Urbana, Ill. – When Auinash Kalsotra, associate professor and the William C. Rose Scholar of biochemistry, attended college at Birla Institute of Technology and Science in India, he knew he wanted to pursue an entrepreneurial career inspired by his family members. Instead of following a traditional business route, Kalsotra’s enterprising genes have led him down a trailblazing scientific journey – uncovering intricacies of cell biological mechanisms that may lead to more targeted and improved cancer therapies.
Kalsotra was not initially interested in studying cancer. In fact, he wasn’t looking to study any particular disease at all. He wanted to understand how the complex machinery of our bodies takes the codes embedded in our DNA and turns them into specific tissues such as the heart and the liver. In other words, he wanted to know how things worked — not why they break or how to fix them.
Kalsotra spent his academic career voraciously consuming information about the biological and pharmaceutical sciences. As he was leaving his graduate studies, he assumed that a career in pharmaceuticals would be where he would make his mark. But as often happens, scientists start on one path and eventually find themselves pulled onto others. In his case, an opportunity to hear Thomas Cooper (Baylor College of Medicine), a world-renowned expert in ribonucleic acid (RNA) and splicing research, speak at his alma mater, the University of Texas, Houston, set Kalsotra down a life-changing path.
“In the Cooper lab, I was able to study how RNA is made and processed differently by various cell types in our bodies. The genomics field was in its infancy at that time, and revolutionary discoveries were being made every day. I was intrigued by the idea that one gene can give rise to multiple types of RNA,” Kalsotra said.
The Kalsotra research group.
In 1977, Phil Sharp, a University of Illinois alumnus, had discovered RNA splicing – a biological process in which precursor (or immature) RNA is transformed into messenger RNA. During splicing, certain regions in the RNA are removed, and other regions are joined together before it is translated into a protein.
“That means there is a tremendous opportunity to mix and match RNA sequences such that one gene can produce many different RNAs, and the production of those RNAs and in turn, proteins, is regulated and dependent on an individual cell type.
“In the past decade, it has become abundantly clear that in most diseases, RNA splicing is not regulated correctly, which produces proteins that are more likely to cause diseases, and of course, in cancer, it is well-established that aberrant splicing is a major contributor to cell transformation and metastasis,” Kalsotra said.
These fundamental discoveries have inspired and guided Kalsotra’s cancer research. Always the entrepreneur, Kalsotra looked at the “splicing research market” and noticed that there was a niche, and a need, for researchers to study liver diseases and cancer.
“The liver is the one organ that regenerates effortlessly in our body, and it is also one of the major organs that develops cancer. In order to replace damaged tissue after alcohol or drug-induced injury, the liver has to turn on its cell cycle and make more cells,” Kalsotra said. “We have learned that splicing is incredibly important for this process. We are now interested in knowing if there is any relationship between liver regeneration and cancer.”
Recently, Kalsotra’s expertise and research in this area have earned him a new National Institutes of Health (NIH) grant to study the roles of RNA splicing and a condition called polyploidy – in which cells carry more than two sets of chromosomes. Not much is known about how this works, but the liver typically carries many of these polyploid cells, whose numbers increase further following injury, stress, or cell damage.
“We want to study whether and how having a polyploid genome protects against liver cancer. For example, if individuals have extra copies of tumor suppressor genes, due to polyploidy in the liver, it may help decrease their chances of developing liver cancer.” Kalsotra said.
Previous CCIL grants have spurred Kalsotra’s progress in both publications and external grants. Since the CCIL’s foundation as an Illinois research institute, his team has collaborated with fellow CCIL scientists on projects that span many disease types and tissues.
In 2019, he worked with Joseph Irudayraj, bioengineering professor, to determine if poly-fluoroalkyl substances, or PFAS, found in plastics and many common household items, are causally linked to fatty liver disease. He has most recently worked on CCIL grant projects with Prasanth Kannanganattu, associate professor of cell and developmental biology, and Sayee Anakk, associate professor in molecular and integrative physiology.
Always thinking about what comes next, Kalsotra lab has also been focused on integrating the latest technology into their research projects to accelerate discovery. His group is the first on campus to use single-cell sequencing to create sequence libraries for hundreds of thousands of cells.
“We are excited to partner with Dr. Anakk’s group and sequence hundreds of thousands of single cells from both normal and cancerous tissues to gain a deeper understanding of what is happening within individual cells as they transition from being benign to metastatic during the course of carcinogenesis,” Kalsotra said.
“It kind of gives me extra motivation to study why normal cells all of a sudden become cancerous,” he said. “Maybe one day, if we understand how normal cells work, we can understand what goes wrong in a cancer cell that makes it divide uncontrollably.”
Like the owner of a successful company, Kalsotra’s vision and leadership has paid off, both financially and scientifically, as his team blazes new trails, earn external funding, and continue to fold in collaborations with other cancer researchers.
“The Cancer Center at Illinois has allowed scientists to explore new areas in cancer research, make fundamental discoveries, and better understand the physiological and pathophysiological processes. The initial project funding support from CCIL is what leads to bigger grants – receiving foundational funding to start a project from a new idea into results is incredibly important because organizations like NIH won’t fund new and risky projects without preliminary data,” Kalsotra said.
Kalsotra is also the assistant director of the School of Molecular and Cellular Biology’s Faculty Mentoring and Advising Program, and he is a member of the Carl R. Woese Institute for Genomic Biology.
– Written by Jordan Goebig, Communications Coordinator