Appendix B

The Landscape of Current Research in Glycoscience: Additional Information

As a starting point to inform its deliberations, the committee sought to better understand the current landscape of major U.S. and international glycoscience efforts. This appendix presents an overview of some of the research, funding, and industry initiatives the committee identified during its data-gathering process. It is not meant to be comprehensive but rather to provide a baseline of current investments in the field, including centers of research activity and funding, in this country and abroad. The examples provided are not meant to imply endorsement by the committee or the National Research Council (NRC).

B.1 AN OVERVIEW OF GLYCOSCIENCE IN THE UNITED STATES

B.1.1 Federal Agency Interests in Glycoscience

Glycoscience research in the United States is conducted within and supported by a number of federal departments and agencies, including the National Institutes of Health (NIH; through multiple individual institutes), the National Science Foundation (NSF), the U.S. Department of Energy (DOE), the Food and Drug Administration (FDA), the U.S. Department of Agriculture (USDA), and the National Institute of Standards and Technology (NIST).

NIH is one of the principal U.S. funding agencies for glycoscience research, reflecting the myriad ways in which carbohydrate glycans are linked to physiology and disease. Despite broad interest in the field, only



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Appendix B The Landscape of Current Research in Glycoscience: Additional Information As a starting point to inform its deliberations, the committee sought to better understand the current landscape of major U.S. and international glycoscience efforts. This appendix presents an overview of some of the research, funding, and industry initiatives the committee identified dur- ing its data-gathering process. It is not meant to be comprehensive but rather to provide a baseline of current investments in the field, including centers of research activity and funding, in this country and abroad. The examples provided are not meant to imply endorsement by the committee or the National Research Council (NRC). B.1 AN OVERVIEW OF GLYCOSCIENCE IN THE UNITED STATES B.1.1 Federal Agency Interests in Glycoscience Glycoscience research in the United States is conducted within and supported by a number of federal departments and agencies, including the National Institutes of Health (NIH; through multiple individual insti- tutes), the National Science Foundation (NSF), the U.S. Department of Energy (DOE), the Food and Drug Administration (FDA), the U.S. Depart- ment of Agriculture (USDA), and the National Institute of Standards and Technology (NIST). NIH is one of the principal U.S. funding agencies for glycoscience research, reflecting the myriad ways in which carbohydrate glycans are linked to physiology and disease. Despite broad interest in the field, only 167

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168 APPENDIX B a relatively small percentage of the total NIH portfolio is devoted to spe- cifically identified glycoscience awards. For example, "in an unofficial search of applications submitted to NIH using an R mechanism for [2010], 107 had glycomic in its abstract/summary statement and 400 had glycan" (McGowan and Bowman, 2010). A search of the NIHReporter system for fiscal year 2011 research grants having the term "glycan" in their project title or abstract produced 159 results (129 projects and 30 subprojects), with total funding of approximately $59 million.1 The National Institute of General Medical Sciences (NIGMS) is a central contributor to many NIH glycoscience efforts, although investments exist for other institutes, such as the National Cancer Institute (NCI), the National Heart, Lung, and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases (NIAID). In addition to funding research individually, the institutes support collaborative initiatives. A long-term glycoscience special-interest group (GlycoSIG) brings together interested researchers from across NIH and FDA. While not meant to be an exhaustive list, key glycoscience programs within NIH include: support for the Consortium of Functional Glycomics (CFG), described in more detail below, through a Glue Grant mechanism that has now ended (NIGMS); continued support to enable researcher access to resources devel- oped by the CFG through Legacy Community-Wide Scientific Resources funding (NIGMS); the Alliance of Glycobiologists for Detection of Cancer and Can- cer Risk, currently in its second phase of funding for 2012-2017 (NCI); support of glycomics laboratories through the Early Detection Research Network (NCI); support of national centers for research resources (recently trans- ferred to NIGMS) emphasizing glycoscience and glycomics; programs of excellence in glycoscience, supporting six awards for 2011-2018 and including a requirement for both glycoscience research and skills development components (NHLBI); 1 Including "Research Project Grants (both SBIR/STTR and non-SBIR/STTR)" and "Other Research Related" but not including "Research Centers." The total funding of approximately $59 million broken down by agency included approximately $12 million at NIGMS, $16 million at NHLBI, $11 million at NIAID, and $8 million at NCI, with other (multiple) insti- tutes making up the remainder (www.projectreporter.nih.gov; search conducted on June 7, 2012). A similar search for fiscal year 2012 projects produced 84 results (68 projects and 16 subprojects) with total funding of approximately $25 million. It should be noted that fiscal year 2012 was ongoing at the time of the search.

