Consacrer 3% du PIB à la R&D, un serpent de mer

Le président de la république a annoncé hier vouloir faire passer de 2,25% à 3% en 10 ans la part du PIB consacrée à la Recherche. Derrière ces chiffres se cache une réalité bien plus ambiguë. Petit tour d’horizon.

 

La stratégie de Lisbonne.

Le conseil européen de Lisbonne en mars 2000 avait fixé pour objectif de faire de l’union européenne ‘l’économie de la connaissance la plus dynamique et la plus compétitive du monde’. En conséquence, l’ensemble des dépenses en matière de R&D doit augmenter pour approcher 3% du PIB d’ici…….. 2010.

Force est de constater que l’intensité de R&D dans l’UE en 2010 atteignait difficilement 2%.

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Europe 2020.

Oh ! qu’à cela ne tienne, ce fameux 3% devient maintenant un objectif pour ….. 2020. Quand on compare les chiffres entre l’Allemagne et la France, cela donne ça. L’Allemagne y est presque, quant à la France…..

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France 2026.

L’objectif de 3% fait donc son 3ème come-back et devient une priorité pour la France dans les 10 ans, c’est-à-dire pour 2026. Comme l’indique le graphique ci-dessus, la tendance actuelle n’incite pas à un grand optimisme. Et puis 2,25%, 3%, ça vous parle à vous ? A moi pas vraiment.

 

Espèces sonnantes et trébuchantes.

En 2015 le PIB de la France était de 2180 milliards d’euros. 3% d’effort de recherche publique et privée correspond donc à un investissement de 65 milliards. C’est là que cela devient intéressant. En 2004 la France consacre 2,09% de son PIB à la R&D soit environ 35 Milliards. En 2014 on passe à 2,25% soit 48 milliards (source). Et donc objectif 3% en 2026 soit 65 milliards, ou encore + 17 milliards. Vous me direz on est bien passé de 35 à 48 milliards entre 2004 et 2014, donc 65 milliards pour 2026 reste un objectif réaliste…. à PIB constant. Pour rappel le PIB de la France (en euros courants) en 2004 était de 1710 Milliards (source). Imaginez un PIB pour 2026 de 2400 milliards, on passe alors à un effort de recherche de 72 Milliards soit cette fois + 24 milliards !

 

Qui veut gagner des milliards ?

La question est aujourd’hui de savoir qui va bénéficier de ces 17 ou 24 milliards supplémentaires ? Deux graphiques montrent la tendance actuelle (source). En 2012, la dépense intérieure de R&D des entreprises représente 1,44% du PIB dont le CIR à hauteur de 0,26% et les financements publics directs de 0,12%. L’augmentation spectaculaire de l’investissement des entreprises en R&D (1,27% en 2005 et 1,44% en 2012) suit étrangement l’augmentation constante du CIR.

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Et si vous avez bien calculé, l’effort de recherche publique correspond donc à 0,78% du PIB, un effort constant depuis 10 ans (source).

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La recherche c’est fondamental !

Je suis le premier à me réjouir de l’exposition médiatique dont bénéficie enfin Emmanuelle Charpentier cette semaine en France pour la remise du prix L’Oréal Unesco ‘Pour les Femmes et la Science’. Une interview dans L’Express, un passage sur Canal Plus et sur France Inter par exemple.

 

Si nos pouvoirs publics ne doivent retenir qu’une chose, c’est que la technologie CRISPR/Cas9 qui est en train de bouleverser la biotechnologie et la médecine, est issue de la recherche purement fondamentale inspirée par la curiosité. Depuis plusieurs années, la recherche fondamentale est malmenée et beaucoup considèrent que ce type de recherche n’est pas rentable et coûte trop cher. C’est oublier un peu vite que la recherche fondamentale représente le socle sur lequel tout le reste est possible. La recherche fondamentale est par essence imprévisible en termes de résultats. Qui aurait pu prévoir il y a seulement 10-15 ans qu’étudier des séquences répétées d’ADN du génome des bactéries aboutirait à cette technologie révolutionnaire ? Personne !

 

Toute nouvelle coupe des financements destinés à la recherche fondamentale est une application de la recherche qui ne verra peut-être jamais le jour.

Ils finiront par comprendre

Ils finiront par comprendre

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Ils finiront par comprendre que le temps de la recherche n’est pas le même que le temps des politiques.

Ils finiront par comprendre qu’il faut souvent 10-15-20 ans de recherche avant de pouvoir développer des applications.

