From Bacterial Immunity to Genome Editing: The 2014 Dr. Paul Janssen Award Symposium

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From Bacterial Immunity to Genome Editing: The 2014 Dr. Paul Janssen Award Symposium

Thursday, September 11, 2014

The New York Academy of Sciences

Presented By

Presented by the Dr. Paul Janssen Award for Biomedical Research and the New York Academy of Sciences

 

Drs. Emmanuelle Charpentier and Jennifer Doudna both share a passion for understanding how RNA controls gene expression and biological processes such as bacterial defense against pathogens. In collaboration, they sought to understand how, in bacteria, RNA molecules transcribed from Clustered Regularly Spaced Palindromic Repeats (CRISPR) mediate adaptive immunity against viruses and foreign plasmids. They discovered that CRISPR-encoded RNAs form dual-RNA structures that guide the CRISPR-associated nuclease Cas9 to degrade invading DNA molecules in a sequence-specific manner. Realizing the great potential of exploiting this system for genomic editing, they showed that dual-RNAs could be engineered as single transcripts to target any DNA sequence of interest. This scientific breakthrough forms the foundation of a new method for precise manipulation of genetic information, which holds the promise to revolutionize genomic engineering and gene therapy. In recognition of their role in understanding and adapting the CRISPR-Cas system for genome editing, Drs. Charpentier and Doudna will receive the 2014 Dr. Paul Janssen Award for Biomedical Research.

This symposium will honor Drs. Charpentier and Doudna, who will reflect on their research leading up to the discovery of the mechanism of dual-RNA-guided DNA cleavage in adaptive bacterial immunity and its potential applications in rewriting the genome. Following their Award lectures, leading scientists in microbiology, molecular genetics, genomics, and other relevant research areas will discuss the implications of this novel technology for basic science, medical research, drug development, and human health.

Featuring

Emmanuelle Charpentier, PhD

Helmholtz Centre for Infection Research

Jennifer Doudna, PhD

Howard Hughes Medical Institute
University of California, Berkeley

Registration Pricing

Symposium registration is free. Although on-site registration may be possible on the day of the event, pre-registration is highly encouraged due to space limitations.


This symposium is made possible with support from

  • Janssen Award
  • Johnson & Johnson

Agenda

* Presentation titles and times are subject to change.


September 11, 2014

8:00 AM

Registration and Breakfast

9:00 AM

Welcome and Introductory Remarks
Seema Kumar, Johnson & Johnson
Ellis Rubinstein, The New York Academy of Sciences

SESSION I: From RNA-programmable DNA Cleavage in Bacteria to Rewriting the Genome

9:15 AM

2014 Dr. Paul Janssen Award for Biomedical Research Announcement
Jay P. Siegel, MD, Johnson & Johnson
Craig C. Mello, PhD, University of Massachusetts Medical School and Howard Hughes Medical Institute

9:30 AM

2014 Dr. Paul Janssen Award for Biomedical Research Lectures

CRISPR-Cas9: A Bacterial Immune System Revolutionizes Life Sciences and Medicine
Emmanuelle Charpentier, PhD, Helmholtz Centre for Infection Research

CRISPR Biology: Basic Science and Biotechnology
Jennifer A. Doudna, PhD, University of California, Berkeley and Howard Hughes Medical Institute

10:30 AM

Networking Break

SESSION II: Adapting Bacterial Immunity: Tool Making for a New Era in Molecular Biology and Medical Research

Session Chair: Brooke Grindlinger, PhD, The New York Academy of Sciences

11:00 AM

Impact of CRISPR-Cas Immunity on the Evolution of Bacteria
Luciano A. Marraffini, PhD, The Rockefeller University

11:30 AM

Custom Redesign of the Human Genome and Epigenome with the CRISPR-Cas9 System
Charles A. Gersbach, PhD, Duke University

12:00 PM

Employing the CRISPR-Cas System for Pharmaceutical Innovation
William R. Strohl, PhD, Janssen Research & Development, LLC

