An Essay on the Prize in Life Science and Medicine 2011
The immune system is central to the survival of humans in a world filled with potentially deadly microbes. Immunity has two major components: (i) the familiar “adaptive” immune system, mobilized by previous infections or vaccines to protect us against subsequent encounters with specific microbes, and (ii) the less well-known, innate immune system, which is immediately mobilized in response to infection through inflammatory responses. Both systems are essential for human survival. Infants born without a functioning adaptive immune system, such as those with “severe combined immunodeficiency”, require heroic measures, such as bone marrow transplantation, if they are to survive. But the lack of a normally functioning innate immune system is also life-threatening, as is seen in the repetitive severe infections in those with mutations in key components of the innate immune system.
The 2011 Shaw Prize in Life Science and Medicine is awarded to Jules Hoffmann, Professor at the University of Strasbourg, Ruslan Medzhitov, David W. Wallace Professor of Immunobiology at Yale University, and Bruce Beutler, Professor of Immunology, University of Texas, Southwestern Medical Center at Dallas. These three scientists have done path-breaking work that established the mechanisms of the innate system and provide new avenues for drug design to improve the overall function of the immune system.
The story begins with Jules Hoffmann who recognized that the innate immune system is evolutionarily ancient while adaptive immunity is only seen in vertebrates. Hoffmann studied the fruit fly, Drosophila melanogaster, identifying mutations that prevented it from making a protective immune response to the fungus, Aspergillus fumagatus. Through analysis of these mutations, Hoffmann showed that antifungal immunity depended on the activation of a surface molecule called Toll. Interestingly, Toll had been previously known in flies for its important role in establishing the orientation of the Drosophila embryo. Its role in innate immunity was entirely unanticipated and this discovery immediately attracted the attention of scientists working on the innate immune responses of higher animals and humans.
Ruslan Medzhitov and his then research mentor Charles A. Janeway, Jr. (now deceased) recognized that humans might have a similar system for the initiation of the innate immune response. Indeed, Janeway had earlier predicted the existence of generalized mechanisms through which cells of the innate immune system could detect or “sense” a pathogen. Medzhitov and Janeway asked whether there were human molecules that resembled Drosophila Toll. By searching a database of human genes, they found a human homolog of Toll that is now referred to as a Toll-like receptor, a TLR. Within a year of Hoffmann’s report, Medzhitov showed that if human n LR molecules on the surface of certain blood cells were stimulated to form aggregates, they caused the production of a series of potent molecules (cytokines) that were capable of initiating inflammatory responses that would mobilize cells to eliminate pathogens.
Still unresolved after Medzhitov and Janeway’s work was what the TLR “sensed”. Bruce Beutler’s key contribution was to prove that the TLRs recognized specific molecules known to be stimulants of inflammatory responses. He had been studying responses of mouse cells to a potent bacterial product, the endotoxin lipopolysaccharide (LPS), a component of an important class of bacteria. LPS was known to cause inflammatory responses in infected humans through production of several inflammatory cytokines. To determine what molecules the cells of the innate immune system used to recognize LPS, Beutler took advantage of the fact that certain mutant mouse strains were unable to respond to LPS. In elegant experiments, he showed that the mutant gene was precisely the TLR gene that Medzhitov and Janeway had identified in the human data base, now known as TLR4. Beutler’s work showed that TLRs were physiologically important activators of the innate immune system of humans and other vertebrates as a result of being stimulated by TLRs. His work established the paradigm that common bacterial products, and later viral and parasite products, mediated their activation of innate immunity by being recognized by TLRs and other sensors of the innate immune system.
These three scientists, through their critical work, laid out the principles underlying the pathogen recognition/response model of the innate immune system. Their work opened the floodgates to an enormous body of work and to a deeper understanding of the TLRs as microbial sensors important in innate resistance to pathogens and to additional work that identifies other microbial sensors in cells. This body of work has revolutionized our understanding of the innate immune system and provides targets for drug development and for the strategy for developing a new generation of vaccines.
Life Science and Medicine Selection Committee
The Shaw Prize
28 September 2011, Hong Kong