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A personal announcement

The text below was first published yesterday as a Twitter thread yesterday.

Attentive followers might have picked a few hints. Time for a personal announcement. Thread.

I am leaving the University of Liverpool at the end of this month, starting as professor of physics at the University Sorbonne Paris Nord, joining @cspbat, a laboratory that is at the interface between chemistry/physics/biology.

It will be a deep dive – it comes with many personal and professional opportunities as well as serious challenges. I’ll document some of those as I go along, e.g. regarding the differences between research and teaching in France versus the UK… watch this space over the coming months if you are interested.

I am, and will remain, a French Scouser. I have lived in Liverpool for 18 years. I love the city, the culture, the parks, and the people. This very special place is where my children have been growing up, where two were born, where we have deep and decade-long friendships. My family home will still be there for some time.

The UK, its Research Councils and the University of Liverpool gave me wonderful opportunities and a top research environment. I have built my research career and international profile thanks to their support, thanks to my academic colleagues, and thanks to the PhD students and post-doctoral researchers who worked with me.

This supportive environment included protecting my academic freedom as I was engaging in scientific controversies, and more recently, as I joined Patricia Murray in her investigations of various scandals related to stem cells and trachea transplants. I know that in many other places I would have been silenced or fired. Thank you. 

So, why am I leaving? Well, Brexit of course. I started surveying opportunities for jobs elsewhere after this fateful day of June 2016. But I did not do just that. I did not just resign myself to leaving a sinking ship.

With others, I founded @Liverpool4EU. I made new friends who like me refused to accept the disintegration of the UK and the undermining of democracy by liars, demagogues, ideologues and charlatans. Friends who were prepared to campaign for values of international solidarity and cooperation. I know they will continue the fight. Join them.

I love the UK but these four years hurt. There is the initial slap in the face and then there are the echoes, too numerous to count, from Theresa May queue jumpers to the current PM awful nationalist rhetoric.

I love Liverpool but the past two years hurt. This is the city that believes it is a beacon of antiracism but bullied 2 Jewish MPs out the Labour Party without its political leaders batting an eyelid. The city who elected, with ridiculously high percentages, MPs who could not even bring themselves to sign a declaration against antisemitism.

I am not naïve. At least I don’t think so. I know that racism and discrimination existed before Brexit. That they exist in France too. That the social and political trends that led to Brexit are a danger in France too. That higher education in France is no paradise.

I thank the USPN and CSPBAT for offering me this professorship. As a citizen, teacher and scientist I hope to be happier and more useful in France.

PS: this is what I wrote on the eve of the vote in 2016) “Come on England

Kostas Kostarelos reponds to my comments re the Nanoscale nights of Covid-19

I wrote a short Twitter thread on Kostas’ Nature Nanotechnology article “the Nanoscale nights of Covid-19“.

He has kindly responded by email and has allowed me to reproduce it here. As usual, the comments box welcomes further discussion.

(((me))):- But, to the question, “where have all the nanoscientists gone?”, my answer would be markedly different. They have gone home to save lives, including those of “our clinical and healthcare colleagues, who work on the frontline of the pandemic”. Right and proper.

Kostas:- If the ‘cancer model’ of early detection, monitoring and targeting (not only in treatment and confinement but ALSO targeted protection) was taking place early on (as some countries attempted to do) the biomedical scientists SHOULD have been mobilised to creatively contribute against this biological outbreak immediately, instead of being locked in at home asked to binge-watch Netflix.

(((me))):- It may be hard to hear that we, “highly trained etc” are non essential whilst people working in our local supermarket are essential. But it is nevertheless a fact.

Kostas:- It is not about being ‘highly trained’, ‘more valuable’, or ‘highly educated’ at all. It is about mobilising your resources to find solutions. If politicians were thinking clearly, free from political manipulations and weightings of voter swings, and the system was properly prepared, we should not have construction workers and nail parlours considered more ‘essential’ than biomedical scientists at a time of biological crisis. That is wrong. I do NOT have anything against any of the above professions at all and as you know I am not snobbish or socially exclusive. But biomedical scientists should be essential in biological crisis. Same as physicists in a radiological crisis.

(((me))): Re the cancer analogy section, on one level, I agree: the 3 principles are key, but they are what everyone (e.g. WHO) is saying : the analogy does not add much.

Kostas:- This is not correct. No country has shown either the willingness and decision or has the capacity to apply all three principles as early in the outbreak as possible. My hypothesis is because everyone thinks it is a ‘biological tsunami’ that will go away. The essence of what I tried to express in the Nature Nanotechnology article is that the situation should not be considered a ‘tsunami’, but a chronic condition. And we have learnt how to deal with chronic conditions better through the years, as in the case of cancer. Yes, some countries and the WHO have applied some of the principles (e.g. test, test, test) but the disasters in most countries in Europe at least have happened and are happening because ‘targeted protection’ did not take place at all. Most elderly care homes were not targeted for protection. Most hospitals that suffered dramatic collapses were not protected. And we are still hearing about lack of protection for a lot of our healthcare, frontline staff.

