Glycoscience: Biology’s Newest Uncharted Frontier
by Kathleen Cason

Like wallflowers at the homecoming dance, complex carbohydrates used to attract few suitors. In the world of giant biological molecules, their sexier cousins — DNA and proteins — commanded the most attention.

But over the past decade, the wallflowers have bloomed and scientists are hastening to uncover their secrets. And researchers at UGA’s Complex Carbohydrate Research Center are helping lead the way.

Complex carbohydrates are the next frontier in understanding the secret molecular messages that rule the life of our cells. These strings and branching “trees” of sugars have eluded study and their roles have long been neglected. But during the past two decades evidence has been mounting that these macromolecules deserve attention: Carbohydrates determine blood type, regulate plant growth, and even have roles in cancer, diabetes and human development.

For all cells — plant, microbe and animal — a sugar coating is at the cell’s outer perimeter. It’s what an invader first encounters; it’s what other cells touch. In it resides information that identifies the cell — this one’s a liver cell, that one a skin cell. It may glue similar cells together or unglue cancer cells, allowing them to break loose and travel throughout the body. When invader molecules from a virus, bacterium or fungus touch the outer perimeter, they may trigger self-defense mechanisms in plants or provoke immune responses in animals.

For several decades, CCRC researchers have been on the forefront of glycoscience (“glyco” means sugar). They not only study normal growth and development in plants and animals but also investigate disease processes. When tools did not exist to answer their research questions, CCRC scientists developed new ones. The methods they’ve developed are fueling plant and medical carbohydrate research, not just at the CCRC but worldwide.

“The biology is hard, the chemistry is hard, everything is hard,” said Gerald Hart, a CCRC adviser from Johns Hopkins University School of Medicine. “In glycobiology, in terms of understanding and technology, we’re back where DNA and proteins were in the 1960s. There’s been a lot of progress in the past 10 years but we have a long way to go.”

The following is a snapshot of current research areas and the faculty pioneering glycoscience at the University of Georgia.

Plant cell walls and regulatory carbohydrates

  • Research in this area focuses on the primary cell walls in plants: uncovering the composition of the walls, the structure of the polymers and how they assemble to form cell walls, and the biochemical pathways involved.
  • Complex carbohydrates that regulate plant growth, development and responses either to the physical environment or to other organisms are studied by several research groups at the center.

New cancer diagnostics, vaccines and therapies

  • Several studies focus on tumor-associated antigens that can be used to develop vaccines or diagnostic tests.
  • Carbohydrate markers in the blood have been identified and used in a diagnostic test for choriocarcinoma — a rare cancer where embryos turn into deadly tumors.
  • New research is under way to find carbohydrate markers to detect breast, prostate and ovarian cancers.
  • Other studies seek to block the cell surface carbohydrates that allow cancer cells to spread.
  • Pectin — a complex carbohydrate from plants — may have a role in prostate cancer prevention. CCRC scientists are examining pectin’s anti-cancer properties in a collaborative project with Medical College of Georgia researchers.

Vaccines and new carbohydrate-based drugs

  • Studies of the polysaccharide coatings of various microbes may lead to new vaccines for bacterial meningitis, strep B infection and pathogenic yeast infection caused by Cryptococcus neoformans, which is a major cause of death in immuno-compromised patients.
  • Other studies may lead to new diagnostic tests or medicines particularly for gonorrhea and the bacterium Pseudomonas aeruginosa, which infects people with cystic fibrosis or who are immuno-compromised, such as cancer and burn patients.
  • New adjuvants — substances added to vaccines to stimulate the immune system — are being tested in collaborative studies with UGA vet school scientists.
  • Research on the identities and structures of polysaccharides from potential bioterrorism agents such as anthrax will help scientists develop better vaccines and treatments.
  • Other health-related topics
    Other CCRC research focuses on:

    • septic shock;
    • immune responses;
    • the mechanism of protein folding;
    • type II diabetes;
    • nervous system development;
    • rheumatoid arthritis; and
    • heparin synthesis.

    Tools to study biologically important carbohydrates

    • New methods using nuclear magnetic resonance (NMR) are being developed and will help advance understanding of how cell surface carbohydrates interact with proteins.
    • Computer simulations help uncover what happens when two molecules come in contact and may guide design of vaccines and drugs.
    • New methods in mass spectrometry are speeding up progress in studying diseases such as ovarian cancer.
    • New methods are being developed to synthesize biologically important oligosaccharides (molecules made of a dozen or so sugar units).

    Robert Woods, a computational carbohydrate chemist, uses computers to study the role of carbohydrates in immune reactions and in diseases like rheumatoid arthritis. His lab developed computer software — called GLYCAM — that enables them to simulate molecular structures, explore how molecules interact and make discoveries about those interactions that are otherwise impossible with currently available experimental technology.

    Russell Carlson, a microbial biochemist, studies how bacteria interact with animal and plant cells. For example, his group studies the polysaccharide coat of the microbe that causes bacterial meningitis, with the idea of developing vaccines. Other studies may lead to new diagnostic tests or medicines particularly for bacteria that cause anthrax, gonorrhea and Pseudomonas aeruginosa ��� a bacterium that infects people with cystic fibrosis or who are immuno-compromised, such as cancer and burn patients.

