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Defining What Causes the ‘Disease of Kings’

A Hopkins reseacher shows that some diseases—including gout—result from defects in how molecules move into and out of cells.

Bill Guggino has spent much of his research career studying cystic fibrosis. But two years ago, an epidemiologist called him to ask for his help on a study of an entirely different disease—gout.

Guggino, who is the director of the Department of Physiology, had never entertained the notion of studying gout, an extremely painful arthritic condition that affects 3 million people in the United States. However, he readily agreed to the request, and in April, he and the epidemiologist, Joe Coresh, and their colleagues will receive an award for a paper that revealed a new cause for gout.

It wasn’t the first time Guggino has worked on a project outside of his specialty. He’s also collaborated on studies of various other proteins, including ones that are involved in polycystic kidney disease, and ones that form channels known as aquaporins, which direct the movement of water across cell membranes—research that garnered his colleague Peter Agre the Nobel Prize.

This list might seem like a random collection of proteins, says Guggino. However, all share a common motif; each is a molecule that helps transport material across cell membranes, and defects in these protein-transport molecules cause a range of diseases. So Guggino doesn’t call himself a disease researcher. “We are transport physiologists,” he says. “We study how molecules move into and out of cells.”

More than 20 years ago, Guggino used an ingenious tool for studying transport proteins. It begins with eggs from the frog species Xenopus. “You can inject the transcript of a human gene into a frog egg and make buckets of mammalian protein,” he notes. If the gene encodes a protein that is normally found in a cell’s membrane, that protein will embed itself in the egg’s plasma membrane. With a protocol he developed, Guggino can determine whether the protein is involved in transporting different molecules across the membrane and if so, in which direction it moves them—into or out of the cell.

Using this system, Guggino in the 1990s demonstrated how mutations in a gene called CFTR lead to cystic fibrosis. A normal CFTR protein forms a membrane channel for the passage of chloride ions, his experiments showed. But mutations in CFTR, he demonstrated, block chloride transport, which leads to the thick mucus, salty sweat and other symptoms seen in CF.

CFTR is only one of dozens of different membrane transport proteins. “Many researchers come to me to study their particular transport protein using the Xenopus tool,” says Guggino.

One such researcher is Coresh, a professor of epidemiology at the School of Public Health. Coresh had been working with an international team of investigators to find a gene for gout.

Historically, gout was blamed on an overindulgence in food and alcohol, leading it to sometimes be called the “disease of kings.” But scientists eventually learned that, although certain foods might exacerbate the condition, gout occurs when uric acid (urate) builds up in the blood; crystals of uric acids then accumulate in the joints, triggering inflammation and acute pain. These findings led scientists to suspect that gout might result from a defect in the kidney’s ability to excrete uric acid, a byproduct of the metabolism of the amino acid purine.

Further evidence suggested that some people were genetically prone to gout. So Coresh and his colleagues conducted a large-scale genetics study to search for a gene associated with high blood levels of urate, the signature of gout. Their hunt led them to a gene called ABCG2. But having the gene in hand didn’t answer the question, What did the gene do? That query led Coresh to Guggino.

Both researchers thought there was a good chance that ABCG2 functioned as some sort of urate pump. But they needed proof. So Guggino and colleagues used the Xenopus egg system to test their hypothesis. The experiments showed that their hunch was correct: ABCG2 pumps urate out of the cell. Mutations in the gene result in a protein with about half the normal pumping strength.

The researchers also showed that ABCG2 occurs in the kidney where uric acid excretion normally takes place. So if the pump fails, the kidneys excrete uric acid more slowly, causing the chemical to build up in the bloodstream.

The team published its results last year in the Proceedings of the National Academy of Sciences. In April, 2010, they will receive the Cozzarelli Prize for the “scientific excellence and originality” of that work, an award the Academy grants to only a handful of the thousands of studies PNAS publishes annually.

Aside from prizes, however, Guggino hopes the research will lead to improved medication, but not just for gout. To that end, he is now turning his attention to yet another seemingly unrelated disease: cancer

Long before Coresh and Guggino began their study, ABCG2 had earned an infamous reputation among cancer researchers. It is one of the proteins responsible for the multidrug resistance that can occur when cancer patients undergo chemotherapy. It appears to pump certain chemotherapeutic agents out of targeted cancer cells—in effect preventing the agents from destroying the cells.

Drug companies are searching for agents that will inhibit ABCG2. “However, if they do that, the patients are going to get gout,” says Guggino. So Guggino has now launched a new research project. He is searching for a drug that will selectively activate the urate pump. Such a drug might be used in conjunction with chemotherapeutic agents designed to counter multidrug resistance. 

–Melissa Hendricks

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