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Committee on Assessing the Importance and Impact of Glycomics and Glycosciences Board on Chemical Sciences and Technology Board on Life Sciences Division on Earth and Life Studies

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THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001 NOTICE: The project that is the subject of this report was approved by the Gov- erning Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engi- neering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This project was supported by the National Institutes of Health under contract N01-OD-4-2139, TO#251, the National Science Foundation under grant CHE- 1138764, the U.S. Department of Energy under contract DE-SC0007069, the Food and Drug Administration under contract HHSF223200810020I, TO#HHSF22301023, and the Howard Hughes Medical Institute. The views expressed herein are those of the authors and do not necessarily reflect the views of the organizations or agencies that provided support for the project. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Any opinions, find- ings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation. International Standard Book Number-13: 978-0-309-26083-1 International Standard Book Number-10: 0-309-26083-3 Additional copies of the report are available from the National Academies Press, 500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313; http://www.nap.edu. Cover: Imaging of glycans in Chinese hamster ovary cells. Glycans are labeled in red and cell nuclei and Golgi apparatus are labeled in blue and green, respectively. Image courtesy of Carolyn Bertozzi, Scott Laughlin, and Jeremy Baskin. Source: Baskin J. M., J. A. Prescher, S. T. Laughlin, N. J. Agard, P. V. Chang, I. A. Miller, A. Lo, J. A. Codelli, and C. R. Bertozzi. 2007. Copper-free click chemistry for dynamic in vivo imaging. Proceedings of the National Academy of Sciences of the United States of America 104(43):16793-16797. Copyright 2012 by the National Academy of Sciences. All rights reserved. Printed in the United States of America

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The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal govern- ment on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its mem- bers, sharing with the National Academy of Sciences the responsibility for advis- ing the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Charles M. Vest is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy's purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in pro- viding services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. Charles M. Vest are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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COMMITTEE ON ASSESSING THE IMPORTANCE AND IMPACT OF GLYCOMICS AND GLYCOSCIENCES DAVID WALT (Chair), Department of Chemistry, Tufts University KIYOKO F. AOKI-KINOSHITA, Department of Bioinformatics, Soka University, Japan BRAD BENDIAK, University of Colorado, Denver CAROLYN R. BERTOZZI, University of California, Berkeley GEERT-JAN BOONS, Complex Carbohydrate Research Center, University of Georgia ALAN DARVILL, Complex Carbohydrate Research Center, University of Georgia GERALD HART, Department of Biological Chemistry, Johns Hopkins University School of Medicine LAURA L. KIESSLING, Department of Chemistry, University of Wisconsin JOHN LOWE, Genentech, Inc. ROBERT J. MOON, Forest Products Laboratory, U.S. Forest Service JAMES C. PAULSON, Departments of Chemical Physiology and Molecular Biology, The Scripps Research Institute RAM SASISEKHARAN, Massachusetts Institute of Technology AJIT P. VARKI, Glycobiology Research and Training Center, University of California, San Diego, School of Medicine CHI-HUEY WONG, Academia Sinica, Taiwan, and The Scripps Research Institute Staff KATHERINE BOWMAN, Co-Study Director and Senior Program Officer, Board on Life Sciences DOUGLAS FRIEDMAN, Co-Study Director and Program Officer, Board on Chemical Sciences and Technology SHEENA SIDDIQUI, Senior Program Associate, Board on Chemical Sciences and Technology RACHEL YANCEY, Senior Program Assistant, Board on Chemical Sciences and Technology JOE ALPER, Consulting Science Writer v

