Saving Lives With Sugar

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Science  23 Mar 2001:
Vol. 291, Issue 5512, pp. 2339
DOI: 10.1126/science.291.5512.2339

The study of slime molds and the development of a lifesaving treatment for a rare genetic disorder may seem worlds apart. But a chance observation recently brought them together in dramatic fashion. Six years ago, Hudson Freeze noticed that cells from one of his molds (more properly known by the name of the organism, Dictyostelium) showed biochemical similarities to cells taken from a child with a disorder in the way cells manipulate sugars. The condition, known as congenital disorders of glycosylation type Ib (CDG1b), causes chronic gastrointestinal problems, including vomiting, diarrhea, bleeding, and blood clot formation. And though not always fatal, it's related to other inherited sugar-processing defects that can cause severe neurological problems and even death.

Children with CDG1b lack an enzyme called phosphomannose isomerase that converts the sugar fructose-6-phosphate to mannose-6-phosphate. The mannose compound is a critical intermediate needed to synthesize N-linked glycosylated proteins, which are involved in myriad biochemical functions. Freeze, who heads the glycobiology program at the Burnham Institute in La Jolla, California, was studying a strain of Dictyostelium engineered to produce no phosphomannose isomerase. He discovered that adding mannose to the mutants' culture medium corrected this deficit by allowing Dictyostelium to use an alternative route for making mannose-6-phosphate. On a hunch, Freeze added mannose to the CDG1b cells and got the same results. Hoping to use mannose to treat CDG1b, Freeze asked the U.S. Food and Drug Administration (FDA) for permission to test the safety of mannose therapy on healthy volunteers. In 1995, the FDA agreed.

Shortly after Freeze and his Burnham Institute colleagues began their initial safety tests with mannose, he got a call from a physician in Germany who had read a paper on the cell work. One of the doctor's patients, a young boy, was about to die from CDG1b—the child was bleeding to death and had already received 20 liters of blood. “I told him how much mannose to give the child and how often,” says Freeze. “Six months later, the physician called back and told me that the boy was completely fine.”

Freeze and chief collaborator Thorsten Marquardt of the Pediatric Clinic in Münster, Germany, published their findings in the April 1998 issue of the Journal of Clinical Investigation. Since then, Freeze has gotten two or three calls a week from physicians wanting to know more about mannose treatment for CDG. “Unfortunately, mannose only works for CDG1b,” he explains with obvious regret, but then he adds that he and Marquardt have found that the sugar fucose works as a treatment for another glycosylation disorder that interferes with the body's ability to fight infections by altering the capacity of immune cells called leukocytes to stick to their targets. Both disorders are easily detected by a simple blood test.

“The real importance of what Hud and Thorsten have done is not just that we can treat these syndromes, but that we have a new perspective on multisystem diseases that we had no way of understanding before,” says William Balistreri, editor of the Journal of Pediatrics and head of pediatric gastroenterology, hepatology, and nutrition at the Children's Hospital Medical Center in Cincinnati. “The fact that a simple biochemical defect causes such a wide range of symptoms involving multiple organ systems has been a revelation.”

Today, Freeze continues to study the biochemistry of CDG and other aspects of carbohydrate assembly. But his biggest passion is getting the word out about potential treatments for these disorders. “We're not talking about a lot of kids, but for the few hundred born every year, these therapies can change their lives,” he says—and even save them.

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