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Human liver cells are dotted across the new
DataChip to quickly determine if various chemicals, drugs, and
drug candidates are toxic. When coupled with the MetaChip, the two
biochips could provide a highly predictive alternative to animal
testing.
Credit: Moo-Yeal Lee/Rensselaer Polytechnic
Institute
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Traditional toxicity testing involves the use of animals to predict
whether a chemical or drug candidate is toxic. However, with the large
number of compounds being generated in the pharmaceutical industry,
and new legislation stipulating that chemicals undergo toxicity
analysis, there is a rapidly emerging need for high-throughput
toxicity testing.
"We looked at the issues facing companies and realized that we needed
to develop something that was low-cost, high-throughput, easily
automatable, and did not involve animals," said co-lead author
Jonathan S. Dordick, the Howard P. Isermann '42 Professor of Chemical
and Biological Engineering at Rensselaer and co-founder of Solidus
Biosciences Inc., the company that is working to commercialize the
chips. "We developed the MetaChip and DataChip to deal with the two
most important issues that need to be assessed when examining the
toxicity of a compound - the effect on different cells in our body and
how toxicity is altered when the compound is metabolized in our bodies."
When the biochips are used together the result is a promising and
affordable alternative to animal-based toxicology screening and a
direct route to developing safe, effective drugs, according to
Dordick, who is also a member of the Rensselaer Center for
Biotechnology and Interdisciplinary Studies.
Currently, detailed toxicity screening does not come into the drug
discovery process until later in the development, when significant
time and money have been invested in a compound by a company. And
animal testing does not always provide information that translates to
predicting the toxicity of a compound or its metabolites in a human,
Dordick said.
The collaborative team sees the combined chips as an efficient, more
accurate way to test drug compounds for toxicity earlier in the
discovery process. But, co-lead author and Solidus Biosciences
co-founder Douglas S. Clark, professor of chemical engineering at the
University of California at Berkeley, views pharmaceutical companies
as only one potential user, and not necessarily the first.
"The initial market will not necessarily be pharmaceuticals," Clark
said. He further explains that the initial market will likely be
chemical and cosmetic companies that are being pushed to eliminate
animal testing or cannot afford such testing. In fact, by 2009
cosmetics companies in Europe will be restricted from using animals in
testing for chemical toxicity. "Obviously cosmetics need to be safe,
and ensuring the safety of new compounds without testing them on
animals presents a new challenge to the industry, especially as the
number of compounds increases. These chips can meet this challenge by
providing comprehensive toxicity data very quickly and cheaply."
The team's most recent achievement outlined in PNAS is the DataChip, a
biochip comprising up to 1,080 three-dimensional human cell cultures.
The three-dimensional structure is more closely in line with how the
cells would be arranged in organs of the human body. The DataChip can
provide companies or academic labs with an extremely fast screen of
potential toxicity of chemicals and drug candidates on different types
of human cells.
In an earlier paper published in a Jan. 25, 2005, edition of PNAS, the
team introduced the MetaChip. The biochip mimics the metabolic
reactions of the human liver, where chemicals and drugs are processed
in the body. Depending on the compound, a seemingly benign chemical
like acetaminophen can become highly toxic when metabolized by the
liver. Because of differences in the type and amount of their
drug-metabolizing enzymes, most of which are in the liver, individuals
can metabolize a drug or other chemical compound differently. What is
harmless to one person may be toxic to another. By arranging the ratio
of enzymes on the MetaChip, scientists could develop a personalized
chip to determine how toxic a drug might be to different people.
"We are still a ways off from personalized medicine, but the MetaChip
offers that future possibility," Dordick said. When coupled with the
new DataChip, the two chips could someday be used to determine the
levels and combinations of drugs that are safe and effective for each
individual patient, Clark explains.
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