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6 Deciphering the Glycome for Human Health and Sustainability: Findings, Recommendations, and Roadmap As this report highlights, glycans are the fourth great class of mac- romolecules on which all life depends for existence, yet our knowledge of these substances continues to lag that of nucleic acids and proteins. Glycans are universal in living systems and play a central role in the eti- ology of all major human diseases. Thus, advances in glycoscience will be needed to realize the full potential of our investments in such areas as genomics and proteomics and in efforts to address and possibly prevent the root causes of human illness. Glycans represent Earth's largest and potentially most versatile natural resource, and advances in glycoscience are needed to turn that resource into a varied and sustainable source of food, fuel, chemicals, and materials. Over the course of its data-gathering efforts and deliberations, the committee concluded there is good reason that our understanding of gly- cans pales in comparison to what is known about nucleic acids, proteins, and lipids: Glycoscience lacks the necessary technologies needed to fully decipher the glycome and make sense of the last step of information flow that transforms genetic information into phenotype. However, the com- mittee also determined that enormous advances in technologies, spurred by the Human Genome Project, the modern molecular biology revolution, nanotechnology, microfluidics, information technologies, and other fields, have created a new opportunity to create the tools and methods needed to bring glycoscience up to par with genomics and proteomics. The committee believes that a concerted effort in glycoscience is now necessary and will be sufficient to create the needed tools and methods. 135
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136 TRANSFORMING GLYCOSCIENCE More importantly, such an effort will attract the attention of researchers in a wide range of disciplines and democratize the field. Glycoscience, like genomics and nanotechnology, will then become a core discipline that is integrated across the entire scientific enterprise, spawning both advances in knowledge and economic activity. The return on an invest- ment in glycoscience, as with genomics and nanotechnology, is likely to be substantial and to contribute significantly to the recently announced effort to develop a national bioeconomy. The committee's recommendations seek to enable the development of better and more readily accessible tools for studying glycoscience and for applying glycoscience knowledge to questions across multiple fields. The committee has sought to prioritize areas where advances will be broadly applicable and where gaps in current capabilities cut across and cur- rently limit research. Such areas include the chemical synthesis of glycans and the determination of glycan structures. Having accessible databases and bioinformatics tools is similarly of fundamental utility to the field. Longer-term, education of the scientific community and students about the functions of glycans will be important to achieving a roadmap for the future of the field. How to most effectively deploy resources to achieve these priorities and to enable glycoscience to contribute to advances in health, energy, and materials science will require additional discussion among multiple federal agencies as well as members of the broader sci- entific community, a discussion that extends beyond the committee's mandate in this report. The committee's findings are detailed in preceding chapters; the find- ings fall into four general categories that can be summarized here. In the area of human health the committee finds that: · Glycans are directly involved in the pathophysiology of every major disease. · Additional knowledge from glycoscience will be needed to realize the goals of personalized medicine and to take advantage of the substantial investments in human genome and proteome research and its impact on human health. · Glycans are increasingly important in pharmaceutical development. In the area of energy the committee finds that: · Plant cell walls, made mostly of glycans, represent the planet's dominant source of biological carbon sequestration, or biomass, and are a potentially sustainable and economical source of non- petroleum-based energy.
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DECIPHERING THE GLYCOME FOR HUMAN HEALTH AND SUSTAINABILITY 137 · Understanding cell wall structure and biosynthesis and overcom- ing the recalcitrance of plant cell walls to conversion into feed- stocks that can be transformed into liquid fuels and other energy sources will be important to achieving a sustainable energy revo- lution. Glycoscience research will be necessary to advance this area. · Glycoscience can contribute significantly to bioenergy develop- ment by advancing the understanding of how to increase biomass production per hectare and how to increase the yield of ferment- able sugar per ton of biomass. In the area of materials the committee finds that: · By fostering a greater understanding of the properties of gly- cans and of plant cell wall construction and deconstruction, glycoscience can play an important role in the development of nonpetroleum-based sustainable new materials. · Glycan-based materials have wide-ranging uses in such areas as fine chemicals and feedstocks, polymeric materials, and nanomaterials. · There are many pathways to create a variety of functionalities on a glycan, creating a wide range of options for tailoring material properties. Based on the above, the committee makes the following findings on the toolkit needed to advance glycoscience: · Scientists and engineers need access to a broad array of chemi- cally well-defined glycans. · Over the past 30 years, tremendous advances have been made in chemical and enzymatic synthesis of glycans, but these meth- ods remain relegated to specialized laboratories capable of pro- ducing only small quantities of a given glycan. For glycoscience to advance, significant further progress in glycan synthesis is needed to create widely applicable methodologies that generate both large and small quantities of any glycan on demand. · A suite of widely applicable tools, analogous to those available for studying nucleic acids and proteins, is needed to detect, describe, and fully purify glycans from natural sources and then to charac- terize their chemical composition and structure. · Continued advances in molecular modeling, verified by advanced chemical analysis and solution characterization tools, can gener- ate insights for understanding glycan structures and properties.