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APPENDIX B 169 Functional Glycomics in HIV Vaccine Design, an RO1 program anticipated to start in 2013 (NIAID); and SBIR contract mechanisms for such areas as production of specific monoclonal antibodies or analytical technologies (various). Glycoscience research is also relevant to the mandates of NSF direc- torates and divisions, including biological sciences, chemistry, and mate- rials research. Although NSF has not developed funding solicitations specifically dedicated to glycoscience, it receives relevant proposals under a range of programs. An approximate and unofficial portfolio estimate indicates that approximately 5 percent of chemical synthesis submissions address carbohydrate synthesis strategies, whereas approximately 5 to 10 percent of biomaterials submissions involve polysaccharides or sugars in some fashion (personal communication from Kelsey Cook, Tingyu Li, and David Berkowitz, NSF Division of Chemistry, and David Brant, NSF Division of Materials Research, phone conversation, 11/18/2010). FDA and NIST both maintain interests in the development of mea- surement technologies and standards relevant to health care products and therapeutics. Research conducted by these agencies includes efforts to bet- ter understand physiological interactions and trafficking of glycosylated protein therapeutics and carbohydrate-based vaccines, methods to moni- tor glycosylation in cell cultures for biologics production, and character- ization and quantification of glycans and glycoproteins. These agencies are also interested in the creation of reference standards and materials, such as standards for the interpretation of glycan mass spectral data. Finally, DOE and USDA are engaged in glycoscience, particularly as it relates to nonmammalian systems. Glycoscience efforts at DOE empha- size areas related to biofuel and bioproduct development, such as cell wall chemistry, synthesis, and deconstruction with a particular focus on plants and on nonmedical aspects of microorganisms. Three bioenergy research centers are supported by the DOE Office of Biological and Environmental Research (BER); the DOE Basic Energy Sciences (BES) office supports a network of 46 Energy Frontier Research Centers, including the Center for Lignocellulose Structure and Formation at Pennsylvania State University. BER also supports the DOE-Michigan State University Plant Research Laboratory and provides funding to one center within the Complex Car- bohydrate Research Center (CCRC) at the University of Georgia--the DOE Center for Plant and Microbial Complex Carbohydrates--while BER supports a component of the DOE BioEnergy Science Center housed within the CCRC (Greene, 2011). Within USDA, glycoscience efforts are focused on improvement to bioconversion processes and on the creation of value-added agricultural materials and products.

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170 APPENDIX B B.1.2 Collaborative Glycoscience Initiatives and Research Clusters Two centers or consortia consistently mentioned as hubs that address multiple challenges in glycoscience research are the Consortium for Func- tional Glycomics (CFG) and the CCRC. The CFG provides glycomics resources directed toward studying the impact of glycans and glycan-binding proteins on human health and disease (www.functionalglycomics.org). The consortium is guided by a steering committee that sets its scientific direction; it also contains two scientific cores (the Bioinformatics Core and the Protein-Glycan Interac- tion Core), along with hundreds of participating investigators located at institutions in this country and around the world organized into sub- groups based on research interests. These groups include glycan synthesis and microarrays, glycans in immune recognition and function, glycans in development and physiology, structural glycobiology, glycans in cancer biology, and glycomics and glycoinformatics. The CFG maintains the functional glycomics gateway (http://www.functionalglycomics.org) and acts as the central hub and clearinghouse for glycomics, offering resources that include glycomics profiling, carbohydrate compounds and reagents, microarray analysis, mouse phenotyping, glycan array screening, and databases to investigators whose projects are approved for scientific rel- evance by the consortium's steering committee. Although NIH funding to support the CFG through its Glue Grant mechanism has now ended, the consortium continues and mechanisms have been established to enable ongoing access to the resources and tools it has developed. The CCRC, housed at the University of Georgia, seeks to foster "cooperation and collaboration among disciplines (biomedical, plant, and microbial glycosciences, synthetic and analytical chemistry) both within the CCRC and with scientists worldwide and to foster analytical service and training" in carbohydrate research (http://www.ccrc.uga.edu). It is funded by a combination of federal, state, industry, foundation, and research funds and is made up of a cluster of centers each addressing dif- ferent aspects of carbohydrate research. These include the Center for Plant and Microbial Complex Carbohydrates (funded by DOE's BES); Inte- grated Technology Resource for Biomedical Glycomics (funded by NIH); Research Resource for Integrated Glycotechnology (funded by NIH); Southeast Collaboratory for Biomolecular NMR (funded by NIGMS and the Georgia Research Alliance; research initiatives on GLYCAM/AMBER Modeling Tools for Glycoscience; Monoclonal Antibodies for Plant Cell Walls (funded by NSF); and Plant Cell Walls and Biomass Recalcitrance (both components of the Bioenergy Science Center [BESC], funded by the DOE Office of Biological and Environmental Research). In addition to the two multidisciplinary organizations described above, a variety of other U.S. research programs and clusters of research

