Deep within the twisting halls of Hall-Atwater, Assistant Professor of Molecular Biology and Biochemistry (MB&B) Manju Hingorani’s lab may seem unremarkable at first glance. Although its white washed walls, whirring instruments, and copious glassware seem rather typical of campus laboratories, it is home to some of the most cutting-edge research on campus, and its being recognized in a big way. In the past few months, Hingorani has received three major grants totaling nearly a million and half dollars for her pioneering research on DNA replication and restoration.

Recognized by national science institutions such as the National Institutes of Health and the Nation Science Foundation, as well as the Connecticut Department of Health, the grants will fund the continuing projects of Hingorani, her post-doctorate, graduate, and undergrad researchers through 2014.

“I’m still giddy,” Hingorani said with a laugh. “While some of the grant money will help to provide necessary instrumentation, most of it will go towards helping pay student researchers. By paying for materials and supplies, and especially research stipends, the grants are really supporting a critical part of students’ education.”

Hingorani and her student researchers are focused on the biological phenomenon of DNA mismatch repair. While DNA is often understood as a fairly stable component of the human body, in reality, it is subject to external and internal damage, which mutates cells and changes their functions. Hingorani studies how the body reacts and corrects these changes in the genome.

“Our bodies have what is basically a crack team of sleuths and engineers,” Hingorani said. “They’re proteins and other biological molecules whose function is to find the places where the genome has changed and to fix them. It’s such a critical property of life– if you had such a high level of unregulated change in your DNA, you wouldn’t be able to survive.”

The body utilizes multiple means to repair alterations and damages in the genome. Professor Hingorani and her lab research one of them, DNA mismatch repair—specifically from a biochemical standpoint. DNA replication, Hingorani attests, is highly accurate, incorporating the wrong nucleotide only once in every million attempts. Yet, in humans, with over 100 trillion cells, each possessing several billion nucleotides, such mistakes are prevalent, and highly dangerous if not corrected.  DNA mismatch repair is a system of proteins, one of which constantly scans DNA for such mistakes and when they are found, quickly signals other proteins to remove and re-synthesize the problematic section of DNA

“We try to understand how these proteins work,” Hingorani explained. “You can work with this science in a few different ways– on the organism level, cellular and molecular level. The approach of biochemistry as a discipline is to extract biological molecules outside the cellular realm and study in the chemical realm.”

While the basic research on DNA mismatch itself is on the cutting edge of modern biochemistry, it is the medical implications of Hingorani’s studies that have drawn much attention to her work. The failure of DNA mismatch proteins to repair damaged DNA can cause cells to mutate. The compounding of cell mutations can cause them to lose the ability to regulate their growth and become cancerous, making Hingorani’s research hugely relevant to the study and treatment of cancer.

Ariel Schwartz ’12, an undergraduate researcher in the lab, studies Hereditary Nonpolyposis Colorectal Cancer (HNPCC), a genetic condition involving defective DNA mismatch repair that results in a high risk of colon and other cancers.

“My current project involves studying mutant proteins,” Schwartz said. “Ineffective DNA mismatch repair is a process that is linked closely with HNPCC. I’m using bacterial relatives of human the MutS protein to look at three mutant MutS proteins that either have been associated with cancer, or molecular dynamics modeling has identified as possibly having improper function. Right now I’m assessing whether these mutants are able to properly bind DNA and utilize ATP for their function.”

The grant from the Connecticut Department of Public Health is specifically for researching the role of mismatch repair in protecting DNA against damage caused by dangerous chemicals in tobacco smoke. If the DNA mismatch repair system is defective, not only do cells mutate faster and may become cancerous, they also lose the ability to destroy themselves for the good of the organism.

“We have 100 trillion cells in our bodies: we can afford to lose a few, but we cannot afford to hold onto these mutant cells– its much more important that the bad cells die,” said Hingorani. “Many drugs that treat cancer cells operate on the principle of causing DNA damage.  They are really blunt instruments, since they are not very selective about the cells they kill, but they’re the most effective tools we have at present. Thus, knowing how mismatch repair proteins work and mediate cell suicide is very very important not only to understanding the genesis of cancer, but also its treatment.”
Notwithstanding her research’s huge implications in medicine, Hingorani asserts that it understanding how life operates that motivates her.

“What we’re doing is very important to develop therapies for disease, but that’s not really what drives me,” Hingorani said. “What drives me is really the question of how does this work? If I can get somebody to care about that enough to support our work, then that’s enough for me.”

Even with the success of her research, Hingorani sees a fundamental importance in the lab community. In such a forward-looking, intense intellectual environment, the bonds between Hingorani and her student researchers become paramount.

“The lab groups ends up becoming kind of a family,” Hingorani said. “The doing of science requires a lot of detailed work and is full of chance. You never know how things will turn out– its like you’re always jumping off a cliff and trying to find a handhold. That requires a lot of emotional support and a really strong community. In some ways that’s the most important aspect of my job, building a working environment and a familial community.”

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