nirenberg, Joseph Speyer, and James Watson, who bore the brunt of the consultation. The task of assembling this volume has been carried out by our editor, assisted by Harriet D. Hershey, Deborah S. Frisch, and Elspeth Cairns. The meeting was held from the 2nd to the 9th of June, 1966, and was attended by about 350 people, including 33 from outside the United States. As in the past, the program was supported by the National Institutes of Health, United States Public Health Service; the National Science Foundation; the United States Atomic Energy Commission; and the United States Air Force Office of Scientific Research (under contract AF 49(638)1727). John Cairns, Editor: Leonora Frisch Director LIST OF PREVIOUS VOLUMES

Volume I (1933) Surface Phenomena, 239 pp. Volume II (1934) Aspects of Growth, 284 pp. Volume III (1935) Photochemical Reactions, 359 pp. Volume IV (1936) Excitation Phenomena, 376 pp. Volume V (1937) Internal Secretions, 433 pp. Volume VI (1938) Protein Chemistry, 395 pp. Volume VII (1939) Biological Oxidations, 463 pp. Volume VIII (1940) Permeability and the Nature of Cell Membranes, 285 pp. Volume IX (1941) Genes and Chromosomes. Structure and Organization, 315 pp. Volume X (1942) The Relation of Hormones to Development, 167 pp. Volume XI (1946) Heredity and Variation in Microorganisms, 314 pp. Volume XII (1947) Nucleic Acids and Nucleoproteins, 279 pp. Volume XIII (1948) Biological Applications of Tracer Elements, 222 pp. Volume XIV (1949) Amino Acids and Proteins, 217 pp. Volume XV (1950) Origin and Evolution of Man, 425 pp. Volume XVI (1951) Genes and Mutations, 521 pp. Volume XVII (1952) The Neuron, 323 pp. Volume XVIII (1953) Viruses, 301 pp. Volume XIX (1954) The Mammalian Fetus. Physiological Aspects of Development, 225 pp. Volume XX (1955) Population Genetics: The Nature and Causes of Genetic Variability in Population, 346 pp. Volume XXI (1956) Genetic Mechanisms: Structure and Function, 392 pp. Volume XXII (1957) Population Studies: Animal Ecology and Demography, 437 pp. Volume XXIII (1958) Exchange of Genetic Material: Mechanism and Consequences, 450 pp. Volume XXIV (1959) Genetics and Twentieth Century Darwinism, 321 pp. Volume XXV (1960) Biological Clocks, 524 pp. Volume XXVI (1961) Cellular Regulatory Mechanisms, 408 pp. Volume XXVII (1962) Basic Mechanisms in Animal Virus Biology, 535 pp. Volume XXVIII (1963) Synthesis and Structure of Macromolecules, 610 pp. Volume XXIX (1964) Human Genetics, 492 pp. Volume XXX (1965) Sensory Receptors, 649 pp. SOME SYMPOSIUM PARTICIPANTS First row: C. Davern, M. C. Ganoza, J. D. Smith, D. H. Levin - - K. Marcker, M. S. Bretscher, E. Gallucei - - H. M. Dintzis, A. Pardee, N. D. Zinder, D. S. Hogness, F. Jacob. Second row: J. Speyer, P. Lengyel, W. M. Stanley, Jr. - - H. G. Wittmann, C. Woese - - C.-T. Yu, P. Ho. Third row: A. Maeda, H. Hayashi, A. Nakata, Y. Okada - - C. Yanofsky, H. Whitfield, B. N. Ames, J. Fink - - G. Streisinger, H. W. Lewis. Fourth row: M. Nirenberg, B. P. Doctor, C. T. Caskey-- 0. Siddiqi, S. E. Bresler, J. Scaife--E. Borek, M. B. Hoagland. SOME SYMPOSIUM PARTICIPANTS First row: H. Feldmann, D. Dfitting, L. Harris, U. Henning - - C. E. Magni, W. Szybalski, G. von Ehrenst,ein, A. O. W. Stretton - - H. G. Khorana, F. H. C. Crick, M. Grunberg-Manago. Second row: A. Peterkofsky, C. Jesensky, J. D. Capra - - J. Kan, W. Gartland, J. R. Fresco, T. Kano-Sueoka, N. Sueoka - - A. Newton, H. D. Hershey, E. Signer, J. Davies, B. D. Davis. Third row: E. Englesberg, F. C. Neidhardt - - R. H. Doi, F. H. C. Crick, A. J. Wahba, J. D. Watson, H. Subak- Sharpe - - J. D. Watson, S. Garen, A. Garen, D. S. Itogness. Fourth row : J. M. Clark, M. E. Reichmann, U. L. RajBhandary - - J. Monod, P. Lengyel, W. Gilbert, L. Gorini - - R. P. Novick, J. tturwitz, B. Weiss. SOME SYMPOSIUM PARTICIPANTS First row: d. T. Madison, S. E. Bresler, H. G. Zachau, B. P. Doctor - - R. G. Martin, G. S. Stent, G. M. Tomkins - - U. Maitra, d. D. Karam, A. Novick, P. Margolin, L. Frisch. Second row: H. J. F. Cairns, P. Leder, R. E. Thach- -M. J. Chamberlin, C. Yanofsky- -F. Jacob, F. Gros. Third row: P. Doty, H. G. Wittmann-- R. C. Wilhelm, B. D. Davis, I. B. Weinstein, F. Frankel, H. G. Khorana - - H. Matthaei, H. G. Khorana, F. Lipmann. Fourth row: G. N. Gussin, A. Tissieres-- P. Berg, A. Rich, It. M. Dintzis-- A. d. Blume, P. Margolin, R. Bauerle (Photographs by A. Bernheimer, Jr. and W. C. Saxinger) List of Those Attending the Symposium

