Two great scientists, Bruce Beutler and Jules Hoffman, who have changed the way we view the immune response of plants and animals, have been awarded the 2011 Nobel Prize in Medicine.
Tragically, Dr. Ralph M. Steinman of Rockefeller University, who discovered a new class of cell, known as dendritic cells, which are key activators of the adaptive immune system dies a few days ago. It is unclear if his family will be able to share the prize because Nobel Prizes are not awarded posthumously.
Hoffman’s group showed that Drosophila Toll, originally known for its function in development, is also important for the response to fungal and Gram-positive bacterial infection. Read the 1996 Cell paper for which he received the Nobel Prize here.
In mammals, the groundwork for receptor discovery was laid as early as the 1890s, when heat-stable molecules of microbial origin were shown to induce fever and shock in the mammalian host. Foremost among the inducers was endotoxin (LPS), represented in most Gram-negative bacteria. Widely known for its ability to induce septic shock, LPS is perhaps the most powerful elicitor of inflammation known in mammals. The identification of the receptors for these molecules was the central challenge in the field of animal innate immunity. Bruce studied two spontaneous mouse mutations that affected the response to Lps. Both mutations rendered mice insensitive to LPS and highly susceptible to Gram-negative infection. These results suggested the existence of a LPS receptor. Bruce’s lab isolated the genes corresponding to these mutations by positionally cloning in 1998. Read the paper here.
Like rice XA21, the protein that my laboratory studies, Toll and TLR4 carry a leucine rich repeat protein motif in the predicted extracellular domain and signal through a subclass of kinases called non-RD (arginine-aspartate) kinases. TLR4 and TOLL also shares the Toll /interleukin-1 (IL-1) receptor (TIR) domain with several plant proteins involved in immune signaling. Thus, the discovery of a role for Toll and TLR4 in the innate immune response provided a structural link between sensors used by plants and animals to detect infection.
Is it a surprise that Jules and Bruce won the Nobel Prize? No. The importance of their discoveries has long been known. Both Bruce and Jules have won one many well-deserved prestigious prizes for their work during their careers. Still, until the prize is awarded, you never know if the research will be recognized by the Nobel committee. I am ecstatic that it was.
Not only am I a great admirer of Bruce’s work but I am going to boast RIGHT HERE that he is my third cousin. I knew his multi-talented, lovely grandmother Kathe, a physician, who told me stories about our family during their escape from Nazi Germany. So I take special pride in this award. Here is a story about our shared ancestry.
I also had the great honor to coauthor with Bruce a review last year in Science magazine about the plant and animal immune responses.
We dedicated the review to our great-great grandparents, Julius Rothstein (1830-1899)
and his wife, Fanny Rothstein née Frank (1834-1911), our last common ancestors.