Fifty Years of the Genetic Code: A Symposium to Honor the Legacy of Marshall Nirenberg

Fifty Years of the Genetic Code:
A Symposium to Honor the Legacy of Marshall Nirenberg

Thursday, July 31, 2014

The New York Academy of Sciences

In the fifty years since the landmark presentation of the preliminary identification of all 64 codons that make up the genetic code (at the IUB meeting in New York City, July 31st, 1964), the deciphering of the code has opened a universe of opportunity in scientific and medical discoveries. Exactly fifty years later, this symposium will honor the legacy of Nobel Laureate Marshall Nirenberg for his discovery and its impact on many aspects of science. The cutting-edge work of other scientists at the frontiers of today’s ongoing research as a result of the code being deciphered will be showcased. Speakers will explore the current state of the genetic code and the use of the many tools and principles within the field of chemistry to probe the molecules and processes of living cells, flow of genetic information from DNA to RNA to protein, and the broader impacts of the application of this knowledge in therapeutic areas such as cancer, Alzheimer’s Disease, and age-related cognitive decline. A panel of experts will turn the focus to legal, ethical, and social considerations that surround applications of the genetic code. Join us for this 50th year anniversary honoring Marshall Nirenberg, reflect on the impact of his discovery, and explore the frontiers of current research as a result of unraveling the code.

*Reception to follow.

Registration Pricing

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Student/Postdoc Member$15
Nonmember (Academia)$65
Nonmember (Corporate)$85
Nonmember (Non-profit)$65
Nonmember (Student / Postdoc / Resident / Fellow)$45

Presented by

  • The New York Academy of Sciences

Mission Partner support for the Frontiers of Science program provided by Pfizer

Agenda

* Presentation titles and times are subject to change.


July 31, 2014

8:30 AM

Registration and Continental Breakfast

Session Chair: Brian Clark, PhD, ScD, University of Aarhus, Aarhus, Denmark

9:00 AM

Welcome
Jennifer Henry, PhD, The New York Academy of Sciences, New York, NY, USA

9:05 AM

Introductory Remarks: The Legacy of Marshall Nirenberg
Gregory A. Petsko, DPhil, Weill Cornell Medical College, New York, NY, USA

9:15 AM

Dr. Marshall Nirenberg: Back to the Future
Frank Portugal, PhD, The Catholic University of America, Washington DC, USA

9:20 AM

Marshall Nirenberg: Looking Back and Moving Forward (via video address)
Craig Venter, PhD, J. Craig Venter Institute, La Jolla, CA, USA

9:25 AM

Reflections on the Legacy of Marshall Nirenberg (via video address)
Francis S. Collins, MD, PhD, NIH, Bethesda, MD, USA

Session I: The Current State of the Genetic Code

Session Chair: Ed Scolnick, MD, Broad Institute, Cambridge, MA, USA

9:30 AM

Monitoring Translation in Space and Time though Ribosome Profiling
Jonathan Weissman, PhD, University of California San Francisco, CA, USA

10:10 AM

Encoding New Bioreactivity
Lei Wang, PhD, The Salk Institute for Biological Studies, La Jolla, CA, USA

10:50 AM

Networking Coffee Break

Session II: Translation of DNA Sequences into Proteins

Session Chair: C. Thomas Caskey, MD, FACP, FRSC, Baylor College of Medicine, Houston, TX, USA

11:20 AM

Reading the Code in Three Dimensions
Venki Ramakrishnan, PhD, MRC Laboratory of Molecular Biology, Cambridge, UK

12:00 PM

Synthetic Genetics
Philipp Holliger, PhD, MRC Laboratory of Molecular Biology, Cambridge, UK

12:40 PM

Special presentation to the New York Academy of Sciences:
Marshall Nirenberg’s First Summary of the Genetic Code, January 18, 1965, and his Summary at the Vatican of the Meaning of the Genetic Code and Evolution, November 1, 2007

Brian Clark, PhD, ScD, University of Aarhus, Aarhus, Denmark
Myrna Weissman, PhD, Columbia University, New York, NY, USA
Ellis Rubinstein, The New York Academy of Sciences, New York, NY, USA

12:45 PM

Networking Lunch Break

Session III: Broader Impacts of the Genetic Code, and the Application of DNA Data in Biological Systems

Session Chair: Joan Massagué, PhD, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

