The renewal of a National Institutes of Health grant will enable a University of Nebraska–Lincoln researcher to continue developing a tool that illuminates the complex, multi-scale interplay of the immune system’s many components.
Tomas Helikar, Susan J. Rosowski Associate Professor of biochemistry, will use the five-year, $1.8 million grant from the NIH’s Maximizing Investigators’ Research Award program to advance his work on a virtual immune system aimed at increasing the understanding of immune-related diseases and ramping up the speed and efficiency of drug development.
Helikar thinks the model could greatly reduce the duration and cost of a drug’s journey from the lab to the marketplace, which often lasts more than 10 years and costs roughly $1.3 billion dollars.
“By being able to map out, model and simulate the human immune system, the goal is that we can identify more effective drug targets and eliminate the bad hypotheses that may take you down a rabbit hole that doesn’t go anywhere,” Helikar said.
The model would fill a gap in human health science. Though the immune system is arguably one of the most complex “machines” in the human body, there’s no computer representation of it that allows scientists to test hypotheses in a low-stakes environment.
“One way to think about it is that we have models of engines and rockets that we simulate before we put them to use, and we’re able to predict the different parameters that will make them work,” he said. “On the human health side, we don’t really have that equivalent. Our long-term goal is to develop a tool like that.”
It’s an ambitious task: The immune system comprises organs, tissues, antibodies, cells, genes and more that are constantly influencing the behavior of one another. These interactions play out across different scales: in different parts of the body, at different points in time and at different levels of organization.
To demonstrate the viability of including each of the scales in a single model, Helikar and a team of Husker collaborators — whose expertise includes software and technology development, immunology, biology, biochemistry and beyond — used the first installment of the MIRA grant to build computational methods and a tool focused on just one type of immune cell. They selected CD4+ T cells, which are “helpers” in the immune system that stimulate other cells to fight pathogens.
As detailed in a study recently published in PLOS Computational Biology, the team successfully built a CD4+ T cell-based model incorporating four different mathematical approaches, three spatial scales and different immune tissues.
The team’s success in launching that model was key, Helikar said, because it established a method for mathematically and computationally connecting the immune system’s different scales. But expanding the model to include more types of cells, molecules, genes and organs will require linking together even more mathematical approaches in a computationally cost-effective way. Clearing that hurdle by improving the speed and efficiency of the model’s algorithms is a major goal of the next five years.
Helikar also plans to enable the model to account for the physiology of an individual person or a particular demographic group. This step may open the door to personalized medicine, where doctors can tailor drug regimens according to a particular patient’s immune function.
Though the project’s scale is daunting, Helikar is motivated by his experiences as a father. In 2014, his son was born with a rare genetic mutation that required a double lung transplant at nine weeks old — making him the second-youngest human ever to undergo that procedure.
The transplant has thus far gifted Helikar’s son with seven years of life — two years beyond the average life expectancy for lung transplant recipients. But one cost of the procedure is a compromised immune system: When a patient undergoes a transplant, their immune system can view the new organ as an invader and attack it.
To blunt that response, transplant recipients take immunosuppressive medications. But those drugs weaken the immune system universally, making patients more susceptible to infectious diseases and cancer.
The trick, Helikar said, is to fine-tune the immune system so it doesn’t destroy the transplanted organ but retains its ability to protect recipients from everything else. Seeing firsthand the need to strike this delicate balance fueled his research ambitions.
“With my son, that made me laser-focused on the immune system,” Helikar said. “I see the importance of understanding fully how the immune system works and how we can actually rewire it and reprogram it to do what we need it to do.”
With support from the University of Nebraska Collaboration Initiative, Helikar is partnering with doctors from the University of Nebraska Medical Center, including a liver transplant expert, to explore how his model can help transplant recipients.
Helikar is also applying the model to other types of diseases. Last year, his team published a study in Systems Biology and Applications that explored how existing FDA-approved drugs can be repurposed to treat three autoimmune conditions — rheumatoid arthritis, multiple sclerosis and primary biliary cholangitis. He’s also used a computational approach to identify antiviral drug treatments for influenza, which is a trajectory that could be relevant to other viruses like COVID-19.
Additionally, Helikar is part of a National Strategic Research Institute team that is carrying out Department of Defense-funded work aimed at developing drug therapies to protect military service members from the effects of radiation exposure.
Long-term, he envisions his model will be versatile enough to apply to any disease involving the immune system.
“With a virtual immune system, you can simulate millions of different conditions, which you can do on a computer much cheaper and faster than you can do in the lab,” he said. “This increases your odds of making the immune system do what you want it to do and challenging many diseases more effectively.”