Systems Immunology: Origins

Fifteen years ago, human immunology was stagnating compared with the rapid pace of work with inbred mice.There was a desperate need for new strategies and methods that would allow us to leverage the advantages of immunology research in humans: the genetic and environmental diversity, the thousands of infectious diseases, and responses to clinically deployed treatments and vaccines.Development of the much-needed approaches led to a new field, systems immunology, with its emphasis on gathering as much information as possible from human blood samples, focusing on the cells and cytokines of the immune system, and organizing studies of vaccine responses in different human cohorts, including twins, the elderly, and children in high versus low pathogen environments.These types of studies have grown exponentially over the years, with great advances in technology and analysis, and have become an important way to understand the vast differences in human responses and what they can tell us about our own immune systems.What follows is a personal account of the role that I and my colleagues played in the early days of systems immunology.For a more extensive treatment of the current state of the field, I recommend some recent reviews (1, 2).For my part, almost two decades ago, I became alarmed that human immunology seemed to be almost at a standstill while murine work was racing ahead.This struck me as unsustainable because if all we do is improve the health of mice, even if the science is wonderful, we will lose public support and become another obscure academic curiosity.Although our work on imaging T cells and understanding the intricacies of cell-cell interactions was going well, I thought this problem was so compelling that I decided to shift my laboratory's focus to human immunology and to help develop more effective technologies and strategies.Both were clearly needed better technologies, because most of what we do in mouse immunology is impossible or very limited in humans, forcing immunologists to use a relatively small set of tools.Moreover, we needed distinct strategies for human immunology, especially because, as far as I could tell, the main strategy in mice was to create or find a model of a disease with the hope of uncovering the key to the human equivalent.But this wasn't working in most cases: lots of interesting data to be sure, but typically falling short of something "translatable" or failing in clinical trials.Some years before we made the switch, my then colleague at Stanford, Alan Krensky, told me, "Mark, we've cured cancer and autoimmunity in mice many times."This suggested to me that we were not facing just a medical problem; there was important immunology we knew very little about.But what should a new strategy look like?I thought it needed to be independent of mouse immunology, not because I think the immune systems of these two species are very different, but because if we wanted to understand why these models of disease or new HHS Public Access

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