1:30 PM

Personalized Medicine
C. Thomas Caskey, MD, FACP, FRSC, Baylor College of Medicine, Houston, TX, USA

2:10 PM

The Application of DNA Data for Characterizing and Rectifying Biological Systems
Huanming Yang, PhD, BGI-China, Shenzhen, China

2:50 PM

Using the Genome as a Drug
Ronald G. Crystal, MD, Weill Medical College of Cornell University, New York, NY, USA

3:30 PM

Networking Coffee Break

Session IV: Panel Discussion

4:00 PM

Evolving Legal, Ethical, and Social Considerations of Applications of New Medical Technology
Moderator: Robert B. Darnell, MD, PhD, New York Genome Center, New York, NY, USA

Panelists:
Arthur L. Caplan, PhD, NYU Langone Medical Center, New York, NY, USA
Jane M. Love, JD, PhD, WilmerHale, New York, NY, USA
Alan N. Schechter, MD, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, USA

4:45 PM

Closing Remarks
President, IUBMB: Gregory A. Petsko, DPhil, Weill Cornell Medical College, New York, NY, USA
President-elect, IUBMB: Joan J. Guinovart, PhD, IRB Barcelona, Barcelona, Spain

5:00 PM

Networking Reception

6:00 PM

Adjourn

Speakers

Organizers

C. Thomas Caskey, MD, FACP, FRSC

Baylor College of Medicine, Houston, TX, USA

C. Thomas Caskey, MD, FACP, FRSC has over 35 years of experience in molecular genetics. Currently serves as Professor of Molecular and Human Genetics at Baylor College of Medicine. Dr. Caskey was the CEO of The Brown Foundation Institute of Molecular Medicine at UTHSC-Houston. Dr. Caskey served as Senior VP, Human Genetics and Vaccines Discovery at Merck Research Laboratories, West Point, and as President of the Merck Genome Research Institute. Dr. Caskey is Board Certified in Internal Medicine, Medical Genetics, and Molecular Genetics with 25 years of patient care experience. Member of: National Academy of Sciences, Institute of Medicine (Chair, Board on Health Sciences Policy), Royal Society of Canada, past President: American Society of Human Genetics & Human Genome Organization, and Texas Academy of Medicine, Engineering and Science. He is an editor of the Annual Reviews of Medicine. Dr. Caskey received numerous academic and industry honors. His genetic research identified genetic basis of 15 major inheritable diseases and clarified the understanding of “anticipation” in triplet repeat diseases (Fragile X, myotonic dystrophy and over 30 others). His personal identification patent is the basis of worldwide application for forensic science and he is also a consultant to the FBI in forensic science. Recent publications address the utility of genome wide sequencing to preventive adult onset diseases. His current research focuses on the genetic basis of schizophrenia and autism.

Brian Clark, PhD, ScD

University of Aarhus, Denmark

Brian Clark is Professor Emeritus of Biostructural Chemistry at the University of Aarhus in Denmark. The department, which he founded in 1974, merged into the new Department of Molecular and Structural Biology in 1996. Research Associate at MIT (1961-62). Visiting Fellow at NIH (1962-64) in Marshall Nirenberg’s Group. Scientific staff member of the British Medical Research Council Laboratory of Molecular Biology from 1964-74 working in the Division of Molecular Genetics co-headed by Francis Crick and Sydney Brenner. His expertise involved decoding of the initiation of protein synthesis and the structural elucidation of transfer RNA, discovery of the Initiation Codon for protein synthesis, First crystallisation of a nucleic acid molecule (tRNA), and determination of the first structure of a GTP-binding domain. His current research interests centre on relation structure and function and identifying functional protein in functional genomics. He also advises on protein engineering and molecular gerontology. His scientific contribution comprises more than 200 articles. He was Vice-Chairman of the European Molecular Biology Organization Council (EMBO), member of the BankInvest advisory board, past chairman of the Federation of European Biochemical Societies (FEBS), past President of the International Union of Biochemistry and Molecular Biology (IUBMB). He is presently Chairman of TGIR (Task Group on International Relations) and Vice President of the European Federation of Biotechnology (EFB), Chief Scientist of PhytAge Aps, Chairman of the EU Expert Advisory Group in International Cooperation to the EU Commissioner for Science, Information and Technology and Coordinator of the EU Integrated Project, Proteomage. He is a member of the King’s College 1441 Foundation.

