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2 The Landscape of Current Research in Glycoscience 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 chapter presents a brief overview of the commit- tee's findings in order to provide a baseline of current investments in the field and a sense of centers of research activity in the United States and abroad. Examples and further details on U.S. and international glycosci- ence programs are included in Appendix B. Although it did not undertake an exhaustive survey to identify U.S. and international glycoscience efforts, the committee reviewed infor- mation provided to it by federal sponsors,1 received community input through its website and through a workshop held in January 2012,2 gained additional perspectives through further data-gathering efforts,3 1 Representatives of the National Institutes of Health (NIH), Food and Drug Administration (FDA), U.S. Department of Energy (DOE), and National Science Foundation (NSF) briefed the committee on their motivations in sponsoring the study and their views on challenges and opportunities for glycoscience at the committee's first meeting on October 10, 2011. 2 For the workshop's agenda and participants, see Appendix B. Information on the study's website (http://glyco.nas.edu) and the questions that members of the community were invited to address can be found in Appendix C. 3 Committee members spoke with several additional scientists to gather information on current glycoscience research outside the United States; information can be found in Appendix C. 29

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30 TRANSFORMING GLYCOSCIENCE conducted a Web of Science review of published literature,4 and drew on a background paper prepared by the National Research Council (NRC) that summarizes a range of federal agency and researcher viewpoints on the field (McGowan and Bowman 2010).5 These materials provided an overview of the current landscape of glycoscience research efforts and informed development of the committee's roadmap. 2.1 AN OVERVIEW OF GLYCOSCIENCE WORLDWIDE Glycoscience research is conducted worldwide in projects that cut across multiple disciplines. As can be seen from Figures 2-1 and 2-2, active glycoscience research is ongoing not only in North America (the United States and Canada) but also in Asia (People's Republic of China, Taiwan, Japan, South Korea, India--and Australia), in many countries in Europe, and in Latin America (Brazil). A number of U.S. federal agencies support or conduct glycoscience research, including NIH (through multiple individual institutes), NSF, DOE, FDA, U.S. Department of Agriculture (USDA), and National Insti- tute of Standards and Technology (NIST). These agencies have comple- mentary interests in the field, including the application of glycoscience for human health and in support of therapeutic drug and vaccine develop- ment (NIH, FDA, NIST), the application of glycoscience to plant biology (DOE, USDA), and advancing basic science understanding and funda- mental tool development for the field (NSF, NIST, NIH, and others). Additional details and further examples are provided in Appendix B, but one notable federally funded initiative is the Consortium for Func- tional Glycomics, which currently receives legacy funding from NIH and involves the participation of hundreds of researchers worldwide. The efforts of participating research groups have made available a range of resources for addressing questions in glycoscience and health, including 4 A search of the Web of Science (WOS) Citation Index Expanded Database was conducted on May 15, 2012, using the following parameters: Topic: glycoscience* OR glycan* OR carbohydrate* OR *cellulos* OR glycobiolog* OR *saccharide*; years: 2005-2012; publication type: articles, meeting abstracts, and proceedings. The search produced 127,602 results. 5 The background paper was prepared at the request of NIH, which asked the NRC to reach out to researchers and federal program managers for their views on the state of glycomics and glycoscience and challenges facing the field, in order to better understand how to frame the design of the current study. The paper summarizes information received during this outreach, in which NRC staff and a small group of glycoscience experts spoke with approximately 40 scientists and program managers from government, academia, and industry. The paper was not reviewed per the NRC's report review procedures and does not necessarily reflect the views of the NRC or its boards. The information it contained did help provide background material for the current study, particularly on the landscape of U.S. research efforts.

