Using Bacteria as Living Test Tubes to Study Human Gene Mutations and Find New Drug Leads
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Traditional biochemical methods of studying human gene mutations are often laborious and costly. Now bioengineers at the University of California San Diego have developed a new simple approach to rapidly check on human gene changes and also screen chemicals as potential drugs by turning everyday bacteria into living test tubes.
The researchers published their new study in the April 30 issue of Nature Biomedical Engineering.
Human cells carry thousands of genes, and tiny changes in these genes can cause serious diseases. Usually, scientists study these changes by testing proteins in a test tube or in human cells. But those methods can be slow, expensive and sometimes hard to do.
So the UC San Diego researchers were curious if simple, fast-growing microbes could do that job instead. The work was led by Bernhard Palsson, Y.C. Fung Endowed Professor of Bioengineering, and Donghui Choe, a postdoctoral fellow in the Palsson lab, both in the Shu Chien-Gene Lay Department of Bioengineering at the UC San Diego Jacobs School of Engineering.
To investigate, the team pioneered a technique called LEICA (live Escherichia coli assay), in which one of the key enzymes in E. coli is swapped out for its human counterpart. E. coli is a bacterium found in the human gut that is commonly used in research. Because the altered bacteria must rely on that replacement human enzyme to grow, their growth rate becomes a direct measure of how well the human enzyme works. If the enzyme is normal, the bacteria would grow quickly; if it carries a harmful mutation, the bacteria would grow slowly or not at all.
Testing Disease-Related Mutations
Using this approach, the team tested many human mutations known to cause—or not cause—diseases. For example, they looked at changes in enzymes tied to hereditary disorders, such as anemia and argininosuccinic aciduria. Bacteria carrying harmless mutations grew almost at the normal rate. Bacteria with disease-causing mutations grew much more slowly. The team found that the speed of growth matched results from traditional biochemical tests, showing that this simple bacterial system does reflect human enzyme performance.
To push LEICA to the next step, the researchers also wanted to test the technique’s capability to find new drug leads. They exposed the bacteria to hundreds of small molecules, one at a time, in small culture tubes and watched the bacterial growth. They easily detected the drugs known to help or block enzyme activity. They also uncovered several new compounds that strongly slowed growth only when the human enzyme was present. These new hits could become starting points for future medicines, according to the researchers, and will be investigated as part of the next steps.
“By turning bacteria into easy, fast test systems, we can rapidly check whether a human gene change is harmful and screen thousands of chemicals to find potential drugs,” said Choe. “This could speed up research into genetic diseases and make it cheaper and simpler to discover new treatments—all by using humble microbes as living test tubes.”
Paper: “A live bacteria enzyme assay for identification of human disease mutations and drug screening” by Donghui Choe and Bernhard Palsson in the journal Nature Biomedical Engineering.
This work was funded by the Y.C. Fung Endowed Chair in Bioengineering at UC San Diego to Bernhard Palsson.
All authors declare no competing interests.
Donghui Choe contributed to this article.
With LEICA, researchers can rapidly screen thousands of chemical compounds for potential drug leads. Image credit: Donghui Choe
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