Gregory A. Petsko, DPhil

Weill Cornell Medical College, New York, NY, USA

Gregory A. Petsko is Professor of Neurology at Weill Cornell Medical College in New York City, and Tauber Professor of Biochemistry and Chemistry, Emeritus, at Brandeis University in Waltham, Massachusetts. He was Professor of Chemistry at MIT from 1978 to 1990, when he moved to Brandeis University, where he served as Director of the Rosenstiel Basic Medical Sciences Research Center. His awards include the Pfizer Award in Enzyme Chemistry of the American Chemical Society (for his development of methods to visualize reaction intermediates in three dimensions at atomic resolution and in 1991 the Max Planck Prize, which he shared with Professor Roger Goody of Heidelberg for their work on the origins of some human cancers. He is a member of the National Academy of Sciences, the Institute of Medicine, the American Academy of Arts and Sciences, and the American Philosophical Society. He is immediate Past-President of the American Society for Biochemistry and Molecular Biology and is President-Elect of the International Union of Biochemistry and Molecular Biology. His research interests include protein structure and function and the development of methods to treat age-related neurodegenerative diseases, including ALS (Lou Gehrig's), Alzheimer's and Parkinson's Diseases. His public lectures on the aging of the population and its implications for human health have attracted a wide audience on the Internet (his TED talk, for example, has been downloaded over a quarter of a million times). For the past twelve years he has also written a widely-read column on science and society, the first ten years of which have just appeared in book form.

Jennifer Henry, PhD

The New York Academy of Sciences, New York, NY, USA

Speakers

C. Thomas Caskey, MD, FACP, FRSC

Baylor College of Medicine, Houston, TX, USA

C. Thomas Caskey, MD, FACP, FRSC has over 35 years of experience in molecular genetics. Currently serves as Professor of Molecular and Human Genetics at Baylor College of Medicine. Dr. Caskey was the CEO of The Brown Foundation Institute of Molecular Medicine at UTHSC-Houston. Dr. Caskey served as Senior VP, Human Genetics and Vaccines Discovery at Merck Research Laboratories, West Point, and as President of the Merck Genome Research Institute. Dr. Caskey is Board Certified in Internal Medicine, Medical Genetics, and Molecular Genetics with 25 years of patient care experience. Member of: National Academy of Sciences, Institute of Medicine (Chair, Board on Health Sciences Policy), Royal Society of Canada, past President: American Society of Human Genetics & Human Genome Organization, and Texas Academy of Medicine, Engineering and Science. He is an editor of the Annual Reviews of Medicine. Dr. Caskey received numerous academic and industry honors. His genetic research identified genetic basis of 15 major inheritable diseases and clarified the understanding of “anticipation” in triplet repeat diseases (Fragile X, myotonic dystrophy and over 30 others). His personal identification patent is the basis of worldwide application for forensic science and he is also a consultant to the FBI in forensic science. Recent publications address the utility of genome wide sequencing to preventive adult onset diseases. His current research focuses on the genetic basis of schizophrenia and autism.

Ronald G. Crystal, MD

Weill Medical College of Cornell University, New York, NY, USA

Ronald G. Crystal, MD, is Professor and Chairman of the Department of Genetic Medicine at NewYork-Presbyterian Hospital/Weill Cornell Medical College, where he is also Bruce Webster Professor of Internal Medicine. After earning a BA in physics from Tufts University, an MS in physics and an MD from the University of Pennsylvania, Dr. Crystal served as Chief of the Pulmonary Branch of the National Heart, Lung and Blood Institute. In 1993 he joined the faculty at Weill Cornell, initially focusing research on the pathogenesis and therapy of inflammatory diseases of the lung. The work of his laboratory formed the basis of the current understanding of the pathogenesis of lung fibrosis and the hereditary form of emphysema associated with alpha 1-antitrypsin deficiency, a disease for which he developed the FDA-approved therapy now used to treat thousands of patients worldwide. In the late 1980's, Dr. Crystal shifted his focus to gene therapy. He was the first to use a recombinant virus as a vehicle for in vivo gene therapy, and has carried out human trials of gene therapy for cystic fibrosis, cardiac ischemia, cancer and central nervous system disorders. Recent studies from his laboratory have focused on using viral gene transfer vectors as platform strategies for vaccines against addiction.

