Artificial molecules can target, attach to specific genes
Synthetic molecules can mimic the proteins that control the expression of certain genes, according to a recently published report by a UW-Madison biochemist. This finding brings scientists closer to being able to activate or suppress genes, which may someday help fight cancer and other diseases.
“Our recent study was an exercise to see if we can do what nature does,” says Aseem Ansari, a professor of biochemistry at the College of Agricultural and Life Sciences. He collaborated with colleagues from the California Institute of Technology on the paper, which was published in 2003 in the Journal of the American Chemical Society.
Segments of genomic DNA control certain traits and functions within the body, says Ansari. He works specifically with Hox genes, which control the development of an organism from a single-cell embryo. Although Ansari studies fruit flies, Hox genes are virtually identical in other species, including humans.
Cells have a mechanism to express genes, or create proteins and enzymes based on the information a gene contains, Ansari explains. Certain proteins, called activators, bind to a specific site on the DNA molecule and attract cellular machinery that transcribes the gene. The cell then uses the information to create proteins and enzymes, which are responsible for building, maintaining, and repairing structures and functions in the body.
Ansari and his colleagues designed a class of synthetic molecules-so-called artificial transcriptions factor, or ATFs-that mimic the ability of the Hox activators to bind at a DNA site and trigger protein assembly. “These regulators recognize a unique genomic DNA site, and depending on how we build them can turn a nearby gene on or off,” Ansari says. The power of natural and artificial regulators is vividly illustrated by images of fruit flies with a set of wings in place of balancing organs on the thorax, the result of having a certain gene turned off during development.
The applications of this work for humans, while still being tested, are potentially significant. In general, the ability to regulate gene expression could change the way we treat and prevent disease, Ansari says. “This is an exciting time,” he adds, “because we are witnessing the dawn of the field of molecular medicine, where therapeutics will be tailored to address specific ailments in individuals.”
In the case of the Hox genes in humans, a common mutation-which occurs when the segment of DNA that contains the genes becomes shuffled-is linked to pediatric leukemia. However, scientists might be able to use the newly created Hox-ATF to turn the cancer-causing gene off, Ansari says.
Ansari, who partners with colleagues across the UW-Madison campus as well as at the California Institute of Technology, the University of Michigan, and other schools, says that trials with human leukemia cells are still to come. He is currently researching other types of artificial transcription factors. Ansari”s work is supported by the March of Dimes Foundation, the National Institutes of Health, a Steenbock Career Development Award from the UW-Madison, an Industrial and Economic Development Research grant from the Wisconsin Alumni Research Foundation, and the state of Wisconsin.