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138 TRANSFORMING GLYCOSCIENCE · An expanded toolbox of enzymes and enzyme inhibitors for manipulating glycans would drive progress in many areas of glycoscience. · A centralized accessible database linked to other molecular data- bases is needed to fully realize advancements in knowledge generated by an expanded effort in glycoscience. Glycan infor- mation is not currently accessible to the research community in an integrated and centralized manner similar to other biological information. Based on these findings, the committee makes the following recom- mendations in order to achieve a more complete understanding of the importance of glycoscience and its impacts on health, energy, and material sciences. Each recommendation is followed by a series of roadmap goals. The capabilities created by the achievement of these recommendations will ensure that all interested researchers can efficiently and effectively incorporate glycoscience into their work. 1. The committee recommends that the development of trans- formative methods for the facile synthesis of carbohydrates and glycoconjugates be a high priority for NIH, NSF, DOE, and other relevant stakeholders. Roadmap Goals Within 7 years, have synthetic tools to be able to synthesize all known carbohydrates of up to octasaccharides, including substituents (e.g., ace- tyl, sulfate groups). This goal encompasses human glycoprotein and glycolipid glycans and proteoglycans, which are currently estimated to be 10,000-20,000 structures, along with plant and microbial glycans and polymers. Within 10 years, have synthetic tools to be able to synthesize uniform batches, in milligram quantities, of all linear and branched glycans that will enable glycan arrays for identifying protein binding epitopes, pro- vide standards for analytical methods development, and enable improved polysaccharide materials engineering and systematic studies for all fields to be conducted. This includes methods for synthesis of structures with isotopic enrichment of specific desired atoms that may be needed for a wide variety of studies. Within 15 years, be able to synthesize any glycoconjugate or carbo- hydrate in milligram to gram quantities using routine procedures. Com- munity access should be available through a web ordering system with rapid delivery.
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DECIPHERING THE GLYCOME FOR HUMAN HEALTH AND SUSTAINABILITY 139 2. The committee recommends that the development of trans- formative tools for detection, imaging, separation, and high- resolution structure determination of carbohydrate structures and complex mixtures be a high priority for NIH, NSF, DOE, FDA, and other relevant stakeholders. Roadmap Goals Over the next 5-10 years, develop the technology to purify, identify, and determine the structures of all the important glycoproteins, glyco- lipids, and polysaccharides in any biological sample. For glycoproteins, determine the significant glycans present at each glycosylation site. Develop agreed upon criteria for what constitutes the acceptable level of structural detail and purity. Within 10 years, have the ability to undertake high-throughput sequencing of all N- and O-linked glycans from a single type of cell in a single week. Within 10 years, have the ability to routinely determine the complete carbohydrate structure of any glycan or polymer repeat sequence includ- ing branching, anomeric linkages between glycans, and substituents. Within 15 years, have the ability to determine glycoforms (a complete description of molecular species within a population that have the same polypeptide sequence) of any glycoprotein in a biological sample. For example, one specific achievable step could be to apply the tools developed in the roadmap to characterize the set of glycomes in blood, including those of blood cells and plasma. 3. The committee recommends that the development of trans- formative capabilities for perturbing carbohydrate and glyco- conjugate structure, recognition, metabolism, and biosynthe- sis be a high priority for NIH, NSF, DOE and other relevant stakeholders. Roadmap Goals Within 5 years, identify the genes involved in glycan and glycocon- jugate metabolism in any organism whose genome has been sequenced, and identify the activities of at least 1,000 enzymes that may have utility as synthetic and research tools. Within 10 years, be able to use all glyco-metabolic enzymes (e.g., glycosyltransferases, glycosidases) as well as other state of the art tools for perturbing and modifying glyco-metabolic pathways (knockouts, siR- NAs, etc.) of utility to the biomedical and plant research communities.
