Matthew David Disney
Department of Chemistry, SUNY at Buffalo
Letting the Drugs Have Their Say
Matt Disney has an idea that could streamline the way drug companies search for the best targets in order to knock out diseases.
Drug companies now try to find uses for drugs by throwing them at targets to see which ones the targets catch. That, he says, is like trying to have one particular person at a baseball game catch a foul ball, when there are thousands of possibilities.
The problem is what if the drugs really want to be caught by someone else, someone or something that's not at the game? It would be nice to know what would make the best targets in advance, which is where Disney comes in.
Disney, a chemist who designs and tests drugs at the University at Buffalo, would prefer to let the molecules say in advance whom they would like to bind with, even if that's thousands of options. That, he says, would be an efficient approach to molecular recognition - binding a drug molecule, or ligand, and a target - to fight, for example, sickle cell disease or cancer.
As a child in Baltimore, he wanted to be a pitcher for the Baltimore Orioles, but he says he quickly realized he was better suited for pitching drugs at targets. He said, "I guess now my aspirations have moved from the baseball field into construction, where my company is making molecules." Disney, a Maryland graduate, began to study the matching of molecules in his doctoral work at the University of Rochester and in postdoctoral work at MIT and at the Swiss Federal Institute of Technology.
He has also constructed the tools - nanoscale hammers and nails - to build a molecule to target any kind of RNA in a specific RNA library. Such a library can test 100 drugs for binding to 64,000 RNAs, testing 6.4 million interactions in a single experiment. That is called two dimensional combinatorial screening, which is like designing a perfectly sized ball for each catcher's mitt. Says Disney, it's like asking drugs: "What types of RNAs do you like to bind to?"
"When a drug molecule binds to a target, it's like throwing a ball to hit the perfect spot," he said. "If the ball does not hit the spot, that's like hitting the batter, or causing side effects. What we want is to know what spots in a cell a drug wants to hit. That way we can use a computer to find all of the types of cells that have a sweet spot that the drugs want to hit."
His lab targets RNA, as few drug discovery labs do - such labs are mostly interested in protein. After his system collects the RNA preferences from the new drug molecules, the information goes into a database. This database, on RNA motif-ligand pairs, is then compared with the RNAs in diseased cells. If there's a match, then his findings can be applied to that disease. That improves the odds that the drugs will hit the designed targets inside cells.
"In the end," Disney said, "everyone is happy. The drugs do the job they want to do, and an RNA that causes a disease is targeted."
Education Component
Disney's teaching proposal for the Cottrell award aims at strengthening science programs at the nearby schools in Buffalo, N.Y., where the student body is economically disadvantaged and racially diverse. Part of the challenge that the country faces, he says, is to develop a new generation of scientists that is racially diverse.
"We are trying to mentor students on the way scientists work by developing new laboratories that focus on antibiotic resistance," he said. "Students sometimes do not realize that people actually use the information in their textbooks. So we try to help students understand resistance by seeing with their own eyes bacteria growing in the presence and absence of different antibiotics. They can relate to this because they know certain bugs can make them sick. We will also develop an online seminar to help mentor teachers to implement this program in their own curriculum. Not only do the students need mentorship but also the teachers. Science moves so fast these days, and it's hard enough for teachers to keep up with their students, much less with the quick pace of science. We want to help them with that and want to enlist their help to develop age-appropriate instruction materials."
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