Philipp Holliger, PhD

MRC Laboratory of Molecular Biology, Cambridge, UK

Phil Holliger is a Program Leader at the MRC Laboratory of Molecular Biology in Cambridge. The work of the Holliger group is focused on the chemical logic and the origins of the genetic apparatus shared by all life on earth. Our work has shown that the fundamental functions of DNA and RNA in biology, that is the capacity for genetic information storage, propagation and evolution, is shared by a range of alternative nucleic acid scaffolds (XNAs) not found in nature. We are also interested in RNA self-replication and the role that structured media such as water ice may have played in its emergence, a process closely connected to the origin of life itself. Our recent work on synthetic genetic polymers has also gained significant media attention and featured in Scientific American’s 10 World Changing Ideas.

Gregory A. Petsko, DPhil

Weill Cornell Medical College, New York, NY, USA

Gregory A. Petsko is Professor of Neurology at Weill Cornell Medical College in New York City, and Tauber Professor of Biochemistry and Chemistry, Emeritus, at Brandeis University in Waltham, Massachusetts. He was Professor of Chemistry at MIT from 1978 to 1990, when he moved to Brandeis University, where he served as Director of the Rosenstiel Basic Medical Sciences Research Center. His awards include the Pfizer Award in Enzyme Chemistry of the American Chemical Society (for his development of methods to visualize reaction intermediates in three dimensions at atomic resolution and in 1991 the Max Planck Prize, which he shared with Professor Roger Goody of Heidelberg for their work on the origins of some human cancers. He is a member of the National Academy of Sciences, the Institute of Medicine, the American Academy of Arts and Sciences, and the American Philosophical Society. He is immediate Past-President of the American Society for Biochemistry and Molecular Biology and is President-Elect of the International Union of Biochemistry and Molecular Biology. His research interests include protein structure and function and the development of methods to treat age-related neurodegenerative diseases, including ALS (Lou Gehrig's), Alzheimer's and Parkinson's Diseases. His public lectures on the aging of the population and its implications for human health have attracted a wide audience on the Internet (his TED talk, for example, has been downloaded over a quarter of a million times). For the past twelve years he has also written a widely-read column on science and society, the first ten years of which have just appeared in book form.

Frank Portugal, PhD

The Catholic University of America, Washington, DC, USA

Frank Portugal received his B.S. in Pharmaceutical Sciences from Columbia University and his Ph.D. in Biochemistry from the University of Illinois. He did his postdoctoral work with Dr. Nirenberg at the National Institutes of Health. He then moved to the scientific staff of the National Cancer Institute. Dr. Portugal is currently Clinical Associate Professor of Biology and Director of the M.S. in Biotechnology Program in the Department of Biology at The Catholic University of America. He is on the editorial Boards of the online journals American Journal of Biochemistry, Journal of Biochemical and Pharmacological Research, and Journal of Immunology and Infectious Diseases. Dr. Portugal is the co-author of A Century of DNA (The MIT Press) and the author of a forthcoming book on Marshall Nirenberg to be published by The MIT Press this year.

Venki Ramakrishnan, PhD

MRC Laboratory of Molecular Biology, Cambridge, UK

Venki Ramakrishnan has a long-standing interest in ribosome structure and function. In 2000, his laboratory determined the atomic structure of the 30S ribosomal subunit and its complexes with ligands and antibiotics. This work has led to insights into how the ribosome “reads” the genetic code, as well as into various aspects of antibiotic function. In the last few years, Ramakrishan’s lab has determined the high-resolution structures of functional complexes of the entire ribosome at various stages along the translational pathway, which has led to insights into its role in protein synthesis during decoding, peptidyl transfer, translocation and termination. Since 1999, he has been on the scientific staff of the MRC Laboratory of Molecular Biology in Cambridge.

Lei Wang, PhD

The Salk Institute for Biological Studies, La Jolla, California, USA

Lei Wang received his PhD from UC Berkeley under the guidance of Peter G. Schultz. His graduate research resulted in the first expansion of the genetic code to include unnatural amino acids (Uaas) in 2001, for which he was awarded the Young Scientist Award by the journal Science. After postdoctoral training with Roger Y. Tsien, Wang started his group at the Salk Institute in 2005, and is currently the Frederick B. Rentschler Associate Professor. His group has developed new methods for the expansion of the genetic code in a variety of cells and model organisms, including mammalian cells, stem cells, C. elelgans, and recently embryonic mouse. Wang discovered that release factor one is nonessential in E. coli, and engineered autonomous bacteria capable of incorporating Uaas at multiple sites with high efficiency. By proposing the concept of proximity-enabled bioreactivity, Wang designed and demonstrated that a new class of Uaas, the bioreactive Uaas, can be genetically encoded in live systems. These bioreactive Uaas enable bioreactivities, inaccessible to proteins before, to be specifically introduced into biosystems, opening the door for new protein engineering and biological research in vivo. Wang is a Beckman Young Investigator, a Searle Scholar, and an NIH Director’s New Innovator Awardee.