ADAMS, ALICE, Dept. of Biology, Princeton Uni- BEERS, W. H., Rockefeller University, New York, versity, New Jersey New York ADAMS, JERRY M., The Biological Laboratories, BELL, DAVID, Dept. of Genetics, Glasgow Univer- Harvard University, Cambridge, Massachusetts sity, Glasgow, Scotland ADESNIK, B., Massachusetts Institute of Tech- BEMSKI, George, Albert Einstein College of Medi- nology, Cambridge, Massachusetts cine, Dept. of Medicine, Bronx, New York AHMED, ASAD, Food and Drug Laboratory, Dept. BENGELSDORF, IRVING S., Science Editor, Los of National Health and Welfare, Ottawa, Angeles Times, California Ontario, Canada BENNETT, THOMASP., Rockefeller University, New York, New York ALBERGHINA, FILIPPA A. M., Dept. of Biology, BERG, PAUL, Dept. of Biochemistry, Stanford McCollum Pratt Institute Johns Hopkins Uni- University, School of Medicine, Palo Alto, versity, Baltimore, Maryland California ALGRANATI, ISRAELD., Dept. of Biochemistry, New BERGQUIST, PETER L., University of Auckland, York University School of Medicine, New Microbiology Dept., Auckland, New Zealand York, New York BERKOWITZ, DAVID, Laboratory of Molecular Biol- ALPERS, David H., Dept. of Medicine, Harvard ogy, National Institutes of Health, Bethesda, Medical School, Boston, Massachusetts Maryland AMATI, PAOLO, International Laboratory of Genet- BERNHEIMER, ALAN, JR., Cold Spring Harbor ics and Biophysics, Naples, Italy Laboratory AMES, BRUCE N., National Institutes of Health, BIRGE, E. A., Dept. of Zoology, University of Bethesda, Maryland Wisconsin, Madison, Wisconsin ANDERSON, PORTER, Harvard University Medical BLUME, ARTHUR J., Dept. of Bacteriology and School, Boston, Massachusetts Botany, Biological Research Laboratories, ANDERSON, W. FRENCH, Laboratory of Biochemical Syracuse University, Syracuse, New York Genetics, National Heart Institute, National BOEZI, JOHN A., Dept. of Biochemistry, Michigan Institutes of Health, Bethesda, Maryland State University East Lansing, Michigan ANDOH, TOSHIWO, Dept. of Molecular Biophysics, BOLLON, ARTHUR, Laboratory of Genetics, C. W. Yale University, New Haven, Connecticut Post College, Brookville, New York APIRIO~, D., Dept. of Microbiology, Washington BOREK, ERNEST, Dept. of Biochemistry, Columbia University Medical School, St. Louis, Mis- University, New York souri BRAM, Stanley, University of Wisconsin, Dept. of ARLINGHAUS, Ralph, U.S. Dept. of Agriculture, Biophysics, Madison, Wisconsin Animal Disease Research Laboratory, Plum BRAUN, VOLKMAR, California Institute of Tech- Island, Orient Point, L.I., New York nology, Pasadena, California ARONOVITCIt, JACOB, Dept. of Bacteriology and BRECKENRIDGE, LEE, Dept. of Bacteriology and Immunology, Harvard Medical School, Boston, Immunology, Harvard Medical School, Boston, Massachusetts Massachusetts BALBINDER, ELIAS, Biological Research Labora- BRESLER, S. E., Institute of High Molecular Com- tories, Dept. of Bacteriology and Botany, pounds, Leningrad, USSR Syracuse University, Syracuse, New York BRETSCHER, MARK S., M. R. C. Laboratory of BARNETT, W. EDGAR, Biology Division, Oak Ridge Molecular Biology, Cambridge, England National Laboratory, Oak Ridge, Tennessee BROWN, DAVID H., Oak Ridge National Labora- BAUERLE, RONALD, Division of Biology, Graduate tory, Biology Division, Oak Ridge, Tennessee Research Center of the Southwest, P0 Box BROWN, J. C., Chemistry Dept., Harvard Univer- 30365, Dallas, Texas sity, Cambridge 38, Massachusetts BAUMBERC, SIMON, Institute of Microbiology, BURGI, ELIZABETH,Cold Spring Harbor Laboratory Rutgers, the State University, New Brunswick, CAFFERATA, ROBERT L., State University of New New Jersey York at Stony Brook, Stony Brook, New York BAUTZ, EKKEHARD, Institute of Microbiology, CAIRNS, JOHN, Cold Spring Harbor Laboratory Rutgers, the State University, New Brunswick, CALVO, Josm'H, Dept. of Biochemistry, Cornell New Jersey University, Ithaca, New York BEAR, PHYLLIS, Cold Spring Harbor Laboratory CALVO, RITA, Cornell University, Ithaca, New York BECKER, A., Albert Einstein College of Medicine, CANTONI, GIULIO L., National Institute of Mental Dept. of Developmental Biology and Cancer, Health, National Institutes of Health, Beth- Bronx, New York esda, Maryland LIST OF THOSE ATTENDING THE SYMPOSIUM xi

CAPRA, J. DONALD, National Institutes of Health, DUGRE, DONALD H., Dept. of Chemistry and Bethesda, Maryland Chemical Engineering, University of Illinois, CASKEY, C. THOMAS, National Heart Institute, Urbana, Illinois National Institutes of Health, Bethesda, Mary- DUTCHER, JAMES D., Squibb Institute, New Bruns- land wick, New Jersey CARBON, JOHN, Dept. of Biochemistry, Abbott DUTTI:NG, DIETER, Institut fiir Genetik, Universitiit Laboratories, N. Chicago, Illinois KSln, Germany CHAMBERLIN, MICHAEL J., Dept. of Molecular EARHART, CHARLES F., JR., Dept. of Biological Biology and Virus Laboratory, University of Sciences, Purdue University, Lafayette, In- California, Berkeley, California diana CHANG, ALBERT, Dept. of Botany, University of EGA:N, BARRY, Dept. of Biochemistry, Stanford Illinois, Urbana, Illinois Medical Center Stanford, California CLARK, JOHN M. JR., Dept. of Chemistry, Univer- EHRE:NSTEI:N, G. vO:N, Dept. of Biophysics, The sity of Illinois, Urbana, Illinois Johns Hopkins University School of Medicine, CLINE, A. L., Dept. of Biochemistry, University of Baltimore, Maryland Wisconsin, Madison, Wisconsin EHRI:NG, RUTH, Cold Spring Harbor Laboratory COCIOBA, ION D., Laboratory of Bacterial Genetics, EIKENBERRY, ERIC F., Biology Dept., Massa- Beth Israel Medical Center, New York chusetts Institute of Technology, Cambridge, CRAMER, F. D., Max-Planck-Institut-ffir Experi- Massachusetts mentelle Medicin, GSttingen, Germany EMRICH, JOu L., Institute of Molecular Biology, CRICK, F. H. C., MRC Laboratory of Molecular University of Oregon, Eugene, Oregon Biology, Cambridge, England ENGELHARDT, DEA:N LEE, The Rockefeller Univer- CRIPPA, MARCO, The Rockefeller University, New sity, New York, New York York, New York DARROW, JANET M., Purdue University, W. E:NGLESBERG, ELLIS, Dept. of Biological Sciences, Lafayette, Indiana University of California, Santa Barbara, Cali- DAVERN, CEDRIC, Cold Spring Harbor Laboratory fornia DAVIES, JULIA:N, Dept. of Bacteriology and Immu- EPLER, J. L., Oak Ridge National Laboratory, nology, Harvard Medical School and Institut Oak Ridge, Tennessee Pasteur, Paris, France EPSTEIN, WOLFGA:NG, Biophysical Laboratory, DAVIS, BEE:NARD D., Dept. of Bacteriology and Harvard Medical School, Boston, Massa- Immunology, Harvard Medical School, Boston, chusetts Massachusetts FANTO:NI, A., Columbia University, New York DAY, LAWRENCE E., Microbiological Research FARO:N, FRA:NCOISE, Public Health Research Insti- Dept., Medical Research Laboratories, Charles tute of New York, New York, Pfizer & Company, Inc., Groton, Connecticut FELDMA:N:N,HORST, Institut of Genetics, University DEUTSCHER, M., Dept. of Biochemistry, Albert of Cologne, Germany Einstein College of Medicine, Bronx, New York FINK, GERALD R., NIAMD, Laboratory of Molec- DICKERMAN, HERBERT, National Heart Institute ular Biology, National Institutes of Health, National Institutes of Health, Bethesda, Bethesda, Maryland Maryland FLAKS, JOEL G., Dept. of Biochemistry, University DINTZIS, HOWARD M., Dept. of Biophysics, Johns of Pennsylvania Medical School, Philadelphia, Hopkins University School of Medicine, Balti- Pennsylvania more, Maryland FRANKEL, FRED, University of Pennsylvania, DOCTOR, B. P., Div. of Biochemistry, Walter Reed Philadelphia, Pennsylvania Army Institute of Research, Washington, D.C. FRESCO, JACQUESR., Dept. of Chemistry, Princeton DOERFLER, WALTER, The Rockefeller University, University, Princeton, New Jersey New York, New York FREU:NDLICH, MARTI:N, State University of New DoI, RoY H., University of California, Dept. of York at Stony Brook, L.I., New York Biochemistry and Biophysics, Davis, California FRICK, HUGH, Dept. of Biology, State University DORFMA:N, BE:N-ZIoN, Dept. of Genetics, Albert of New York at Stony Brook, L.I., New Einstein College of Medicine, Bronx, New York York DOTY, Paul, Dept. of Chemistry, Harvard Univer- FRIEDMAN, Hannah, Massachusetts Institute of sity, Cambridge, Massachusetts Technology, Cambridge, Massachusetts DUDA, GEORGE D., Biology Branch, Div. of FRIEDMA:N, S., Cold Spring Harbor Laboratory Biology and Medicine, Atomic Energy Com- FRIEDMAN, S. M., Dept. of Medicine, Francis mission, Washington, D.C. Delafield Hospital, New York, New York xii LIST OF THOSE ATTENDING THE SYMPOSIUM

