The evolution of the danger theory. Interview by Lauren Constable, Commissioning Editor.

Polly Matzinger, now Chief of the Ghost Laboratory and the section on T-cell Tolerance and Memory at the NIH, has previously worked as a bartender, carpenter, jazz musician, Playboy bunny and dog trainer. She completed her PhD at the University of California, San Diego (USA) and was a postdoctoral fellow at the University of Cambridge (UK). She has worried for years that the dominant model of immunity does not explain a wealth of accumulated data and has recently suggested an alternative, the danger model, which suggests that the immune system is far less concerned with things that are foreign than with those that do damage. This model, whose two major tenets Matzinger admits were thought up in a bath and on a field while herding sheep, has very few assumptions and yet "explains most of what the immune system seems to do right, as well as most of what it appears to do wrong", covering such areas as transplantation, autoimmunity and the immunobiology of tumors. The model has been the subject of a BBC Horizon film and has featured in two other films about immunity and countless articles in both the scientific and the lay press. In her spare time, Matzinger trains border collies for competitive shepherding trials and, in her own words, "composes songs that are not really worth listening to, and worries about the next major question in the immune system", namely "once it decides to respond, how does the immune system know what kind of response to make?"