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APPENDIX B 171 expertise were noted by respondents who provided input through the committee's website or were identified during other data-gathering efforts. Several of these are listed here to help underscore that research is occurring nationwide. It should be emphasized that the list below (in alphabetical order by university and/or geographical "cluster") does not reflect the only places in which important and useful glycoscience research is under way: Baltimore-Washington cluster, including Johns Hopkins Univer- sity, University of Maryland, and intramural research at NIH, such as the Carbohydrate Section of the National Institute of Diabetes and Digestive and Kidney Diseases; Cornell University; Emory University School of Medicine; Harvard University; Memorial Sloan-Kettering Cancer Center; National Center for Glycomics and Glycoproteomics, Indiana University; National Renewable Energy Laboratory; C3Bio, Purdue University; San Diego, California, cluster, including the Glycobiology Research and Training Center; University of California, San Diego, which incorporates researchers at Salk, Scripps, and Sanford-Burnham in La Jolla; and glycoscientists elsewhere throughout California; University of California, Davis; Glycomics Center, University of New Hampshire; USDA-ARS Laboratory and USDA-Forest Service Forest Products Laboratory; and Virginia Polytechnic Institute and State University. B.2 AN OVERVIEW OF GLYCOSCIENCE OUTSIDE THE UNITED STATES Active clusters of glycoscience research are located around the world, and a few of these regions are highlighted below. Different research orga- nizations or even different countries may have greater expertise in cer- tain aspects of glycoscience, such as medical applications, biofuels and biomass, mammalian glycoscience, bacterial glycoscience, or enzyme research. The data gathering conducted by the committee was intended to be fairly broad in scope in order to identify centers of expertise beyond the intersection of glycoscience with human health. Again, the list below should not be considered comprehensive; it is meant to provide a sense of major ongoing efforts.

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172 APPENDIX B B.2.1Canada Glycoscience programs in Canada include the Alberta Glycomics Centre (www.glycomicscentre.ca), a partnership between the University of Alberta and the University of Calgary that conducts multidisciplinary research in glycoscience and carbohydrate chemistry, such as the develop- ment of analytical methods, structural studies, and research on carbohy- drate therapeutics. Other ongoing efforts in Canada include those at the University of Toronto and the National Research Council Canada Institute for Biological Sciences in Ottawa. B.2.2 United Kingdom and Europe Within the United Kingdom, glycoscience research is supported by such organizations as the Wellcome Trust, the Engineering and Physical Sciences Research Council, the Biotechnology and Biological Sciences Research Council, and the Medical Research Council; centers of activ- ity include Imperial College London and the University of Oxford and University of Dundee. Collaborative efforts include the UK Glycoarrays Consortium (http://www.glycoarrays.org.uk), which draws on scien- tists from the universities of Dundee, Liverpool, Manchester, Oxford, East Anglia, and Imperial College London to develop carbohydrate microarrays. In Europe glycoscience research is supported by both national funding organizations such as the Deutsch Forschungsgemeinschaft in Germany and through programs such as the European Commission (EC). One cur- rent EC-supported initiative is the Euroglycosciences Forum (http://www. egsf.org), supported through the European Science Foundation Research Network Programme for 2009-2014. The forum seeks to provide access to glycoscience tools and supports meetings and workshops to link members of the glycoscience community. A variety of database and bioinformatics resources are housed in Europe, including EuroCarbDB (http://www. eurocarbdb.org), funded under the 6th Research Framework Program of the European Union, and subsequent related efforts such as UniCarb-DB (http://unicarb-db.biomedicine.gu.se), supported as a partnership by the University of Gothenburg (Sweden), Macquarie University, Swiss Institute for Bioinformatics, and the National Institute for Bioprocessing Research and Training (Ireland), along with support from the Swedish Foundation for International Cooperation in Research and Higher Educa- tion and the Australian Research Council. Other resources include Glyco- sciences.de (http://www.glycosciences.de); the CASPER tool for analysis of nuclear magnetic resonance spectra developed at Stockholm Univer- sity; the GlycoWorkbench suite of tools for mass spectrometry-based gly- comics (http://www.glycoworkbench.org) developed at Imperial Col-