FRISCH, LEONORA, Cold Spring Harbor Laboratory GUSSIN, GARYN., The Biological Laboratories, Har- GALIZZI, ALESSANDROM., Johns Hopkins School of vard University, Cambridge, Massachusetts Medicine, Dept. of Biophysics, Baltimore, HARTMAN, PHILIP E., Dept. of Biology, Johns Maryland Hopkins University, Baltimore, Maryland GALLUCCI, ENRICO, Dept. Molecular Biophysics, HATFIELD, DOLPH, Lab. of Biochemical Genetics, Yale University, New Haven, Connecticut National Heart Institute, National Institutes GANOZA, M. CLELIA, The Rockefeller University, of Health, Bethesda, Maryland New York, New York HAYASI4I, HIROSHI, Institute of Molecular Biology, GAREN, ALAN, Dept. of Molecular Biophysics, Yale Faculty of Science, Nagoya University, University, New Haven, Connecticut Chikusaku Nagoya, Japan GARTLAND, W. J., Dept. of Biology, Princeton HAYASHI, SHIN-mHI, Laboratory of Molecular University, Princeton, New Jersey Biology, National Institutes of Health, GELEHRTER, THOMAS, NIAMD Lab. of Molecular NIAMD, Bethesda, Maryland Biology, National Institutes of Health, Beth- HAYWARD, JEREMY, Massachusetts Institute of esda, Maryland Technology, Cambridge, Massachusetts GHEI, OM K., Biology Dept., Brookhaven National HAYWARD, RICHARD S., Argonne Cancer Research Laboratory, Upton, New York Hospital, University of Chicago, Chicago, GILBERT, WALTER, Dept. of Physics and Biology, Illinois Harvard University, Cambridge, Massachusetts HEINTZ, R., Dept. of Cell Biology, University of GLASS, BENTLEY, State University of New York at Kentucky, Lexington, Kentucky Stony Brook, Stony Brook, L.I., New York HENLEY, DAVID D., Dept. of Chemistry, Frick GOLD, MARVIN, Dept. of Developmental Biology Laboratory, Princeton, New Jersey and Cancer, Albert Einstein College of Medi- HENNING, Ulf, Institut fiir Genetik, Universitat cine, Bronx, New York KSln, Germany GOLDBERG, IRVING H., Dept. of Medicine, Harvard HERSHEY, ALFRED D., Cold Spring Harbor Labo- Medical School, Boston, Massachusetts ratory GONANO, FABIO, International Laboratory of HEYTLER, PETER G., DuPont de Nemours Com- Genetics and Biophysics, Naples, Italy pany, Central Research Department, Wilming- GOODGAL, S., University of Pennsylvania, Phila- ton, Delaware delphia, Pennsylvania HILLE, MERRILL,Dept. of Biochemistry, New York GORDON, JULIAN, The Rockefeller University, New University School of Medicine, New York, York, New York New York GORINI, LVIGI, Harvard Medical School, Dept. of HIRstt, DAVID I., The Rockefeller University, New Bacteriology and Immunology, Boston, Massa- York, New York chusetts Ho, PETER P. K., Div. of Biology and Pharma- GOTTESMAN, MAX E., The Rockefeller University, cology, Lilly Research Lab., Eli Lilly and New York, New York Company, Indianapolis, Indiana GRODZICKER, TERRI, Dept. of Biological Sciences, HOAGLAND, M_AHLON B., Dept. of Bacteriology, Columbia University, New York, New York Harvard MedicalSchool, Boston, Massachusetts GROS, FRANCOIS, Institut de Biologia Pbysico- HOGNESS, DAVID S., Dept. of Biochemistry, Stan- chimique, Service de Physiologie Microbienne, ford University Medical School, Palo Alto, Paris, France California GROSS, JULIAN, MRC-Microbial Genetics Research HOLLEY, ROBERT W., Dept. of Biochemistry and Unit, Hammersmith Hospital, London, Eng- Molecular Biology, Cornell University, Ithaca, land New York GROSSMAN, LAWRENCE I., Dept. Biochemistry, HORIUCHI, KENSUKOE, The Rockefeller University, Albert Einstein College of Medicine, Bronx, New York, New York New York HOTC~KISS, ROLLIN D., The Rockefeller University, GRVNBERG-MANAGO, M., Institut de Biologie New York, New York Physico-chimique, Biochimie Division, Paris, HOWARD, BRUCE, Dept. of Biochemistry, Albert France Einstein College of Medicine, Bronx, New York GUERON, M. L., Massachusetts Institute of Tech- HUANG, SAM, Biology Department, State Univer- nology, Cambridge, Massachusetts sity of New York, Stony Brook, New York GUFTA, NABA K., Institute for Enzyme Research, HUNG, P. P., Dept. of Molecular Biology, Abbott University of Wisconsin, Madison, Wisconsin Laboratories, North Chicago, Illinois GUNSALUS, I. C., Dept. of Biochemistry, University HURWITZ, JERARD, Albert Einstein College of of Illinois, Urbana, Illinois Medicine, Bronx, New York LIST OF THOSE ATTENDING THE SYMPOSIUM xiii

IMAMOTO, FUMIO, Dept. of Biological Sciences, LAST, JEROLD A., Dept. of Biochemistry, New Stanford University, Stanford, California York University School of Medicine, New INGRAHAM, Laura, Cold Spring Harbor Laboratory York, New York INGRAM, VERNON M., Div. of Biochemistry, Dept. LAUFER, LOUIS, Schwarz Bioresearch Inc., Research of Biology, Massachusetts Institute of Tech- Dept., Orangeburg, New York nology, Cambridge, Massachusetts LAVER, W. G., Microbiology Dept., Australian INO, IKuo, Biology Department, Brookhaven National University, Canberra, Australia National Laboratory, Upton, New York LEBOWlTZ, Massachusetts Institute of Technology, ITAKAWA, Hiraku, Biology Department, C. W. Cambridge, Massachusetts Post College, Greenvale, New York LE BoY, PHOEBE, Dept. of Biochemistry, Univer- JACOB, FRANCOIS,Institut Pasteur, Dept. Microbial sity of Pennsylvania, Philadelphia, Pennsyl- Genetics, Paris, France vania JACOBSON, K. BRUCE, Biology Division, Oak Ridge LEDER, PHILIP, Biochemistry Section, Weizmann National Laboratory, Oak Ridge, Tennessee Institute of Science, Rehovoth, Israel JACOBSON, LEWIS A., Biochemistry Division, LEFKOVITS, IVAN, International Laboratory of University of Illinois, Urbana, Illinois Genetics and Biophysics, Naples, Italy JACOBY, GEOROE A., Dept. of Bacteriology and LENGYEL, PETER, Dept. of Molecular Biophysics, Immunology, Harvard Medical School, Boston, Yale University, New Haven, Connecticut Massachusetts LENNY, ALBERT, Cold Spring Harbor Laboratory JEN, LINDA C., Biochemistry Division, University LEWN, DANIEL H., Lab of Biophysics, Division of of Illinois, Urbana, Illinois Laboratories, Beth Israel Medical Center, New JESENSKY, CELIA, National Institute of Dental York, New York Research, National Institutes of Health, LEVIN, JUDITH G., Lab. of Biochemical Genetics, Bethesda, Maryland National Institutes of Health, Bethesda, JUKES, THOMAS H., Space Sciences Laboratory, Maryland University of California, Berkeley, California LEWIS, HERMAN W., Genetic Biology Program, KAJI, AKIRA, Dept. of Microbiology, School of National Science Foundation, Washington, Medicine, University of Pennsylvania, Phila- D.C. delphia, Pennsylvania LINDAHL, TOMAS, Dept. of Chemistry, Princeton KAN, JAMES, Dept. of Biology, Princeton Univer- University, Princeton, New Jersey sity, Princeton, New Jersey LIPMANN, F., The Rockefeller University, New KANIZIR, Dept. of Molecular Biophysics, Yale York, New York University, New Haven, Connecticut LIPSETT, MARIE N., National Institute of Arthritis KARAM, J. D., Cold Spring Harbor Laboratory and Metabolic Diseases, National Institutes of KELLER, ELIZABETH B., Dept. of Biochemistry, Health, Bethesda, Maryland Cornell University, Ithaca, New York LITTAUER, URIEL Z., Biochemistry Section, KEMPER, Josw, Cold Spring Harbor Laboratory Weizmann Institute of Science, Rehovoth, KERNAGHAN, R. PETER, Dept. of Biology, Univer- Israel sity of the State of New York, Stony Brook, LLANES, BARBARA, Dept. of Medical Biology, New L.I., New York York University Medical School, New York, KHORANA, H. GOBIND, Institute for Enzyme New York Research, University of Wisconsin, Madison, LODISH, HARVEY, The Rockefeller University, New Wisconsin York, New York KING, JONATHAN, Division of Biology, California Lu, PoNzY, Dept. of Biology, Massachusetts Institute of Technology, Pasadena, California Institute of Technology, Cambridge, Massa- KNIPPENBERO, P. H. VAN, National Institutes of chusetts Health, Bethesda, Maryland LUBART, KATHERINE J., Dept. of Biology, Purdue KONmSBERG, WILLIAMH., Dept. of Biochemistry, University, Lafayette, Indiana Yale University School of Medicine, New LvBr~, MARTIN, Dept. of Pharmacology, Harvard Haven, Connecticut Medical School, Boston, Massachusetts KULA, MARIA-REGINA,The Johns Hopkins Univer- LUCAS-LENARD, JEAN M., The Rockefeller Univer- sity School of Medicine Dept. of Biophysics, sity, New York, New York Baltimore, Maryland LUZZATI, MARIO, Dept. of Molecular Biophysics, KURLAND, CHARLES G., Dept. of Zoology, Univer- Yale University, New Haven, Connecticut sity of Wisconsin, Madison, Wisconsin MCCARTHY, B. J., Dept. of Microbiology and KURLAND, JEFFREY, Cornell University, Ithaca, Genetics, University of Washington, Seattle, New York Washington xiv LIST OF THOSE ATTENDING THE SYMPOSIUM