Ils finiront par comprendre que sans 20 ans de recherche en microbiologie fondamentale sur les mécanismes de défense des bactéries contre les bactériophages, il n’y aurait pas de CRISPR Cas aujourd’hui et pas d’applications en thérapie génique.

Ils finiront par comprendre que sans 30 ans de recherche sur les mécanismes fondamentaux de la régulation des gènes, il n’y aurait pas aujourd’hui de cellules souches pluripotentes induites.

Ils finiront par comprendre que la recherche fondamentale est fondée sur la curiosité pure, la créativité, le hasard, qu’elle est le terreau nécessaire aux applications.

Ils finiront par comprendre que pour récolter, il faut semer chaque année et que l’on ne construit pas une maison sans fondation.

Ils finiront par comprendre que l’on ne peut pas décider à l’avance des résultats de la recherche.

Ils finiront par comprendre que la recherche est un bien public.

Ils finiront par comprendre que la privatisation de la recherche est une catastrophe.

Ils finiront par comprendre que dans R&D il y a développement ET Recherche et que sans la Recherche, il n’y a pas de développement.

Ils finiront par comprendre qu’avec des taux de sélection de 10% à l’ANR, cela devient une loterie et que la majorité des chercheurs se sent démotivé.

Ils finiront par comprendre qu’avec des taux de sélection de 10% à l’ANR se sont des centaines de jeunes chercheurs brillants à qui l’on ne donnera jamais la possibilité d’exploiter leur talent.

Ils finiront par comprendre qu’avec des taux de sélection de 10% à l’ANR se sont des dizaines de thématiques qui ne sont plus financées et tout un savoir-faire et une expertise qui sont en train de se perdre.

Ils finiront par comprendre qu’il n’y a pas de recherche appliquée mais uniquement des applications de la recherche.

Ils finiront par comprendre que l’excellence est l’objectif à atteindre, pas le critère pour sélectionner.

 

 

Ils finiront par comprendre tout cela mais il est déjà bien trop tard.

#Classicpaper

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Recently I started a Twitter thread highlighting a couple of seminal discoveries in molecular biology going back in the 40’s 50’s #classicpaper. I received many positive feedback and the thread was quite popular. I am of course very pleased but this was also quite unexpected. Unexpected because it’s classic textbook knowledge really, unexpected (but again a pleasant surprise) because I wrongly thought apparently that nobody anymore read old scientific papers.

I certainly did not read all these papers when I was a student but as I am getting older, I have a growing interest in the history of science. The birth of molecular biology is a fascinating golden period from the revelation of the double helix of DNA to the cracking of the genetic code and first glimpses of gene regulation. This thread was inspired by reading ‘She has her mother’s laugh’ by Carl Zimmer, ‘Life’s greatest secret’ by Matthew Cobb, ‘The eighth day of creation’ by Horace Judson, ‘Brave genius’ by Sean B Carroll and ‘Histoire de la Biologie Moléculaire’ by Michel Morange (that is going to be translated in English by Matthew Cobb).

I strongly encourage students to read these books and these seminal papers (unfortunately many of these seminal papers are still under paywall but you know what to do*). Again, this golden age of creative thought and hypothesis-driven research is such an inspiration. The strategies and methodologies created from scratch for almost each experiments, the concepts developed that are still true and central to modern biology, pure joy. As I sometimes said, if time travel was possible I would love to have lived in the 50’s-60’s to witness the birth of Molecular Biology and meet all these fantastic scientists.

 

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1⃣ 1944 Oswald Avery, Colin MacLeod & Maclyn McCarty – DNA, not protein as was commonly believed, is the hereditary material for bacteria, and the cause of bacterial transformation.

2⃣ 1947 André Boivin & Roger Vendrely – a near forgotten 2 pages in French that suggest almost explicitly that DNA –> RNA –> protein.

3⃣ 1952 & 1953 Alexander Dounce – like Boivin & Vendrely, Dounce is one of the first to propose that DNA might serve as a template for the synthesis of RNA, which in turn serves as a template for the synthesis of proteins.

4⃣ 1952 Alfred Hershey & Martha Chase – They confirmed that DNA was the molecule of heredity a.k.a as the blender experiment. (However as Matthew Cobb told me, After the experiment, after the double helix, Hershey still thought protein played a role. See this recount for example).

5⃣ 1953 The structure of DNA – Watson & Crick, Franklin & Gosling, Wilkins Stokes Wilson.

