Sweeter Opportunities in Carbohydrate Research

Karin Jegalian

Carbohydrates are not just a much-maligned food group—they are vital to all living systems. They take part in everything from communication between cells to the immune response, growth, and brain function. Made up of long, often highly branched chains of sugar molecules, carbohydrates are notoriously difficult for researchers to work with. As a result, the molecules are not nearly as well understood as DNA or proteins. Three recent advances reveal new insights into how carbohydrates work and how researchers can work with them. These findings promise to open new ways to diagnose and treat a host of diseases.

Ajit Varki, M.D., of the University of California, San Diego, has unexpectedly found that the carbohydrates people eat can actually infiltrate into their cells and may increase the risk of certain diseases. Previously, scientists believed that ingested carbohydrates were broken down into simple building blocks and that cells contained only carbohydrate molecules that the body synthesized from these smaller compounds.

Varki studied a carbohydrate molecule that is present in high levels in red meat and milk. Although humans do not make this carbohydrate, Varki had earlier found small amounts of it in human tissues. He has now shown that the source is meat and dairy products and that the molecule, which the body recognizes as alien, provokes an immune response that he believes could cause long-term inflammatory reactions in body tissues.

Eating large quantities of red meat has been linked to heart disease and some forms of cancer, and recent research suggests that meat in the diet may increase the risk for some autoimmune diseases like rheumatoid arthritis. Although most scientists think the primary culprit for such associations is saturated fat, Varki speculates that an immune response to foreign carbohydrates might also contribute.

Carbohydrates, like the one Varki studied, often coat the surfaces of cells, where they are crucial to cell interactions. Using a specially designed cell-surface carbohydrate, Carolyn Bertozzi, Ph.D., of the University of California, Berkeley, has accomplished the feat of tagging certain cells in living mice.

First, Bertozzi injected mice with an artificial carbohydrate that wended its way through their bodies, finally lodging on the outer surfaces of their cells. Then she fed the mice a chemical that reacts specifically with the synthetic carbohydrate but nothing else in their bodies. Taking advantage of the light-absorbing properties of the chemical tag, Bertozzi confirmed that the chemical had reached and reacted with the artificial carbohydrate, without causing any harm to the mice.

Bertozzi's ability to customize the carbohydrates on cell surfaces represents a powerful new way to study the molecules and promises a wide range of clinical applications, such as potentially tagging cancer cells with lethal chemicals.

To capitalize on opportunities like the one provided by Bertozzi, biotech and pharmaceutical companies will need to be able to synthesize carbohydrates efficiently. Currently, the process is labor-intensive and time-consuming. In a chemical tour de force, David MacMillan, Ph.D., of the California Institute of Technology in Pasadena developed a new method for building carbohydrates that is simple and straightforward, requiring just two steps. This technique will revolutionize the study of carbohydrates and could be used to produce a wide range of drugs and diagnostic tools, including those targeting the heart, immune system, and brain.

Still the most mysterious of biology's big molecules, carbohydrates have always been just as important as proteins and DNA to the lives of cells. Now, through these recent advances in tracking, customizing, and synthesizing carbohydrates, scientists are poised to understand the molecules better and use them in new medical applications.