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THE LANDSCAPE OF CURRENT RESEARCH IN GLYCOSCIENCE 31 Biochemistry Molecular Biology (14.5%) Energy Fuels (2.2%) Biotechnology Applied Microbiology (8.4%) Endocrinology Metabolism (2.3%) Chemistry Organic (6.5%) Chemistry Medicinal (2.5%) Chemistry Multidisciplinary (6.4%) Biochemical Research Methods (2.7%) Pharmacology Pharmacy (6.3%) Cell Biology (3.2%) Immunology (6.3%) Chemistry Physical (3.2%) Food Science Technology (6.2%) Chemistry Analytical (3.4%) Chemistry Applied (6.1%) Engineering Chemical (3.5%) Polymer Science (6.1%) Nutrition Dietetics (3.6%) Microbiology (5.7%) Plant Sciences (4.0%) FIGURE 2-1 Glycoscience research spans a diversity of fields, as indicated by the Web of Science subject categories associated with published research. Results from the WOS citation search described above were sorted by WOS subject category, and the top 20 subject areas are depicted above. Figure 2-1 resources for glycomics profiling, carbohydrate compounds and reagents, microarray analysis, mouse phenotyping, glycan array screening, and glycan databases. Similarly, a number of U.S. research programs and clusters of research expertise were identified during the committee's data-gathering process. These span the country and may involve multiple researchers, provid- ing a concentration of expertise across different aspects of glycoscience. Although many more examples are provided in Appendix B, one example of a center of excellence for glycoscience research in the United States is the Complex Carbohydrate Research Center (CCRC), located at the Uni- versity of Georgia. The CCRC includes a cluster of centers that address plant, microbial, and human carbohydrates, along with research resources in areas such as nuclear magnetic resonance analysis and computational modeling. Glycoscience research is also conducted across the globe in projects that cut across disciplines. Although not described here, examples of research activities and investments from Canada, the United Kingdom, Germany, Japan, China, Taiwan, Australia, New Zealand, and Brazil are provided in the appendix. Glycoscience also has significant relevance to companies invested in the development of protein-based biotherapeutics or vaccines containing carbohydrate antigens (discussed in Chapter 3). Other compa- nies interested in glycoscience include those that use carbohydrate-based materials for drug delivery and tissue engineering applications, those interested in the development of cellulose-based biofuels and products derived from agricultural sources and by custom chemical producers. Representative examples are provided in Appendix B.

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Canada Japan South Korea USA PR China Taiwan India Germany UK France Spain Brazil Italy Netherlands Sweden Russia Australia Poland Switzerland Belgium Denmark Finland Turkey Austria Portugal FIGURE 2-2 Glycoscience research occurs worldwide, with centers of activity around the globe. Results from the WOS citation search described above were sorted by country of author, with the top 25 countries depicted in the figure. The size of the bubbles represents the relative proportion of glycoscience papers published. Underlying world map adapted from David Niblack. Found 32 at: http://imagebase.davidniblack.com.

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THE LANDSCAPE OF CURRENT RESEARCH IN GLYCOSCIENCE 33 In addition to the many programs and collaborations identified by the committee, several scientific forums bring together members of the gly- coscience community both in the United States and internationally. These include scientific meetings such as the annual Society for Glycobiology conferences; biennial Gordon Research Conferences on Glycobiology, on Glycolipid and Sphingolipid Biology, and on Plant Cell Walls; the biennial international carbohydrate symposium organized by the International Carbohydrate Organization); and the biennial meeting by the Interna- tional Glycoconjugate Organization (IGO). The long-standing Annual San Diego Glycobiology Symposium involves glycoscientists from throughout California and regularly attracts participants from all over the world. Other scientific forums include the biennial Charles Warren workshops on glycoscience characterization and analysis and the Beilstein Symposia on Glyco-Bioinformatics. 2.2 AN "OMICS" FIELD--GLYCOSCIENCE IN ITS INFANCY The citation search in the WOS database undertaken by the commit- tee was intended to be broad so as to include research on cellulose and other carbohydrate polymers as well as glycoconjugates. By this measure the number of papers published annually in the overarching field of gly- coscience is similar to those published in genomics or proteomics alone6 (see Figure 2-3). Glycomics,7 however, clearly remains in its infancy, with annual publications several orders of magnitude lower. When the Human Genome Project was initiated in 1990, genomics publications also were substantially lower in number than they are today.8 Over the ensu- ing decades a massive expansion of gene-sequencing capabilities and a decrease in costs have occurred (see Figure 2-4). Enabling genome analy- sis to advance to its current state required integrated efforts across the scientific community, including both international collaborations (such 6 A WOS search was conducted on May 15, 2012, using the following parameters: (A) A "Glyco (all terms)" search was conducted as identified above, except that Years: 1995- 2011, producing 253,658 total results. (B) Topic: genom*; Citation database: Citation Index Expanded; Years: 1995-2011; Publication type: article, meeting abstract, and proceeding, producing 285,067 total results. (C) Topic: glycom*; Citation database: Citation Index Expanded; Years: 1995-2011; Publication type: article, meeting abstract, and proceeding, producing 1,624 total results. (D) Topic: proteom*; Citation database: Citation Index Expanded; Years: 1995-2011; Publication type: article, meeting abstract, and proceeding, producing 45,370 total results. 7 Analogous to genomics (the study of the full set of nucleic acid genetic material) and proteomics (the study of the full set of proteins), glycomics involves comprehensive study of the full set of glycans present in a cell or an organism. 8 A WOS search for the term "genom*" similar to that described above produced 5,700 results for the year 1990.

