A Nobel Prize not Immune from Error?

(December 12th, 2011) From 1993-1997, Bruno Lemaitre made ground-breaking discoveries on innate immunity in insects. Yet, although he clearly did this research, the lab’s administrative manager, Jules Hoffmann, has now received the Nobel Prize. A case of mistaken identity? Jeremy Garwood looks at the evidence.



Disputes about the relative contributions of authors on scientific reports are common but when the article in question wins the Nobel Prize, with all of its associated aura, the question of deserved credit becomes much more acute. And sometimes the evidence appears irrefutable. On the website, Behind Discoveries, Bruno Lemaitre has provided extensive documentary evidence supporting his claims of injustice.

“For a long time now, I have wanted to express my feelings about events relating to my work on immunity in Drosophila and the Cell 1996 paper in which the role of Toll in the antifungal response is described. The 2011 Nobel prize has now precipitated my response. I know some of you may think this is a little too late but this has not been easy for me,” writes Lemaitre, now a Professor at the Ecole Polytechnique Fédérale de Laussanne (EPFL).

More deserving candidates?

Contacted by telephone, Bruno Lemaitre told me it was important to stress that he was not simply claiming the Nobel Prize for himself. Rather, he said that the overall discovery of TLRs had been “a very complicated one” involving many labs (he discusses this at length in: ‘Repositioning the ‘Cell 1996’ discovery in the context of Toll/TLRs’).

However, what was certain was that “other researchers in the domain were far more deserving than Jules Hoffmann”. In particular, he cited Ruslan Medzhitov, who had displayed enormous creativity, and Shizuo Akira, whose laboratory had clarified numerous key aspects of TLRs. Furthermore, both of these researchers had the additional merit of presenting their results in a straightforward manner, without denigrating the work of others. In this respect, he added, Bruce Beutler had also been a poor choice for the Nobel Prize honouring the discovery of TLRs.

The evidence against Hoffmann

This is divided into 4 main sections but you don’t need to start at the beginning:

This is where you can read the original papers describing the Nobel Prize-winning discovery. Although ‘Cell 1996’ is the most prominent, it was in fact the middle of three key papers that Lemaitre published (Lemaitre et al. 1995, 1996, 1997) describing how his genetic studies had revealed that flies respond to infections by two different pathways: the response to bacterial infections passes through the Imd (immune deficiency) receptor, a mutation he discovered, while fungal infections elicit a response through the Toll receptor, a protein that had been previously identified for its role in embryonic development.

This work in itself represented a big advance but gained extra significance when it helped mammalian immunologists to discover that the homologous Toll-like receptors (TLRs) are pattern recognition receptors regulating innate immunity in man. Suddenly this fly story took on a bigger meaning!

For those of you who prefer a more readable scientific story, try the personal account that Lemaitre published in 2004 for Nature Review Immunology. He features a researcher’s lab bench view of the discovery, complete with key moments when chance, other labs, and good luck aided him. Presumably, the Nobel Prize committee didn’t get as far as reading this personal record of the creative process that led him to discover the role of Toll (and Imd); however he does note that the ‘I’ in his original manuscript was often changed to ‘we’ upon the insistence of a reviewer from Hoffmann’s institute. For Lemaitre, these ‘I’ to ‘we’ changes are significant because they served to hide what was largely his individual research effort.

“I feel bitter about this award for the reasons I explain below. In short, I feel disappointed because at the time I performed the critical work on Toll, Jules Hoffmann was not very supportive of the genetics approach I had undertaken. Subsequently, he has never been able to fully recognize my contribution, yet somehow it is he who is now collecting the honours for my work.”

In ‘Mixed feelings about the Nobel Prize 2011’, Lemaitre writes a very wide-ranging account of where he’s coming from – literally! He goes back 20 years to the University of Paris and his PhD studies on transposable genetic elements in Drosophila. He explains how this environment gave him a solid grounding in fly genetics.

