Abstract
The said interest shall be divided into five equal parts, which shall be apportioned as follows: One part to the person who shall have made the most important discovery within the domain of physiology or medicine …
Continuing a long, illustrious tradition of investigation in inflammation and immunity (Table 1), the Nobel Prize in Physiology or Medicine for 2011 was awarded, one-half jointly to Bruce A. Beutler and Jules A. Hoffmann “for their discoveries concerning the activation of innate immunity,” and the other one-half to Ralph M. Steinman “for his discovery of the dendritic cell and its role in adaptive immunity.” Congratulations to them all, and condolences to the family of Ralph Steinman, who succumbed to pancreatic carcinoma unaware, three days prior to the announcement of the prize.
The importance of their discoveries to clinical medicine is highlighted by this quote from the award citation: “These two defense lines of the immune system provide good protection against infections but also pose a risk. If the activation threshold is too low, or if endogenous molecules can activate the system, inflammatory disease may follow [1].”
Knowledge of their observations may be gleaned from the writings of these individuals. Citations are provided to pertinent review articles authored by the Nobel laureates so that trainees, junior investigators, and all who are interested in science can learn and follow the trail of thought and hard work that culminates in a Nobel Prize.
Beutler [2] wrote in 2002 that “The identification of the Toll-like receptors (TLRs) as the primary sensors of the innate immune system was the culmination of inquiry into the pathogenesis of sepsis, a line of investigation that has spanned three centuries. The function of the TLRs was first disclosed by the positional cloning of Lps, the central endotoxin response gene, which proved identical to the orphan receptor TLR4. Subsequent gene knockout studies established the functions of TLRs 2 and 9. Each has a discrete role in pathogen sensing. Collectively, the TLRs probably sense most bacteria, fungi, and protozoa. The future of innate immune exploration will lie largely with the concerted application of forward genetic methods.”
According to Hoffmann [3], “Drosophila mounts a potent host defense when challenged by various microorganisms. Analysis of this defense by molecular genetics has now provided a global picture of the mechanisms by which this insect senses infection, discriminates between various classes of microorganisms and induces the production of effector molecules, among which antimicrobial peptides are prominent. An unexpected result of these studies was the discovery that most of the genes involved in the Drosophila host defense are homologous or very similar to genes implicated in mammalian innate immune defenses. Recent progress in research on Drosophila immune defense provides evidence for similarities and differences between Drosophila immune responses and mammalian innate immunity.”
In Steinman's words [4], “B and T lymphocytes are the mediators of immunity, but their function is under the control of dendritic cells. Dendritic cells in the periphery capture and process antigens, express lymphocyte co-stimulatory molecules, migrate to lymphoid organs and secrete cytokines to initiate immune responses. They not only activate lymphocytes, they also tolerize T cells to antigens that are innate to the body (self-antigens), thereby minimizing autoimmune reactions. Once a neglected cell type, dendritic cells can now be readily obtained in sufficient quantities to allow molecular and cell biological analysis. With knowledge comes the realization that these cells are a powerful tool for manipulating the immune system.”
Of note for the surgical infection community, Beutler (who gave the 2007 William Altemeier Lecture of the Surgical Infection Society) and Steinman deserve acknowledgment and thanks for their willingness to collaborate with surgeon-scientists and mentor our promising young investigators [5–7]. Nothing could be better for a young surgical investigator than to be exposed meaningfully to the greatest minds in the biological sciences, and to be mentored to a first-author publication in Science [5] or Immunology [7].