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APPENDIX B 173 lege London; the Carbohydrate-Active EnZymes database (http://www. cazy.org), developed by CNRS and Aix-Marseille University (France); the EuroGlycoArrays training network (http://www.euroglycoarrays.eu), supported under the Seventh Framework Programme of the EC; and the Euroglycanet network for congenital disorders of glycosylation (http:// www.euroglycanet.org). A range of additional research centers and programs were noted by participants who provided input through the committee's website or were identified through the Web of Science citation search. In Europe these included: Carlsberg Laboratory, Denmark, which researches barley, yeast, brewing, and fermenting technology; Centre de Recherches sur les Macromolecules Vegetales of the Centre National de la Recherche Scientifique (CNRS), France; Ghent University, Belgium; Institut d'Investigaci Biomdica de Bellvitge, Spain; Institut National de la Recherche Agronomique, France; and Carbohydrate Competence Center, The Netherlands. B.2.3Asia Asia is a center of glycoscience research, and there is significant and emerging interest in such countries as Japan, South Korea, and China. In Japan glycoscience research is supported by the Ministry of Educa- tion, Culture, Sports, Science and Technology (MEXT) and the Japan Soci- ety for the Promotion of Science, as well as by such organizations as the Mitzutani Foundation for Glycoscience. A recently established initiative is the Japan Consortium for GlycoBiology and Glycotechnology (http:// www.jcgg.jp/index_e.html), supported by MEXT, which has developed the JCGGDB database to house data, including the GlycoGeneDataBase, the Glycan Mass Spectral DataBase, the Lectin Frontier DataBase, and the Glycoprotein Database. MEXT is also supporting a neuroglycobiology project (2011-2015) with the goal of deciphering sugar chainbased signals that regulate integrative neuronal functions. Glycoscience research centers in Japan include the National Institute of Advanced Industrial Science and Technology, Kyoto University, University of Tokyo, and RIKEN, which includes the RIKEN Omics Science Center, the RIKEN Bioinformatics and Systems Engineering Division, and the System Glycobiology Research Group. Through a program on exploratory research for advanced technol- ogy, RIKEN is leading a 5-year glycotrilogy project linking molecular biol- ogy, synthetic chemistry, and analytical chemistry to study glycans and glycan derivatives. RIKEN recently partnered with the Max Planck Insti-

