Author: Raphaël Lévy

Lettre d’Angleterre: Souveraineté

English version below.

Le Front National veut soi-disant redonner à la France sa souveraineté en la sortant de l’Union Européenne. Aux oreilles d’un résidant en Angleterre, ce discours est familier : c’est celui, répété ad nauseam par Leave.eu et les supporters du Brexit : reprenons le contrôle de nos lois et de nos frontières (‘Take back control’). C’est aussi une illusion. Pour deux raisons.

La première raison est que le parlement du Royaume-Uni était souverain. Ce n’est pas moi qui le dis mais le livre blanc produit par le gouvernement de Theresa May lui-même : « La souveraineté du Parlement est un principe fondamental du Royaume-Uni. Bien que le Parlement soit resté souverain durant toute la période où nous avons été membre de l’Union Européenne, on n’en pas toujours eu le sentiment. »

La deuxième raison, peut-être contre-intuitive, est que, au-delà de la souveraineté du processus législatif, la capacité du Royaume-Uni à prendre en main son destin de manière indépendante est mise à mal de manière spectaculaire par le Brexit. Son gouvernement, isolé, sera encore moins capable de résister aux lobbys, comme l’explique admirablement… Rupert Murdoch répondant à la question pourquoi êtes-vous tellement opposé à l’Union Européenne : « c’est facile, quand je vais au 10 Downing Street, ils font ce que je leur demande, quand je vais à Bruxelles, ils m’ignorent complètement. »  On voit mal un Royaume-Uni isolé faire face à Microsoft, Google ou Apple. De plus, quittant le marché commun, le Royaume-Uni doit négocier des accords bilatéraux avec d’autres pays, et, ces pays, vont imposer leurs conditions, d’autant plus qu’il est clair que le Royaume-Uni est en position de faiblesse. Theresa May a choisi d’aller en Inde pour l’un de ses premiers voyages après le referendum. L’Inde insiste que tout accord économique devra s’accompagner d’un assouplissement des règles d’immigration et de visa. Theresa May devra donc choisir entre le contrôle de l’immigration (‘Take back control’) et un accord commercial avec l’Inde. Chaque pays (y compris ceux de l’Union Européenne) aura ses propres demandes auxquelles le Royaume-Uni devra bien souvent se soumettre.

Le Brexit est un abandon de souveraineté.

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The National Front is pretending that it will give France its sovereignty back from Brussels. To my ears, this is familiar discourse: it is the one peddled ad nauseam by Leave.eu and other Brexit supporters: Take back control (of laws, borders). It is an illusion. For two reasons.

The first reason is that the UK Parliament was sovereign. Not my word, but the white paper produced by the government of Theresa May herself: “The sovereignty of Parliament is a fundamental principle of the UK constitution. Whilst Parliament has remained sovereign throughout our membership of the EU, it has not always felt like that.

The second reason, maybe counter-intuitive, is that, beyond the sovereignty of the legislative process, the UK capacity to shape its own destiny is badly damaged by Brexit. Its government, isolated, will be even less able to resist pressures from lobbies, as explained transparently by…  Rupert Murdoch, who, replying to the question of why he was so opposed to the European Union, replied. ”That’s easy, when I go into Downing Street they do what I say; when I go to Brussels they take no notice.’ It is hard to imagine the UK, isolated, courageously facing Microsoft, Google ou Apple. Furthermore, leaving the common market, the UK must negotiate new bilateral agreement with third countries, and, these countries will impose their conditions, especially since it is clear the UK is in a weak position. Theresa May chose to go to India for one of her first travel after the referendum. India insists that any agreement will need to include a softening of immigration and visa rules. Theresa May will therefore need to choose between control of immigration (‘Take back control’) and a commercial agreement with India. Each country (including those of the EU will have their own demands to which the UK will often need to submit.

Brexit is a loss of sovereignty.

Lettre d’Angleterre

J’ai cru que la doctrine et l’histoire d’un peuple si extraordinaire méritaient la curiosité d’un homme raisonnable.

Voltaire, 1734, Lettre d’Angleterre.

Je ne suis certes pas Voltaire, mais, peut-être puis-je prétendre être un homme raisonnable?