McCLINTOCK, BARBARA,Cold Spring Harbor Labo- NAKATA, ATSUO, Institute of Molecular Biology, ratory University of Oregon, Eugene, Oregon McLAuGHLIN, CALVIN S., Dept. of Cell Biology, NATHANS, DANIEL, Dept. of Microbiology, Johns University of California, Irvine, California Hopkins University, Baltimore, Maryland M~AS, WERNER K., Dept. of Microbiology, New NEELON, FRANCIS A., Laboratory of General and York University School of Medicine, New York Comparative Biochemistry, National Institute New York of Mental Health, NIH, Bethesda, Maryland MADISON, J. T., U.S. Plant, Soil and Nutrition NEIDHARDT, FREDERICK C., Dept. of Biological Laboratory, U.S. Dept. of Agriculture, Ithaca, Sciences, Purdue University, Lafayette, In- New York diana MAEDA, AKIO, Dept. of Chemistry, Harvard NEIMAN, SUSAN, Dept. of Biology, Massachusetts University, Cambridge, Massachusetts Institute of Technology, Cambridge, Mass. M~GNI, C. E., Institute of Genetics, University of NEWTON, W. AUSTIN, Service de Biochimie Cellu- Parma, Parma, Italy laire, Institut Pasteur, Paris, France MAITRA, UNIADAS,Dept. of Developmental Biology NIRENBER~, MARSHALL W., Laboratory of Bio- and Cancer, Albert Einstein College of Medi- chemical Genetics, National Heart Institute, cine, Bronx, New York N.I.H., Bethesda, Maryland MALAMY, MICHAEL H., Princeton University, NOLL, HANS, Dept. of Biological Sciences, North- Program in Biochemical Sciences, Princeton, western University, Evanston, Illinois New Jersey NOTANI, G. W., University of California, San MARCKER, K., MRC Laboratory of Molecular Diego Campus, La Jolla, California Biology, University Postgraduate Medical NovIcE, AARON, University of Oregon, Eugene, School, Cambridge, England Oregon MARCUS, PHILIP, Dept. of Microbiology and NOVICK, RICHARD P., Dept. of Virology, The Immunology, Albert Einstein College of Public Health Research Institute, East 16th Medicine, Bronx, New York Street, New York, New York MARGOLIN, PAUL, Cold Spring Harbor Laboratory OCHOA, MANUELJR., Dept. of Medicine, Columbia MARKS, PAUL A., Dept. of Medicine, Columbia University College of Physicians & Surgeons, University College of Physicians and Surgeons, New York, New York New York, New York ODA, Kinichiro, Dept. of Cell Biology, Albert MARMUR, JULIUS, Dept. of Biochemistry, Albert Einstein College of N[edicine, Bronx, New York Einstein College of Medicine, Bronx, New York OESCHGER, MAX P., Dept. of Microbiology, Johns MARSHALL, RICHARD, National Heart Institute, Hopkins University, Baltimore, Maryland Laboratory of Biochemical Genetics, National OESCHGER, NICOLE SPALDING, Dept. of Biology, Institutes of Health, Bethesda, Maryland Johns Hopkins University, Baltimore, Mary- MARTIN, ROBEnT G., Laboratory of Molecular land Biology, NIAMD, National Institutes of OFENGAND, JAMES, Dept. of Biochemistry, Univer- Health, Bethesda, Maryland sity of California Medical Center, San Fran- M~TTHAEI, H., Max-Planck-Institut fiir Experi- cisco, California mentelle Medicine, G6ttingen, Germany OKADA, YOSHIMI, Institute of Molecular Biology, MERRYMAN, P., 444 Central Park West, New York, University of Oregon, Eugene, Oregon New York OKAMOTO, KOJI, Dept. of Biochemistry, Albert MILLER, B., Cold Spring Harbor Laboratory Einstein College of Medicine, Bronx, New York MOLLER, MARYL., Princeton University, Princeton, O'NEAL, CHARLES H., The Rockefeller University, New Jersey Biochemistry Dept., New York, New York M6LLER, W., Dept. of Biophysics, Johns Hopkins 0PPENHEIM, A~OS B., Dept. of Bacteriology, Medical School, Baltimore, Maryland University of California, Davis, California MONOD, JACQUES, Dept. of Cellular Biochemistry, 0RGEL, LESLIE E., The Salk Institute for Biological Institut Pasteur, Paris, France Studies, La Jolla, California MORRIS, ALLANJ., Dept. of Biochemistry, Michigan ORIAS, EDUARDO, Dept. of Biological Sciences, State University, East Lansing, Michigan University of California, Santa Barbara, MOSIG, GISELA, Dept. of Molecular Biology, California Vanderbilt University, Nashville, Tennessee OSMUNDSEN, John A., Science Editor, Look MUENCH, KARL H., Dept. of Medicine, University Magazine, Madison Avenue, New York of Miami, Miami, Florida PARDEE, ARTHUR,Princeton University, Princeton, MULLER-HILL, BENNO, Biological Laboratories, New Jersey Harvard University, Cambridge, Mass. PESTKA, SIDNEY, Laboratory of Biochemical LIST OF THOSE ATTENDING THE SYMPOSIUM xv