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174 APPENDIX B tute of Colloids and Interfaces in Germany to establish a joint research center in systems chemical biology on areas such as disease glycomics and oligosaccharide synthesis. In China glycoscience research is funded under the National Basic Research Program of the Ministry of Science and Technology and by the National Natural Science Foundation of China, which manages the National Natural Science Fund and promotes basic and applied research. Active glycoscience research is carried out in laboratories within the Chi- nese Academy of Sciences. Glycoscience research is also conducted in Taiwan--for example, at the Academia Sinica and at several national universities. The Taiwan GlycoForum (https://sites.google.com/site/taiwanglycoforum/home) was established in 2011 to provide a mechanism for communication and collaboration. The Australia and New Zealand Glycosciences Group seeks to pro- vide a forum for the glycoscience community in these countries. Well- known programs include the Institute for Glycomics at Griffith Univer- sity (http://www.griffith.edu.au/science-aviation/institute-glycomics), which focuses on understanding the roles of glycans in disease through investigations of both mammalian and microbial glycomics and on devel- opment of enabling technologies such as new synthesis and analytical tools. Glycomics research is also conducted at Macquarie University in Sydney, and established programs that analyze plant cell walls include those at the University of Melbourne and the ARC Centre of Excellence in Plant Cell Walls at the University of Adelaide (http://www.adelaide. edu.au/plant-cell-walls). B.2.4 Latin America Glycoscience research is supported in Brazil by the Conselho Nacio- nal de Desenvolvimento Cientfico e Tecnolgico, the Coordenao de Aperfeioamento de Pessoal de Nvel Superior, and the Fundao de Amparo Pesquisa do Estado de So Paulo. Respondents to the com- mittee's website included scientists from Chile and Mexico, indicating ongoing research efforts in these countries as well. The international nature of glycoscience research and the existence of significant centers of excellence outside the United States are important factors to keep in view as the U.S. research community and federal agen- cies look toward the future development and transformative potential of the field. Key challenges to advance glycoscience may be shared, and the development of many types of resources, such as common standards for interpretation and sharing of glycan structural data, will necessarily need to be achieved within the framework of a global community to be truly effective.

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APPENDIX B 175 B.3 INDUSTRY INTEREST IN GLYCOBIOLOGY This very brief summary is not meant to capture the totality of indus- try interest across the field but rather to highlight just a few of the existing investments in research, development, and application of glycoscience. Mention of specific companies is made solely for illustrative purposes and reflects information obtained during the committee's data gathering or from committee members' knowledge of the field. Such mention does not in any way imply committee, NRC, or study sponsor endorsement of any commercial product or service.2 Companies with interests in therapeutic glycoproteins include Amgen (e.g., erythropoietin) and Genentech (e.g., antibodies and the antiinflu- enza drug Tamiflu, originally involving Gilead Sciences). Genzyme's drug Cerezyme, approved in 1994, provides enzyme replacement for the treat- ment of Type 1 Gaucher disease and uses carbohydrate targeting. Other companies such as GlaxoSmithKline (manufacturer of the antiinfluenza drug Relenza, originally developed in part with Biota Holdings), Baxter (with its drug heparin), and Wyeth (now Pfizer, for glycoconjugate vac- cines) have major programs in glycoscience or aspects of glycoscience. GlycoFi, established in 2000 to develop yeast-based production systems for protein-based drugs, was acquired by Merck in 2006. Novo Nordisk conducts clinical trials for the hemophilia treatment GlycoPEGylated fac- tor IX, which contains polyethylene glycol groups linked to glycan chains through carbohydrate engineering to prolong the pharmacokinetics. Smaller companies active in aspects of glycoscience include GlycoMimet- ics, Inc. (focused on compounds that target cellular adhesion molecules such as selectins); ProtAffin (development of glycan-binding pharmaceu- ticals); GlycoMira Therapeutics (development of heparin derivatives); Sialix, Inc. (focused on pathological effects and a nonhuman sialic acid); Momenta (heparin and heparan sulfate); Biomarin (carbohydrate-based targeting for enzyme replacement therapy); Hyalose (tissue engineering and therapeutics based on hyaluronic acid), Zacharon (therapeutics and diagnostics for rare storage diseases); Ancora (carbohydrate-based vac- cines and custom synthesis); and Selexys Pharmaceuticals (antibodies to P-selectin and its ligand). International companies include Dextra (syn- thetic oligosaccharides) and Seikagaku (oligosaccharides and enzymes). Companies in the energy industry, including large corporations such as BP and ExxonMobil, are interested in cellulose-based biofuels, an area that will rely on glycoscience as it develops. 2Several members of the committee are associated with companies or have received fund- ing from companies identified above, including Genentech, Inc. (Bertozzi; Lowe); GlaxoS- mithKline (Bertozzi); GlycoMimetics, Inc. (Bertozzi); and Sialix, Inc. (Varki).

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