Upon completion of his PhD in 1992, he moved (with his own finances) to Strasbourg to study insect immunity in a CNRS Unité. The overall administrative director of this research institute was Jules Hoffmann but, as Lemaitre explains, the researchers, students and technicians were divided into their own lab groups – he even provides an organigram (see also text S1) for the period to help you get around.

“My first year’s research was devoted to a collective teamwork, led by Jean Marc Reichhart, to study Dorsal’s function in immunity. At this time, I also ordered on my own initiative all the fly lines I could find that carried mutations affecting any of the genes involved in the pathways regulating dorso-ventral formation, including the famous Toll mutation. However, our work on Dorsal turned out to be rather disappointing since its role in immunity was, in fact, minor.”

The lone geneticist

Lemaitre explains that at this point, in mid-1993, Hoffmann and Reichhart decided to pursue the biochemical purification of the immune regulatory protein(s). However, this left Lemaitre, the lone geneticist, with dozens of fly lines that he had already ordered for the analysis of Dorsal and related pathways (including Toll). He chose to continue with his own genetic analysis to see if any of the other mutations might affect Drosophila’s immune response.

“During this time (1993-95), neither Jules nor Jean-Marc Reichhart were very supportive of my genetics’ work: none of the five students starting their PhDs in 1993 began projects involving any genetics” – as shown on the organigram in which he traces the allotted activities of all the lab’s researchers, technicians and students.

In fact, he says, none of the lab’s technical support was given to him for another year, when finally he received part-time help to maintain his burgeoning fly collection. Despite this, in early 1994, he found the imd mutation, and “a year later, after an intensive quest, I discovered Toll’s function”.

Meanwhile, Jules Hoffmann appears to have been a fairly typical French research director in his 50s, that’s to say, someone who had chosen to become the administrative representative for the Unité, reducing his research time in return for bureaucratic power.

“Jules never provided any ideas for my project, being very far from the realities of experimental bench work. This is why, for example, I still have all of my laboratory notebooks in my office with me – neither of my lab chiefs ever looked carefully at my data. In fact, Jules’ time was mainly devoted to lab organization and communication, although he did help me a lot in writing the papers (at that time, my English was poor).”

Lemaitre says he wrote the first version of each of his scientific papers, getting feedback from a close colleague, Marie Meister. “It would only be then that I would start working on the final text with Jules.” He says Hoffmann provided a real input for ‘shaping’ the manuscript.

However, “being naïve and young, I did not pay too much attention to the co-authorship issue. It did not seem important to me since I was obviously the first author”.

‘The tale(nt) of Hoffmann’

Except that once Lemaitre left the Strasbourg lab, it seems that Hoffmann began claiming more and more personal credit for the discovery: “I feel disappointed with how Jules Hoffmann (unintentionally, or consciously) has devoted his communication skills to turning the discovery of “Toll” into a team work. He has never fully acknowledged my individual contributions, portraying the story as a joint effort. This is a statement that I consider to be entirely wrong.”

Bruno Lemaitre has clearly thought a lot about what happened. He now provides all kinds of supplementary information to support his claims.

Analysis of Hoffmann’s co-authorships

In addition to the organigram outlining how the lab’s researchers were organised, he has attached a list of all the publications that Hoffmann co-authored. Here, he indicates which authors were the actual project leaders on the published research.

For the 4-year period when Lemaitre was in the Strasbourg institute (1993-1997), he notes that, upon closer analysis, only one out of the 18 publications that Hoffmann co-authored, could really be assigned to him as ‘project leader’ and even then, credit ought to be shared with the first author, JL Dimarq. Meanwhile, Philippe Bulet was project leader on 7 publications, Lemaitre on 4, and JM Reichhart on 6 (of which 3 were shared with other researchers).

Who did what on ‘the’ Cell 1996 paper

Here (described in text S2), Lemaitre explains the respective roles of his 4 co-authors, and 4 other contributors (thanked in the acknowledgements). He himself “ordered the Toll pathway mutant lines, designed all the experiments, organized the work with other people, analyzed all the experiments, and wrote the paper.” Meanwhile, the two PhD students aided with his Northern blots, Reichhart’s name appeared as group chief, and Hoffmann helped write the final version of the manuscript.