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6⃣ 1956 & 1958 Francis Crick – The Central Dogma: once ‘information’ is passed into protein it cannot get out again.

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7⃣ To read a clear explanation of the 2 unrelated hypotheses ‘The Central Dogma’ and ‘DNA -> RNA -> Proteins’, have a look at Dan Graur blog post.

8⃣ 1958 Francis Crick – The adaptor hypothesis (in On protein Synthesis): to explain how information encoded in DNA is used to specify the amino acid sequence of proteins.

9⃣ 1958 Mahlon Hoagland – Discovery of the adaptors = soluble RNAs a.k.a. tRNA.

1⃣0⃣ 1957 Vernon Ingram – The first demonstration that the abnormal haemoglobin in sickle cell anaemia patients is caused by an alteration in one amino acid.

1⃣1⃣ 1958 Matthew Meselson and Franklin W. Stahl – experimental proof of Semi-Conservative DNA replication.

1⃣2⃣ 1959 Pardee, Jacob & Monod – The PaJaMo experiment that supported the hypothesis that a molecule mediated the production of proteins from DNA (cytoplasmic messenger).

1⃣3⃣ 1961 Jacob & Monod – The fundamental basis of gene regulation, one of the most influential paper in the history of modern biology (& I am not saying that because Jacob & Monod were French).  And yes RNA was already proposed by Jacob and Monod in 1961 to control the operon.

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1⃣4⃣ 1961 Brenner, Jacob, Meselson Gros, Hiatt, Gilbert, Kurland, Risebrough, Watson The discovery of messenger RNA (mRNA).

1⃣5⃣ For an historical point of view of the discovery of mRNA, see also this great recount by Matthew Cobb.

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1⃣6⃣ 1961 Marshall W. Nirenberg & J. Heinrich Matthaei – A poly-U RNA was translated into polyphenylalanine in a cell-free system. This experiment provided the initial clue to breaking the genetic code. See also the didicated NIH web site.

1⃣6⃣ bis 1965 Marshall W. Nirenberg Philip Leder – The template activities of 26 additional trinucleotides are described in this paper. (source image)

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1⃣7⃣ 1961 Crick, Barnett, Brenner & Watts-Tobin – The existing knowledge in 1961 & the experimental procedures were certainly not sufficient to allow anyone to deduce the general nature of the genetic code but they nearly solved the riddle.

1⃣8⃣ 1965 Margarita Salas – The first experimental results indicating that the direction of reading of the genetic message is from the 5’ to the 3’ end  (see also My scientific life by Margarita Salas in 2016).

1⃣9⃣ 1964 K. Marcker & F. Sanger and 1966 B. F. C. Clark & K. A. Marcker  – A role for methionine in polypeptide chain initiation.

2⃣0⃣ 1966 Francis Crick – The Wobble hypothesis. A visionary Crick again explains why multiple codons can code for a single amino acid.

2⃣1⃣ 1967 Brenner – The last of the 64-Triplet Genetic Code is cracked.

2⃣1⃣ bis 1964 Allfrey Faulkner Mirsky –  Acetylation & methylation of histones & their possible role in the regulation of RNA synthesis.

2⃣2⃣ 1969 Britten & Davidson – Like the Monod & Jacob paper in 1961, a very influential paper on gene regulation. Their theory stated the hypothesis that repetitive non-coding sequences are at the core of genetic regulation.

2⃣3⃣ 1968 Karin Ippen-Ihler – Studies using the lac operon identified the promoter as a cis controlling element for gene transcription.

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(source image)

2⃣4⃣ 1969 Bob Roeder & William J. Rutter – the discovery of 3 chromatographically separable forms of eukaryotic RNA polymerase from sea urchin embryos (I, II and III).

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(Source image)

2⃣5⃣ 1970 Kedinger, Gniazdowski, Mandel, Gissinger & Chambon – Pierre Chambon also isolated 2 activities from calf thymus, Pol A (Pol I) & Pol B (Pol II), of which only Pol B was inhibited by the Amanita toxin α-amanitin.

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2⃣6⃣ 1974 Roger Kornberg – The organizing principle of the nucleosome, a histone octamer, and its mode of interaction with DNA. Here and here.

2⃣7⃣ 1975 P. Oudet, M. Gross-Bellard, & P. Chambon – The first electron microscopy of reconstituted histone–DNA complexes a.k.a. beads on a string.