J’habite Liverpool depuis 15 ans. Les événements politiques en Angleterre durant les 12 derniers mois sont extraordinaire, et, particulièrement important à considérer à trois jours du premier tour de l’élection présidentielle française.

Ce qui se passe ici, c’est une dislocation de la société, travaillée par les mensonges et la haine. Avec la légitimation toujours plus grande d’un discours qui fait appel à « la volonté du peuple » pour « écraser les saboteurs » . Un discours violent qui rejette toute discussion rationnelle et informée, au profit d’un tribalisme viscéral, émotionnel et souvent xénophobe.

C’est pourquoi je tremble lorsque j’entends ce même appel au peuple, « le gros animal, un monstre qui ne connaît ni la vertu ni la raison » (Philippe Val/Socrate) chez deux candidats qui peuvent se qualifier pour le second tour (Au-Nom-Du-Peuple-LePen et La-Force-du-Peuple-Mélenchon): je suis affolé.

Ces deux candidats qui ont des amitiés particulières pour divers dictateurs.

Ces deux candidats qui partagent la volonté explicite ou implicite de détruire l’Europe et ses institutions. L’Europe qui a contribué énormément à la prospérité retrouvée de cette belle ville de Liverpool et de beaucoup d’autres régions défavorisées sur le continent. L’Europe qui a garanti la paix pendant les derniers 70 ans (un ex-dirigeant du parti conservateur a proféré des menaces de guerre contre l’Espagne à propos de Gibraltar. En Avril 2017). L’Europe qui, seule, nous donne une voix suffisamment forte pour défendre nos principes démocratiques, parler d’égal à égal avec les autres grandes puissances, qu’elles soient des états ou des multinationales, et, affronter le défi majeur du changement climatique.

L’enjeu ne pourrait être plus grand.

SmartFlare controversy: independent confirmation of endosomal localization

Check this previous post for a quick summary of the SmartFlare controversy, or read all SmartFlare-related posts if you are really passionate.

At the centre of the SmartFlare controversy is the rather simple question, from an experimental point of view, of how many Spherical Nucleic Acids (to use Chad Mirkin’s terminology), if any, escape the endosomal pathway.

In contradiction with Chad Mirkin’s many peer reviewed articles and EMD Millipore marketing material, we concluded (Mason et al, 2016) that the Spherical Nucleic Acids do not escape endosomes and do not detect cytosolic mRNAs.

A few days ago, Sven Budik et al, an Austrian group published their evaluation of the SmartFlare in the context of equine embryo development. They write: “In all positive cells,
regardless of whether they occurred in equine conceptus, trophoblastic vesicle or fibroblast cell culture, the fluorescence signal showed a spotted pattern that is in accordance with the observations of Mason et al. (2016).

They also used electron microscopy to look at the intracellular localization of the particles. Here is the relevant part of their discussion and conclusion (emphasis mine):

The present study indicates that the intracellular process of nanogold particle uptake is endocytic and endosomal with a lysosomal sorting after longer incubation periods. This finding is in agreement with results from HeLa cells in vitro (Gilleron et al. 2013). Similarly, nanoparticles injected intravenously were taken up by endocytosis and later
clustered in lysosomes primarily in macrophages (Sadauskas et al. 2007). The incorporation time of lipid nanoparticlecontaining short interfering RNA gold particles in HeLa cells was similar (Gilleron et al. 2013) to that demonstrated in equine trophoblast vesicles in the present study. Accumulation of SmartFlare probes in residual bodies may be a consequence of increased stability of the immobilised oligonucleotides adjacent to the nanogold particles due to enhanced nuclease resistance (Rosi et al. 2006). In accordance with the results of Mason et al. (2016), we observed no or very few nanogold particles free in the cytoplasm, confirming a primarily endosomal and lysosomal localisation.

This observation raises the question how a specific SmartFlare probe is able to detect its target mRNA located in the cytoplasm. One possible explanation for the generation of lysosome-located specific fluorescence signals by SmartFlare probes could be the existence of specific RNA sequences imported for subsequent degradation into lysosomes (Fujiwara et al. 2013). Further studies using qRT-PCR investigating the isolated lysosomal fraction before and after incubation with specific SmartFlare probes are necessary to confirm this hypothesis. An 18S RNA nano-flare probe had a dose-dependent cytotoxic effect on porcine fetal fibroblasts (Fu et al. 2016). In contrast, no cytotoxic effects or changes in morphology after incorporation of antisense oligonucleotide nanogold particles in a mouse endothelial cell line were observed by Rosi et al. (2006). In addition, in the present study, there was no evidence that incubation with the SmartFlare probes had a toxic effect on the equine cells tested, even at higher concentrations. This is in accordance with the results of Pan et al. (2009) demonstrating that 15-nm gold particles have only low cytotoxic effects compared with the detrimental effects of small 1.4-nm gold particles.

