Article

Nobel Prize in Physiology or Medicine for 2011

DOI: 10.1134/S0006297912020149

The Nobel Prize in Physiology or Medicine for 2011 was awarded for discoveries in immunology to Jules A. Hoffmann (France) and Bruce A. Beutler (USA) “for their discoveries concerning the activation of innate immunity” (first half) and to Ralph M. Steinman (USA) “for his discovery of dendritic cells and their role in adaptive immunity” (second half).

On one hand, immunologists, as well as molecular biologists and geneticists dealing with problems of immunity have to be delighted (and many of them are indeed). These discoveries really are from the cutting edge of modern science and some underlying concepts are not yet included into textbooks. On the other hand, the Nobel Committee decision leaves a bitter aftertaste, and not for only a single reason.

First, the awarded Canadian Ralph A. Steinmann who for many years had been working in the Rockefeller University (USA) died three days before the announcement of the award. As differentiated from secrecy of the Nobel Committee activities, the death of R. Steinmann was not a secret. Everybody knew that he was incurably ill, that he was nominated not once, and it was said last year that if he did not receive it in 2010, he would not be alive until the next year’s Prize (and just this occurred). The discovery of dendritic cells by Ralph Steinmann in the laboratory of Zanvil Cohn in the early 1970s [1] is a fundamental discovery of great theoretical and practical importance. Because Z. Cohn died long ago, Steinmann undoubtedly deserved the Prize (especially as in 2007 he received alone the Lasker award, which is the main “pre-Nobel” prize in medicine). Thus, he deserved the Prize – but being alive.

There are rules of the game. For instance, the Hero of the Soviet Union title may be awarded postmortem, and the Statute of this title contains the corresponding entry. But the Nobel Prize (similarly to many other international and national prizes) is not meant to be given posthumously. Such was the decision of Alfred Nobel, and one should not argue with sponsors. By the way, no deceased person can be elected to the Russian Academy of Sciences  and if were ever attempted technically, the multi-stage system of approval would nearly certainly prevent such a case (even if a very decent scientist was suggested for election).

Jules Hoffmann and Bruce Beutler were awarded the other half of the Prize essentially for establishment of one of the first molecular mechanisms responsible for triggering innate immunity. In both cases there are definite “Nobel” papers published in 1996 and 1998 [2, 3]. In the titles of these two genetic works (one was performed on Drosophila and the other on mice) the Toll or Toll-like receptor are mentioned. Thus, only one molecular mechanism has been distinguished among multiple regulatory mechanisms of immunity described during the last 15-20 years. Obviously, it should be the most important mechanism stimulating the progress of science. In fact, it was shown for the first time that a specific chemical structure of a pathogen (bacteria or fungi), which is absent from human cells, could be recognized by receptors of the host’s cells that triggered the defense mechanism. Thus, a hypothetical principle of recognizing “microbial non-self” was shown to be associated with a specific molecular cascade inside the cell. Note that many essential details were unknown in 1996-1998.

However, not lowering the contribution of the Laureates, it should be emphasized that the development of this trend of immunology was stimulated by the works of Charles A. Janeway [4] and his laboratory, and in the late 1990s the major role belonged to activities of our former compatriot Ruslan Medzhitov (who was also bypassed for the award – but this we shall discuss further).

But who are the living Nobel Prize winners in Physiology or Medicine for 2011?

Jules Hoffmann is well known in Russia not only as a scientist but also as a lecturer of the education program on immunology and oncoimmunology (www.oncoimmunology.ru). As he modestly speaks about himself, he is an entomologist and a son of entomologist. The introductory slide of his lectures presents the scheme of Drosophila created long ago by his father.

Hoffman’s contribution to medicine is especially interesting because it has been realized on a most non-medical object – on Drosophila. Thus, his awarding is just a triumph of pure science – and therefore, is the reason for delight. In Russia it would be nearly impossible to get good support for such studies...

Jules Hoffmann moved to France from Luxemburg after the Second World War and lived all his life in Strasbourg, where he graduated and worked afterwards. In the key experiment of his laboratory (the first author of the “Nobel” paper was Bruno Lemaitre, a young geneticist from Paris who brought genetic approach to Hoffmann’s lab) fruit flies with particular mutant genes were experimentally infected by various pathogens, and it was recorded what infection the mutant flies could overcome and what they could not. Normal flies with the normal defense system were used as control. The presence of innate defense mechanisms in insects and plants was known earlier, but nobody thought that the same mechanisms could be relevant for humans and medicine.

The “Nobel” observation by Lemaitre and Hoffmann was that a particular kind of mutant fly was unable to resist the fungal pathogen, whereas the normal flies survived the infecting dose [2]. The susceptible flies carried a mutation in the Toll gene that had been discovered in another laboratory in the course of studies (also awarded the Nobel Prize!) not of innate defense mechanisms but of embryogenesis of Drosophila. It seems that the Toll gene was predestined to bring Nobel Prizes. Jules Hoffmann comprehended well the importance of the discovery, and during the following years he did his best to make it widely known. His laboratory continued works on Drosophila and studied in detail molecular mechanisms of antibacterial, antiviral, and antifungal defense in insects. The works of J. A. Hoffmann have been undeniably acknowledged – he is a winner of many national and international awards, a foreign member of academies of some countries, including Germany (Academia Leopoldina), Russia (2006), and USA (2009). In France he was the President of the Academy of Sciences during 2007-2009 (as discriminated from the Russian Academy of Sciences, the president of the French Academy is elected one time and only for two years).