Genetics, National Institutes of Health, SCHWARTZ, FRANCES M., The Rockefeller Univer- Bethesda, Maryland sity, New York, New York PETERKOFSKY,ALAN, National Institutes of Health, SCHWARTZ, JAMES H., Dept. of Microbiology, New Bethesda, Maryland York University School of Medicine, New PHILIPS, JOHN B., Cold Spring Harbor Laboratory York, New York PIERCE, RUTH, 15 Lewis Lane, Port Washington, SCHWEET, R., Dept. of Cell Biology, University of New York Kentucky, Lexington, Kentucky POLJAK, ROBERTO, Johns Hopkins School of SHAHN, EZRA, Wistar Institute of Anatomy, Medicine, Baltimore, Maryland Philadelphia, Pennsylvania POTTER, MICHAEL,Laboratory of Biology, National SHELDRICK,PETER, McArdle Memorial Laboratory, Cancer Institute, National Institutes of University of Wisconsin, Madison, Wisconsin Health, Bethesda, Maryland SHEN, T. Y., Synthetic Chemical Research, Merck, RAACKE, I. DOROTHEA, Dept. of Biology, Boston Sharpe & Dohme Research Labs, Rahway, University, Boston, Massachusetts New Jersey RAJBHANDARY, UTTAM L., Institute for Enzyme SIDDIQI, OBAID, Molecular Biology Unit, Tata Research, University of Wisconsin, Madison, Institute of Fundamental Research, Bombay, Wisconsin India RAPPAPORT, HARRY P., Biology Department, SIGNER, ETHAN R., Institut Pasteur, Paris, France Temple University, Philadelphia, Pennsylvania SILBERT, DAVID F., NIAMD, Laboratory of REBOUD, J. PAUL, Biochemistry Dept., The Molecular Biology, National Institutes of Rockefeller University, New York, New York Health, Bethesda, Maryland REICHMANN, M. E., Dept. of Botany, University of SILVER, SIMON D., Virus Laboratory, University of Illinois, Urbana, Illinois California, Berkeley, California RICH, ALEXANDER, Biology Dept., Massachusetts SIMON, SANFORD R., The Rockefeller University, Institute of Technology, Cambridge, Massa- Dept. of Biochemistry, New York, New York chusetts SIMPSON, MELVINV., Dartmouth College, Hanover, RIFKIN, DANIEL B., The Rockefeller University, New Hampshire New York, New York SKALKA, A., Cold Spring Harbor Laboratory RIFKIN, Mary R., The Rockefeller University, New SMITH, DAVID H., Dept. of Bacteriology, Harvard York, New York Medical School, Boston, Massachusetts RILEY, MONICA, Bacteriology Department, Univer- SMITH, J. D., M.R.C. Laboratory of Molecular sity of California, Davis, California Biology, Cambridge, England ROBEINS, DEANNA, Cold Spring Harbor Laboratory SMITH, MARVIN A., Dept. of Biochemistry, New RON, ELIORA, Dept. of Bacteriology, Harvard York University School of Medicine, New Medical School, Boston, Massachusetts York, New York ROTHSCHILD, HENRY, Biology Dept., Johns Hop- SOBELL, HENRY M., River Campus, University of kins University, Baltimore, Maryland Rochester, New York ROTTMAN,FRITZ, Biochemistry Department, Michi- SSLL, DIETER G., Institute for Enzyme Research, gan University of Wisconsin, Madison, Wisconsin RoY, ARUN K., Dept. of Biological Sciences, SONNENBERG, BETH P., Dept. of Biology, Columbia Columbia University, New York, New York University, New York, New York RUDNER, RIVKA, Dept. of Zoology, Columbia SPEYER, JOSEPH, Cold Spring Harbor Laboratory University, New York, New York SPYRIDES, GEORGE J., Central Research Dept., SABATINI, DAVID D., The Rockefeller University, E. I. duPont de Ncmours Company, Inc., New York, New York Wilmington, Delaware SAGER, RUTH, Dept. of Biology, City University of STAEHELIN,TIIEOPHIL, The Biological Laboratories, New York, New York Harvard University, Cambridge, Massachusetts SALAS, MARGARITA, Dept. of Biochemistry, New STANLEY,WENDELL M., JR., Dept. of Biochemistry, York University School of Medicine, New York, New York University School of Medicine, New New York York, New York SARACHEK, ALVIN, United States Atomic Energy STEINBERG, ROBERT, Harvard University, Cam- Commission, Washington, D.C. bridge, Massachusetts SAXINGER, W. C., University of Illinois, Urbana, STENT, GUNTHER S., Dept. of Molecular Biology, Illinois University of California, Berkeley, California SCAIFE, J., Dept. of Bacteriology and Immunology, STREISINGER, GEORGE, Institute of Molecular Harvard Medical School, Boston, Mass. Biology, University of Oregon, Eugene xvi LIST OF THOSE ATTENDING THE SYMPOSIUM

STRETTON, A. O. W., MRC Laboratory of Molecular Biology, NIAMD, National Institutes of Biology, Cambridge, England, Presently: Har- Health, Bethesda, Maryland vard University, Cambridge, Massachusetts WAHBA, ALBERT J., Dept. of Biochemistry, New STRIGINI, PAOLO, Dept. of Bacteriology and Immu- York University School of Medicine, New York, nology, Harvard Medical School, Boston, New York Massachusetts WARE, J., Massachusetts Institute of Technology, STULBERO, MELVIN P., Nuclear Division, Oak Cambridge, Massachusetts Ridge National Laboratory, Oak Ridge, WATSON, J. D., Biological Laboratories, Harvard Tennessee University, Cambridge, Massachusetts SUBAK-SHARPE, H., MRC Institute of Virology, WEBSTER, ROBERT E., The Rockefeller University, University of Glasgow, Glasgow, Scotland New York, New York SUEOKA, NOBORV, Dept. of Biology, Princeton WEmERT, MARTIN, Dept. of Molecular Biophysics, University, Princeton, New Jersey Yale University, New Haven, Connecticut SUEOKA, TAMIKO, Dept. of Biology, Princeton WEINSTEIN, I. B., Dept. of Medicine, Francis University, Princeton, New Jersey Delafield Hospital New York, New York SUSKIND, S., Johns Hopkins University, Baltimore, WEmBERG, ROBERT, Oak Ridge National Labo- Maryland ratory, Post Office Box Y, Oak Ridge, SUSSMAN, JOEL L., Massachusetts Institute of Tennessee Technology, Cambridge, Massachusetts WEISBLUM, BERNARD, Dept. of Pharmacology, SZYBALSKI,WACLAW, McArdle Laboratory, Univer- University of Wisconsin, Madison, Wisconsin sity of Wisconsin, Madison, Wisconsin WEISS, BERNARD, Dept. of Biological Chemistry, TAKAnAMI, M., Space Sciences Laboratory, Univer- Harvard Medical School, Boston, Massa- sity of California, Berkeley, California chusetts THACH, ROBERT E., Dept. of Chemistry, Harvard WEISS, SAMUEL B., Argonne Cancer Research University, Cambridge, Massachusetts Hospital and the Dept. of Biochemistry, THOMPSOn, E. BRAD, NIAMD, National Institutes University of Chicago, Illinois of Health, Laboratory of Molecular Biology, WERNER, RUDOLPH, Cold Spring Harbor Labo- Bethesda, Maryland ratory TILLEY, ROBERT J., Columbia University, New WETTSTEIN, FELIX 0., Virus Laboratory, Univer- York, New York sity of California, Berkeley, California TISSIERES, A., Laboratory de Biochimie Genetique, WHITFIELD, HARVEY, Laboratory of Molecular Geneva, Switzerland Biology, NIAMD, National Institutes of TGMASZ, ALEXANDER, Dept. of Genetics, The Health, Bethesda, Maryland Rockefeller University, New York, New York WILCOX, MICHAEL, Laboratory of Biochemical TOMASZ, MARIA, The New York Blood Center, Genetics, National Heart Institute, NIH, Virology Department, New York, New York Bethesda, Maryland TOMKINS, GORDON M., Laboratory of Molecular WILHELI~r ROBERT C., Dept. of Molecular Bio- Biology, NIAMD, National Institutes of physics, Yale University New Haven, Con- Health, Bethesda, Maryland necticut TORRIANI, ANNA MARIE, Dept. of Biology, Massa- WILLSON, CLYDE D., Dept. of Biochemistry, chusetts Institute of Technology, Cambridge, University of California, Berkeley, California Massachusetts WITTMANN, H. G., Max-Planck-Institut fiir Molek- TRUPIN, JOEL S., Laboratory of Biochemical ulare Genetik, Berlin-Dahlem, Germany Genetics, N.H.I., National Institutes of Health, WOESE, C. R., Dept. of Microbiology, University of Bethesda, Maryland Illinois, Urbana, Illinois UZIEL, Mayo, Biology Division, Oak Ridge National YAMANE, TETSUO, Bell Telephone Laboratories, Laboratory, Oak Ridge, Tennessee Murray Hill, New Jersey VANDE WOUDE, G. F., Plum Island Animal Disease YANOFSKY, C~ARLES, Dept. of Biological Sciences, Laboratory, Greenport, New York Stanford University, Stanford, California VESTRI, RITA, Dept. of Biophysics, Johns Hopkins YOURNO, JOSEeH, Brookhaven National Labora- Medical School, Baltimore, Maryland tory, Upton, New York VI~UELA, ELADIO, Dept. of Biochemistry, New Yu, CHUAN-TAo, The Rockefeller University, New York University School of Medicine, New York, New York York, New York ZACHAU, HANS G., Institut fiir Genetik der VOGEL, HENRY, Rutgers University, New Bruns- Universitat K61n, K61n, Germany wick, New Jersey ZINDER, NORTOn D., The Rockefeller University, VOLL, MARY JANE, Laboratory of Molecular New York, New York Contents