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BOARD ON CHEMICAL SCIENCES AND TECHNOLOGY Members PABLO DEBENEDETTI (Co-chair), Princeton University, New Jersey C. DALE POULTER (Co-chair), University of Utah, Salt Lake City ZHENAN BAO, Stanford University, California ROBERT BERGMAN, University of California, Berkeley HENRY BRYNDZA, E. I. du Pont de Nemours & Company, Wilmington, Delaware EMILY CARTER, Princeton University, New Jersey DAVID CHRISTIANSON, University of Pennsylvania MARY JANE HAGENSON, Chevron Phillips Chemical Company, LLC, The Woodlands, Texas CAROL J. HENRY, The George Washington University, Washington, D.C. JILL HRUBY, Sandia National Laboratories, Albuquerque, New Mexico MICHAEL KERBY, ExxonMobil Chemical Company, Baytown, Texas CHARLES E. KOLB, Aerodyne Research, Inc., Billerica, Massachusetts JOSEF MICHL, University of Colorado, Boulder SANDER MILLS, Merck, Sharp, & Dohme Corporation, Kenilworth, New Jersey DAVID MORSE, Corning International, Corning, New York ROBERT E. ROBERTS, Institute for Defense Analyses, Washington, D.C. DARLENE J. S. SOLOMON, Aligent Laboratories, Santa Clara, California JEAN TOM, Bristol-Myers Squibb, West Windsor, New Jersey DAVID WALT, Tufts University, Medford, Massachusetts National Research Council Staff DOROTHY ZOLANDZ, Director AMANDA CLINE, Administrative Assistant DOUGLAS FRIEDMAN, Program Officer KATHRYN HUGHES, Senior Program Officer TINA M. MASCIANGIOLI, Senior Program Officer SHEENA SIDDIQUI, Senior Program Associate RACHEL YANCEY, Senior Program Assistant vi

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BOARD ON LIFE SCIENCES JO HANDELSMAN (Chair), Yale University, New Haven, Connecticut VICKI L. CHANDLER, Gordon and Betty Moore Foundation, Palo Alto, California SEAN EDDY, HHMI Janelia Farm Research Campus, Ashburn, Virginia SARAH C. R. ELGIN, Washington University, St. Louis, Missouri DAVID R. FRANZ, Former Cdr USAMRIID, Frederick, Maryland LOUIS J. GROSS, University of Tennessee, Knoxville, Tennessee RICHARD A. JOHNSON, Arnold & Porter, LLC, Washington, D.C. JUDITH KIMBLE, University of Wisconsin, Madison, Wisconsin CATO T. LAURENCIN, University of Connecticut Health Center, Farmington, Connecticut ALAN I. LESHNER, American Association for the Advancement of Science, Washington, D.C. BERNARD LO, University of California, San Francisco, California KAREN E. NELSON, J. Craig Venter Institute, Rockville, Maryland ROBERT M. NEREM, Georgia Institute of Technology, Atlanta, Georgia CAMILLE PARMESAN, University of Texas, Austin, Texas ALISON G. POWER, Cornell University, Ithaca, New York MARGARET RILEY, University of Massachusetts, Amherst, Massachusetts BRUCE W. STILLMAN, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York JANIS C. WEEKS, University of Oregon, Eugene, Oregon CYNTHIA WOLBERGER, Johns Hopkins University School of Medicine, Baltimore, Maryland MARY WOOLLEY, Research!America, Alexandria, Virginia Staff FRANCES E. SHARPLES, Director JO L. HUSBANDS, Scholar/Senior Project Director JAY B. LABOV, Senior Scientist/Program Director for Biology Education KATHERINE W. BOWMAN, Senior Program Officer INDIA HOOK-BARNARD, Senior Program Officer MARILEE K. SHELTON-DAVENPORT, Senior Program Officer KEEGAN SAWYER, Program Officer BETHELHEM M. BANJAW, Financial Associate ORIN E. LUKE, Senior Program Assistant CARL G. ANDERSON, Program Associate SAYYEDA AYESHA AHMED, Senior Program Assistant vii

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Preface Although I was trained as a synthetic organic chemist and was involved in carbohydrate research early in my scientific career, my research has primarily been focused on developing new technologies for making analytical measurements. This work has led to the development and commercialization of some of the technologies that are presently used for the revolution in genetics and genomics that has taken place over the past decade. I have seen the transformation in scientific capabil- ity enabled by these new genetic tools. Access to both the tools and the public databases by virtually any scientist and engineer has democratized the field and has made genetic information an essential component of many fields of science. Science has benefitted tremendously, and many fields are decades ahead of where they would have been without these capabilities. In addition, genetic technologies are beginning to have a big impact on practical applications--diagnostics, therapeutics, and animal breeding to name a few. The economic benefit is in the billions of dollars per year and growing. This study can be viewed as an opportunity to elevate the importance and possibilities of glycoscience, which is equally pervasive and certainly more directly linked to biological activity than genetics. For example, gly- cans are responsible for virtually all cell-cell recognition. Moreover, they play a central role in recent burgeoning biofuels efforts. But glycoscience has much more to offer, as described in this report. It was identifying these opportunities and providing a roadmap that was the challenge to ix

