DNA-damage test could aid drug development
CAMBRIDGE, Mass. (May 14, 2007) – In the daunting marathon that
leads to successful drugs, promising drug candidates must pass
toxicity tests before entering clinical trials.
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, making it much more efficient.
Like the current FDA-approved test, the new test looks
for DNA damage in red blood cells formed in the bone marrow of mice.
The precursors to red blood cells are handy for this because
such cells normally lose their nucleus during the last stage of red cell formation,
and 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 hundreds or thousands
of tests to be performed from the bone marrow of a single mouse, and potentially from human bone marrow.
Joe Shuga, the graduate student in chemical engineering who developed the assay,
is in the unusual position of being a graduate student in three labs,
those of Professors Linda Griffith, Harvey Lodish (a Whitehead Member) and Leona Samson.
“We’re all faculty in the Biological Engineering department,
and collaborative projects like this are what the department was intended to do,”
comments Griffith, senior author on a paper to be published online in the
Proceedings of the National Academy of Science the week of May 14.
| “This research is the first stage in a new type of clinical drug toxicity test,” says Lodish. |
“This is an example of taking fundamental lab science and doing
something useful with it,” says Lodish, whose lab has extensively
studied the process by which red blood cells are generated.
Shuga first worked with postdoctoral researcher Jing Zhang in
the Lodish lab to adapt techniques from an established cell-culture
system based on mouse fetal liver cells to create a new system
based on adult red cell precursors from mouse bone marrow.
Shuga patiently optimized 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.
Shuga then studied the way these developing cells reacted to
three toxic DNA-damaging agents whose effects had been studied
by Samson’s lab, and found the results correlated well with results
from the existing test. Additionally, he experimented with mutant
mice created by Samson’s lab that are deficient in certain DNA-repair systems.
The bone marrow cells derived from these mice, and the cells
cultured from that bone marrow, proved more sensitive to the
toxic agents than were the cultured cells from normal mice,
further confirming the results.
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 says.
“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,” emphasizes Griffith, “and drug developers
can afford to use it a lot earlier in the drug development process.”
It also could help to avoid issues with animal testing.
“The European Union is trying to minimize animal testing,” Shuga points out.
“A ban on animal testing of cosmetic products goes into effect in 2009.”
Next steps in the research, which may be carried out
by industry partners, will be to test the assay in
rats and other organisms, and 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. Humans are the gold standard in that one wants
an assay that directly predicts toxicity in humans, not
animals, and you could obtain human bone marrow that’s
left over from medical procedures.”
“If you could change the micronucleus assay to
have a human cell readout, that would be pretty amazing,”
says Samson. Down the road, she suggests, such a test
might offer a new way to examine how different
individuals respond to chemotherapeutic agents.
"The presumption is that, for some biological processes,
in vitro human models could be closer to in vivo human than in vivo mouse," notes Shuga. "That
premise will be tested in coming years as
new systems become available."
Shuga has additional affiliations with
Whitehead Institute and MIT’s Center for
Environmental Health Sciences (CEHS); Samson
is director of CEHS and has an appointment in
MIT’s Department of Biology; Lodish also has
an appointment in biology; and Griffith has
appointments in biology and in the
Department of Mechanical Engineering.
This work was funded by the Cambridge-MIT Institute,
Amgen, the National Institutes of Health,
and the National Science Foundation.
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