Millimetre-Long Worms Could Hold Key To Medical Marvels

Millimetre-long worms show remarkable potential to act as models for medical testing and analysis, says University of Toronto research, especially when it comes to high blood pressure.


The study outlined in the May 4 issue of Nature shows how the Caenorhabditis elegans worm can provide a platform for identifying the proteins in the body that are targeted by drugs and drug-like molecules to produce therapeutic effects, otherwise known as target identification. In the study, researchers screened 14,100 drugs and drug-like molecules and identified 308 that cause death and defects in growth, movement or shape in worms. In revealing the bioactive molecules, researchers are developing new tools to study biology and some of these could lead to new therapies for disease.


"A major bottleneck in developing new potential drugs is to identify the proteins in the cell targeted by small bioactive compounds," says Professor Peter Roy of the Department of Medical Genetics and Microbiology, the study's co-author. "Because we are able to create hundreds of thousands of mutant worms in a matter of days, we can let these tiny creatures tell us which proteins are being targeted by the small molecules."


The researchers discovered a new small molecule called nemadipine-A that kills worms at high concentrations. Nemadipine-A is similar to a class of drugs called the 1,4-dihydropyridines that are used to treat high blood pressure in humans by blocking calcium from entering cells. This in turn relaxes blood vessels and lowers blood pressure. To find the protein target of nemadipine-A, the team screened 180,000 mutant worms for those that live in nemadipine-A and found that it blocks the function of the egl-19 gene product, which just so happens to be a calcium channel.


"So long as you have a molecule that causes some defect in worms, we are betting that you will be able to identify the protein target relatively quickly by screening for mutants that are resistant to it," says Roy, a Canada Research Chair in molecular neurobiology. Other authors in the study include three other Canada research chairs: Sean Cutler, plant genomics, Peter McCourt, plant molecular biology and Elise Stanley, brain and behaviour.


"This research team has developed a major new approach to drug discovery, and the findings have important implications for the pharmaceutical industry. Using only the lowly laboratory worm, they demonstrated the power of their novel strategy by finding a new class of drugs that inhibit a class of proteins called calcium channels, which are important in hypertension," said Roderick McInnes, scientific director of the Canadian Institutes of Health Research (CIHR) Institute of Genetics. "These exciting findings demonstrate once again that fundamental biological research is the cornerstone of profound discoveries in clinical medicine."


The study was supported by CIHR, a Premier's Research Excellence Award, the Canada Foundation for Innovation and the Ontario Innovation Trust.


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