12:30 PM

Panel Discussion: The Transformative Power of Basic Research for Bioengineering and Biomedicine
Moderator: Craig C. Mello, PhD, University of Massachusetts Medical School and Howard Hughes Medical Institute

Panelists:
Emmanuelle Charpentier, PhD, Helmholtz Centre for Infection Research, Hannover Medical School, and The Laboratory for Molecular Infection Medicine Sweden
Jennifer A. Doudna, PhD, University of California, Berkeley and Howard Hughes Medical Institute
Charles A. Gersbach, PhD, Duke University
Luciano A. Marraffini, PhD, The Rockefeller University
William R. Strohl, PhD, Janssen Research & Development, LLC

12:50 PM

Luncheon

2:00 PM

Adjourn

Speakers

Featuring

Emmanuelle Charpentier, PhD

Helmholtz Centre for Infection Research
website

Emmanuelle Charpentier studied biochemistry and microbiology at the University Pierre and Marie Curie, Paris, France where she received her PhD in Microbiology for her research performed at the Pasteur Institute. She then moved to the United States, where she held Research Associate positions at the Rockefeller University, New York University Langone  Medical Center, and the Skirball Institute of Biomolecular Medicine (all in New York, NY) and at St Jude Children’s Research Hospital (in Memphis, TN). Charpentier returned to Europe to establish her own research group at the Max F. Perutz Laboratories of the University of Vienna in Austria where she habilitated in the field of Microbiology. She was then recruited as an Associate Professor at the Laboratory for Molecular Infection Medicine Sweden (MIMS, Swedish Node of the European Molecular Biology Laboratory (EMBL) Partnership for Molecular Medicine) at Umeå University where she habilitated in the field of medical microbiology. In 2012 she was appointed Professor at Hannover Medical School and head of the department “Regulation in Infection Biology” at the Helmholtz Centre for Infection Research. In 2013, Charpentier was awarded an Alexander von Humboldt Professorship. Charpentier is an EMBO Member and a recipient of the Erik K. Fernström Prize and the Göran Gustafsson Prize from the Royal Swedish Academy of Sciences. Dr. Charpentier’s international research has been supported by a number of national (Austria, Germany, Sweden) and European funding organizations. Dr. Charpentier’s entrepreneurial activities include the recent founding of CRISPR Therapeutics.

Speaker Disclosures:
Emmanuelle Charpentier, PhD is Consultant for CRISPR Therapeutics and Horizon Discovery and a Shareholder of CRISPR Therapeutics.

Jennifer Doudna, PhD

Howard Hughes Medical Institute
University of California, Berkeley
website

A native of Hawaii, Jennifer Doudna studied biochemistry at Pomona College, where she received her BA degree. Moving eastward, she conducted her PhD research with Dr. Jack Szostak at Harvard University. She then pursued postdoctoral research with Dr. Tom Cech at the University of Colorado, Boulder as a Lucille Markey Fellow. Jennifer Doudna established her first research group at Yale University, where she became a full Professor and an Investigator of the Howard Hughes Medical Institute. She then joined the faculty at the University of California, Berkeley. Jennifer Doudna is member of the US National Academy of Sciences, a member of the Institute of Medicine, a Fellow of the American Academy of Arts and Sciences, and a recipient of both the Alan T. Waterman Award from the National Science Foundation and the Lurie Prize in Biomedical Sciences from the Foundation for the National Institutes of Health. Professor Doudna has published widely in the peer-reviewed literature, including a cover article in Nature in 2014.

Speaker Disclosures:
Jennifer Doudna, PhD is Co-Founder & Scientific Advisory Board Member of Caribou Biosciences Inc., Co-Founder of Editas Medicine, and Consultant for Monsanto.

