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Father of chemical genetics to start new program here

Mario Geysen
Photo by Rebecca Arrington
Mario Geysen

By Elizabeth Kiem

Mario Geysen takes delight in casting himself outside of the mold. “I like to say I’ve never worked a day in my life as a proper chemist,” he declares.

Geysen is used to breaking new ground, both personally and professionally. As U.Va.’s newest Alfred Burger Professor in Biological and Medicinal Chemistry, he is experiencing academia for the first time in his career.

He also is the father of combinatorial chemistry, a field that draws on engineering, chemistry and robotics to make possible large-scale molecular testing. He developed the technique in the mid-1980s, creating the world’s first “library” of mimotopes, peptides that mimic the reaction of antibodies and antigens and are key to drug discovery.

The collection of 1.28 billion compounds was actually made in duplicate; one of the libraries now resides with the Smithsonian Institution, the other in a drawer in Geysen’s new office, casually wrapped in a plastic bag.

In citing Geysen as one of its 2000 laureates, the Kilby International Awards Foundation described him as “the father of combinatorial chemistry, a new science that allows multiple drug candidates to be screened simultaneously. This extraordinary new process dramatically accelerates the pace of pharmaceutical analysis, development and delivery, ultimately providing medicines to patients throughout the world.”

Terms to know

Combinatorial chemistry • a set of techniques for creating a multiplicity of compounds and then testing them for activity; particularly effective in drug discovery.

Mimotopes • peptides that mimic the reaction of antibodies and antigens and are key to drug discovery.

Small molecules • synthetic structures with an atomic weight of 500 or less. Nearly 98 percent of all newly discovered drugs are small molecules.

Neural network • an artificial network of information processing units capable of sophisticated computations similar to the sort that the human brain performs.

Chemistry department chair Timothy McDonald said Geysen’s arrival is a landmark for the University. “This is an extraordinarily accomplished person who revolutionized the pharmaceutical industry by creating an extremely powerful tool that goes by the trendy term of ‘chemical genetics,’” he said.

The Australian-born Geysen brought his expertise to the United States in 1993 when he agreed to develop a combinatorial program for GlaxoSmithKline, thereby introducing the U.S. pharmaceutical industry to the practice. From Triangle Research Park in North Carolina, the move to Charlottesville has been just another step up for Geysen in terms of quality of life.

“[U.Va.’s] a very attractive campus. We’re not city people at all, and Chapel Hill had lost a lot of its charm,” he said.

Part of Charlottesville’s appeal is its proximity to other points of interest.

“There are lots of interesting day trips around,” said Geysen, who owns and pilots a small plane. He plans on getting out of town frequently with his wife, Kay, who is “wintering” in Australia for the next few months, to visit spots such as Tangier Island and the National Air and Space Museum in Washington.

While teaching in a professional forum has always struck Geysen as an ideal way to wind up his career, it was the interdisciplinary eagerness among the U.Va. faculty about his molecular library that secured his contract.

“I’ve been a strong advocate for a long time of the need for universities to address the supply of small molecules for their internal research programs in the area of drug discovery,” he said. “Drug companies have a total monopoly on that. … In part, I am here to supply this University.”

With $10 million worth of state-of-the-art technology and equipment from Glaxo, Geysen will attempt to create a working inventory of small molecules on the second floor of the chemistry building. Three graduate researchers will become the first of Geysen’s team, occupying four renovated labs. Only Harvard University has undertaken a comparable task, but on a scale that Geysen says “leaves a lot to be desired.”

“It’s a statistics thing. It’s a lottery. It’s no good having a few hundred molecules … you just have to have a lot of molecules. And it’s a very expensive operation,” said Geysen, noting that a single molecule in Glaxo’s supply of 100,000 was valued at $7,000. Combinatorial chemistry, with its assembly-line efficiency, eases some cost, but the development and maintenance costs of equipment can be pricey.

U.Va. is clearly committed. “We want to develop a center for chemical genetics in order to modulate proteins rationally,” said McDonald. “Harvard’s the leader, and we want to beat them.”

Geysen’s hope is that when combinatorial chemistry becomes indispensable for firms and industries beyond pharmacy, U.Va. will be the premier school for training young chemists.

But don’t assume that Geysen’s biggest legacy will be in combinatorial chemistry. He is building his seventh company around a totally unrelated patent in artificial intelligence that would develop a “hardware equivalent” of the human brain.
“The idea that underpins the neural networks is the most important idea I’ll ever have in my career,” he said.


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