Jonathan Weissman, PhD

University of California - San Francisco, San Francisco, CA, USA

Jonathan Weissman is a Howard Hughes Medical Institute Investigator and Professor of Cellular and Molecular Pharmacology and of Biochemistry and Biophysics at the University of California, San Francisco. He received his undergraduate physics degree from Harvard College. After obtaining a Ph.D. in Physics from the Massachusetts Institute of Technology, where he worked with Peter Kim, Dr. Weissman pursued postdoctoral fellowship training in Arthur Horwich's laboratory at Yale University School of Medicine. Dr. Weissman's numerous honors include the 2008 Raymond and Beverly Sackler International Prize in Biophysics, as well as election to the National Academy of Sciences and to the American Academy of Microbiology. Dr. Weissman's laboratory focuses on understanding how cells ensure that proteins fold into their correct shape, as well as the role of protein misfolding in disease and normal physiology. In addition to his laboratory's exploration of protein quality control and homeostasis, his group also develops novel experimental and analytical approaches for exploring the organizational principles of biological systems. The Weissman Lab recently described a ribosome-profiling approach, based on deep sequencing of ribosome-protected mRNA fragments, that enables genome-wide investigation of protein translation with a speed, depth, and precision that rivals the best microarray experiments. Such technologies, in addition to the lab's experience in using genetic interaction maps to gain biological insights, make Dr. Weissman's group uniquely well suited to provide a general framework for obtaining a holistic understanding of complex biological systems.

Huanming Yang, PhD

BGI, Shenzhen, China

Dr. Yang is the co-founder and President of BGI-China, one of the major genomics centers in the world. He and his partners have made a significant contribution to the International HGP, HapMap Project, 1000 Genomes Project, and other human omics research, as well as sequencing and analyzing genomes of many other animals, plants, and microorganisms, with many publications in Science, Nature, Cell and other internationally prestigious journals. Dr. Yang obtained his PhD from University of Copenhagen (Denmark) and postdoctoral trainings in France and USA. He has received many awards and honors, including Research Leader of the Year by Scientific American in 2002 and Award in Biology by the Third World Academy of Sciences (TWAS) in 2006. He was elected as a foreign member of European Molecular Biology Organization (EMBO) in 2006, an academician of Chinese Academy of Sciences in 2007, a fellow of TWAS in 2008, a foreign academician of Indian National Science Academy in 2009, German National Academy of Science in 2012 and the USA National Academy of Science in 2014.

Panelists

Arthur L. Caplan, PhD

NYU Langone Medical Center, New York, NY, USA

Currently the Drs. William F and Virginia Connolly Mitty Professor and founding head of the Division of Bioethics at New York University Langone Medical Center in New York City. Prior to coming to NYU he was the Sidney D. Caplan Professor of Bioethics at the University of Pennsylvania Perelman School of Medicine in Philadelphia where he created the Center for Bioethics and the Department of Medical Ethics. Caplan has also taught at the University of Minnesota, where he founded the Center for Biomedical Ethics, the University of Pittsburgh, and Columbia University. He was the Associate Director of the Hastings Center from 1984-1987. Caplan is the author or editor of thirty-two books and over 600 papers in peer reviewed journals. His most recent books are Contemporary Debates in Bioethics (Wiley 2013) and Ethics in Mental Healthcare: A Reader (MIT Press, 2013). Caplan writes a regular column on bioethics for NBC.com. He is a monthly commentator on bioethics and health care issues for WebMD/Medscape. He appears frequently as a guest and commentator on various other national and international media outlets.

