Life, Sugar-Coded

By Jason Socrates Bardi

"She had a sweet child-fancy that her playmates understood her language as she did theirs, and that birds, flowers, animals, and insects felt for her the same affection which she felt for them."

—Louisa May Alcott, from A Modern Cinderella


Glycomics—the systematic identification and characterization of all the carbohydrates (sugar) chains used by organisms—is a young and relatively undeveloped field when compared to genomics and proteomics. And this comparison has caused glycomics to be likened to a scientific Cinderella: she's hard working, but put upon, and has to stay home while her big sisters genomics and proteomics go to the ball.

Of course, the fairy-tale analogy is not so much to say that the genome and the proteome are evil stepsisters as to point out that, like Cinderella, the glycome has much beauty and grace ripe for discovery.

"Carbohydrates carry information just like DNA and proteins do," says James Paulson, who is a professor in The Scripps Research Institute (TSRI) Department of Molecular Biology. "But glycomics is a field that has lagged behind progress in these other[s] by about 20 years."

The nature of the complex branched structures of carbohydrates has contributed to this lag by slowing the development of efficient and routine methods for structure analysis and synthesis that are key to unraveling the information content and biological functions that they mediate. As a result, progress in elucidating the functions of information-carrying carbohydrates has been slow.

Now, to rectify this, a large grant to study the functions of carbohydrates—a field that Paulson calls "functional glycomics"—is bringing together a consortium of some 50 independently funded researchers at nearly 40 different institutions around the world, including several here in San Diego.

The National Institute of General Medical Science, which supports basic biomedical research, has awarded a multi-year grant to TSRI. The grant carries a five-year package of $34 million, including $7.4 million for the first year.

"It was [the National Institute of General Medical Science's] idea to glue together the work of independently funded investigators," says Paulson, "to provide the funds to accelerate the rate of research for [this] important field." The beneficiaries are the scientific and biomedical community as a whole, and, ultimately, the public as discoveries are translated into treatments for disease and improved health. Information generated by the consortium will be rapidly disseminated to participants and the public alike through web-based databases.

"The goal of the Consortium for Functional Glycomics to understand the paradigms by which carbohydrate-binding proteins mediate cell function through recognition of their carbohydrate ligands" he adds. "We know enough to say that carbohydrates can carry zip code-like addresses to aid the proper trafficking of cells in the body, and that carbohydrates can modulate signaling from the outside of a cell to the inside, but what we know so far is just the tip of the iceberg."

The Third Alphabet

Carbohydrate structures are very much a part of the language of life. They are like the accents on spoken words—they change the meaning without changing the spelling.

Some even call carbohydrates the third alphabet, behind DNA and proteins. Though they are not charged with storing genetic information like DNA or acting as enzymatic workhorses like proteins, carbohydrates nevertheless do carry information and are responsible for important biological functions, playing a central role in many types of intercellular communication events, particularly in the immune system.

"This program is looking at the third alphabet," says Paulson. "It's a smaller alphabet than the genome or proteome but is nevertheless critically important to understanding many aspects of biology."

Carbohydrates are particularly important in the immune system because all cells, foreign or human, are covered with them. Some viruses, like HIV and influenza, use sugars on the outside of human cells to gain entry, and immune system cells use carbohydrate-binding proteins to detect subtle differences in sugar structures on the surface of cells to recognize foreign pathogens. Sometimes the carbohydrate-binding proteins and their sugar ligands are expressed on the same cell, and the sugar is part of the regulation machinery of the cell. Indeed, the major histocompatability complex, which is responsible for the recognition, is composed almost entirely of glycosylated proteins.

Moreover, sugar structures differ among cells and are regulated in development and differentiation. "And, the differences are important," adds Paulson. "If the right sugars are not there, the biology is altered."

For instance, one of the participating investigators, Jamey Marth at the University of California, San Diego (UCSD), has shown that the absence of a single carbohydrate expressed in T cells and displayed on their surfaces will not affect CD4+ helper T cells, but will cause CD8+ killer T cells to die prematurely.

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James Paulson is professor of molecular biology and molecular and experimental medicine.