Pretty clearcut. So how did Hoffmann come to be considered the great discoverer?

Distorting the facts

Within his own institute, Hoffmann may have made claims to glory but what interests Lemaitre is how he managed to publicly ‘sell’ his version of the story in scientific seminars and at research meetings: “In seminars, Jules Hoffmann never mentions my contribution as the key step. The story is described as an «epopee» (“epic”) that started a long time ago and my contribution, i.e the one that has made him famous and got him the Nobel prize, is never really acknowledged. I am usually cited in a general acknowledgement with the photos of all the other lab members at the end of the talk.”

You can also analyse one of Hoffmann’s seminars: in text S3, there is a video link to a seminar he gave at the NIH in June 2011. Lemaitre wants us to notice how the talk proceeds. For example, when Hoffmann describes the discovery of Toll and Imd (from 10 minutes – 14 minutes 30 seconds), no individual researcher is named – everything is indiscriminately lumped together as ‘we’ and ‘our’, with the obvious implication that it was all directed by Hoffmann himself, from above.

Remembering the details

For a bit of light relief, try reading the transcript of the phone interview Hoffmann gave to Nobel Media (text S3B). The interviewer asks him directly why he started to study fly immunity. Hoffmann’s answer is a confused meandering - to put it mildly!

But, to Lemaitre’s irritation, Hoffmann then says “We hired in a Drosophila geneticist, Bruno Lemaitre.” When, in fact, for the first year, Lemaitre came with his own money: “There was no open position for a geneticist to my knowledge.” Furthermore, Lemaitre stresses that Hoffmann has also airbrushed other researchers out of the equation: all of the fly’s antimicrobial peptides were discovered and purified by Philippe Bulet and his group, but Hoffmann never mentions him either, yet this work on the peptides was the “compulsory initial step before we could even begin to investigate their regulatory pathways!”

A cursory look on the internet also turns up comments about “Jules Hoffmann, along with his brilliant student Bruno Lemaitre”! (e.g. at www.umassmed.edu). Where on earth did such sites get the idea that Lemaitre was a PhD student with Hoffmann? (Remember Lemaitre completed his PhD in Paris in 1992 – 4 years before publishing the Toll paper!).

Meetings and networking

From the onset of the Toll-TLR story, Lemaitre says “communication has been monopolized by just a few speakers. This is especially true for Drosophila for which Jules Hoffmann became a real peddler”!

In order to continue to present his own version of the Toll discovery, Hoffmann seems to have made sure that Bruno Lemaitre was not present at his meetings: “During the 10 years that followed the 1996 Cell paper, I was rarely invited to present at ‘immunology’ meetings, especially at key meetings on innate immunity that were frequent at that time. I was certainly never invited to any meeting organized by Jules Hoffmann.”

Although Lemaitre continued to actively study innate immunity with his own dynamic lab group at Gif (near Paris), he says it was not until 2006 (10 years after the Cell paper), that he began to be regularly invited to Toll meetings, where he finally met some of the main vertebrate immunologists.

Meanwhile it seems that Hoffmann did a very good job of self-promotion, establishing networks, especially with important figures in immunology, who might not have noticed that his knowledge of Drosophila genetics was very superficial. But, who knows, if Hoffmann hadn’t spent so much time and effort promoting the Toll discovery, it may not have received the Nobel Prize at all. Another irony of modern scientific research?

Turning the page

Lemaitre says he cannot remain embittered by what has happened. He has had a successful research career, received other prizes for his research, and is now a Professor at the EPFL. He is only in his mid-40s, and still has plenty of research discoveries to make. However, he will no doubt continue to be careful when attributing fair credit to his own research collaborators!

Jeremy Garwood

Photo: EPFL, Lemaitre

 




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