    Geert-Jan Boons, a synthetic carbohydrate chemist, develops methods to make the difficult task of synthesizing carbohydrates a bit easier. His lab uses these methods to synthesize biologically important carbohydrates or glycoconjugates (carbohydrates that attach to specific proteins), such as compounds related to cancer, inflammation and septic shock. Boons’ research may lead to development of novel carbohydrate-based drugs and vaccines. He received the 2003 Carbohydrate Research Award for Creativity in Carbohydrate Chemistry from the European Carbohydrate Association.

    Debra Mohnen, a plant biochemist, devotes most of her research effort to understanding the enzymes and biosynthetic pathways involved in making pectin, a plant cell wall polysaccharide that is a natural gelling agent and has positive effects on human health. Her research not only increases current understanding of pectin’s function, synthesis and role in plant development but also may lead to ways to alter pectin’s gelling properties for use in the food industry. Her lab also investigates pectin’s surprising anticancer effects, especially as related to prostate cancer.

    Ron Orlando, an analytical chemist, specializes in the mass spectrometer — an instrument that lets scientists detect small changes in a molecule undergoing a biological process. New methods developed in his lab help Orlando and his collaborators hunt for molecular markers to detect ovarian cancer and Chagas disease.

    William York, a plant biochemist, studies the molecular structures of polymers that make up the walls surrounding growing plant cells. He has compiled his research results in databases that are accessible online, allowing other scientists to rapidly and accurately determine the structural features of these polymers. York’s databases provide fundamental information required to understand the molecular basis for plant growth and development.

    Lance Wells, a protein biochemist and Georgia Cancer Coalition Distinguished Cancer Scientist, is interested in understanding how the body senses nutrients. He studies a simple sugar — known by the abbreviation O-GlcNAc — that changes protein function when added to or removed from the protein. Excess O-GlcNAc on certain proteins may lead to type II diabetes and may be linked to cancer. Wells’ research may help identify new strategies for developing therapeutic agents for type II diabetes and cancer.

    Michael Tiemeyer, a developmental glycobiologist, investigates cell surface carbohydrates related to nervous system development and is trying to uncover how cells know which carbohydrates to put on their surfaces. Prior to arriving at UGA, Tiemeyer discovered a protein called Tollo, which instructs nerve cells to present specific carbohydrates. His research findings may lead to ways to regenerate nerves, increase understanding of innate immunity and uncover ways to prevent tumor cells from spreading.

    Michael Pierce, a cancer glycobiologist, investigates how cells recognize each other and what makes them adhere to one another. Specific sequences of sugars (called oligosaccharides) attached to cell membrane proteins determine whether cells stick together or slip apart. Pierce’s group looks for differences in oligosaccharides that distinguish cancer cells from healthy cells. Changes in oligosaccharides cause cancer cells to lose stickiness, slip loose, and become invasive (malignant) and metastatic cancers. His findings are being used to develop new serum-based cancer diagnostics and may lead to more targeted delivery of chemotherapeutic agents. (See Research Reporter Summer 1999)

    Kelley Moremen, a molecular glycobiologist, focuses on understanding how certain proteins are modified from the time they are first made until they are released from cells. Proteins that undergo this modification process move through a series of cell compartments where carbohydrates are attached, trimmed and extended. The addition of sugars to proteins assists in protein folding (a necessary step for proper protein function), targeting defective proteins for disposal, as well as controlling protein stability, cell-cell communication and receptor binding. Moreman’s research has broad application to cancer and several human genetic diseases.

    Michael Hahn, a plant biochemist, studies how plants perceive signals from the physical environment or from other organisms, and the cascade of specific events that leads to a response to those signals. Specifically, he looks at carbohydrate signals released from cell walls that “tell” plants to defend against attack or change metabolism to adapt to the cold. He also looks at how plant cell walls change as plants grow and develop or respond to their environment.

    Peter Albersheim, CCRC co-director and plant biochemist, studies small carbohydrate molecules called oligosaccharins that act as signal molecules in plants. Once his research team determines the structures and functions of specific oligosaccharins, the scientists then try to uncover the mechanism by which these molecules function. Albersheim’s lab has discovered that these signal molecules trigger plant defenses as well as regulate plant growth and development. His lab also continues long-term research on the structures of the six polysaccharides found in plant cell walls.

    James Prestegard, the Varian/GRA Eminent Scholar of NMR Spectroscopy, develops methods using nuclear magnetic resonance to study how cell surface carbohydrates interact with proteins that are involved in quite a variety of biological processes. His team’s new methods are used to study molecules involved in spread of cancer cells, inflammatory responses and neurological development, to name a few.

    Alan Darvill, CCRC co-director and plant biochemist, studies the structure and function of complex carbohydrates in plant cell walls. His lab has studied five major types of complex carbohydrates apart from cellulose that comprise primary walls of plants. Researchers in his lab have undertaken the difficult task of unraveling the structure and functions of these polysaccharides. Darvill was named Regents Professor of Biochemistry and Molecular Biology in 2003.

    Maor Bar-Peled, a biochemist and cell biologist, investigates the carbohydrate polymers that make up plant cell walls. He is interested in how and where they are made, the enzymes that make the molecules and the biological function of these polymers in plants. Bar-Peled’s group also studies the genes involved in nucleotide-sugar biosynthetic pathways. The nucleotide-sugars are important precursors for production of the thick polysaccharide capsule in the pathogenic yeast, Cryptococcus neoformans — a major cause of death in AIDS and immuno-compromised patients.

    For more information, check out the CCRC Web site at or contact Alan Darvill at and Peter Albersheim at

    Kathleen Cason is associate director of Research Communications at the University of Georgia.