The two new grants are from the National Institute of Allergy and Infectious Diseases (NIAID), the nation's lead institution for research into vaccines against potential bioterror agents. One grant will establish the Center for Biodefense Immune Modeling, which will seek to develop mathematical models and computer simulations of how the human immune system responds to influenza A and smallpox, two of the worst threats. Such simulations could help researchers devise countermeasures, including new ways to boost the body's ability to fight disease.
"The infection simulator would allow us to think like would-be bioterrorists, testing in cyberspace how the body responds to viruses that have been engineered to be even deadlier," said Hulin Wu, Ph.D., professor and division chief, Department of Biostatistics and Computational Biology, and director of the new modeling center. "We must plan ahead for potential attacks, that if not countered, could cause a global epidemic that takes tens of millions of lives. Should bioweapons never be used, the work better prepares us for a future attack by nature itself, perhaps in the form of a bird flu pandemic."
The second grant will establish the Program for Biodefense of Immunocompromised Populations. Its goal will be to find new ways to help those most vulnerable to bioterrorist attack to survive despite having weaker immune systems. Along with children and the elderly, also vulnerable are millions of patients with diseases like cancer or rheumatoid arthritis (RA) where leading treatments weaken the immune system as a side effect. The team will look to determine how RA treatments render vital immune cells defective and how the process might be reversed by tailored vaccines.
Inside the Mind of a Bioterrorist
The most accurate way to study genetically modified viruses is to actually create the more deadly versions for the purposes of experiment. The risk that the new extra lethal pathogen could escape despite precautions, however, makes computer modeling the safest approach. But can a model be built that is accurate enough to enable useful guesses about reality?
Researchers within the new Center for Biodefense Immune Modeling will attempt to create comprehensive computer simulations of the body's reaction to the viruses. Project leaders hope the process will reveal unforeseen properties of the immune response that arise from simulated interactions between millions of virtual immune cells. The ultimate value of the simulations will be to anticipate threat scenarios.
"Common viruses can now be easily transformed into more lethal versions," said Martin S. Zand, M.D., Ph.D., medical director of Kidney and Pancreas Transplant Programs at the Medical Center and co-director of the new immune modeling center. "An intelligent terrorist will likely design pathogens that evade the immune system, or impair it long enough so that carriers have more time to pass it on to others. The right computer model can provide a precise, hands-on way of measuring just how good our theories are about how the system responds to a bioweapon, and how to strengthen our defenses." Beyond biodefense, Zand's interest in the effort stems from its potential to also offer insights on how to overcome immune system rejection of transplanted organs.
Mathematical models capture the behavior of systems in sets of variables, and in equations that establish relationships between them. Variables might include the likelihood that a certain event will occur, or the timing of actions taken. To simulate the human immune system response to a virus, researchers need to capture the actions of the cells involved in mathematical equations and probability statements.
Central to the ability of the immune system to recognize and destroy foreign invaders are two types of white blood cells, B cells and T cells, which destroy organisms that they recognize as invaders. The model will capture how well and how quickly immune cells recognize a virus (activation), how fast they make copies of themselves after recognizing the virus (proliferation and differentiation), and how quickly they destroy the virus and cells infected with it (clearance).
With the simulator up and running, researchers can feed into it data from the many ongoing clinical trials and new experiments on the immune system to see how well the simulation mimics reality. Along with Zand, key immunology investigators on the project team are John Treanor, M.D., David Topham, Ph.D., Tim Mosmann, Ph.D., Xia Jin, M.D., Ph.D., and Brian Ward, Ph.D. Along with Wu, lead modelers and computer scientists include Andrei Yakovlev, M.D., Ph.D., Hua Liang, Ph.D., Jingming Ma, Ph.D. and Ollivier Hyrien, Ph.D. Alan Perelson, Ph.D., of the Los Alamos National Lab and Richard Webby, Ph.D., from St. Jude Children's Research Hospital in Memphis will play consulting roles.
Protecting the Vulnerable
The Program for Biodefense of Immunocompromised Populations will focus first on rheumatoid arthritis patients because they represent well all patients with weaker immune systems. RA is a chronic, autoimmune disorder that causes the immune system to attack the joints, causing inflammation. As a key part of the immune system, tumor necrosis factor (TNF) is a protein that normally amplifies the attack on recognized intruders, but causes disease when it takes part in the mistaken targeting of the body's own tissues.
Drugs that interfere with TNF have become the leading method for countering joint inflammation seen in RA. Most RA patients also receive regular flu shots, so it is
possible to watch the interaction of the immune system, influenza (the weakened form used in vaccines), and effects of anti-TNF treatment that weaken immune cells. Would anti-TNF therapy compromise the ability of patients to be successfully vaccinated against an influenza-based bioweapon? If so, can the effect be countered?
Specifically, defects in immune cell function created by anti-TNF therapy may impair patients' response to vaccines by interfering with the creation, or survival, of memory cells. Crucial to the function of the immune system is the ability of specialized cells to remember diseases once encountered. Memory cells respond more quickly and fiercely to the same virus upon a second infection. Vaccine makers rely on this quality, introducing weakened versions of a pathogen to the system, so that it develops memory cells ready to turn on the minute the system encounters the more potent, actual disease. Strategies that hold potential to correct anti-TNF immune cell defects include changing the timing and make-up of immunization to enhance memory.
"Along with RA, anti-TNF drugs are now used to treat psoriasis, psoriatic arthritis and Crohn's disease and our studies, therefore, apply to a growing sector of the population," said Iñaki Sanz, M.D., chief of the Division of Clinical Immunology & Rheumatology at the Medical Center and director of the program. "What we learn in RA patients may very well hold for all patients with weaker immune systems, including our children and parents."