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xPREFACE the Committee on Assessing the Importance and Impact of Glycomics and Glycosciences. The National Academies assembled a stellar group of glycoscientists for this committee. They came from disparate fields--biology, chemis- try, and computer science--and work on equally diverse problems in fundamental biology, synthetic chemistry, health, energy, and materials science. I have been so impressed with the passion of these glycoscience committee members for their field. They have worked for many years to advance this important yet underappreciated area--and, despite my limited knowledge of the field, they welcomed me both as a colleague and a friend. It has been a genuine pleasure to work with this dedicated and passionate group of scientists. They have worked tirelessly to help advance the field and, more importantly, science in general with their contributions to this study and to this report. The community is indebted to their service. The National Academies staff are the real heroes. In particular, Dr. Katherine Bowman and Dr. Douglas Friedman were essential to the suc- cess of this study. Katie and Doug pushed the committee to meet dead- lines, dealt with the challenging logistics of committee members spanning 12 time zones, helped pull the report together, and worked tirelessly. Even with difficult deadlines, I never heard them complain. They brought ideas and creativity to the discussions. Their selfless dedication to science is admirable and should be a model for us all. In addition to Katie and Doug, Sheena Siddiqui and Rachel Yancey provided superb administra- tive support. I also want to thank Dr. Fran Sharples, director of the Board on Life Sciences, and Dr. Dorothy Zolandz, director of the Board on Chemical Sciences and Technology, for their support and vision. This report has the potential to transform the field of glycoscience, but--more significantly--it should transform science in dramatic ways. Sugars are ubiquitous, and scientists in all fields will realize the full poten- tial of their research only by embracing and incorporating glycoscience. The tools for realizing this potential are not available yet. It is the hope of the committee that this report will bring glycoscience into the scientific mainstream. David Walt, Chair Committee on Assessing the Importance and Impact of Glycomics and Glycosciences

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Acknowledgments This report has been reviewed in draft form by persons chosen for their diverse perspectives and technical expertise in accordance with procedures approved by the National Research Council's Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making the pub- lished report as sound as possible and to ensure that it meets institutional standards of objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We wish to thank the following for their review of this report: Richard D. Cummings, Emory University Samuel Danishefsky, Memorial Sloan-Kettering Cancer Center Anne Dell, Imperial College London Stephen S. Kelley, North Carolina State University Nicolle Packer, Macquarie University (Sydney, Australia) Robert Sackstein, Harvard Medical School Chris Somerville, University of California, Berkeley George M. Whitesides, Harvard University Although the reviewers listed above have provided many construc- tive comments and suggestions, they were not asked to endorse the con- clusions or recommendations, nor did they see the final draft of the report before its release. The review of this report was overseen by Kenneth xi

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xiiACKNOWLEDGMENTS Moloy, Dupont Central Research and Development and Johanna Dwyer, Tufts Medical Center. Appointed by the National Research Council, they was responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authors and the institution.

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Contents SUMMARY 1 1 Introduction 13 1.1 Understanding the Language of Life: The Centrality of Sugars, 13 1.2 Genes and Proteins Are Not Enough: The Rich Information Content of Glycans, 21 1.3 How Glycoscience Builds on Genomics and Proteomics, 22 1.4 Why Now? The Case for Change, 23 1.5 Charge to the Committee, 25 1.6 Organization of the Report, 26 2 The Landscape of Current Research in Glycoscience 29 2.1 An Overview of Glycoscience Worldwide, 30 2.2 An "Omics" Field--Glycoscience in Its Infancy, 33 2.3 Common Concerns Among U.S. and International Glycoscientists, 34 2.4 Conclusion, 36 3 Glycoscience in Health, Energy, and Materials 37 3.1 Glycoscience and Health, 38 3.1.1 Glycans' Regulation of Inflammation, 38 3.1.2 Glycans' Essential Role in Regulation of the Immune System, 40 xiii