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2⃣8⃣ 1977 several papers reporting the discovery of interrupted ‘split’ genes a.k.a introns. Berget Sharp, Chow, Breathnach Chambon, Klessig, Dunn Hassell, Lewis.

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2⃣9⃣ 1980 Corden Chambon – One of the first comparisons of promoter sequences from efficiently transcribed protein-coding genes.

3⃣0⃣ 1981 Julian Banerji Sandro Rusconi & Walter Schaffner – Discovery of enhancers (see also this historical perspective by Walter Schaffner).

 

See also Cell Annotated Classics, PNAS Classics, Nature Milestones in gene expression,

 

 

* If you really don’t know what to do, click here.

Unfinished project

 

I am often wondering how others are dealing with their unpublished data. Do you have a drawer full of unfinished projects which will never see the light of day? There are a number of drivers that may cause projects to be stopped before completion: Unfunded, priorities changes, data are not worth the additional energy to convert them into a publication, wrong hypothesis,……

 

Here is the story of a project I have abandoned.

 

When I came back in France after my post-doc (a long time ago), one of my project seeks to define the role of sumoylation (an ubiquitin-related post-translational modification) in controlling the functional properties of proteins focusing on the possible structural and dynamic consequences of this modification. Did sumoylation act as structurally independent docking module rather than through the induction of a conformational change in the modified protein?

One obvious target, at least for me, was the transcriptional co-repressor CtBP. It was my post-doc favorite protein and CtBP was known to be sumoylated (ref 1) within its unstructured C-terminal domain (ref 2).

To promote the recombinant expression of SUMOylated proteins in bacteria, we decided to transfer the complete set of enzymes essential for this post translational modification (E1 and E2 enzymes + SUMO-1) to E. coli based on previous work (ref 3). Separating the sumoylated protein from the undesired unmodified fraction (you seldom obtain 100% modification) is often technically challenging so we decided to introduce a 6xHis tag SUMO-1 (ref 4). This strategy did work for IĸBα (ref 4) but I have never been able to optimize the protocol for CtBP. We did obtain roughly 50% of modified and 50% of unmodified CtBP (see the figure below) but because CtBP dimerizes/multimerizes, the separation of the modified from the unmodified substrate in this case was unsuccessful (a single peak in gel filtration).

CTBPS1

 

As the saying goes, every cloud has a silver lining. At the time, I was very positive thinking that the structural study was still possible and even more exciting if I could obtain the structure of a CtBP dimer, one unmodified monomer and one modified monomer. Ah, the foolishness of youth.

 

Frustration, Frustration

So it was time to set up crystallization screenings and we did obtain some exciting crystal ‘hits’. In crystallography, salt crystal is frustration, crystal optimization is frustration, and no diffraction is frustration. CtBP may have a high degree of structural instability in its C-terminus, one modified and one unmodified monomer may lead to sample heterogeneity, whatever but unfortunately NO diffraction. So after a couple of tries (additives, drop ratios, other conditions), I have finally abandoned this project.

affinage ctbp1 E

Maybe I did not try hard enough, maybe one day someone will solve the structure of sumoylated CtBP or maybe one day, I will try again.

Eventually they will understand

Eventually they will understand

 

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Eventually they will understand that there are no such things as applied science, only applications of science (Louis Pasteur).

 

Eventually they will understand that it takes 15-20 years for basic research evidence to reach clinical practice.

 

Eventually they will understand that it is impossible to predict what questions will actually find practical applications in the future.

 

Eventually they will understand that spending on Basic research now provides the raw material for the next generation of technological advances that fuel our economic growth.

 

Eventually they will understand that Basic research is the pacemaker of technological progress.

 

Eventually they will understand that Science is a public good.

 

Eventually they will understand that the power of CRISPR Cas9 –based genome editing is something nobody could have predicted at the outset.

 

Eventually they will understand that without more than 30 years of research about gene expression, Transcription factor-based cellular reprogramming would have never opened the way to converting somatic cells to a pluripotent state.

 

Eventually they will understand that accidental discoveries continue to flourish in basic research with direct consequences for everyday life.

 

Eventually they will understand that human curiosity, creativity and inquisitiveness are the driving forces behind basic research.

 

Eventually they will understand that excellence should be the goal of funding, not a barrier to it (Mike Galsworthy).

 

Eventually they will understand that if you can accurately predict outcome, what you are doing is not research, it is development (Jim Woodgett).

