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Summary
In response to a request from the National Institutes of Health (NIH),
the Food and Drug Administration (FDA), the U.S. Department of Energy
(DOE), and the National Science Foundation (NSF), the National Research
Council convened a committee to assess the importance and impact of
glycoscience, explore the landscape of current research, and identify the
challenges that will need to be addressed to enable the field to move for-
ward. The committee was charged to "articulate a unified vision for the
field on glycoscience and glycomics" and to "develop a roadmap with
concrete research goals to significantly advance [the field]" (see Statement
of Task, Box 1-5). The committee's consensus findings, conclusions, and
recommendations in addressing this charge are summarized below.
WHY GLYCOSCIENCE?
Glycans are one of the four fundamental classes of macromolecules
that comprise living systems, along with nucleic acids, proteins, and lip-
ids, and are made up of individual sugar units linked to one another in a
multitude of ways. Understanding the structures and functions of glycans
is central to understanding biology. One of the most common reactions
on the planet--photosynthesis--uses energy from sunlight to ultimately
combine carbon dioxide and water into polymers of sugars such as starch,
glycogen, or cellulose--glycans used in our metabolic pathways to pro-
vide us with energy, that provide structural support in such materials as
wood, and that other animals are able to use as energy sources.
1
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2 TRANSFORMING GLYCOSCIENCE
BOX S-1
Carbohydrate, Glycan, Saccharide, or Sugar?
Carbohydrate: A generic term used interchangeably in this report with sugar, sac-
charide, or glycan. This term includes monosaccharides, oligosaccharides, and
polysaccharides as well as derivatives of these compounds.
Glycan: A generic term for any sugar or assembly of sugars, in free form or at-
tached to another molecule.
Saccharide: A generic term for any carbohydrate or assembly of carbohydrates, in
free form or attached to another molecule.
Sugar: A generic term often used to refer to any carbohydrate, but most frequently
to low molecular weight carbohydrates that are sweet in taste.
Glycans (see Box S-1) are ubiquitous. All living cells are coated on
their cell membranes with glycans or include glycan polymers as integral
components of their cell walls. They play diverse roles, including critical
functions in the areas of cell signaling, molecular recognition, immunity,
and inflammation. They are the cell surface molecules that define the
ABO blood groups, influencing an individual's ability to receive anoth-
er's blood. Glycans are attached to specific locations on many proteins,
modulating aspects of their biological activity through molecular recogni-
tion or affecting their circulation time in blood. The difference between
glycan molecules added by humans when they naturally produce the
protein erythropoietin, which affects red blood cell production, and gly-
can molecules present when this protein drug is produced commercially
in cell culture, serves as the basis for antidoping tests in athletes. They
are also central components of plant cell walls, which enable plants to
grow upright and to resist degradation from the environment and from
microbes.
Advances in the life sciences over the past several decades have led
to a greater understanding of many of the basic mechanisms present in
biological systems. Stimulated by the Human Genome Project, there have
been improvements in understanding the central dogma of molecular
biology. Sequences of DNA--genes--are transcribed into RNA, which
in turn are translated to form proteins. This basic understanding, along
with advances in the tools used to study biology, underpins the expansion
of both genomics and proteomics. The wide array of posttranslational
modifications that occur on proteins are also part of this increasingly clear
picture. Protein glycosylation, one of the most common forms of post-
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SUMMARY 3
translational modification, is important for many biological processes and
often serves as an analog switch that is capable of carefully modulating
protein activity.
Relatively little attention has been paid to this class of molecules, and
glycoscience remains a relatively understudied field. It is hard to predict
what advances in glycoscience will bring as the contributions from the
life sciences and chemical sciences to numerous areas of applied science
continue to expand. This report provides an overview of the current
knowledge and state of glycoscience and illustrates why glycoscience
is central to multiple avenues of research. An expanding understand-
ing of glycan functions and structures will complement and strengthen
other areas of research, building on advances made in such fields as
genomics, proteomics, chemical synthesis, materials science, and engi-
neering. Understanding glycans and applying this knowledge can help
find problem-driven solutions to a diverse set of challenges. Examples
include the early detection of cancer and other diseases through identifi-
cation of disease biomarkers, protection against infectious diseases such
as influenza through increased understanding of the role of glycans in
host-pathogen interactions and the immune response, and creation of
products and fuels derived from carbohydrate raw materials.