In conclusion, SmartFlare probes pass into early equine conceptuses at stages used for embryo transfer, as well as trophoblast vesicles and cells cultured in vitro. In these early ZP equine conceptuses, the time frame (.5 and ,24 h) for SmartFlare uptake would be suitable for practical applications in commercial embryo transfer programs. Therefore, these probes are suggested to be applicable to pre-implantation genetic diagnosis before transfer of these conceptuses to the recipient.

In summary, the authors’ results are entirely consistent with our observations. They conclude, quite reasonably, that if SmartFlares detect mRNAs whilst being in endosomes, they cannot directly detect cytosolic mRNAs. This is in direct contradiction with Mirkin et al and EMD Millipore. Then, they propose that if the SmartFlares work, they maybe detect mRNAs which are in endosomes. This an interesting hypothesis that will require further study and is very different from anything published by Mirkin and EMD Millipore (the relevant reference is here). Since Budik et al do not provide any evidence that the SmartFlares actually detect mRNAs in the first place, maybe a simpler explanation is that the SmartFlares signal is unspecific and result from the probe degradation by nucleases in endosomes.

Thoughts on #LiveTweeting

Dave Mason on why you should be live-tweeting at conferences

Blog and Log

As a part of the Centre for Cell Imaging and a member of the Microscopy and BioImage Analysis community, I occasionally get away to conferences like the recent NEUBIAS training school and symposium in Portugal.

vessels_neubias_banner

Since having joined Twitter last year (@dn_mason), this is the second conference that I’ve been to, and as a result, was the second time I tried (with reasonable success) to Live Tweet at the conference.

Live What Now?

Going right back to basics, Twitter is a platform for broadcasting small messages (of ~140 characters). Some describe it as micro-blogging. To many, the brevity of each tweet is both it’s greatest strength and also one of the most frustrating features.

Live tweeting, is basically the act of providing a running commentary of a seminar, event or even a whole conference. All of the tweets associated with such an event can be tied together using…

View original post 1,117 more words

Publication bias. Grant bias.

All academics writing grants will tell you this: if you want to be successful when applying to a thematic research grant call, you must tick all of the boxes.

Now, imagine that you are a physicist, expert in quantum mechanics. A major funding opportunity arises, exactly matching your interest and track record. That is great news. Obviously you will apply. One difficulty however is that, amongst other things, the call specifies that your project should lead to the “development of highly sensitive approaches enabling the simultaneous determination of the exact position and momentum of a particle“.

At that point, you have three options. The first one is to write a super sexy proposal that somehow ignores the Heisenberg principle. The second option is to write a proposal that addresses the other priorities, but fudges around that particular specification, maybe even alluding to the Heisenberg principle. The third option is to renounce.

The first option is dishonest. The second option is more honest, but, in effect, is not so different from the third: your project is unlikely to get funded if you do not stick to the requirements of the call, as noted above. The third option demonstrates integrity but won’t help you with your career, nor, more importantly with doing any research at all.

And so, you have it. Thematic grant calls that ask for impossible achievements, nourished by publication bias and hype, further contribute to distortion of science.

OK, I’ll confess: I have had a major grant rejected. It was a beautiful EU project (whether BREXIT is partly to blame I do not know). It was not about quantum mechanics but about cell tracking. The call asked for simultaneous “detection of single cells and cell morphologies” and “non-invasive whole body monitoring (magnetic, optical) in large animals” which is just about as impossible as breaking the Heisenberg principle, albeit for less fundamental reasons. We went for option 2. We had a super strong team.

How to Characterize Gold Nanoparticles’ Surface?

Guest post by Elena Colangelo

Our Topical Review on the characterization of gold nanoparticles (GNPs) has just been published in the Bionconjugate Chemistry Special Issue “Interfacing Inorganic Nanoparticles with Biology”.

