Immunology takes prize for medicine, but award comes three days too late for one recipient.
Before the immune system can attack an invading pathogen, it must identify the intruder. Breakthroughs in understanding this process have garnered three scientists this year's Nobel Prize in Physiology or Medicine, which was announced on 3 October in Stockholm.
But the award was quickly overshadowed by sadness when it emerged that the winner of half the 10-million-Swedish-krona (US$1.5-million) prize, Ralph Steinman of the Rockefeller University in New York, had died on 30 September. Although Nobel prizes are not awarded posthumously, the Nobel committee was not aware of Steinman's death when it reached its decision. The committee has since confirmed that the award still stands. Ironically, Steinman was being treated for his pancreatic cancer with a therapy derived from his original discovery.
Together, his work and that of the other two winners — Jules Hoffmann at the French National Centre for Scientific Research (CNRS) Institute of Cell and Molecular Biology in Strasbourg and Bruce Beutler of the Scripps Research Institute in La Jolla, California — help to describe how two separate arms of the immune system work.
Steinman discovered a type of immune cell, known as a dendritic cell, that is vital to the 'adaptive' immune system, which works out exactly which pathogen has invaded the body in order to trigger a targeted response. Hoffmann and Beutler earned their share of the prize for discovering a key to a more immediate line of defence, the 'innate' immune system, which identifies a foreign body as a potential pathogen. They identified the molecular sentinels that first sound the alarm by recognizing features shared by numerous pathogens.
Steinman's efforts to understand the immune system began in the early 1970s, when he joined the laboratory of Zanvil Cohn at Rockefeller as a postdoc. Cohn's group was studying an immune cell called the macrophage, which engulfs pathogens and other debris. Most researchers thought that macrophages then alerted adaptive immune cells called T cells to the presence of a specific pathogen. Once activated, T cells multiply and combat infection, either by killing pathogen-infected cells or by steering another type of immune cell, the B cell, to produce pathogen-blocking antibodies.
In Cohn's lab, Steinman identified another type of immune cell, which he named the dendritic cell because of its long, tree-like arms (R. M. Steinman and Z. A. Cohn J. Exp. Med. 137, 1142–1162; 1973). Cohn and Steinman showed that these cells are much more important than macrophages in activating T cells.
At first, dendritic cells "were a minor cell and everybody was loath to accept them", recalls Siamon Gordon, an immunologist at the University of Oxford, UK, who worked with Cohn and Steinman. "It was a bit like having two Popes — it was the dendritic cells versus the macrophages." Steinman continued doggedly collecting data, and eventually won over his critics.
Two decades after the discovery of dendritic cells' crucial role, a team led by Hoffmann was investigating why fruitflies, which lack an adaptive immune system, don't succumb to fungal infection. In 1996, they reported that the Toll gene, previously linked to embryo development, was also important for battling infections (B. Lemaitre et al. Cell 86, 973–983; 1996). Flies with mutations in Toll died when exposed to bacteria or fungi.
At around the same time, a team led by Beutler, then at the University of Texas Southwestern Medical Center in Dallas, had spent six years looking for an immune-system gene in mice that produces a protein to recognize lipopolysaccharide (LPS), a molecule produced by certain bacteria that can cause septic shock. "We were obsessed," says Alexander Poltorak, an immunologist now at Tufts University in Boston, Massachusetts, who worked on the project. "We always thought we would find the gene tomorrow."
The team eventually found its LPS-sensing gene, and it looked remarkably like Hoffmann's Toll (A. Poltorak et. al. Science 282, 2085–2088; 1998). Linking the two findings paved the way for the discovery of other Toll-like receptors that sense molecules made by pathogens but not their hosts, and form a critical part of the innate immune system.
The discoveries of dendritic cells and innate immune receptors have already had an impact on medicine. Vaccines are typically administered with an adjuvant, such as a metal, to prompt a rapid immune response. Drug companies such as GlaxoSmithKline are now developing adjuvants that activate Toll-like receptors.
"By doing this we are mimicking what actually happens during an infection without having an infection," says Vincenzo Cerundolo, associate director of the UK Medical Research Council Immunology Unit in Oxford.
Meanwhile, Provenge (made by the biotechnology company Dendreon of Seattle, Washington), the only cellular immune therapy against cancer to be approved by the US Food and Drug Administration, exploits dendritic cells that recognize a molecule produced by prostate tumours. Culturing and reinjecting the cells back into the patient fortifies the immune response against the tumour.
"The reason why the field has progressed so much and is now in the clinic is because we understand how to activate the immune system," says Cerundolo.