Bruce A. Beutler was born 1957 in USA. His father E. Beutler is a known hematologist and medical geneticist. Beutler graduated from the University of California San Diego, then from the University of Chicago Medical School. The research work he started at Rockefeller University (New York) in the laboratory of Anthony Ceramy, where he had cloned the gene of Tumor Necrosis Factor (TNF) and was one of the first to propose the idea of therapeutic inhibition of TNF. His genetic studies resulting in the Nobel Prize were performed at the Southwestern Medical Center in Dallas and then at the Scripps Research Institute where his father was working. At present, he is affiliated with both these institutions. He has been a member of the United States Academy of Sciences since 2009.

The “Nobel” work of Beutler was performed with mice [3]. Previously mouse strains were selected which possessed a very low sensitivity to a highly toxic substance – bacterial endotoxin, or lipopolysaccharide (LPS), a unique chemical component of the cell wall of Gram-negative bacteria. The structure and properties of LPS were studied in many laboratories, in particular, at the Max Planck Institute in Freiburg, Germany. And although physiological effects of LPS were known, the putative LPS receptor was not characterized.

The purpose of Beutler (and of some other laboratories) was to find the gene responsible for resistance/sensitivity of mice to LPS. Using so-called positional cloning, his laboratory succeeded in detecting the chromosome locus containing the mutation and then in identification of the affected gene: it was the gene TLR4 encoding Toll-like receptor 4. The mutation character was also determined. A paper by Alexander N. Poltorak (our compatriot) and coauthors of 1998 [3] led to the Nobel Prize to Bruce Beutler 13 years later.

Thus, Hoffmann’s laboratory was the first to determine the Toll receptor as an element of the molecular cascade associated with the organism’s innate defense (not knowing in detail how the fungal pathogen activated this receptor) and Beutler’s laboratory found the first ligand of the Toll-like receptor to be the well-studied component of the cell wall of bacteria – a potential pathogen. Suppose that the Toll-like receptor of mammals should trigger a signaling cascade similar to that in Drosophila (as it really occurs), and then the picture seems to be more or less complete. However, there are important nuances: fruit flies cannot recognize LPS and Gram-negative bacteria are recognized through a mechanism not associated with the Toll receptor, whereas recognition of these bacteria by mammals is mainly mediated through LPS.

The theory by Janeway described in a brilliant essay [4] and presented as an introductory lecture at a representative immunological conference (Cold Spring Harbor Symposium on Quantitative Biology in 1989) postulated that molecular activators of the innate immunity system should be searched for just among unique chemical components of pathogens. Knowing the findings from Hoffmann’s laboratory, Ruslan Medzhitov in the laboratory of C. Janeway cloned in 1997 the first human Toll-like receptor [5], which occurred to be just... TLR4 (the genetic work from Beutler’s laboratory was published a year later). Not knowing a ligand for TLR4, Ruslan prepared a hybrid receptor that could be triggered by a cytokine and verified the other important prediction of Janeway’s theory: the signal transduction should result in expression of co-stimulatory molecules, the so-called signal 2 for activation of T-cell adaptive immunity [5].

Thus, if Charles Janeway had not died of cancer in 2003, he would have been the major candidate for the Nobel Prize. After his death, Ruslan Medzhitov was the main person to continue the work of his teacher. He not only was the first to clone and characterize the first Toll-like human receptor but he also greatly contributed, both theoretically and experimentally, to the field of innate immunity. The world immunological community was expecting that, if studies on Toll and Toll-like receptors would be recognized with important awards, including the Nobel Prize, Ruslan Medzhitov should receive it “for himself and for Janeway”. In fact, during recent years Hoffmann, Beutler, and Medzhitov received many prestigious awards including the “Asian Nobel Prize 2011” – the Shaw Prize in Hong Kong. But the Nobel Committee has decided otherwise – and this decision cannot be revised even by the letter of 24 leading immunologists to Nature [6] indicating the first rung significance of the contribution made by Janeway–Medzhitov.

Thus, again Russian science was very unlucky (we can consider Ruslan Medzhitov to be a Russian scientist despite his current American citizenship, because he has done so much for immunological education in Russia). The next chance to receive the Nobel Prize in Physiology or Medicine seems not likely to happen soon for Russian or Post-Soviet researchers.

REFERENCES

1.Steinman, R. M., and Cohn, Z. A. (1973) J. Exp. Med., 137, 1142-1162.
2.Lemaitre, B., Nicolas, E., Michaut, L., Reichhart, J. M., and Hoffmann, J. A. (1996) Cell, 86, 973-983.
3.Poltorak, A., He, X., Smirnova, I., Liu, M. Y., van Huffel, C., Du, X., Birdwell, D., Alejos, E., Silva, M., Galanos, C., Freudenberg, M., Ricciardi-Castagnoli, P., Layton, B., and Beutler, B. (1998) Science, 282, 2085-2088.
4.Janeway, C. A. (1989) Cold Spring Harb. Symp. Quant. Biol., 54, Pt. 1, 1-13.
5.Medzhitov, R., Preston-Hurlburt, P., and Janeway, C. A. (1997) Nature, 388, 394-397.
6.Allison, J. P., Benoist, C., Chervonsky, A., et al. (2011) Nature, 479, 178.

S. A. Nedospasov
Professor, Corresponding Member
of the Russian Academy of Sciences