Immune System Research
I encountered the limits of a reductive approach based on Occam’s razor as a graduate student at Caltech in the early 1960s, studying the complexities of the mouse and human immune systems.1-3
I was initially interested in how B cells generate the diversity of antibodies required to defend a vertebrate organism again viruses, bacteria, and, perhaps, even cancer. I extended these studies to include T-cell receptors and molecules of the major histocompatibility locus over the first 30 or so years of my career.4-6
Increasingly, I came to appreciate the incredible complexity of the immune system. Indeed, we came to understand many of the details of the molecular basis of antibody and T-cell receptor diversity.
However, the deeper mysteries of the immune response itself, both adaptive and innate, immunological tolerance, and autoimmunity did not yield their mechanisms to simple molecular, cellular, and biochemical approaches. I gradually came to realize that one needed to take a more holistic or systems approach to studying these complexities.
Max Delbruck, also at Caltech in the 1970s, argued that these immune mechanisms could only be revealed by a more global systems approach—similar to his attempts to understand the complexities of the fungus phycomycetes. I came to realize that new tools and novel strategies were necessary to be able to deal in a more comprehensive and quantitative manner with the complexities of biology in general and immunity specifically.
So how could one go about creating the holistic system strategies and measurement (or visualization) tools for generating global or comprehensive datasets? These thoughts led to my participating in a series of paradigm changes that paved the way for dealing with biological complexity.