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34 TRANSFORMING GLYCOSCIENCE 100,000 Number of Publications (Log Scale) 10,000 1,000 Genom* Glycom* 100 Glyco (all terms) Proteom* 10 1 95 97 99 01 03 05 07 09 11 19 19 19 20 20 20 20 20 20 Year FIGURE 2-3 Comparison of WOS search results for annual genomics, proteomics, glycomics, and glycoscience research. Figure 2-3 as the Human Genome Organization, HUGO), and the contributions of many individual scientists. It is beyond the committee's charge to propose a similar formal glycoscience initiative comparable to that of the Human Genome Project or the National Nanotechnology Initiative. Rather, the committee seeks to describe the current status of the field of glycoscience and explore its potential, while clearly recognizing that advancing the field in a similar dramatic fashion, as with genetics and genomics, would require engagement by and the efforts of multiple stakeholders beyond the current community of glycoscience specialists. 2.3 COMMON CONCERNS AMONG U.S. AND INTERNATIONAL GLYCOSCIENTISTS During its data-gathering efforts, the committee did not observe sig- nificant differences among the viewpoints shared by U.S. and interna- tional researchers. Although individual scientists might vary in the chal- lenges or opportunities they choose to highlight, several common themes emerged as being of fundamental importance to the field. Many of the technical challenges that make up the core toolkit to enable the next gener- ation of glycoscience discoveries are addressed later in this report and are reflected in the committee's recommendations for a roadmap to advance the field. This section focuses on several other significant messages:

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THE LANDSCAPE OF CURRENT RESEARCH IN GLYCOSCIENCE 35 FIGURE 2-4 The rapid decline in the cost of sequencing a human genome. SOURCE: Wetterstrand 2012; Image courtesy of The National Human Genome Project. Found at: genome.gov/sequencingcosts. Figure 2-4 Bitmapped Visibility and vision of the field: Both U.S. and international glyco- scientists noted that relevant work taking place in a variety of disciplines may not be labeled with the term "glycobiology" and thus may not be well recognized as falling under the glycoscience umbrella. The field would benefit from having a clear picture to present to nonexperts, as well as compelling goals behind which the community could rally. Because glycoscience provides a level of data that can build from and complement genomic and proteomic information, inclusion of glycoscience components in international Human Genome Organization (HUGO) and Human Proteome Organization (HUPO) projects could help draw out these connections.9 9 One example is the Human Disease Glycomics/Proteome Initiative (HGPI) through HUPO. HGPI investigates glycosylation changes in efforts to identify possible biomarkers relevant to the diagnosis or progression of disease (see http://www.hupo.org/research/ hgpi/).

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36 TRANSFORMING GLYCOSCIENCE Education and awareness: Both students and peer researchers who are not experts in glycoscience lack an understanding of why gly- coscience is significant, they lack a comprehensive view of what the glycoscience field encompasses, and they do not see how glycoscience relates to their own interests. Researchers expressed concerns about the limited coverage of carbohydrates in academic programs when compared to classes of molecules such as nucleic acids and proteins and about how the field suffers from a percep- tion that it is too complex to study effectively or is not exciting. Critical role of collaborative approaches: Many glycoscience chal- lenges are likely to benefit from synergistic efforts that bring communities of people together to address problems from differ- ent perspectives. As the field seeks to advance to the next level of discoveries, there will be a need to foster collaboration and understanding between, for example, clinicians and laboratory researchers, between biologists and chemists, and between com- putational/informatics experts and experimental scientists. 2.4CONCLUSION The landscape of glycoscience research provides a picture of a global field with a range of ongoing research efforts, both academic and commer- cial, and one for which the community sees significant opportunities as well as common challenges. The following chapters of this report attempt to present a holistic view of glycoscience's contributions to critical areas such as human health, energy, and materials science; to bring new atten- tion from both experts and nonexperts to the field; and to point the way toward a roadmap and a vision for the future of the field.