CONVENTIONAL wisdom on finding cures for diseases needs to be turned on its head, claims an Australian team. 鈥淔or therapeutics you don鈥檛 want to know which genes are causing the disease. You want to know which ones give you a cure,鈥� says Doug Hilton of the Walter and Eliza Hall Institute in Melbourne.
The standard way to study a disease is to find a strain of mouse that develops it, or a way of triggering the disease in mice. Then the mechanism is studied. Understand the disease, the thinking goes, and you can design drugs to treat it.
Hilton and his colleagues also starts with a mouse strain with a particular disease. But instead of studying the mechanism, their idea is to create thousands of mutants in the hope of finding gene variants that protect against the disease. Then the search can begin for drugs that have the same effect as these gene variants.
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The team has put the concept to the test on a disorder called thrombocytopenia, in which too few blood platelets are produced. The researchers injected a chemical that causes random mutations into several hundred mice with a genetic defect that causes the condition. They then screened thousands of offspring, and found seven that remained healthy.
Further experiments enabled the team to determine that any one of three different mutations could cure the disease, though so far they have only identified one of the three genes involved (Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.0401496101). Drugs that target the protein coded for by the normal gene could in theory cure thrombocytopenia, at least in mice.
This technique, called suppressor screening, has long been used to unravel basic biology in worms and fruit flies, but has not been tried in vertebrates before, and not to find cures. It is laborious and slow, but could be a short cut compared with trying to work out the mechanism behind a disease. It would only work for diseases that can be induced in mice, but Hilton says there are many that fit the bill, including Alzheimer鈥檚, Huntington鈥檚 and even malaria.