Jane M. Love, JD, PhD

WilmerHale, New York, NY, USA

Dr. Jane M. Love, co-vice chair of the firm's Intellectual Property Department, is a patent attorney with a practice focused on life sciences issues in the areas of patent litigation, patent prosecution, patent interferences, reexaminations, and strategic patent portfolio advice and diligence. Dr. Love is experienced in providing strategic patent advice to large and small companies, biotech and pharmaceutical start-up companies, universities and research institutions and has deep experience serving clients in the fields of biotechnology, molecular biology, biology, biochemistry, immunology, nanotechnology and chemistry. Her practice encompasses ANDA litigation, biologics litigation, advice related to biosimilars, post-grant proceedings under the AIA and global coordination of prosecution and enforcement of patent rights. Dr. Love prepares and prosecutes patent applications and manages large portfolios of patents in the US and globally. She has been entrusted with obtaining IP protection on significant innovations such as gene and protein therapeutics, molecular diagnostics, vaccines, treatment methods, pharmaceutical compounds, and formulations.

Alan N. Schechter, MD

National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, USA

Dr. Alan N. Schechter received his AB degree in 1959, with distinction in all subjects, from Cornell University in Ithaca, NY and his graduate education at the Columbia University College of Physicians and Surgeons, in New York, NY, from which he received the MD degree in 1963. Dr. Schechter is currently the Chief of the Molecular Medicine Branch of the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health. For a decade he served as Chair of the Advisory Committee of the DeWitt Stetten, Jr. Museum of Medical Research at NIH and from 2006 to 2008 served as Acting NIH Historian. He also served on the NIH Director's Committee on Scientific Conduct and Ethics and from 1995 to 2002 on the American Association for the Advancement of Science's Committee on Scientific Freedom and Responsibility. He is a co-author of the NIH's "Guidelines for the Conduct of Research" and "Guide for Training and Mentoring". Since 2004 he has been on the Council of the NIH Assembly of Scientists, which he chaired for five years. He serves, or has served, on multiple scientific review committees for the NIH, the Food and Drug Administration, the National Science Foundation and the Howard Hughes Medical Institute. For more than thirty years he has been an officer of the Foundation for Advanced Education in the Sciences (FAES) at NIH. During this period he also was on the teaching faculty of the FAES, the Johns Hopkins University in Baltimore, Maryland, and the George Washington University School of Medicine in Washington, DC. He is a member of many professional societies and has served on multiple national and international committees and the editorial boards of several scientific journals. For the last ten years he was Co-Editor of “Perspectives in Biology and Medicine,” published by the Johns Hopkins University Press.

Moderator

Robert B. Darnell, MD, PhD

New York Genome Center, New York, NY, USA

Dr. Darnell received his undergraduate degrees in biology and chemistry from Columbia University in 1979 and earned his MD and PhD in 1985 from Washington University School of Medicine in St. Louis, where he specialized in molecular biology. Dr. Darnell trained in internal medicine at Mount Sinai School of Medicine and in neurology at Weill Cornell Medical College with Fred Plum and Jerome Posner, where he was chief neurology resident. Dr. Darnell joined The Rockefeller University in 1992 as assistant professor and associate physician at The Rockefeller University Hospital. He was named associate professor in 1997 and professor and senior physician in 2000. In 2002 Dr. Darnell was appointed investigator at the Howard Hughes Medical Institute and named Heilbrunn Professor at Rockefeller. He is also attending neurologist at Memorial Sloan-Kettering Cancer Center, associate professor at Weill Cornell and president of the New York Genome Center. Dr. Darnell’s awards include the Burroughs Wellcome Fund Clinical Scientist Award in Translational Research in 2000, the Derek Denny-Brown Young Neurological Scholar Award in 1998 and the Irma T. Hirschl Trust Career Scientist Award in 1996. In 2010 he was elected to the Institute of Medicine of the National Academies and became a member of the Association of American Physicians and a fellow of the American Association for the Advancement of Science.

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Presented by

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Abstracts

Dr. Marshall Nirenberg: Back to the Future
Frank Portugal, PhD, The Catholic University of America, Washington, DC, USA

Marshall Nirenberg came to the National Institutes of Health in the summer of 1957 after graduating from the University of Michigan with a Ph.D. in biochemistry. Almost immediately, he began recording scientific ideas for possible future studies. A reading of these notebooks with 50 years of hindsight shows that Marshall had an almost astonishing insight into future developments in molecular biology despite not yet having trained in this discipline. A few examples will suffice to support this assertion. While DNA had just been shown to effect transformation, and messenger RNA was still unknown, Marshall in 1958 envisioned RNA as also being capable of transforming cells. Later, in 1961, Marshall and Heinrich Matthaei discovered messenger RNA. Although not often so credited, their discovery preceded that of James Watson, Sydney Brenner, and their associates. This discovery led Marshall to speculate in early fall of 1961 that double stranded DNA had a dual function. One strand made template – messenger RNA – whereas the other strand made repressor – the complement of the template. Although at this point Marshall erroneously thought that the code consisted of just 20 triplets, the idea of complementary RNA anticipated the future development of antisense RNA. At the same time, Marshall further speculated that small pieces of template RNA could interfere with translation, thereby anticipating the recent discoveries of microRNA, small inhibitory RNA, and other non-template forms of regulatory RNA.

