The origins of innate immunity
This year’s Nobel Prize in Physiology or Medicine was announced this week, and was jointly awarded to Bruce Beutler (Scripps Clinic), Jules Hoffman (Centre National de la Recherche Scientifique; CNRS), and Ralph Steinman (Rockefeller University). Beutler and Hoffman were recognized together for “for their discoveries concerning the activation of innate immunity,” while Steinman was recognized “for his discovery of the dendritic cell and its role in adaptive immunity.” The recipients will share a monetary prize worth approximately $1.5 million. There has been over a century of Nobel Prizes recognizing the work on how pathogens are seen by our immune system, going all the way back to the award to Emil von Behring in 1901 for his work on passive serum therapy in the treatment of diphtheria. In 1908, Ilya Mechnikov was also awarded the Nobel Prize for his identification of the process of phagocytosis, which was again recognized this year in Steinman’s work with dendritic cells. Sadly, Ralph Steinman died just a few days ago, however this was not known by the Nobel Prize committee before their announcement. The committee was actually alerted to this when they tried to call Steinman to notify him on Monday morning.
The work of Beutler and Hoffman very nicely demonstrates how scientists can approach the same problem from two different sides, with all of the work beautifully complementing one another, and their work was recognized previously in 2007 by the Balzan Prize. Beutler is a geneticist and microbiologist, and has been interested in how mammalian immune cells are able to recognize microbial patterns as distinct from our own. His specific interest was in lipopolysaccharides, or LPS, a component of the Gram negative outer membrane. His work utilized a forward genetic approach to understanding this question, by creating mutants of cells and then identifying those mutants that were then unable to respond to the presence of LPS. The response was measured indirectly by measuring the production of a messenger that is released by LPS-stimulated cells. This approach was laborious, and the final identification of the gene sequence for binding LPS on mammalian cells required approximately 3 decades from the first identification of the activity on human cells to the sequencing of the gene in the late 1990’s.
Hoffman’s work heavily utilized the model organism Drosophila melanogaster, or the fruit fly. The picture at the top of this post is a fruit fly that has a single gene mutation in the toll gene. Unlike wild-type fruit flies, this mutant is incredibly susceptible to infections by fungi, and in this case the surface of the fly is covered by the mold Aspergillus. Hoffman and his co-workers characterized the highly conserved transcription factor pathways that interacted with the Drosophila toll protein as pathogen-specific receptors that produced an appropriate antimicrobial responses. Once all the dust had settled, it was very apparent that these parallel lines of investigation were looking at a phenomenon conserved across almost a billion years of evolutionary divergence between insects and mammals.
This year’s Nobel Prize selection again demonstrates that serendipitous and initially unrelated observations can converge and complement one another. In the case of the human immune response, it was known for a long time that LPS receptors existed, but the identification of the gene sequence proved difficult due to the complexity of the human genome. In Drosophila, a mutant in toll had been identified early as well, however the main phenotype associated with the gene deletion was developmental in nature, playing a part in the proper formation of the embryo. It wasn’t until later that the gene product’s role in recognizing patterns on pathogens was clearly delineated. As the stories unfolded, each then was able to explain the observations of the other. We can only hope that our individual scientific questions can work so well!
Posted on October 5, 2011, in Microbes in the News and tagged Balzan Prize, Beutler, Hoffman, Nobel Prize in Physiology or Medicine. Bookmark the permalink. Comments Off on The origins of innate immunity.