COMPUTATIONAL MODELING AND SIMULATION AS ENABLERS FOR BIOLOGICAL DISCOVERY 163
might further help identify those patients who are likely to relapse up to 4 years later, the expression
profiles of four groups of leukemic samples with different outcomes were compared. Distinct gene
expression profiles for each of these groups were identified.
5.4.4.3 Immunology
The immune system provides protection for human beings from pathogens. (For purposes of this
discussion, the immune system of interest here refers to the adaptive immune system. The human body
also has an innate immune system that provides a first response to pathogens that is essentially inde-
pendent of the specific pathogen—in essence, its role is to give the adaptive immune system time to
build a more specific response.) To do so, the immune system must first identify an entity within the
body as a harmful pathogen that it should attack or eliminate and then mount a response that does so.
In principle, the identification of harmful pathogens might be based on a list of known pathogens.
If an entity is found within the human body that is sufficiently similar to a known pathogen, it could be
marked for later attack and destruction. However, a list-based approach to pathogen identification
suffers from two major weaknesses. First, any such list would have to be large enough to include most
of the possible pathogens that an organism might encounter in its lifetime; some estimates of the
number of different foreign molecules that the human immune system is capable of recognizing are as
high as 10^16.^92 Second, because pathogens evolve (and, thus, new pathogens are created), an a priori list
could never be complete.
Accordingly, nature has developed an alternative mechanism for pathogen identification based on
the notion of “self” versus “nonself.” In this paradigm, entities or substances that are recognized as self
are deemed harmless, while those that are nonself are regarded as potentially dangerous. Thus, the
immune system has developed a variety of mechanisms to differentiate between these two categories.
Note that this distinction is highly simplistic, as not all nonself entities are bad for the human body (e.g.,
transplanted organs that replace original organs damaged beyond repair). Nevertheless, the self-non-
self distinction is not a bad point of departure for understanding the human immune system.
The immune system relies on a process that generates detectors for a subset of possible pathogens
and constantly turns over those detectors for new detectors capable of identifying a different set of
pathogens. When the immune system identifies a pathogen, it selects one of several immunological
mechanisms (e.g., those associated with the different immunoglobulin [Ig] groups) to eliminate it.
Furthermore, the immune system retains memory of the pathogen, in the form of detectors that are
specifically configured for high affinity to that pathogen. Such memory enables the immune system to
confer long-lasting resistance (immunity) to pathogens that may be encountered in the future and to
mount a stronger response to such future encounters.
Many of the broad outlines of the immune system are believed to be understood, and computa-
tional modeling of the immune system has shed important light on its detailed workings, as described
in Box 5.13. A medical application of simulation models in immunology has been to evaluate the effects
of revaccinating someone yearly for influenza. Because of the phenomenon of immune memory, a
vaccine that is too similar to a prior year’s vaccine will be eliminated rapidly by the immune response (a
negative interference effect). A simulation model by Smith et al. has examined this effect and suggests
some circumstances under which individuals who are vaccinated annually will have greater or less
protection than those with a first-time vaccination.^93 The Smith et al. results also suggested that in the
production of flu vaccine, a choice among otherwise equivalent strains (i.e., strains thought to be
(^92) J. Inman, “The Antibody Combining Region—Speculations on the Hypothesis of General Multispecificity,” Theoretical Immu-
nology, G. Bell, ed., Dekker, New York, 1978.
(^93) D.J. Smith, S. Forrest, D.H. Ackley, and A.S. Perelson, “Variable Efficacy of Repeated Annual Influenza Vaccination,” Pro-
ceedings of the National Academy of Sciences 96(24):14001-14006, 1999.