Speakers

Charles A. Gersbach, PhD

Duke Center for Genomic and Computational Biology
website

Dr. Charles A. Gersbach is an Assistant Professor in the Departments of Biomedical Engineering and Orthopaedic Surgery and the Center for Genomic and Computational Biology at Duke University.  He has research interests in gene therapy, regenerative medicine, biomolecular and cellular engineering, synthetic biology, and genomics.  Dr. Gersbach received his Bachelor’s degree in Chemical Engineering from the Georgia Institute of Technology, where he studied protein adsorption to biomaterials.  He received his PhD in Biomedical Engineering from the Georgia Institute of Technology and Emory University School of Medicine focusing on the genetic reprogramming of adult stem cells for musculoskeletal tissue regeneration.  Dr. Gersbach completed his postdoctoral training at The Scripps Research Institute in molecular biology and biochemistry.   His work at Scripps involved the engineering of synthetic enzymes for targeted genome editing in human cells, with applications in biotechnology and gene therapy.  Dr. Gersbach’s laboratory at Duke University is focused on applying molecular and cellular engineering to applications in gene therapy, regenerative medicine, and basic science.  In particular, his research aims to develop new methods to genetically modify genome sequences and cellular gene networks in a precise and targeted manner.  These new methods are then applied to directing stem cell differentiation, tissue regeneration, correction of genetic diseases, or answering fundamental biological questions regarding gene regulation and genome structure and function.  Examples of technologies used in his research include genome editing, protein engineering, directed evolution, genetic reprogramming, gene delivery, and optogenetics.  Dr. Gersbach’s recognitions include the NIH Director’s New Innovator Award, the NSF CAREER Award, the Hartwell Foundation Individual Biomedical Research Award, the March of Dimes Basil O’Connor Scholar Award, and the Outstanding New Investigator Award from the American Society of Gene and Cell Therapy.

Speaker Disclosures:
Charles A. Gersbach, PhD is Consultant for Editas Medicine.

Luciano A. Marraffini, PhD

The Rockefeller University
website

Dr. Marraffini received his undergraduate degree from the University of Rosario in Argentina in 1998 and his PhD from the University of Chicago in 2007, studying bacterial pathogenesis in the laboratory of Dr. Olaf Schneewind. He was a postdoc at Northwestern University from 2008 to 2010, where he begun to investigate the molecular mechanism of CRISPR-Cas immunity with Dr. Erik Sontheimer. In 2010, he joined Rockefeller University as assistant professor. He is a 2012 Rita Allen Foundation Scholar and a 2011 Searle Scholar, and is the recipient of a 2012 NIH Director’s New Innovator Award and a 2010 RNA Society Award.

Craig C. Mello, PhD

University of Massachusetts Medical School
Howard Hughes Medical Institute
website

Dr. Craig C. Mello is an Investigator of the Howard Hughes Medical Institute, the Blais University Chair in Molecular Medicine and Co-director of the RNA Therapeutics Institute at the University of Massachusetts Medical School.

Dr. Mello’s lab uses the nematode C. elegans as a model system to study embryogenesis and gene silencing.  His collaborative work with Dr. Andrew Fire led to the discovery of RNA interference (RNAi), for which they shared the 2006 Nobel Prize in Physiology or Medicine.  Together they showed that when C. elegans is exposed to double-stranded ribonucleic acid – dsRNA, a molecule that mimics a signature of viral infection, the worm mounts a sequence-specific silencing reaction that interferes with the expression of cognate cellular RNAs. Using readily produced short synthetic dsRNAs, researchers can now employ RNAi to silence any gene in organisms as diverse as corn and humans.  RNAi allows researchers to rapidly “knock out” the expression of specific genes and to thus define the biological functions of those genes.  RNAi also provides a potential therapeutic avenue to silence genes that contribute to disease.

Before the Nobel Prize, Dr. Mello’s work on RNAi was recognized with several awards including the National Academy of Sciences Molecular Biology Award, the Canadian Gairdner International Award, the Paul Ehrlich-and Ludwig Darmstaedter Award, and the Dr. Paul Janssen Award for Biomedical Research.  He is a member of the National Academy of Sciences, the American Academy of Arts and Sciences, and the American Philosophical Society.