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140 TRANSFORMING GLYCOSCIENCE Within 10 years, develop methods for creating specific inhibitors to any human, plant, or microbial glycosyltransferase suitable for in vitro and in vivo studies in order to perturb the biology mediated by these enzymes. Within 15 years, develop imaging methods for studying glycan struc- ture, localization, and metabolism in both living and non-living systems. 4. The committee recommends that robust, validated informat- ics tools be developed in order to enable accurate carbohydrate and glycoconjugate structural prediction, computational mod- eling, and data mining. This capability will broaden access of glycoscience data to the entire scientific community. Roadmap Goals Within 5 years, develop an open-source software package that can automatically annotate an entire glycan profile (such as from a mass spec- trometry experiment) with minimal user interaction. Within 5 years, develop the technology to perform computer simula- tions of carbohydrate interactions with other entities such as proteins and nucleic acids. Within 10 years, develop the software to simulate a cellular system to predict the effects of perturbations in glycosylation of particular glyco- conjugates and polysaccharides. 5. The committee recommends that a long-term-funded, stable, integrated, centralized database, including mammalian, plant and microbial carbohydrates and glycoconjugates, be estab- lished as a collaborative effort by all stakeholders. The carbo- hydrate structural database needs to be fully cross-referenced with databases that provide complementary biological informa- tion (e.g., PDB and GenBank). Furthermore, there should be a requirement for deposition of new structures into the database using a reporting standard for minimal information. Roadmap Goals Within 5 years, develop a long-term-funded, centralized glycan struc- ture database with each entry highly annotated using standards adopted by the community and all the world's repositories of glycan structures. The database should be cross-referenced and open source to allow the community to develop database resources that draw on this resource and
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DECIPHERING THE GLYCOME FOR HUMAN HEALTH AND SUSTAINABILITY 141 improve its utility to investigators that wish to incorporate glycoscience in their work Within 5 years, employ an active curation system to automatically validate glycan structures deposited into a database so that journals can provide authors with an easily accessible interface for submitting new glycan structures to the database. To achieve the roadmap goals articulated in its recommendations, the committee notes that it will be of critical importance for the field to reach agreement on the standards of evidence and the nature of the assump- tions that will be used to annotate and validate glycan structures within the next 2 to 3 years. For example, a level of certainty should be assigned to each linkage in the database, using a defined convention. Agreement on these standards is needed to avoid depositing large numbers of structures into databases that will ultimately prove more confusing than useful. Finally, the committee noted that there is widespread lack of under- standing and appreciation of glycoscience within the scientific and medi- cal communities and among the general public. Glycans are integral com- ponents of living organisms, whether human, animal, plant, or microbe, and glycan products have applications in health, energy, and materials science. The committee concludes that integrating glycoscience into rel- evant disciplines in high school, undergraduate, and graduate education, and developing curricula and standardized testing for science competency would increase public as well as profes- sional awareness. Roadmap Goals Within 5 years, integration of glycoscience as a significant part of the science curriculum would include glycoscience as both lecture materials and hands-on experiments or activities. Within 10 years, glycoscience will be integrated and taught at every level wherever it is relevant to understand the scientific content. Compe- tency in glycoscience could also be included in all standardized testing wherever relevant (for example, as part of the SAT and GRE Subject Tests, the MCAT, and Medical Board Exams). To achieve these goals, the committee notes that mechanisms would need to be implemented to define appropriate glycoscience competency and to incorporate glycoscience topics into educational frameworks at multiple levels. The process of setting education policies and develop- ing and implementing curricula varies from state to state, university to university, and country to country. Although the committee cannot define
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142 TRANSFORMING GLYCOSCIENCE the specific steps needed to achieve its recommended education goals, the committee encourages the engagement of glycoscience experts in these processes. Glycoscience is a vibrant field filled with challenging problems. Research can make significant contributions toward understanding and improving human health, creating next-generation fuels and materials, and contributing to economic innovation and development. Now is the time for glycoscience to be embraced broadly by the research community. Drawing in members from the full spectrum of chemistry, biology, materi- als science, engineering, medicine, and other disciplines will be needed to address the technical challenges described here. Although these chal- lenges are substantial and complex, the results of achieving these goals have the potential to impact science in exciting ways.