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xivCONTENTS 3.1.3 Glycans' Key Role in Infectious Diseases and Vaccine Development, 43 3.1.4 Glycans' Multifaceted Role in Cardiovascular Disease, 46 3.1.5 Glycans and the Molecular Mechanisms of Chronic Diseases, 47 3.1.6 Glycans' Roles in Cancer Progression and Early Detection, 49 3.1.7 Critical Roles of Glycans in Human Development, 51 3.1.8 Bioactivity and Pharmacokinetics of Drugs, 52 3.1.9 Key Messages on Glycoscience and Health, 54 3.2 Glycoscience and Energy, 55 3.2.1 Biomass--Plant Cell Walls, 56 3.2.2 Recalcitrance to Degradation of Biomass Feedstock, 58 3.2.3 Key Messages on Glycoscience and Energy, 60 3.3 Glycoscience and Materials, 61 3.3.1 Fine Chemicals and Feedstocks, 62 3.3.2 Polymeric Materials, 64 3.3.3 Nanomaterials, 65 3.3.4 Key Messages on Glycoscience and Materials, 69 3.4 Summary, 70 4 Examples of Outstanding Questions in Glycoscience 71 4.1 What Are the Mechanisms and Roles of Glycan Diversification in Evolution?, 72 4.2 How Can Single Glycoforms and Polysaccharides Be Synthesized and How Can Specific Glycans at Specific Sites on Glycoproteins Be Modified?, 73 4.3 How Does Glycan Microheterogeneity Occur, What Does It Do, and What Is Its Impact?, 74 4.4 What Are the Three-Dimensional Structures of Intact Glycoproteins?, 75 4.5 How Does Nuclear and Cytoplasmic Protein Glycosylation Regulate Cellular Physiology?, 75 4.6 How Does the Glycocalyx Affect the Organization of Molecules on the Cell Surface?, 76 4.7 How Can the Glycans and Glycoproteins on a Single Cell Be Determined?, 77 4.8 What Are the Functions of Microbial and Host Interactions Involving Glycans?, 78 4.9 How Do Glycan Binding Proteins Decode the Glycome?, 79 4.10How Can Plant Recalcitrance to Degradation Be Understood and Overcome?, 80

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CONTENTS xv 4.11 How Can Sugars Be Reassembled to Develop Materials with Tailored Properties and Functionality?, 81 4.12 Summary, 82 5 The Toolkit of Glycoscience 85 5.1 Synthesis, 86 5.1.1 General Aspects, 86 5.1.2 Synthetic Tools, 90 5.1.3 Manipulating Glycans by Pathway Engineering, 95 5.1.4 Synthesis of Standards for Mass Spectrometry, 97 5.1.5 Key Messages on Glycan Synthesis, 98 5.2 Analysis, 98 5.2.1 Analysis of Primary Glycan Structures, 100 5.2.2 Analysis of Glycoconjugates, 108 5.2.3 Analysis of Glycan-Protein Interactions, 109 5.2.4 Analysis of the Roles of Some Glycans in Metabolic Pathways Related to Energy Metabolism, 111 5.2.5 Analysis Techniques That Relate Glycan Structures and Their Synthetic Enzymes, 111 5.2.6 Analysis of Locations of Specific Glycan Structures in Organisms Through Various Imaging Techniques, 112 5.2.7 Key Messages on Glycan Analysis, 114 5.3 Computational Modeling, 114 5.3.1 Computational Modeling of Oligo- and Polysaccharides, 114 5.3.2 Protein-Glycan Interactions, 115 5.3.3 Atomistic Modeling of Crystalline Cellulose, 116 5.3.4 Key Messages on Computational Analysis of Glycans, 118 5.4 Glycoenzymes, 118 5.4.1 Classes of Glycoenzymes, 118 5.4.2 Applications of Glycosyltransferases and Other Glycoenzymes, 120 5.4.3 Key Messages on Glycoenzymes, 125 5.5 Systems Glycobiology, 125 5.6 Informatics and Databases, 126 5.6.1 Limited Successes in Developing Broadly Available Informatics Tools, 127 5.6.2 Critical Need for Development of a Single Integrated Database, 129 5.6.3 Key Messages on Glycan Bioinformatics and Databases, 132 5.7 Summary and Findings, 133

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xviCONTENTS 6Deciphering the Glycome for Human Health and Sustainability: Findings, Recommendations, and Roadmap 135 REFERENCES 143 APPENDIXES A Committee Member Biographies 159 B The Landscape of Current Research in Glycoscience: Additional Information167 C Workshop on the Future of Glycoscience: Agenda and Participants177 D Input Received Online and Through Other Data Gathering 185 E Glossary 187