Much of the fundamental biology and chemistry being explored in
glycoscience has the ability to influence what are often viewed as dispa-
rate fields. Researchers in health, energy, and materials science can lever-
age discoveries in each other's disciplines to help strengthen the field as
a whole. For example, efforts to understand the biochemical pathways of
glycans and the roles of carbohydrate polymers inside cells are of use to
scientists working to better understand cancer biology and plant biology
alike. The conversion of biomass into novel starting materials can have
implications for both materials scientists working to develop new plastics
based on renewable resources or synthetic chemists working to synthesize
novel drug targets. This report provides a holistic vision for glycoscience
by suggesting a research roadmap for the scientific community that, while
undoubtedly challenging, may ultimately help democratize the field and
help realize the broad benefits from this important area. This roadmap
will enable the tools to address glycoscience questions to be available
to scientists and engineers who wish to incorporate them into their
research. To address the roadmap goals, glycoscience will require input
from researchers not currently working in this field and glycoscientists
will need to reach out to bring these researchers into their community.
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4 TRANSFORMING GLYCOSCIENCE
WHY NOW?
While genomics and proteomics have advanced rapidly, glycoscience
and glycomics have made strides that are enabling scientists to better
understand the role that glycans play in biological systems. Glycoscience
researchers have already developed a fundamental knowledge base that
can be utilized to help address many of today's major research problems.
This knowledge base, when combined with the current set of tools avail-
able to probe glycan structure and function, is a powerful resource to
better understand human, plant, and microbial biology.
Glycoscience has, until recently, been explored by a small group of
experts, working with a more limited set of information and resources
than are available in fields such as genomics and proteomics. What is
known about glycoscience and glycomics, the study of the complete set
of glycans in an organism, is still incomplete. But current knowledge
now makes it possible to integrate glycoscience broadly into the fields of
health, energy, and materials science, and the set of available tools, while
not perfect, provides a base to enable further development and discovery.
A CENTRAL FIELD WITH LINKS TO MANY DISCIPLINES
Glycoscience is a highly interdisciplinary field that aims to better
understand the structures and functions of glycans and how they can be
used. It is a global field with a dedicated community of researchers in the
United States and abroad. Glycoscientists do not have a single training/
education background. They come from various fields, including physi-
ology and developmental biology, where glycans are involved in pro-
cesses such as cell movement and tissue development. They are in medi-
cine, where glycans are involved in the development and progression of
chronic and infectious diseases. In microbiology, glycans are key players
in interactions among and between microbes and host cells. Glycoscien-
tists are chemists developing new synthetic and analytical methods for
glycans, and biochemists working to understand glycan synthesis and
metabolism. In materials science, glycans can be used as polymeric mate-
rials having a wide range of properties. In computational science and
informatics, modeling studies and the effective analysis of large amounts
of experimental data are also necessary to better understanding glycans.
CONTRIBUTIONS TO IMPROVING HEALTH,
DEVELOPING ALTERNATIVE FORMS OF ENERGY,
AND CREATING NEW MATERIALS
This report focuses on three areas in which glycoscience can make
significant contributions: health, energy, and materials science. The com-
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SUMMARY 5
mittee identified these three areas because they illustrate the diverse
roles played by glycans and because glycoscience is relevant to research-
ers from a range of backgrounds. These focus areas demonstrate how
improved understanding of glycans can make concrete impacts in soci-
ety, particularly as part of the development of a bio-enabled innovation
economy, as recently articulated by both the Organisation for Economic
Co-operation and Development and the White House. This report does
not address the roles of carbohydrates as food sources and nutritional
supplements. Although these are also important areas to be explored,
they are outside the scope of this study and outside the expertise of the
study committee.
In human health, glycans are involved in myriad processes that are
part of normal physiology, development, and cell signaling, along with
the development of both chronic and infectious diseases. For example,
glycans on cell surfaces are important in molecular recognition. One
example of this function is their role in the movement of white blood cells
through the body to a site of infection, enabling the immune system to
respond where needed. Much of the information content in cells is encom-
passed in the glycome. Glycans contain key biological information that
complements the information stored in DNA to help complete the link
between genotype and phenotype or between the genome and expressed
traits. Many advances in understanding human health and diseases are
the result of current knowledge about nucleic acids, proteins, and glycans
and how these vary in different circumstances and in different people.
However, much is still unknown. Continued advances in understanding
the biological roles played by glycans, along with the factors that influ-
ence or alter their functions, will have consequences for the fundamental
understanding of biology and will contribute to the development of new
therapeutic medicines.
