Thinking outside the cell

Melissa Marino, Ph.D.
Published: July, 2005

While most researchers plumb the depths of the cell to find drug targets for modern-day ailments, Billy Hudson, Ph.D, advances into the great expanse beyond the cells’ margins to uncover drug targets hidden in this extracellular netherworld.

Billy Hudson, Ph.D., (left) discusses a research project with graduate student Roberto Vanacore.
Photo by Anne Rayner
All cells exist in a sea of amorphous protein called the extracellular matrix. Composed primarily of insoluble collagens and proteoglycans, the matrix is more than just filler. It shapes tissues and supports and influences a multitude of cellular processes.

“Matrix components are specifically involved in the etiology and pathogenesis of disease, making the matrix a valuable drug target,” said Hudson, director of the Vanderbilt Center for Matrix Biology.

Changes within the matrix underlie several of the complications of diabetes, particularly those involving the kidney. When glucose concentrations remain high for long periods, matrix proteins can be altered by glucose reacting with the amino groups of the proteins.

This process, called glycation, results in large, cross-linked molecules that inhibit normal cell function. In the kidney, glycation can limit the organ’s filtering function and lead to kidney failure.

After several years of studying matrix changes involved in diseases of the kidney, Hudson was challenged to “do something” to stop the process by a former postdoctoral fellow at the University of Kansas, J. Wesley Fox, Ph.D.

“We were making strides in understanding the process, when Wes Fox says, ‘Why don’t you develop a drug to prevent that?’” Hudson recalls. “I said, ‘That sounds good, but I don’t really have the money to do that.’” Fox replied that he would find the money if Hudson worked on the drug.

With a unique combination of scientific expertise and a sharp business sense, Fox found investors to support Hudson’s new line of inquiry. In 1994, Fox, Hudson and colleagues at the Karolinksa Institute in Sweden founded BioStratum, a biotech company dedicated to pursuing the matrix as a drug target.

Efforts to pharmacologically arrest glycation-related pathology had shown some progress, but the most promising drug candidate, aminoguanidine, had proven too toxic in clinical studies. Drawing on his studies of the extracellular matrix, where diabetes-induced glycation is very active, Hudson found an effective compound that inhibited multiple pathways of glycation-related pathology, but was entirely natural in the body.

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