General News: Nobel Prize 2011

This blog is back up and running. For a while, I put it on hold since I was busy helping teach introductory biology, but now that it is over, I am now going to return to working on articles. Many exciting things have happened since so I thought I’d write about two major events that occurred in the last four months.

First, the Nobel Prizes! The 2011 Nobel Prize in Physiology and Medicine were awarded to Bruce Beutler and Jules Hoffmann "for their discoveries concerning the activation of innate immunity" and the late Ralph Steinman, "for his discovery of the dendritic cell and its role in adaptive immunity". This is the first immunology prize since 1996, and so the immunology community is really excited!

Our species is constantly under attack by other microorganisms, which our body defends against using the complex immune system. Mammals have two arms of the immune system, the ancient innate immune response and the more recently-developed adaptive immune response. The innate immune response is the first line of defense, a non-specific response that leads to immune cell recruitment, inflammation and attack of foreign material. The second line of defense is the adaptive immune response, in which the body mounts a more effective, specific attack against the microorganism after studying it for some time. Since this takes time to develop, the innate immune response is critical for immune function.

THE ROAD TO INNATE IMMUNITY
Insects have a relatively short lifespan, so it doesn’t seem apparent that they require a powerful immune system to fight pathogens, yet insects are highly resistant to microbial infection. Yet early inquiries into understanding how this happened lead nowhere, because it turns out insects are unlike humans in that they do not have an adaptive immune response. The first glimpse into this mystery occurred in 1981, when Hans Boman discovered that moths induced the antimicrobial peptides Cecropin and Attacin. By the 90s, several genes encoding these antimicrobial compounds were identified in the Drosophila genome. Yet no one understood what was turning on expression of these antimicrobials, a process that Beutler and Hoffmann coined “the black box.”

They explored the promoters of these antimicrobial genes and found they contained binding sites for something similar to the mammalian NF-kB (discovered by Nobel laureate David Baltimore - from MIT!), which has been linked to immune system activation. Previous work by the Nobel laureate Nusslein-Volhard had found a critical development pathway that set up the axes for dorsoventral establishment, the Toll pathway that ended in Dorsal, a NF-kB-like molecule. Through a long line meandering experiments and wrong leads, Dr Hoffmann eventually discovered a mutant, Toll which was highly susceptible to fungal and bacterial infections, for the first time proving that Toll was somewhat essential in immune responses.

In a parallel line of research, septic shock is a debilitating syndrome that causes multiple-organ failure at the end-stage of a bacterial infection. It was recognized that this was induced by a molecule common to most bacterial cells, LPS. Dr Beutler wanted to try to find the receptor that could bind LPS, so they soon discovered that mice resistant to LPS had a mutation in a gene similar to the Toll gene of the fruit fly. They demonstrated that LPS-binding to the Toll receptor activated inflammation, and when the doses were very high, the organ systems in the body would go into inflammation overload and cause septic shock.

Thus, in the grand picture of things, Bruce Beutler and Jules Hoffmann discovered a set of receptors that we now call the pattern-recognition receptors, which recognize a set of molecules that are broadly found in microorganisms but not humans. They demonstrated that it was a very ancient pathway, conserved from flies to humans. Moreover, in later work, they picked apart the pathway, allowing the development of drugs that can target the innate immune response. Indeed the fundamentalness of this pathway is indeed one reason why these two have been awarded Science's Highest Award.


THE ROAD TO DENDRITIC CELLS AND THE ADAPTIVE IMMUNE RESPONSE
One characteristic of the immune system is its incredible diversity of cells; in fact when Dr Steinmann first entered the field in 1970, it was known as God (for generation of diversity). At the time, clonal selection theory suggested that there was an infinite variety of cells in the immune system, each which recognized one antigen. Binding to a specific antigen caused one specific clone to multiply thousand-fold and promote an immune response against that antigen. This hypothesis was further enriched when Nobelist Susumu Tonegawa (also MIT ) demonstrated that the great diversity of clones was generated through genetic recombination. Yet one problem with the theory was that injection of antigens into animals did not always generate an immune response, an idea which would have critical impacts on vaccine generation.

In 1973, Steinman found that purifications of lymphocytes (mixtures of B and T cells) could not produce antibodies unless they were supplemented with “accessory cells.” Looking under the microscope, he explored the accessory cells and found the usual culprits (macrophages) but also, a weird stellate elongated cell, which he named the dendritic cells. Further studies revealed he only needed to mix 1 dendritic cell per 100 lymphocytes to induce strong clonal selection.

We now know that dendritic cells are the critical link between the innate and adaptive immune response. The innate immune response (which half this year’s Nobel is awarded for ) turns on these dendritic cells, which then go on to activate T cells for priming the adaptive immune response. Indeed, these cells have been so influential that pharmaceutical companies are now trying to develop vaccines using dendritic cells as well as treatments for allergies.

However, it is with great sadness that Dr Ralph Steinman passed away on Friday Sept 30, 3 days shy of him finding out about his Nobel Prize. Dr Steinman was a consummate scientist of the highest caliber and many colleagues value his contributions greatly. In one of his essays, he recalls Palade’s quote “For a scientist, it is a unique experience to live through a period in which his field of endeavor comes to bloom—to be witness to those rare moments when the dawn of understanding finally descends upon what appeared to be confusion only a while ago—to listen to the sound of darkness crumbling.” And indeed Dr Steinman helped clear the darkness.


REFERENCES:
Beutler's Discovery of TLRs
Hoffmann's Discovery of TLRs
Steinman's Discovery of Dendritic Cells