Foreword ...... v List of Previous Volumes ...... vi Photographs of Some Symposium Participants ...... vii List of Those Attending the Symposium ...... x Milislav Demerec ...... xxi

INTRODUCTION THE GENETIC CODE ...... 1 CRICK, F. H. C. The Genetic Code: Yesterday, Today, and Tomorrow ...... 3

CODONS IN VITRO NIRENBERG, M., T. CASKEY, R. MARSHALL, R. BRIMACOMBE, D. KELLOGG, B. DOCTOR, D. HATFIELD, J. LEVIN, F. ROTTMAN, S. PESTKA, M. WILCOX, and F. ANDERSON. The RNA Code and Protein Synthesis ...... 11 MATTHAEI, J. H., H. P. VOIGT, G. HELLER, R. NETH, G. SCHOCH, H. KUBLER, F. AMELUNXEN, G. SANDER, and A. PARMEGGIANI. Specific Interactions of Ribosomes in Decoding ...... 25 KHORANA, H. G., H. BUCHI, H. GHOSH, N. GUPTA, T. M. JACOB, H. KOSSEL, R. MORGAN, S. A. NARANG, E. OHTStTKA,and R. D. WELLS. Polynucleotide Synthesis and the Genetic Code ...... 39 SOLL, D., J. CHERAYIL, D. S. JONES, R. D. FAULKNER, A. HAMPEI~, R. M. BOCK, and H. G. KHORANA. sRNA Specificity for Codon Recognition as Studied by the Ribosomal Binding Technique ...... 51 HAYASm, H. and K. MXURA. Anticodon Sequence as a Possible Site for the Activity of Transfer RNA ...... 63 LETENDRE, C., A. M. MICHELSON, and M. GRUNBERG-M_ANAGO.Oligonucleotide Inhibition of Amino Acid Attachment ...... 71

DIRECTIONS OF READING STREISINGER, G., Y. OKADA, J. EMRICH, J. NEWTON, A. TSUGITA, E. TERZAGHI, and M. INOVYE. Frameshift Mutations and the Genetic Code ...... 77 THAC~, R., T. A. SUNDARARAJAN, K. F. DEWEY, J. C. BROWN, and P. DOTY. Translation of Synthetic Messenger RNA ...... 85 STANLEY, W. M., JR., M. A. SMITH, M. B. HILLE, and J. A. LAST. Studies on the Translation of the Genetic Message: I. Preparation of 01igonucleotide Messengers of Specified Base Sequence ...... 99 WAHBA, A. J., M. SALAS, and W. M. STANLEY, JR. Studies on the Translation of the Genetic Message: II. Translation of Oligonucleotide Messengers of Specified Base Sequence ...... 103 MAITRA, U., S. N. COHEN, and J. HURWITZ. Specificity of Initiation and Synthesis of RNA from DNA Templates ...... 113 SZYBALSKI, W., H. KUBINSKI, and P. SHELDRICK. Pyrimidine Clusters on the Transcribing Strand of DNA and their Possible Role in the Initiation of RNA Synthesis ...... 123 HOGNESS, D. S., W. DOERFLER, J. B. EGAN, and L. W. BLACK. The Position and Orientation of Genes in 2 and ~ dg DNA ...... 129

IN VIVO CODE AND POLARITY REICHMANN, M. E., A. Y. CHANG, L. FAIMAN, and J. M. CLARK, JR. The Satellite Tobacco Necrosis Virus in Studies of Genetic Coding ...... 139 WEIGERT, M. G., E. GALLUCCI, E. LANKA, and A. GAREN. Characteristics of the Genetic Code in vivo ...... 145 xvii xviii CONTENTS

YANOFSKY,C., J. ITO, and V. HORN. Amino Acid Replacements and the Genetic Code ...... 151 WITTMANN, H. G. and B. WlTTMANN-LIEBOLD. Protein Chemical Studies of Two RNA Viruses and their Mutants ...... 163 STRETTON, A. 0. W., S. KAPLAN, and S. BRENNER. Nonsense Codons ...... 173

POLARITY

NEWTON, A. Translation of the lactose Operon ofEscherichia coli ...... 181 MALAMY, M. H. New Jersey: Frameshift Mutations in the Lactose Operon of E. coli ...... 189 BAUERLE, R. H. and P. MARGOLIN. A Multifunctional Enzyme Complex in the Tryptophan Pathway of Salmonella typhimurium: Comparison of Polarity and Pseudopolarity Mutations ...... 203 MARTIN, R. G., H. J. WHITFIELD, JR., D. B. BERKOWITZ, and M. J. VOLL. A Molecular Model of the Phenomenon of Polarity ...... 215 AMES, B. N. and H. J. WHITFIELD,JR. Frameshift Mutagenesis in Salmonella 221 HENNING, U., G. DENNERT, R. HERTEL, and W. S. SHIPP. Translation of the Structural Genes of the E. coli Pyruvate Dehydrogenase Complex ...... 227 IMAMOTO, F., J. ITO, and C. YANOFSKY. Polarity in the Tryptophan Operon of E. coli ...... 235

PUNCTUATION

ZINDER, N. D., D. L. ENGELHARDT,and R. E. WEBSTER. Punctuation in the Genetic Code ...... 251 GUSSIN, G. N., M. R. CAPECCHI, J. M. ADAMS, J. E. ARGETSINGER, J. TOOZE, K. WEBER, and J. D. WATSOn. Protein Synthesis Directed by RNA Phage Messengers ...... 257 GANOZA, M. C. Polypeptide Chain Termination in Cell-free Extracts of E. coli 273 MARCKER, K. A., B. F. C. CLARK, J. S. ANDERSON. N-Formyl-Methionyl-sRNA and its Relation to Protein Biosynthesis ...... 279 DICKERMAN, H., E. STEERS, B. G. REDFIELD, and HERBERT WEISSBACH. Formylation of Escherichia coli Methionyl-sRNA ...... 287 BRETSCHER, M. S. Polypeptide Chain Initiation and the Characterization of Ribosomal Binding Sites in E. coli ...... 289 LEDER, P. and H. BURSZTYN. Initiation of Protein Synthesis. The Role of Formyl-aceepting Methionyl-tRNA ...... 297 RICH, A., E. EIKENBERRY, and L. MALKIN. Experiments on Hemoglobin Polypeptide-Chain Initiation and on the Shielding Action of the Ribosome 303