William R. Strohl, PhD

Janssen Research & Development, LLC

Dr. William Strohl received his PhD in Microbiology from Louisiana State University, and worked as a guest researcher at GBF, Braunschweig, Germany. From 1980 to 1997, Dr. Strohl rose from Assistant to Full Professor in the Department of Microbiology and Program of Biochemistry at The Ohio State University, researching natural product biosynthesis and generating novel polyketide natural products using genetic engineering approaches. In 1997, Dr. Strohl moved to Merck to lead Natural Products Microbiology, and was appointed as leader of Merck Monoclonal Antibody Discovery in 2001. In April 2008, Dr. Strohl joined Janssen Biologics B.V. (formerly Centocor B.V.) to lead Antibody Drug Discovery, and subsequently was promoted to VP, Biologics Research, Biotechnology COE, Janssen R&D. In October 2013, Dr. Strohl was promoted to the position of Head, Biotechnology Center of Excellence. Dr. Strohl has over 120 publications and has recently written the book: "Therapeutic Antibody Engineering: Current and Future Advances Driving the Strongest Growth Area in the Pharma Industry" (Woodhead Publishing, October, 2012).

Speaker Disclosures:
William R. Strohl, PhD is Employee of Janssen R&D, a subsidiary of Johnson & Johnson.

Abstracts

CRISPR-Cas9: a Bacterial Immune System Revolutionizes Life Sciences and Medicine
Emmanuelle Charpentier, PhD Helmholtz Centre for Infection Research, Department of Regulation in Infection Biology, Braunschweig, Germany
The Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå Centre for Microbial Research (UCMR), Department of Molecular Biology, Umeå University, Umeå, Sweden
Hannover Medical School, Hannover, Germany

The RNA-programmable CRISPR-Cas9 system has recently emerged as a transforming technology in biological sciences, enabling rapid and efficient targeted genome editing, chromosomal marking, and gene regulation. In this system, the endonuclease Cas9 or catalytically inactive Cas9 variants are programmed with single guide RNAs (sgRNAs) to target site-specifically any DNA sequence of interest given the presence of a short sequence (Protospacer Adjacent Motif, PAM) juxtaposed to the complementary region between the sgRNA and target DNA. The system is efficient, versatile, and easily programmable.
 
Originally, CRISPR-Cas is an RNA-mediated adaptive immune system that protects procaryotes from invading mobile genetic elements (phages, plasmids). Short CRISPR RNA (crRNA) molecules containing unique genome-targeting spacers commonly guide Cas protein(s) to the invading cognate nucleic acids to affect their maintenance. CRISPR-Cas9 originates from the type II CRISPR-Cas system that has evolved unique mechanisms for the maturation of crRNAs and targeting of invading DNA, identified in Streptococcus pyogenes. On the basis of the discovery of the DNA targeting mechanism, we proposed that RNA-programmable Cas9 could offer considerable potential for genome editing in cells of the three kingdoms of life for biotechnological and biomedical purposes. As demonstrated by a large number of studies published in the last 18 months, DNA targeting by CRISPR-Cas9 has quickly been adopted by the scientific community to edit and silence genomes in a large variety of cells and organisms. This talk will discuss the biological roles, mechanisms, and evolution of CRISPR-Cas9 in bacteria and the applications of the system as a novel genome engineering technology.
 

CRISPR Biology: Basic Science and Biotechnology
Jennifer A. Doudna, PhD
Howard Hughes Medical Institute, Berkeley, California, United States
Department of Molecular & Cellular Biology and Department of Chemistry, University of
California, Berkeley California, United States
Physical Biosciences Division, Lawrence Berkeley National Lab, Berkeley, California, United States

Many bacteria and archaea use adaptive immunity based on clustered regularly interspaced short palindromic repeat (CRISPR) loci to defend against invading foreign nucleic acids. CRISPR systems include specific enzymes that produce short RNA molecules capable of base pairing with viral and plasmid sequences to block their propagation. The discovery of RNA-programmable DNA binding and cleavage by the CRISPR-associated protein Cas9 has opened the door to facile genome engineering in a wide variety of cells and organisms. This presentation will discuss recent work in our laboratory to uncover the molecular basis for RNA-directed DNA recognition and cleavage by Cas9, as well as new applications of this technology.
 

