NHLBI Special Emphasis Panel
Approaches to Complex Biological Problems:
Inflammation and Risk
Minutes of Meeting
Chairperson: William J. Martin, M.D.
Department of Medicine, Indiana University Medical
Paul Albert, Ph.D.
National Heart, Lung, and Blood Institute, National
Institutes of Health
Timothy Buchman, Ph.D., M.D.
Chief, Burn, Trauma, Surgical, and Critical Care
Section, Washington University School of Medicine
Ronald G. Collman, M.D.
Pulmonary and Critical Care Division, University of
Pennsylvania School of Medicine
Division of Microbiology and Immunology, University
of Michigan Medical School
Raymond Mejia, Ph.D.
National Institute of Diabetes and Digestive and
Kidney Diseases, National Institutes of Health
Homer L. Twigg, III, M.D.
Indiana University Medical Center; NHLBI Staff
Hannah H. Peavy, M.D.
Lung Biology and Disease Program (LBDP), Division
of Lung Diseases
Mary S. Reilly, M.S., LBDP
Division of Lung Diseases
Observer: Scott D. Somers, Ph.D.
Division of Pharmacology, Physiology, and
Biological Chemistry, National Institute of General Medical Sciences
Dr. Martin opened the meeting at 8:00 a.m. with
introductions. Dr. Peavy explained the purpose of the meeting and reviewed the
charge to the Panel. The panel members were informed about the requirement to
read and sign the conflict of interest statement. All members signed the
The panel was charged with the following tasks:
- Identify the most important needs and opportunities
and promising possibilities relating to mathematical modeling of complex
biological processes that might advance lung research in the areas of TB/AIDS
and ARDS. This process includes review of current scientific concepts and
making recommendations concerning areas of scientific opportunity.
- Formulate major questions and issues in the areas
- Identify steps needed to address the questions and
issues. Indicating, if possible which are steps are most urgent, where
obstacles to progress exist and what is needed to overcome these.
- Discuss training issues when these are
Each panel member gave a brief presentation that
included background information, new concepts and data on various aspects of
inflammation in the lung and modeling. This was followed by delineation of gaps
in our understanding of those areas as well as recommendations to help to fill
those gaps. First, clinical and biological presentations outlined issues
associated with TB and AIDS, the roles of lung macrophages, lymphocytes,
chemokines and their receptors in HIV, disease, and acute respiratory distress
syndrome (ARDS). This was followed by an overview of the role of mathematical
modeling in medicine, examples of models in other organ systems, examples of
statistical models and modeling applied to TB-HIV interactions. A short
discussion followed each presentation. In the afternoon members of the panel
prepared a list of specific recommendations.
Tuberculosis and Opportunistic
Dr. Martin discussed mechanisms of disease
transmission for opportunistic pulmonary Infections. He concluded that for
respiratory pathogens, the pattern of transmission and the incidence of disease
are not well linked. Better knowledge of how epidemics arise and why specific
individuals become affected would greatly enhance our understanding of the
disease and potentially its control.
We need to learn more about how epidemics arise and
why specific individuals become affected. This would greatly enhance our
understanding of the disease and potentially its control.
Lung Macrophages and Lymphocytes in HIV
Dr. Twigg reviewed normal pulmonary immune responses,
how pulmonary immune responses are thought to be altered in HIV infection, and
how mathematical modeling might be applied to dissect specific abnormalities in
HIV progression is associated with a loss of
diversity in potential immune responses to invading pathogens leaving the lung
in a state of chronic cellular activation (macrophages and T cells) and
resulting in chronic inflammation. Mathematical modeling of how these changes
occur in the lung would provide important clues to the mechanisms involved.
HIV in the Lung: Chemokines and
Dr. Collman reviewed how HIV infects cells in the
lung, how this affects local immune responses, interactions between chemokines,
chemokine receptors and HIV, and what this may imply for progression of disease
in the lung.
During HIV infection of the lung what determines
whether pulmonary inflammation or immune incompetence predominates? How do
local pulmonary and systemic immune changes interact to determine the level of
pulmonary immune competence? What roles are played by chemokine receptors CCR5,
CXCR3, CCR2 and others? How do viral, host genetic, immune, and environmental
factors interact to determine systemic viral load and disease progression? How
do these factors interact to regulate viral burden in the lung?