CONTROL OF GENE EXPRESSION

MakRGOLIN,P. and R. H. BAUERLE. Determinants for Regulation and Initiation of Expression of Tryptophan Genes ...... 311 CLINE, A. L. and R. M. BOCK. Translational Control of Gene Expression ..... 321 MARCUS, P. I. and J. M. SALB. Control of Viral RNA Translation as the Mecha- nism of Interferon Action ...... 335 SHEPPARD, D. and E. ENGLESBERG. Positive Control in the L-arabinose Gene- Enzyme Complex of E. coli B/r as Exhibited with Stable Merodiploids .. 345 TOMKINS, G. M., E. B. THOMPSON, S. HAYASHI, T. GELEHRTER, D. GRANNER, and B. PETERKOFSKY. Tyrosine Transaminase Induction in Mammalian Cells in Tissue Culture ...... 349 MARKS, P. A. and F. CoNcoNI. Polyribosomes and Control of Hemoglobin Synthesis ...... 361 CONTENTS xix

NAONO, S. and F. GROS. Control and Selectivity of 2 DNA Transcription in Lysogenic Bacteria ...... 363 SKALKA, A. Multiple Units of Transcription in Phage Lambda ...... 377 SIDDIQI, 0., B. N. APTE, and M. P. PITALE. Genetic Regulation of Aryl Sulphatases in Aspergillus nidulans ...... 381 ROTH, J. R., D. F. SILBERT, G. R. FINK, M. J. VOLL, D. ANTON, P. E. HARTMAN, and B. N. AMES. Transfer RNA and Control of the Histidine 0peron ...... 383 BECKWITH, J. R., E. R. SIGNER, and W. EPSTEIN. Transposition of the lac Region of E. coli ...... 393 SCAIFE, J. and J. R. BECKWITH. Mutational Alteration of the Maximal Level of lac Operon Expression ...... 403

TRANSFER RNA: CHEMISTRY MADISON, J. T., G. A. EVERETT, and H. K. KUNG. The Nucleotide Sequences of Yeast Tyrosine Transfer RNA ...... 409 ZACHAU, H. G., D. DUTTING, H. FELDMAN, F. MELCHERS, and W. KARAU. Serine-Specific Transfer Ribonucleic Acids. XIV. Comparison of Nucleotide Sequences and Secondary Structure Models ...... 417 RAJBHANDARY, U. L., A. STUART, R. D. FAULKNER, S. H. CHANG, and H. G. KHORANA. Nucleotide Sequence Studies on Yeast Phenylalanine sRNA .. 425 BERQUIST, P. L. Degenerate Transfer RNAs from Brewers Yeast ...... 435 LIPSETT, M. N. Disulphide Bonds in sRNA ...... 449 DoI, R. H. and B. GOEHLER. Conformation and Binding Efficiency of Lysyl- tRNA to a Poly A ribosome Complex ...... 457 HAYWARD, R. S., G. L. ELICIERI, and S. B. WEISS. Ribonucleic Acid Sulfur Transferase Activity in Extracts from E. coli ...... 459 OFENGAND, J. A New Nucleotide in the tRNA of E. coli ...... 465 WEISS, B. and C. C. RICHARDSON. End-group Labeling of Nucleic Acids by Enzymatic Phosphorylation ...... 471

TRANSFER RNA: FUNCTION SMITH, J. D., J. N. ABELSON, B. F. CLARK, H. M. GOODMAN, and S. BRENNER. Studies on amber suppressor tRNA ...... 479 CARBON, J., P. BERG, and C. YANOFSKY. Missense Suppression due to a Genetically Altered tRNA ...... 487 GUPTA, N. K., U. L. RAJBHANDARY,and H. G. KHORANA. M_issense Suppression in Trypophan Synthetase ...... 499 LITTAUER, U. Z., M. REVEL, and R. STERN. Coding Properties of Methyl- deficient Phenylalanine Transfer RNA ...... 501 PETERKOFSKY, A., C. JESENSKY, and J. D. CAPRA. The Role of Methylated Bases in the Biological Activity of E. coli Leucine tRNA ...... 515 WAINFAN, E., P. n. SRINIVASAN,and E. BOREK. Can the Methylation of tRNA Serve a Regulatory Function? ...... 525 FRESCO, J. R., A. ADAMS, R. ASCIONE, D. HENLEY, and T. LINDAHL. Tertiary Structure in Transfer RNAs ...... 527 MUENCH, K. H. Chloroquine-mediated Conversion of Transfer Ribonucleic Acid of Escherichia coli from an Inactive to an Active State ...... 539

TRANSFER RNA: INTERACTIONS DOCTOR, B. P., J. E. LOEBEL, and D. A. KELLOGG. Studies on the Species Specificity of Yeast and E. coli Tyrosine tRNAs ...... 543 BARNETT, W. E., and J. L. EPLER. Multiple Aminoacyl-RNA Synthetase Systems and the Genetic Code in Neurospora ...... 549 xx CONTENTS

NEIDHARDT, F. C. and C. F. EARHART. Phage-induced Appearance of a Valyl sRNA Synthetase Activity in Escherichia coli ...... 557 Yu, C. -T. Multiple Forms of Leucyl sRNA Synthetase of E. coli ...... 565 SUEOKA, N., T. KANo-SuEoKA, and W. J. GARTLAND. Modification of sRNA and Regulation of Protein Synthesis ...... 571 DoL R. H. and I. KANEKO. Transfer RNA Patterns of Bacillus subtilis during Sporulation and Growth ...... 581 SUBAK-S~ARPE, H., W. M. SHEPHERD, and J. HAY. Studies on sRNA Coded by Herpes Virus ...... 583

TRANSFER RNA AND RIBOSOMES

WETTSTEIN, F. 0. Differential in vivo Aminoacylation and Utilization of Homologous Species of E. coli Transfer RNA ...... 595 McLAuGHLIN, C. S., J. DONDON, M. GRUNBERG-MANAGO, A. M. M.ICHELSON and G. SAUNDERS. Stability of the Messenger RNA-sRNA-Ribosome Complex ...... 601 TAKANAMI, M. The 5'-Termini of E. coli Ribosomal RNA and f2 Bacteriophage RNA ...... 611 HATFIELD, D. Oligonucleotide-Ribosome-AA-sRNA Interactions ...... 619 FLAKS, J. G., P. S. LEBOY, E. A. BIRGE, and C. G. KURLAND. Mutations and Genetics Concerned with the Ribosome ...... 623 HErNTZ, R., H. MCALLISTER, R. ARLr~GHAUS, and R. SCHWEET. Formation and Function of the Active Ribosome Complex ...... 633 PESTKA, S. and M. NIRENBERG. Code-word Recognition on 30 S Ribosomes ... 641

INFIDELITY OF INFORMATION TRANSFER

GORINI, L., G. A. JACOBY, and L. BRECKENRIDGE. Ribosomal Ambiguity .... 657 DAvIEs, J. Streptomycin and the Genetic Code ...... 665 WEINSTEIN, I. B., S. M. FRIEDMAN, and M. 0CHOA, JR. Fidelity During Translation of the Genetic Code ...... 671 McCARTHY, B. J., J. J. HOLLAND, and C. A. BUCK. Single-stranded DNA as a Template for in vitro Protein Synthesis ...... 683 SPEYE~, J. F., J. D. KARAM, and A. B. LENNY. On the Role of DNA Polymerase in Base Selection ...... 693 MAGNI, G. E. and P. P. PUGLISI. Mutagenesis of Super-Suppressors in Yeast 699 EHRENSTEI~, G. vow. Translational Variations in the Amino Acid Sequence of the s-chain of Rabbit Hemoglobin ...... 705 RIFKIN, D. B., D. I. HIRSCH, M. R. RIFKIN, and W. KONIGSBERG. A Possible Ambiguity in the Coding of Mouse Hemoglobin ...... 715 JACOBSON, K. B. A Test of tRNA as Amino Acid Adaptor in Hemoglobin Synthesis ...... 719