Impact of CRISPR-Cas Immunity on the Evolution of Bacteria
Luciano A. Marraffini, PhD, The Rockefeller University, New York, New York, United States

Organisms of all kingdoms of life have developed immune systems with the ability to combat infection. Adaptive immune systems have the ability to create an antigenic memory of the invader to defend the cell more efficiently during recurring attacks. In archaea and bacteria, adaptive immunity is encoded by Clustered, Regularly Interspaced Short Palindromic Repeats (CRISPR) loci and their associated proteins (Cas). These loci create an antigenic memory through the incorporation of short (~40 bp) sequences from prokaryotic viruses (bacteriophages) and other mobile genetic elements during infection. Immunity is achieved by the transcription of these sequences into small antisense RNAs, known as crRNAs, which make base pair contacts with their target in the viral genome. This base-pair interaction specifies the site of cleavage of crRNA-guided Cas nucleases that destroy the invader to protect the cell. While many crRNAs target lethal bacteriophages and provide a fitness advantage to the bacterium, many others target antibiotic-resistant plasmids and other mobile genetic elements that are maintained as chromosomal or extra-chromosomal elements and that can carry beneficial genes for the host. Therefore these mobile genetic elements can be considered commensals and their destruction by CRISPR immunity can be detrimental for the cell fitness. I will discuss how different CRISPR-Cas immune systems deal with this problem and the implications of beneficial tolerance of mobile genetic elements or the lack of it for the evolution of bacteria.
 

Custom Redesign of the Human Genome and Epigenome with the CRISPR-Cas9 System
Charles A. Gersbach, PhD
Department of Biomedical Engineering, Duke University, Durham, North Carolina, United States
Center for Genomic and Computational Biology, Duke University, Durham, North Carolina, United States

The impact of reverse genetics, synthetic biology, and gene therapy has been restricted by the limitations of conventional genetic engineering technologies. However the advent of the CRISPR-Cas9 system for genome engineering of mammalian cells has enabled the precise editing and regulation of endogenous mammalian genes and epigenetic states. For example, we have engineered CRISPR-Cas9-based RNA-guided transcriptional activators targeted to human genes relevant to medicine, science, and biotechnology. Delivery of combinations of transcription factors led to synergistic effects on gene activation and tunable expression levels. This approach recapitulates the previously intractable complexity of natural regulation of mammalian genes that is the product of cooperative actions of many transcription factors. Genome-wide analysis of DNA-binding, gene regulation, and chromatin remodeling by these targeted epigenome modifiers has demonstrated their exceptional specificity. We are now applying these technologies to controlling cell fate decisions. In other studies, we have used CRISPR-Cas9-based gene editing to correct mutations causing genetic disease. We engineered synthetic nucleases targeted to the human dystrophin gene that is mutated in Duchenne muscular dystrophy patients. When we delivered these nucleases to cells from patients with this disease, the correct gene reading frame and expression of the functional dystrophin protein were restored in vitro and following cell transplantation in vivo. We further demonstrated that these nucleases were well-tolerated and did not lead to significant off-target effects on genome integrity in patient cells. Collectively, these studies demonstrate the potential of the engineered CRISPR-Cas9 system to transform medicine, science, and biotechnology.
 

Employing the CRISPR-Cas System for Pharmaceutical Innovation
William R. Strohl, PhD, Biotechnology Center of Excellence, Janssen R&D, Spring House, Pennsylvania, United States

The CRISPR-Cas9 gene editing system, which has been developed as a highly useful gene editing tool just within the past few years, already has made a large impact on the biopharmaceutical industry. This gene editing system is used widely for the rapid generation of specific gene knock-out animals, for generation of mutant cell lines used in screening and testing pharmaceuticals, and as a part of potential therapeutics in both the gene therapy and cell therapy areas. This talk will discuss ways in which Janssen R&D and other biopharmaceutical companies are using the CRISPR-Cas9 gene editing system to help discover novel therapeutics to improve healthcare for patients.
 

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