The literature is abounding in works on GNPs for applications in biology, catalysis and sensing, among others. GNPs’ appeal resides in their optical properties, together with the well-developed methods of synthesis available and the possibility of functionalizing their surface with small molecules of interest, which can readily self-assemble on the GNPs’ surface forming a monolayer.

However, allegedly the structure and organization of self-assembled monolayers (SAMs) at the GNPs’ surface are in fact aspects too often neglected [though surely not on this blog; RL]. Such elucidation is challenging experimentally, but it is crucial not only to ensure reproducibility, but also to design nanosystems with defined (bio)physicochemical and structural properties, which could then be envisioned to assemble in more complex systems from a “bottom-up” approach.

Our Topical Review gives an overview of the current knowledge and methods available to characterize the GNPs’ surface with different molecular details.

capture

Cartoon illustrating the different levels of GNPs’ surface characterization discussed in the Topical Review.

First, the experimental methods commonly used to provide the basic characterization of functionalized GNPs, such as identification and quantification of the ligands within the monolayer, are detailed with the aid of some examples.

Second, the experimental methods providing information on the monolayer thickness and compactness are reviewed.

Third, considering that the SAM’s thickness and compactness do not only depend on the amount of ligands within the monolayer, but also on their conformation, the experimental methods that can provide such insights are recapitulated. However, we also stressed on the limitations intrinsic to these methods and on the challenges associated to the determination of the structure of SAMs on GNPs.

Fourth, we summarized some of the approaches used to give insights into the organization of different ligands within a SAM. Indeed, mixed SAMs on GNPs are useful since they can impart to the nanoparticles different functionalities and offer a way to tune their stability.

Fifth, highlighting again the limited insights into the SAM’s structure and organization that can be gathered with experimental techniques, we detailed some examples where a combination of experimental and computational approaches was able to provide a compelling description of the system and to assess molecular details that could not have been revealed experimentally.

Overall, this Topical Review gives emphasis on the importance of GNPs’ surface characterization and on fact that even though a number of experimental techniques are available, they are intrinsically limited and they cannot provide a fully detailed picture. Hence, it is advantageous to combine experimental and theoretical approaches to design nanoparticles with desired (bio)physicochemical properties [such as, e.g., our paper under review, currently available as a preprint; RL].

Time to reclaim the values of science

This post is dedicated to Paul Picard, my grand dad, who was the oldest reader of my blog. He was 17 (and Jewish) in 1939 so he did not get the chance to go to University. He passed away on the first of October 2016. More on his life here (in French) and some of his paintings (and several that he inspired to his grandchildren and great-grandchildren). The header of my blog is from a painting he did for me

A few recent events of vastly different importance eventually triggered this post.

A  (non-scientist) friend asked my expert opinion about a campaign by a French environmental NGO seeking to  raise money to challenge the use of nanoparticles such as E171 in foods. E171 receives episodic alarmist coverage, some of which were debunked by Andrew Maynard in 2014. The present campaign key dramatic science quote “avec le dioxyde de titane, on se retrouve dans la même situation qu’avec l’amiante il y a 40 ans {with titanium dioxide, we are in the same situation than we were with asbestos 40 years ago}” is from Professor Jürg Tschopp. It comes from an old media interview (2011, RTS) that followed a publication in PNAS. We cannot ask Professor Tschopp what he thinks of the use of this 5 years old quote: unfortunately he died shortly after the PNAS publication. The interpretation of this article has been questioned since: it seems likely that the observed toxicity was due to endotoxin contamination rather than the nanomaterials themselves. There is on the topic of nanoparticles a high level of misinformation and fear that finds its origins (in part) in how the scientific enterprise is run today. Incentives are to publish dramatic results in high impact factor journals which lead many scientists to vastly exaggerate both the risks and the potential of their nanomaterials of choice. The result is that we build myths instead of solid reproducible foundations, we spread disproportionate fears and hopes instead of sharing questions and knowledge. When it comes to E171 additives in foods, the consequences of basing decisions on flawed evidence are limited. After all, even if the campaign is successful, it will only result in M&M’s not being quite as shiny.