ORIGINS OF THE CODE

WOESE, C. R., D. H. DUGRE, S. A. DUGRE, M. KONDO, and W. C. SAXINGER. On the Fundamental Nature and Evolution of the Genetic Code ...... 723 SUBAK-SHARPE, H., R. R. Bi)RK, and L. V. CRAWFORD, J. M. MORRISON, J. HAY, and H. M. KEIR. An Approach to Evolutionary Relationships of Mammalian DNA Viruses through Analysis of the Pattern of Nearest Neighbor Base Sequences ...... 737 Milislav Demerec

1895-1966

In 1919, when a certain young Yugoslav agri- Drosophila melanogaster, and the identification of cultural student came to Cornell University to a mutability-stimulating gene in the Florida stock. pursue graduate study in genetics under R. A. By the 1940's, Demerec was studying the effects Emerson, the first great decade of American of ultraviolet radiation and of neutrons in inducing genetical studies was just drawing to a close. The gone mutations and chromosome aberrations, but ensuing four and a half decades, to the very time the advent of the phage group, which summered in of his recent death, have been identified with Cold Spring Harbor for the first time in 1941, and Milislav Demerec's own career and contributions the practical demands of World War II, brought as with few others. He was among the dozen or so about a shift of activity in his laboratory at Cold giants whose work has made the United States Spring Harbor. Of enormous practical importgnce preeminent in this biological science. His own was the work performed to induce, in PeniciUium, contributions reflected not only good judgment in mutations that would increase the yield of penicillin. recognizing the most important problems but Of greater long range value were the parallel studies astounding initiative and flexibility in shifting of mutations evoking resistance on the part of from one area of significance to another, at the cost Staphylococcus to penicillin and other antibiotic of abandoning tried techniques and acquiring skill agents or to drugs. The 1945 paper of Demerec and in entirely new ones. Yet equally important to the Ugo Fano on bacteriophage-resistant mutants in advancement of science, have been his services as Escherichia coli marked a definite change in direc- scientific leader and administrator. Even the tion in Demercc's work. By the end of the 1940's briefest account must not ignore their value. Drosophila studies had been fully replaced by Dcmerec began his genetic investigations with a studies of chemical mutagens and their effects on study of the basis of variable phenotypic traits. the genes of bacteria, especially in relation to The striping of leaves and the variegations of mutations promoting bacterial resistance. This maize seeds and the virescence of seedlings that at work in turn led, in the 1950's, to the studies that first are albino but later turn green evoked in him were to occupy Demerec until the end, namely, the a deep interest in the basis of somatic mosaicism. investigation of recombination and the fine struc- Suspecting somatic mutation to be a prevalent ture of the gene in Salmonella. Independently, and cause of such changes, he very early directed in collaboration with Philip Hartman and others, attention to this phenomenon, and shifted from Dcmercc analyzed the functional organization of maize to Drosophila virilis and to delphiniums as the bacterial chromosome and discovered a remark- appropriate organisms for probing the nature of the able parallelism between the sequence of genes and factors that control mutation rates. His classic the sequence of steps in a biosynthetic chain. papers on the unstable genes of Drosophila virilis Aside from his earliest scientific studies while a remain basic to an understanding of the mutation graduate student, and his years following retire- process. ment, which were spent at the Brookhaven National A second period in Demerec's genetic investi- Laboratory and at C. W. Post College, all of gations began with the study of X-ray-induced Demerec's long career was identified with Cold mutations and deficiencies in Drosophila in the Spring Harbor, from that first day in 1923 when he early 1930's. Here, too, an interest in the role of arrived as a fresh Ph.D. to join the staff of the gone mutation in ontogcny was evident, since one Department of Genetics of the Carnegie Institution of his most important early contributions to this of Washington, to the day in 1960 when he new area was the relation of induced deficiencies to retired as Director of both the Carnegie Institution's cell lethality. With the introduction of salivary Department of Genetics and of the Long Island gland chromosome analysis, the work on deficien- Biological Laboratory. In that span of nearly cies and other types of chromosome aberrations forty years of activity, Demerec had not only made advanced rapidly, in collaboration first with scientific contributions that earned him member- Margaret Hoover, and later with B. P. Kaufmann, ship in the National Academy of Sciences, the Eilecn Sutton, and others. Demerec's interest in American Academy of Arts and Sciences, the the factors controlling spontaneous mutability was American Philosophical Society; and honorary not lost, however. From this period date also memberships in the British Genetical Society, those extremely significant studies of the differences Yugoslav Academy of Sciences, and the Royal in mutability in various wild-type strains of Danish Academy, as well as the highest award xxi xxii M_ILISLAV DEMEREC

among geneticists, the Kimber Medal (1962), he Somehow, year after year, Demeree made this had also made Cold Spring Harbor a worldwide possible on a financial shoestring. The Carnegie focus of inspiration and leadership in genetics. Institution provided new laboratories for its own This role began when he became Director of the staff, and grants were obtained to support the Biological Laboratory in 1941, and in 1943 Director permanent staff of the Biological Laboratory and of the Carnegie Institution's Department of the summer courses, and to maintain the charming Genetics. The close and fruitful collaboration of but ancient buildings. Year after year local the two neighboring biological institutions thus friends of the Cold Spring Harbor community were started toward the fusion that eventually took encouraged to help maintain the Laboratory place. The outstanding series of Cold Spring Harbor through their gifts. The scientific community Symposia on Quantitative Biology brought scien- throughout the United States was canvassed. In tists from all over the world to engage in relaxed, mysterious ways, and with real courage, for two informal conversations on the sandspit and the decades Demerec found the means not only to keep veranda of Blackford Hall, as well as in the formal the summer programs and the year-round research sessions where interesting and sometimes epochal going, but to expand them in significant directions papers were presented and discussed. From 1941, of the new molecular biology that was springing when the symposium on "Genes and Chromosomes" into being. was held, until the year of his retirement, it was Demerec served the scientific community in chiefly the foresight and wisdom of Milislav many ways. For twenty years he helped to organize Demerec in choosing subjects of most timely the International Congresses of Genetics, both as a interest, selecting participants of worldwide emi- member of the Permanent International Committee nence, organizing the program, and editing the and as a member of Organizing and Program Com- proceedings that made Cold Spring Harbor in June mittees. He filled every office, including that of the mecca of genetic biology, where genetics, president, in the Genetics Society of America. He evolution, and biochemistry came together in fruit- was treasurer and later president of the American ful interaction. Stimulating contacts spread through Society of Naturalists. He served on the U.S. the summer as visiting research workers exchanged Committee of the International Union of Biological ideas with each other and with members of the Sciences and on the Committee on the Genetic permanent staffs of the Biological Laboratory and Effects of Atomic Radiation of the National the Carnegie Institution. At least one visitor can Academy of Sciences. He served as chairman of testify that he never worked harder than during the Section of Zoology and Anatomy of the those summers and never had a better vacation for National Academy of Sciences. lie started Droso- himself and his family than in those years when phila Information Service, the first of the pro- Cold Spring Harbor was a summer home and fessional newsletters and information services in laboratory. By judicious appointments to the genetics; and he established the Drosophila stock research staffs of the two institutions, Demerec center at Cold Spring Harbor in the Carnegie kept the spearheads of investigation probing into Department of Genetics, the first of such stock significant new fields. Especially noteworthy was centers to maintain the important experimental the arrival of A. D. Hershey in 1950. Cold Spring stocks of Drosophila and to supply them to Harbor had already become a center of the phage Drosophila workers around the world. He founded group. Summer meetings had led in 1945 to the the series Advances in Genetics (Academic Press) establishment of a special summer course for and served as editor for nine volumes, from 1947 instruction in the theory and techniques of through 1958; and he served on the editorial genetic investigation with bacterial viruses. A boards of several genetical journals. Yet in the parallel summer course in the genetics of bacteria end those of us who knew him well will remember was started in 1955. These and later additions to him as the characteristic spirit and impulse of Cold the summer courses have made Cold Spring Harbor Spring Harbor, the man who made it a nerve center the biological center where germinated much of the of modern genetics. work that resulted in present.day microbial and H. Bentley Glass viral genetics. State University of New York at Stony Brook