DNA-damage test could aid drug development

Researchers from Massachusetts Institute of Technology and Whitehead Institute have developed a cell culture test for assessing a compound's genetic toxicity that may prove dramatically cheaper than existing animal tests. This assay would allow genetic toxicity to be examined far earlier in the drug development process.

The new test looks for DNA damage in red blood cells formed in the bone marrow of mice. DNA-damaged precursors generate red blood cells containing an easily detected micronucleus consisting of fragments of nuclear DNA.

Unlike the current procedure, which injects the compound into a live mouse, the new assay is a cell-culture system that could allow many tests to be performed from the bone marrow of a single mouse and potentially from human bone marrow.

Joe Shuga, the chemical engineering graduate student who developed the assay conducted his research in three laboratories, those of Professors Linda Griffith, Harvey Lodish and Leona Samson.

"This is an example of taking fundamental laboratory science and doing something useful with it," said Lodish, whose laboratory has extensively studied the process by which red blood cells are generated. Shuga worked in the Lodish laboratory to adapt techniques from an established cell-culture based on mouse fetal liver cells, to create a new system based on adult red cell precursors from mouse bone marrow. Shuga optimised the system, which allows the precursor cells to proliferate and differentiate in the normal way, dividing four or five times before losing their nucleus and becoming immature red blood cells.

With the new assay, "instead of testing one chemical and one dose in one animal, you'll be able to take one animal, get the bone marrow out and test a thousand different conditions", Samson said. "You'll be able to look in more detail at different doses given at different times in the cell differentiation process.

"This is a much cheaper assay that's at least as predictive as previous assays," said Griffith, "and drug developers can afford to use it a lot earlier in the drug development process."

The assay now needs to be tested in rats and other organisms, with a wide variety of other toxic chemicals.

"This research is the first stage in a new type of clinical drug toxicity test," says Lodish. "And although we haven't done it, you may be able to extend the technique to humans."