(((me))): On another level, I draw different conclusions from looking at “cancer nanotech” in the context of COVID. Cancer nanotech is an area where vast amount of money have been invested on the basis of hyped promises and flawed concepts. Not exactly a model to follow right now.

Kostas:- I know your views about cancer nanotech and I disagree, but I am happy to keep discussing with you and other critics or sceptics. This discussion I think is for another time though.

Hot (biochemistry-related) topics

I am in charge of a module entitled “Advanced Skills for Biochemistry“. Our third year Biochemistry (Honours) students take this course. One of their tasks is to prepare and present a poster on a hot topic or technique. I have therefore asked the world (via Twitter) and my colleagues at the Institute of Integrative Biology to come up with suggestions of topics for these posters, as well as references that students could use as a starting point.

[I have done so in previous years too].

  1. T cell quiescence and activation; suggested by Neill Liptrott. Reference: Metabolic coordination of T cell quiescence and activation; Chapman et al, 2019.
  2. Microbes and preeclampsia; suggested by Doug Kell. Reference: A Dormant Microbial Component in the Development of Preeclampsia; Kell & Kenny, 2016.
  3. How drugs get into cells; suggested by Doug Kell. How drugs get into cells: tested and testable predictions to help discriminate between transporter-mediated uptake and lipoidal bilayer diffusion; Kell & Oliver, 2014.
  4. Microbes and Alzheimer’s Disease; suggested by Doug Kell. Reference: Microbes and Alzheimer’s Disease; Itzhaki et al, 2016.
  5. Evolutionary covariance for protein structure prediction; suggested by Dan Rigden via email: “The topic of evolutionary covariance, with myriad uses but particularly for protein structure prediction, goes from strength to strength. Unfortunately, Google decided not to make the code available or (I think) to publish anything in a journal [there’s a bit of a separate lesson to the students there]. However, they can read about it here and here. This paper, out this week, is the most similar approach I’m aware of and works extremely well. It has a server (that the students could try…) and the code is available.”
  6. Synthetic biology for faster enzymes, suggested by Doug Kell. Reference: Synthetic biology for the directed evolution of protein biocatalysts: navigating sequence space intelligently. Currin et al, 2015.
  7. Nutraceuticals and longevity, suggested by Doug Kell. Reference: Prolonging healthy aging: Longevity vitamins and proteins; Ames, 2018.
  8. Mitochondrial Breakups, suggested by Violaine See. The Good and the Bad of Mitochondrial Breakups; Sprenger, 2019
  9. Signalling controlled by frequency modulation, suggested by Violaine Sée, e.g. this article.
  10. CryoEM – suggested by Steve Royle via Twitter; advances in electron detectors and software has led to explosion of new fascinating structures. Pat Eyers agrees and provides these examples of CryoEM of the anaphase promoting complex.
  11. Organoids cultures, suggested by Dada Pisconti, e.g. this review Modeling mouse and human development using organoid cultures
  12. Oxygen sensing across kingdoms, Masson et al; Conserved N-terminal cysteine dioxygenases transduce responses to hypoxia in animals and plants – see also 2019 Nobel Prize announcement.

The stem cell trachea scandal

Yesterday night, BBC Newsnight broadcasted an investigation by journalist Deborah Cohen featuring interviews with my colleague Prof Patricia Murray as well as extremely moving testimony by the mum of Shauna Davidson. Shauna’s mum had been misled on the nature of the intervention on her daughter and even on the cause of her death.

Patricia is a stem cell expert and we’ve had a long term (and ongoing) collaboration on using imaging to track stem cells for evaluation of their safety and efficacy. When, a few years ago, she started to get interested in the Macchiarini scandal and realised that similar experiments on patients had been done in the UK (and continued to be done), she contacted me knowing my interest in ethical issues and scientific misconduct. I am proud to have supported her sterling work in uncovering this scandal – I am also pleased that legal threats have failed to silence us. The extent of conflicts of interest and unresolved matters involving major institutions in the UK is massive. So much so that we have had to go all the way to Parliament (see our two contributions to the Science and Technology committee on Research Integrity inquiry) to get (so far unsatisfactory) responses. We hope that the BBC reporting will help bring much needed clarity, but the obfuscating responses of GOSH and MRC to Deborah’s questions are deeply worrying.

See also the excellent and detailed work of Leonid Schneider on this same scandal.

 

The war on (scientific) terror…

Thank you Philip for this post and your support.

Symptoms Of The Universe

I’ve been otherwise occupied of late so the blog has had to take a back seat. I’m therefore coming to this particular story rather late in the day. Nonetheless, it’s on an exceptionally important theme that is at the core of how scientific publishing, scientific critique, and, therefore, science itself should evolve. That type of question doesn’t have a sell-by date so I hope my tardiness can be excused.

The story involves a colleague and friend who has courageously put his head above the parapet (on a number of occasions over the years) to highlight just where peer review goes wrong. And time and again he’s gotten viciously castigated by (some) senior scientists for doing nothing more than critiquing published data in as open and transparent a fashion as possible. In other words, he’s been pilloried (by pillars of the scientific community) for daring to suggest that we do science…

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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…

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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.