Mother Nature and Bioterrorists: Rochester Battles Both with $11.9 Million Award

Nov. 10, 2010
Researchers Use Mathematical Modeling to Intensify Study of Potentially Deadly Flu Viruses
Martin Zand, M.D., Ph.D.
Martin Zand, M.D., Ph.D.

Flu viruses are a great threat, whether they stem from Mother Nature or are modified by human hands to create a deadly bioweapon. The University of Rochester Medical Center will tackle both scenarios head on with a five-year contract, totaling approximately $11.9 million, from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). The contract will further research into how we can use computer modeling to find ways of boosting human immune responses against and identify new areas of investigation into treatments for a variety of potentially lethal viruses.

“This type of research is extremely important because it is going to make the United States better, stronger and faster at developing new vaccines and therapies for flu infections that we don’t yet have vaccines for,” said Martin Zand, M.D., Ph.D., co-director of the Center for Biodefense Immune Modeling and medical director of Kidney and Pancreas Transplant Programs at the University of Rochester Medical Center.

Throughout the five year contract, researchers will design mathematical models and simulation tools to study how the immune system responds to flu vaccines, attempting to uncover why some people have a good response to a vaccine and others don’t. Using data from mice and humans, they hope to use these models to simulate different flu scenarios and test medical interventions that might be developed to limit the extent of a dangerous flu infection in people.

Hulin Wu, Ph.D.
Hulin Wu, Ph.D.

“The wonderful thing about models is that we can get some idea of how a virus might evade the immune system, how the immune system might respond, and how we can enhance the immune response without ever having to create or live through a pandemic or bioterrorist attack,” Zand noted.

The contract is a five-year renewal of the Center for Biodefense Immune Modeling at the Medical Center, which was initially funded with a $10 million contract in 2005 as part of NIAID’s Modeling Immunity for Biodefense program. Researchers spent the past five years developing models of different flu infections, and now they will use this knowledge to further model and study animal and human immune responses to new and existing flu vaccines.

In addition to the modeling and experimental work, the contract will fund development of new mathematical approaches and software tools that will be made available to the entire research community.

DEDiscover screens
Zand, Wu developed DEDiscover, a software tool for mathematically modeling the immune response to flu and other infectious diseases

NIAID also awarded contracts to three other centers as part of the Immune Modeling for Biodefense program: Mount Sinai Medical Center School of Medicine, Duke University and the Virginia Bioinformatics Institute at Virginia Polytechnic Institute and State University.

This particular NIH program differs from past NIH-funded immunology research by its emphasis on mathematical modeling, combined with cutting-edge immunology experiments and the development of new computational tools for immunology research. Such approaches allow scientists to look at the behavior of the whole immune system over time, as opposed to getting a snapshot of one or two points in time, such as after someone is vaccinated or infected with the flu. Researchers believe this more comprehensive and mathematically-based approach will yield greater understanding of how the flu and other viruses attack the body, how the immune system reacts and how we might be able to intervene.

“Using models and simulations is commonplace in many industries, such as the auto and airline industries, where manufacturers test designs before they actually produce cars and planes,” said Hulin Wu, Ph.D., co-director of the Center for Biodefense Immune Modeling and professor in the Department of Biostatistics and Computational Biology at the Medical Center. “Biomedical research has adopted this same way of doing business, using models to gather information that will help scientists design the most effective vaccines and therapies in the shortest amount of time.”

David Topham, Ph.D.
David Topham, Ph.D.

Wu added that models are essential because many immunology experiments can’t be done in a lab: “We can’t infect people with a new strain of the flu virus, but we can use a mathematical model of a human in the computer to learn more about the virus and test potential therapies.”

Biomedical research that integrates methods and techniques from mathematical modeling, biocomputing, biostatistics and bioinformatics is an emerging discipline known as systems biology, and is helping fuel biomedical science discoveries in the new century. Wu and Zand are utilizing a systems biology approach to help guide their research.

An example of a study Wu and Zand will begin this year involves collecting blood samples from small groups of people each day, for 11 days after they receive the seasonal flu vaccine. Each day, these samples will be analyzed in a battery of cutting-edge cell, protein and gene expression tests. The research team will do a similar study in mice and compare the human and animal data to garner valuable information about where antibodies or immune cells are and when, what genes are expressed in different places and what cellular markers are present following vaccination: This detailed data will then be used to create models that predict responses to current and future flu vaccines in mice and hopefully one day in people.

According to Zand, “This initiative is really exciting because it is the beginning of a new way of doing immunology research.” In the past, the use of models was usually restricted to mathematicians and modelers, but now, with support from NIH and the development of new software tools, immunologists, modelers and statisticians are collaborating at a very intense level. “In essence, this new approach is teaching experimental immunologists how to use another language in science – the language of mathematics,” said Zand.

In addition to Zand and Wu, John Treanor, M.D., David Topham, Ph.D., Tim Mosmann, Ph.D., Stephen Welle, Ph.D., Alexandra Livingstone, Ph.D., Mark Sangster, Ph.D., Luis Martinez-Sobrido, Ph.D., Brian Ward, Ph.D., Hongyu Miao, Ph.D., Hua Liang, Ph.D., Gregory Warnes, Ph.D., Jingming Ma, Ph.D., Anthony Almudevar, Ph.D., and Jeanne Holden-Wiltse, M.P.H. from the University of Rochester Medical Center are involved in the research. Alan Perelson, Ph.D., and Ruy Riberio, Ph.D., of the Los Alamos National Laboratory are also part of the research team.

The Center for Biodefense Immune Modeling has great synergy with other flu-related projects at the University of Rochester Medical Center, including the New York Influenza Center of Excellence (NYICE), the Center for Biodefense of Immunocompromised Populations (CBIP), and the Health Sciences Center for Computational Innovation (HSCCI). Between 2005 and 2015, total funding for these projects, which comes from NIH and a corporate partnership for HSCCI, is approximately $64 million.

In addition, Rochester’s Division of Biomedical Modeling and Informatics in the Department of Biostatistics and Computational Biology, founded by Wu in 2004 to develop integrated quantitative sciences approaches and to support biomedical research at the Medical Center, provides modeling, statistics and bioinformatics support to several large biomedical research projects, such as the Developmental Center for AIDS Research, the Rochester Prevention Research Center, NYICE and CBIP.

Taken together, this broad expertise and infrastructure makes the Medical Center one of the few institutions in the country with a combination of advanced computational biology, biostatistics and vaccine immunology that can conduct large scale, translational human immunology projects.

“Rochester has a long-standing clinical infrastructure and an outstanding track record in vaccine research. Now, we are building on this expertise, taking vaccine research into the twenty-first century by applying mathematical and computational approaches,” said David Topham, Ph.D., co-director of the New York Influenza Center of Excellence and an expert on how the body fights the flu. “There is also tremendous collaboration and cross pollination among researchers and between programs – another reason why we are able to conduct complicated clinical studies that many other universities would have a hard time doing.”