Carbohydrates are fundamental to plant biology. Constituents of plant
cell walls include glycans such as cellulose and hemi-cellulose combined
in a matrix of other biopolymers. As society explores sources of energy
that can provide alternatives to fossil fuels, harnessing the energy stored
in these plant carbohydrates is one attractive option. Effectively convert-
ing plant glycans into liquid biofuels requires breaking down the struc-
tures of plant cell walls in order to release the constituent carbohydrate
molecules for subsequent processing. Advances in understanding the
glycans that comprise the cell wall, the enzymes that help assemble and
degrade it, and how it can be altered to improve the degradation process
can all make significant contributions to improving the feasibility of this
energy source.
Glycans such as cellulose, starch, chitin, and others also provide the
basis for creating new materials with useful physical and chemical prop-
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6 TRANSFORMING GLYCOSCIENCE
erties. Such materials can take the form of bulk polymers or be processed
into forms such as nanoparticles. In addition, other molecules can be
attached to the glycans to alter the functional properties of the material
or to affect how the polymer interacts in biological systems. These glycan-
based materials provide potential substitutes for many petroleum-based
plastics and have wide-ranging uses in medicine and industrial applica-
tions. For example, they can serve as carriers to encapsulate and deliver
drugs and as scaffolds for tissue engineering, and they can be used in
flexible coatings and films.
A TOOLKIT THAT INCLUDES MANY COMPONENTS
BUT THAT ALSO HAS KEY GAPS
Because glycans are made of different types of individual sugar units
linked in multiple ways, large numbers of different glycan structures can
be created from the same constituent carbohydrate molecules. Unlike
DNA and proteins, glycans are not created by following a sequence tem-
plate but rather through enzymatic reactions that depend on several fac-
tors, including the concentrations of many different enzymes and many
different substrates. The diversity of possible glycan structures makes
them scientifically interesting. The large number of structures and the
various ways in which glycans interact with other biological molecules
create diversity beyond what can be encoded in an organism's genome
alone. However, these characteristics also pose challenges to probing gly-
can structure and function and to being able to control and manipulate
them in research.
The explosion in genetic research and understanding of gene func-
tions that has occurred over the past 25 years was enabled by the devel-
opment of new tools, such as high-throughput DNA sequencers and
synthesizers. Tools to study DNA are now part of the repertoire of many
biologists and chemists. Glycoscience, too, relies on a toolkit of techniques
that enable key questions to be explored and answered. Although much
can be accomplished by using existing tools, large gaps remain in such
areas as the chemical and enzymatic synthesis of glycans and analytical
techniques to determine glycan structures and functions. Glycoscience
also lacks accessible, integrated, and well-annotated databases similar to
those that exist for proteins and nucleic acids. New tools and techniques
will be needed to enable glycoscience to live up to its potential to contrib-
ute to areas in health, energy, and materials. Creating these new tools and
techniques will require engaging scientists and engineers from multiple
disciplines who can bring new ideas and solutions to the field to help fill
these identified gaps.
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SUMMARY 7
OVERARCHING FINDINGS
Glycoscience is a broad field, and the committee's findings capture
only an overview of the information the committee considered in making
its recommendations and developing a roadmap for the field. The find-
ings are organized under the topics of human health, energy, materials
science, and the toolkit needed to advance the field.
Health
· 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 develop-
ment.
Energy
· 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.
· 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.
Materials Science
· By fostering a greater understanding of the properties of glycans
and of plant cell wall construction and deconstruction, glyco-
science can play an important role in the development of non-
petroleum-based sustainable new materials.
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8 TRANSFORMING GLYCOSCIENCE
· 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
regarding 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.
· 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.
A ROADMAP TO ADVANCE GLYCOSCIENCE
Based on these findings, the committee makes the following recom-
mendations in order to achieve a more complete understanding of glyco-
science and to realize its impacts on health, energy, and materials science.
Each recommendation is followed by a series of roadmap goals.
The capabilities created by the achievement of these recommen-
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SUMMARY 9
dations 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 gly-
colipid glycans and proteoglycans, which are currently estimated to be
10,000 to 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.
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.
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10 TRANSFORMING GLYCOSCIENCE
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,
siRNAs, etc.) of utility to the biomedical and plant research communities.
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.
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SUMMARY 11
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
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.
Finally, the committee notes that there is widespread lack of under-
standing and appreciation of glycoscience in the scientific and medical
communities and among the general public. Glycans are integral com-
ponents of living organisms, whether human, animal, plant, or microbe,
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12 TRANSFORMING GLYCOSCIENCE
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).
CONCLUSION
Glycoscience is a vibrant field filled with challenging problems. It
can make 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, materials science, engineer-
ing, medicine, and other disciplines will be needed to address the techni-
cal challenges described here. Although these challenges are substantial
and complex, the results of achieving these goals have the potential to
impact science in exciting ways.
