A unique approach to understanding how cells develop resistance to drugs has won a scientist at The University of Texas M. D. Anderson Cancer Center a New Innovator Award from the National Institutes of Health.
G-bor Bal-zsi, Ph.D., assistant professor in M. D. Anderson's Department of Systems Biology, will receive $1.5 million over five years under the highly competitive program. The NIH announced awards Thursday in three prestigious programs that fund bold ideas with the potential to speedily translate research into improved human health.
"Therapy fails when cancer cells or disease-causing microbes become resistant to drugs. We will apply new, non-conventional methods to control expression of a drug-resistance gene in cells that are then treated with chemotherapy," Bal-zsi, said. "We expect to discover new mechanisms underlying the emergence of drug resistance, which could improve treatment of cancer and of microbial infections as well."
National Institutes of Health Director Francis Collins, M.D., Ph.D., announced the winners of: the NIH Director's Transformative R01 (T-R01) Awards, Pioneer Awards, and New Innovator Awards all supported by the NIH Common Fund's Roadmap for Medical Research.
"The appeal of the Pioneer, New Innovator, and now the T-R01 programs, is that investigators are encouraged to challenge the status quo with innovative ideas, while being given the necessary resources to test them," Collins said.
Bal-zsi, is the first winner from M. D. Anderson.
"These are highly competitive awards for the most innovative science; therefore, being chosen as a recipient is a significant accomplishment," said M. D. Anderson Provost and Executive Vice President Raymond DuBois, M.D., Ph.D. "Bal-zsi's research concept is exciting and holds promise for improving our ability to adjust very specific cellular levels of a variety of genes and then test drug resistance, among other things."
Tuning Gene Expression
Bal-zsi and colleagues have created gene circuits that allow them to tightly control expression of a gene, dialing it from completely off through varying levels of expression to full saturation. A newly developed circuit also will permit them to control fluctuations in gene expression. This unique degree of control allows more detailed investigation of the gene's effects.
The gene circuits are taken up by cells in a yeast culture, which will then be treated by a drug. Applying measured doses of a chemical that regulates the gene circuits will allow the researchers to tune "demographic" characteristics of gene activity over the yeast cell population, such as the average expression, deviations from the average and the rate of fluctuations in the expression of the drug-resistance gene.
Yeast is an excellent proxy for cancer, Bal-zsi explained. "Yeast cells are always "cancerous" because they grow indefinitely as long as we supply them with nutrients. Take a normal differentiated human cell, or any mammalian, plant or insect cell, put it in a dish: it will die very soon. Take a yeast cell, put it in a dish: it will divide until it runs out of sugars, just like cancer."
Many drug resistance proteins, such as those that pump drugs out of a cell, are similar between human and yeast cells, Bal-zsi said.
The cell cultures will be kept under treatment long enough to monitor how they evolve under stress and to gauge the durability of the gene circuits. "We put together synthetic gene circuits, but what happens to them over time? How stable is the gene activity that they confer? Is it inheritable? We hope to find out," Bal-zsi said.
Bal-zsi and colleagues are synthetic biologists, a growing field that involves applying engineering principles to design and build new biological parts or devices.
"G-bor Bal-zsi is a leader in the field of synthetic biology. By exploring how levels of proteins are controlled in model organisms, he is developing a new understanding of how the processes work in humans and how they become dysfunctional in cancer," said Gordon Mills, M.D., Ph.D., professor and chair of the Department of Systems Biology.
"Importantly, based on this new understanding, Bal-zsi is developing new tools that can be used to explore human and cancer biology. These tools are expected to have wide impact in all fields of human physiology and disease. This combination of theoretical and practical science is being recognized by the granting of the highly prestigious Director's New Innovator Award," Mills said.
"It's impossible to accomplish anything without the right atmosphere and the right colleagues." Bal-zsi said. "I have excellent lab members and collaborators in the Department of Systems Biology. It all keeps research exciting. I was thrilled to be given the opportunity to come to M. D. Anderson where I have been encouraged to dream and innovate. This support and culture helped me do the studies that led to this recognition."
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