Monitoring Translation in Space and Time using Ribosome Profiling
Jonathan Weissman, PhD, University of California San Francisco, CA, USA

The ability to sequence genomes has far outstripped approaches for deciphering the information they encode. We have developed a suite of techniques based on ribosome profiling (deep sequencing of ribosome protected fragments) that dramatically expand our ability to follow translation in vivo. I will present recent applications of our ribosome profiling approach including the following: (1) Development of ribosome profiling protocols for a wide variety of eukaryotic and prokaryotic organisms. (2) Uses of ribosome profiling to globally monitor when chaperones, targeting factors or processing enzymes engage nascent chains. (3) Deciphering the driving force and biological consequences underlying the choice of synonymous codons.

Encoding New Bioreactivity
Lei Wang, PhD, The Salk Institute for Biological Studies, La Jolla, CA, USA

The genetic code can be expanded to include unnatural amino acids (Uaas) by engineering orthogonal components involved in protein translation. To be compatible with live cells, side chains of Uaas have been limited to either chemically inert or bio-orthogonal (i.e., nonreactive toward biomolecules) functionalities. To introduce bioreactivity into live systems, we engineered the code to encode a new class of Uaas, the bioreactive Uaas. These Uaas, after being incorporated into proteins, specifically react with target natural amino acid residues via proximity-enabled bioreactivity, enabling the selective formation of new covalent linkages within and between proteins in live systems. These diverse bioreactivities, inaccessible to natural proteins, open doors to novel protein engineering and biological research. I will present the design principle of proximity-enabled bioreactivity, the genetic incorporation of Uaas in mammalian cells, stem cells and embryonic mouse, and the harnessing of bioreactive Uaas to generate new protein properties and to probe biological processes in vivo.

Reading the Code in Three Dimensions
Venki Ramakrishnan, PhD, MRC Laboratory of Molecular Biology, Cambridge, UK

Translation of the genetic code into protein depends on base pairing between the codon on mRNA and the anticodon on tRNA. However this pairing is not sufficient to ensure the speed and accuracy of protein synthesis. The ribosome recognizes the unique shape of Watson-Crick base pairs at the first two positions of the codon. The additional interactions made by the ribosome with these base pairs provide additional binding energy that is used to stabilize large scale conformational changes that eventually lead to the selection of the cognate tRNA with high accuracy. This talk will discuss how structures of the ribosome in various stages of this decoding process have shed light on the mechanism of tRNA selection.

Synthetic Genetics
Philipp Holliger, PhD, MRC Laboratory of Molecular Biology, Cambridge, UK

Synthetic biology seeks to probe fundamental aspects of biological form and function by construction (i.e. resynthesis) rather than deconstruction (analysis). Synthesis thus complements reductionist and analytic studies of life, and allows novel approaches towards fundamental biological questions. We have been exploiting the synthesis paradigm to explore the chemical etiology of the genetic apparatus shared by all life on earth. Specifically, we ask why information storage and propagation in biological systems is based on just two types of nucleic acids, DNA and RNA. Is the chemistry of life’s genetic system based on chance or necessity? Does it reflect a "frozen accident", imposed at the origin of life, or are DNA and RNA functionally superior to simple alternatives. I’ll be presenting recent progress on the development and application of strategies to enable the enzymatic synthesis and reverse transcription and hence replication and evolution of novel synthetic genetic polymers, which we term XNAs. We show that eight different synthetic polymers, based on nucleic acid architectures not found in nature, can also mediate genetic information storage and propagation.1, 2, 3 Beyond heredity, we demonstrate a capacity for Darwinian evolution by the de novo selection of specific aptamers based entirely on 1,5 anhydrohexitol nucleic acids (HNA), one of the synthetic genetic polymers.1 Thus, both heredity and evolution are likely to be emergent properties of polymers capable of information storage and are not limited to DNA and RNA.
 