 

Eventually they will understand that with funding rate for NSF/NIH/NHMRC/CIHR/ANR/…. less than 15%, very talented junior scientists will be leaving research.

 

Eventually they will understand that with funding rate for NSF/NIH/NHMRC/CIHR/ANR/…. less than 15%, basic research will suffer from the loss of knowledge and expertise.

 

 

Eventually they will understand but it is already too late.

 

A scientist’s account to Twitter

Some of my colleagues often asked me what I am doing on Twitter. Below are some of my answers.

Twitter, the micro-blogging platform may be viewed as fascinating for some people but also frightening and boring for others. It is certainly a controversial subject. But Twitter is a diamond in the rough for the scientific community: keeping up with current research in real time, follow conferences, improve your professional network, bibliography search,…

This post does not aim to be a scientist’s guide to social media in general and to Twitter in particular. The objective is simply to share my experiences as a scientist in social media. As Zen Faulkes (@DoctorZen) quite rightly stated here : ‘Everything that happens on social media has been happening at conference for as long as there have been conference (informal conversations). Social media is just the biggest research conference in the world’.

(click to enlarge the images)

 

1- A bibliography search tool

1a- Scientific journals twitter accounts. Forget Pubmed, RSS feed or eTOCs. Just follow your favorite journal on Twitter. So far, I have a list of 291 journals.

 

suivre journaux

1b- Keeping up using Twitterbots. An increasing number of people are exploring the use of twitterbots for more productive academic purposes (for more info see here a great explanation by @caseybergman). For example, I have a list of domain-specific literature bots here.

twitterbot

1c- The keyword search. Twitter has of course a search engine. Simply use keyword search as you would search Google or Pubmed. Below is an example with ‘CRISPR’.

recherche mot clé

1d- Sharing information. Twitter is particularly well suited to sharing information from your own scientific readings. A classical tool in your Twitter belt is the ability to share a link (and a photo) to the article.

parler de ses coups de coeur

1e- #icanhazpdf. The famous hashtag used to coordinate the exchange of scholarly papers. Suppose that you need a certain journal article but do not have a subscription to the journal. Anyone who notices checks to see if they have access, such as via their university’s institutional subscriptions, and if they do, they download the article and send it to you.

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2- To keep you updated and engaged

2a- Outreach from scientific conferences. Looking for a forthcoming conference? Many scientific societies that organized academic conferences are on twitter: CSHL meetings, Keystone Symposia, Cell Symposia. 2014 saw the increased interaction with many conference twitter accounts with delegates actively tweeting about the meetings. For example with the Annual scientific meeting of the Australian diabetes society @ADS ADEA.

 

info congrès

 

2a-bis Conference live-tweeting. Twitter lends itself particularly well to sharing information from a conference and live-tweeting is a growing trend. Live-tweeting is simply when twitter users tweet key points from presentations that they attend at conferences. Just follow the hashtag for the conference.

conference à distance

2b- Funding opportunities and notices. Many funding opportunities can be found on Twitter.

nih fundings

2c- Pharma and biotech companies. Find company information such as new products, promotional items.

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2d- Career opportunities. Many principal investigators do advertises their PhD and postdoctoral positions on Twitter.

 

offre these post doc

 

3- Help, share, discuss

3a- Lauching a new topic. Do you have a particular question ? Is there any specific topic you would like to discuss ? Twitter is the place to be for the scientific community.

 

discuter

3b- Direct contact. Do you have a particular question for a biotech company ? Ask directly your question via Twitter. Communication is faster than ever.

 

contact direct avec des sociétes

3c- Promoting your research. Publicise yourself, promote and present your work, your papers, your blog. Twitter is as a global science communication tool.

  selfpromotion

 

3d- Networking. Having real-time scientific discussions from your bedroom with people across the world, conversations that you would not necessarily have otherwise, expending your network.

 

se creer un reseau

 

4- Further reading

Online collaboration : scientists and the social network (link) by Richard Van Noorden (@Richvn)

Burning platforms: friending social media’s role in #scicomm (link) by Jim Woodgett (@jwoodgett)

10 simple rules of live tweeting at scientific conferences (link) by Ethan O. Perlstein (@eperlste)

Science and social media: some academics still don’t ‘get it’ (link) by Kirk Englehardt (@kirkenglehardt)

 Social media : a network boost (link) by Monya Baker (@Monya_science)

My Twitter achievements (link) by Sylvain Deville (@DevilleSy)