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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.
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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.