1. Pinheiro VB, Taylor AI, Cozens C, Abramov M, Renders M, Zhang S, Chaput JC, Wengel J, Peak-Chew S-Y, McLaughlin SH, Herdewijn P & Holliger P (2012) Synthetic Genetic Polymers Capable of Heredity and Evolution. Science. 336: 341-44.
 
2. Cozens C, Pinheiro VB, Vaisman A, Woodgate R, Holliger P. (2012) A short adaptive path from DNA to RNA polymerases. Proc Natl Acad Sci USA. 109:8067-72
 
3. Pinheiro VB, Holliger P (2012) The XNA world: progress towards replication and evolution of synthetic genetic polymers. Curr Opin Chem Biol. 16:245-52

Personalized Medicine
C. Thomas Caskey, MD, FACP, FRSC, Baylor College of Medicine, Houston, TX, USA

The Trinucleotide holds the key to translation of DNA stored information to protein structure. Approximately 94% of all disease producing mutation resides in the protein coding of man’s estimated 22,000 genes found within 3.2 megabases of DNA. Today’s single molecule sequencing technology has accelerated new gene/disease associations and enabled disease risk predictions for adult onset diseases. A special class of mutations involves triplet repeats which can be found in both coding and non-coding DNA. Unstable repeats can expand generation to generation, thus, causing increasing disease severity accounting for the clinical feature of “anticipation”.  Examples include Fragilex, Myotonic Dystrophy, and 34 other diseases. Stable triplet repeats are polymorphic (# of repeats) and are the basis of personal identification technology used worldwide for forensic purposes. Their automation, sensitivity (PCR), and multiplex approach have led to standard data bases used to search for criminals, terrorists, and missing persons at an international level.

The Application of DNA Data for Characterizing and Rectifying Biological Systems
Huanming Yang, PhD, BGI-China, Shenzhen, China

The Genetic Code, the first human-decoded “natural language”, has explained how genes control biological functions and therefore has stimulated and promoted sequencing technology which digitalizes life and lays the foundation for the cyber era of life sciences. Beginning with the international Human Genome Project, extraordinarily large amounts of DNA sequence data have been generated for humans, other animals, plants, and microbes. The advent of de novo assembly tools, in combination with the large-scale and high throughput sequencers, has opened the gate to sequencing large genomes without the help of conventional preconditions such as genetic and physical maps. Sequencing has revolutionized and established our knowledge about life by redrawing a digitalized or sequence-based “Tree of Life”. Human genome sequence data have been widely applied to characterizing disease-related variations, as well as to clinic practice such as non-invasive prenatal detection of certain genetic diseases. The data of other animals and plants, especially those of hundreds or thousands of sub-species of domestic animals and/or plants, have provided numerous biomarkers for further improvement of their breeding. Metagenomic and single-cell sequencing technology would dramatically expand our views of the microbiological world, especially those closely related to human diseases and environment. BGI, as one of the most influential genomics organizations in the world, has not only contributed approximately one third of the genome sequencing data, but also has been persistent in the free-sharing of genomics data, in close collaboration with its global partners.

Using the Genome as a Drug
Ronald G. Crystal, MD, Weill Medical College of Cornell University, New York, NY, USA

The deciphering of genetic code not only enabled the revolution in understanding the biology of life and the pathogenesis of disease, but enabled the concept of gene therapy, in which each of the genes in the genome can be considered as potential drugs to treat and/or prevent human disease. The laboratories where Marshall Nirenberg unraveled the genetic code in 1964 in the Clinical Center, NIH, are close to the patient rooms where the first human ex vivo gene therapy administration was carried out in 1989 and the first human in vivo gene therapy in 1993. These initial attempts of using genes as drugs have become a reality, with several “gene therapy drugs” moving toward regulatory approval for diverse diseases such as hereditary lipid disorders, eye disease, hemophilia and leukemia. With a battery of recombinant viruses as gene transfer vehicles, genes can be effectively turned into drugs ex vivo, where bone marrow stem/progenitor cells are genetically modified to delivery gene products, kill tumor cells or make bone marrow-derived cells resistant to infection. Likewise, viral gene transfer vectors can be used in vivo, where direct administration to patients is used to modify any human organs, including brain, eye, skin, liver, heart and lung, to treat hereditary disorders, malignancy, a variety of acquired disorders and as vaccines against not only infectious agents, but additive drugs.

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