In a stack of black plastic plates with row upon row of small wells are tiny fish that could lead to big - and faster - breakthroughs in drug development, according to research at Georgia Health Sciences University.
In a paper published this month in the journal Public Library of Science ONE, researchers at GHSU and the biotechnology company Luminomics, which is housed inside a research building at GHSU, show they have taken a big step forward in bringing biology to rapid through-put testing.
That rapid testing, in which about 50,000 samples a day are quickly analyzed for different reactions, primarily looks at chemical-to-chemical reactions or cell reactions in labs. It allows for an enormous number of chemicals from a large library of compounds to be tested against samples to see if they can engender a particular reaction, a first step in searching for new drugs, said corresponding author Dr. Jeffrey S. Mumm, who works with both the company and GHSU.
That kind of rapid run through a large number of compounds can lead to thousands of “hits” that appear to be potential drugs, he said. That becomes the problem - testing each of those thousands of compounds in an animal model, such as a mouse, is prohibitively expensive, Mumm said. And that has had the opposite effect of speeding up drug discovery.
“As high through-put screening got more and more commonplace, the actual number of new drugs has actually gone down,” he said.
A big part of that is the need to see how a large number of candidate compounds actually behave inside living organisms.
“Then you’ve got to be lucky enough to have the smartest guy in the room figure out which one of those 4,000 (candidate drugs) is the one you want,” Mumm said.
Some other systems can screen whole animals, but at nowhere near the speed of high through-put screening, he said.
So the GHSU team put together its own using the versatile zebrafish, prized for its relatively low cost, rapid reproduction, and see-through skin that can allow examination without opening up the animal. The group bred the fish to attach fluorescent “reporters” that would show up on a scan that were tied to certain biological functions, such as the loss or regeneration of certain cells in the eye or pancreas or if an important cell-signaling pathway was activated. They were able to do it at high through-put speed, which could provide important information on thousands of candidate drugs early in the process after they have been identified, he said.
“Now (researchers) want to know, does it do so also in the living animal and secondarily or even primarily, are any of these compounds toxic?” Mumm said.
With a robot shuffling plates between three or four readers at a time, running around the clock, the potential is there to even run different compounds at different doses, he said.
“Just toxicity alone” would be useful and provide cost-savings in drug development, Mumm said. It could also allow tinkering around with known drugs using the fish as the analyzer to see if, for instance, the current dose of a drug could be tweaked and lowered to get the same effect, he said.
“It’s up to the imagination of people that are hopefully smarter than me to take this in as many directions as it can possibly be applied,” Mumm said. “The number of things you can do with it is legion.”