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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