I have been worried for some time that the crisis of the scientific enterprise illustrated by this anecdote may affect the confidence of the public in science. In a way, it should; the problems are real, lead to a waste of public money, and, they slow down progress. In another way, technological (including healthcare) progress based on scientific findings has been phenomenal and there are so many critical issues where expertise and evidence are needed to face pressing humanities’ problems that such a loss of confidence would have grave detrimental effects. Last week, in the Spectator, Donna Laframboise published an article entitled “How many scientific papers just aren’t true? Enough that basing government policy on ‘peer-reviewed studies’ isn’t all it’s cracked up to be“. The article starts by a rather typical and justified critique of peer review, citing (peer-reviewed) evidence, and then, moves swiftly to climate change seeking to undermine the enormous solid body of work on man-made climate change. It just happens that Donna Laframboise is working for “a think-tank that has become the UK’s most prominent source of climate-change denial“.

One of the Brexit leaders famously declared that “people in this country have had enough of experts”. A conservative MP declared on Twitter that he”Personally, never thought of academics as ‘experts’. No experience of the real world. Yesterday, Donald Trump, a climate change denier was elected president of the USA: “The stakes for the United States, and the world, are enormous” (Michael Greshko writing for the National Geographic). These are attacks not just on experts, but on knowledge itself, and, the attacks extends to other values dear to science and encapsulated in the “Principle of the Universality of Science“:

Implementation of the Principle of the Universality of Science is fundamental to scientific progress. This Principle embodies freedom of movement, association, expression and communication for scientists, as well as equitable access to data, information and research materials. These freedoms are highly valued by the scientific community and generally well accepted by governments and policy makers. Hence, scientists are normally able to travel to international meetings, associate with colleagues and freely express their opinions regardless of factors such as ethnic origin, religion, citizenship, language, political stance, gender, sex or age. However, this is not always the case and so it is important to have mechanisms in place at the local, national and international levels to monitor compliance with this principle and intervene when breaches occur. The International Council for Science (ICSU) and its global network of Members provide one such mechanism to which individual scientists can turn for assistance. The Principle of the Universality of Science focuses on scientific rights and freedoms but implicit in these are a number of responsibilities. Individual scientists have a responsibility to conduct their work with honesty, integrity, openness and respect, and a collective responsibility to maximize the benefit and minimize the misuse of science for society as a whole. Balancing freedoms and responsibilities is not always a straightforward process. For example, openness and sharing of data and materials may be in conflict with a scientist’s desire to maintain a competitive edge or an employer’s requirements for protecting intellectual property. In some situations, for example during wars, or in specific areas of research, such as development of global surveillance technologies, the appropriate balance between freedoms and responsibilities can be extremely difficult to define and maintain. The benefits of science for human well-being and development are widely accepted. The increased average human lifespan in most parts of the world over the past century can be attributed, more or less directly, to scientific progress. At the same time, it has to be acknowledged that technologies arising from science can inadvertently have adverse effects on people and the environment. Moreover, the deliberate misuse of science can potentially have catastrophic effects. There is an increasing recognition by the scientific community that it needs to more fully engage societal stakeholders in explaining, developing and implementing research agendas. A central aspect of ensuring the freedoms of scientists and the longer term future of science is not only conducting science responsibly but being able to publicly demonstrate that science is being conducted responsibly. Individual scientists, their associated institutions, employers, funders and representative bodies, such as ICSU, have a shared role in both protecting the freedoms and propagating the responsibilities of scientists. This is a role that needs to be explicitly acknowledged and embraced. It is likely to be an increasingly demanding role in the future.

It is urgent that we, scientists, reclaim these values of humanity, integrity and openness and make them central (and visibly so) in our Universities. To ensure this transformation occurs, we must act individually and as groups so that scientists are evaluated on their application of these principles. The absurd publication system where we (the taxpayer) pay millions of £$€ to commercial publishers to share hide results that we (scientists) have acquired, evaluated and edited must end. There are some very encouraging and inspiring open science moves coming from the EU which aim explicitely at making “research more open, global, collaborative, creative and closer to society“. We must embrace and amplify these moves in our Universities. And, as many, e.g. @sazzels19 and @Stephen_curry have said, now more than ever, we need to do public engagement work, not with an advertising aim, but with a truly humanist agenda of encouraging curiosity, critical thinking, debates around technological progress and the wonders of the world.