Acute Respiratory Distress
Dr. Buchman discussed multiple organ dysfunction
syndrome (MODS) as a consequence of inflammation and a cause of death. He
proposed novel strategies for analysis and possibly for intervention.
Using MODS as an example, linear models are not
adequate representations of human pathophysiology. The stability of biological
systems appears to be a function of their interconnectedness. There is a
pressing need to develop and test complex systems models as representations of
human pathophysiology to identify therapeutic strategies which will promote
transitions to basal, healthy physiologic states.
Overview of math modeling in
Dr. Kirschner provided a general overview on the role
of mathematical modeling in medicine. Models are an abstraction, not a
reflection of reality and must achieve a balance between simplicity and detail.
They are based on available knowledge and may provide insight into
interactions. However the model's results are based on the original
assumptions. Mathematical models can be used to compare and contrast existing
controversies, extend intuition about biological process, and can be done
without data. Creating models generally requires input from many disciplines.
They are useful in testing the understanding of a system, explaining phenomena,
when experimental resolution is difficult, expensive or impossible (based on
cost, physical, ethical constraints, etc.). Models may be able to provide
details or understanding about an experimental system. Models have made an
impact in many areas of science, e.g. neurophysiology, cardiology,
epidemiology, health economics, immunology, pathogenesis of disease (cancer),
physiology, radiology and other types of imaging. Differential equations are a
major component of the models. Parameters in models represent rate constants of
the processes. They can help identify key interactions, and allow for
sensitivity and uncertaintly analyses as well as aid in obtaining bifurcation
information. These methods can lead to a greater understanding of the important
porcesses of the biological system. Because of the nature of these parameters,
it is easy to perturb the system to explore changes in the biological
assumptions. Applications which are already underway include models for control
strategies of TB epidemics and models to understand the dynamics of HIV
infection including, production, turnover, half-life, and possible reservoirs
of infection. Modeling HIV changed concepts about viral growth and lead to the
realization of the highly dynamic growth of the virus. Problems inherent in the
use of models include validation, gaps in communication, difficulty in
obtaining appropriate expertise for reviews, lack of funding. Research dealing
with models is usually published in journals not read by basic scientists and
Models can contribute to the understanding of complex
biological processes and may offer new perspectives, clarify ideas, and raise
new questions. They are constructed to test ideas and are process driven.
Validation of the models is an important issue. A major obstacle is lack of
communication between the clinical and basic scientists and theoretical
scientists, who develop models.
Examples of models in organ systems other
Dr. Mejia provided a framework for thought using
examples from renal models.
Mathematical modeling in other organ systems has
provided insights at the molecular, cellular and organ level. These include
protein identification and information on structure and function, improved
imaging techniques and understanding of blood flow. An essential factor in
creating models is close collaboration between clinicians or bench scientists
Dr. Albert discussed basic strategies used in
developing statistical models for characterizing a disease process. He outlined
the purposes of these models, the issues in making statistical inferences about
model parameters, and the types of questions that can be addressed with these
approaches. Statistical modeling has been used to model disease processes in
all areas of medicine including AIDS, multiple sclerosis, epilepsy, bipolar
disorder, and asthma.
Statistical modeling has been used to model disease
processes in all areas of medicine including AIDS, multiple sclerosis,
epilepsy, bipolar disorder, and asthma. Examples presented included a model of
relapsing-remitting multiple sclerosis and a model of monotonic responses.
Mathematical Modeling of TB-HIV
Dr. Kirschner presented a model she developed of
A mathematical model of dual infection with
tuberculosis and HIV predicts interactions. The predictions appear to fit well
with clinical findings.
- The panel explored the role of modeling techniques
and concluded that these are a resource that can be used to enhance
experimental design especially to define important variables and questions, but
validation remains an issue.
- The chief priority is to improve communication and
cooperation between modelers clinical and basic scientists.
Suggestions for achieving this included integration
of pilot studies with larger grants, use of meetings, journal supplements and
training to alert scientists to the existence and the potential of techniques
that might be helpful in the study of a wide variety of lung diseases and
processes with an inflammatory component.
These include HIV related lung disease, tuberculosis
and other lung infections, interstitial lung disorders, obstructive airway
diseases, trauma, lung injury and ARDS as well as inhalation injury secondary
to environmental toxicities.
The meeting was adjourned at 3:00 p.m. on September
I hereby certify that the foregoing minutes are
accurate and complete.
William J. Martin, M.D.
Hannah H. Peavy, M.D.
Last Updated April 2011