How many people are using the #SmartFlares? Freedom of Information request provide insights

Quick summary of previous episodes for those who have not been following the saga: Chad Mirkin’s group developed a few years ago a technology to detect mRNAs in live cells, the nano-flares. That technology is currently commercialised by Merck under the name smartflares. For a number of reasons (detailed here), I was unconvinced by the publications. We bought the smartflares, studied their uptake in cells as well as their fluorescent signal and concluded that they do not (and in fact cannot) report on mRNAs levels. We published our results as well as all of the raw data

This question – how many people are using the SmartFlares? – is interesting because surely, if a multinational company such as Merck develops, advertises and sells products, to scientists worldwide, these products have to work. As Chad Mirkin himself said today at the ACS National Meeting in Philadelphia “Ultimate measure of impact is how many people are using your technologies“.

So, we must be wrong. SmartFlares must work.

But our data say otherwise, so what is going on?

One hint is the very low number of publications using the smartflares and the fact that some of those are not independent investigations. This, however does not tell us how many groups in the world are using the smartflares.

Here is an hypothesis: maybe lots of groups worldwide are spending public money on probes that don’t work… and then don’t report the results since the probes don’t work. That hypothesis is not as far fetched as it may seem: it is called negative bias in science publishing and it is one of the causes of the reproducibility crisis.

To test this hypothesis, we would need to know how many research groups worldwide have bought the smartflares, an information that I suspected Merck was not going to volunteer. So, instead, I made Freedom of Information requests to (nearly) all UK research intensive universities (the Russell group) asking whether they had evidence of smartflare purchase orders.

Some Universities (6) declined because it would have been too much work to retrieve the information but most (14) obliged. The detailed results are available here. They show that a minimum of 76 different purchases were made between the launch of the product and June 2016. The money spent is £38k representing 0.0013% of these UK universities research income. As far as I can see, none has resulted in a publication so far.

All I can say is that these data do not falsify our hypothesis.

And if after reading this, you are still unconvinced of the need to publish negative data, check the upturnedmicroscope cartoon (warning: scene of violence).

 

 

 

PhD student at the Frontiers in BioImaging conference

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65787098 Jennifer presents her poster at the conference

Guest post by Jennifer Francis, PhD student in the Institute of Integrative Biology.

I recently attended the Frontiers in BioImaging conference in London (14th-15th July 2016), organised by the Royal Microscopical Society (RMS). Since this highly specialised conference was relatively small, I got the opportunity to speak one-to-one with experts within the field of super-resolution microscopy about their cutting-edge imaging techniques. A number of microscopy companies, including Carl Zeiss and Leica, also showcased their latest products. The highlight of this trip, was presenting my poster entitled “Exploiting Fluctuations to Enhance Imaging Resolution of Biological Structures“, which generated lots of encouraging interest. Whilst in London, I also got the chance to explore the famous landmarks, whose architecture never fails to impress.

76544879As well as, attending the talks, I also sat in on the Annual General Meeting (AGM), where the…

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Chad Mirkin on Nano Hype

Chad Mirkin did a Reddit AMA yesterday (h/t Neil Withers).

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(highlight mine)

Of these 1800 commercial products, 1700+ are in fact a single product, the famous Spherical Nucleic Acids/SmartFlares.

More on this blog and our paper (The spherical nucleic acids mRNA detection paradox) here.

With the risk of being accused of having cynical views…

The Internet of NanoThings

Nanosensors and the Internet of Nanothings” ranks 1st in a list of ten “technological innovations of 2016” established by no less than the World Economic Forum Meta-Council on Emerging Technologies [sic].

The World Economic Forum, best known for its meetings in Davos, is establishing this list because:

New technology is arriving faster than ever and holds the promise of solving many of the world’s most pressing challenges, such as food and water security, energy sustainability and personalized medicine. In the past year alone, 3D printing has been used for medical purposes; lighter, cheaper and flexible electronics made from organic materials have found practical applications; and drugs that use nanotechnology and can be delivered at the molecular level have been developed in medical labs.

However, uninformed public opinion, outdated government and intergovernmental regulations, and inadequate existing funding models for research and development are the greatest challenges in effectively moving new technologies from the research lab to people’s lives. At the same time, it has been observed that most of the global challenges of the 21st century are a direct consequence of the most important technological innovations of the 20st century.

Understanding the implications of new technologies are crucial both for the timely use of new and powerful tools and for their safe integration in our everyday lives. The objective of the Meta-council on Emerging Technologies is to create a structure that will be key in advising decision-makers, regulators, business leaders and the public globally on what to look forward to (and out for) when it comes to breakthrough developments in robotics, artificial intelligence, smart devices, neuroscience, nanotechnology and biotechnology.

Given the global reach and influence of the WEF, it is indeed perfectly believable that decision-makers, regulators, business leaders and the public could be influenced by this list.

Believable and therefore rather worrying for – at least the first item – is, to stay polite, complete utter nonsense backed by zero evidence. The argument is so weak, disjointed and illogical that it is hard to challenge. Here are some of the claims made to support the idea that “Nanosensors and the Internet of Nanothings” is a transformative  technological innovations of 2016.

Scientists have started shrinking sensors from millimeters or microns in size to the nanometer scale, small enough to circulate within living bodies and to mix directly into construction materials. This is a crucial first step toward an Internet of Nano Things (IoNT) that could take medicine, energy efficiency, and many other sectors to a whole new dimension.

Except that there is no nanoscale sensor that can circulate through the body and communicate with internet (anyone knows why sensors would have to be nanoscale to be mixed into construction materials?).

The next paragraph seize on synthetic biology:

Some of the most advanced nanosensors to date have been crafted by using the tools of synthetic biology to modify single-celled organisms, such as bacteria. The goal here is to fashion simple biocomputers [Scientific American paywall] that use DNA and proteins to recognize specific chemical targets, store a few bits of information, and then report their status by changing color or emitting some other easily detectable signal. Synlogic, a start-up in Cambridge, Mass., is working to commercialize computationally enabled strains of probiotic bacteria to treat rare metabolic disorders.

What is the link between engineered bacteria and the internet? None. Zero. I am sorry to inform the experts of the WEF that bacteria, even genetically engineered ones, do not have iPhones: they won’t tweet how they do from inside your gut.

I could go on but will stop. Why is such nonsense presented as expert opinion?

Gold nanorods to shine light on the fate of implanted stem cells

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Joan Comenge

This is a guest post by Joan Comenge

Our work regarding the use of gold nanorods as contrast agents for photoacoustic tracking of stem cells has been just published (or here*). You can find all the technical details of the work there, so I will try to explain here the work for the readers who are not very familiar with our field.

It is important to have the appropriate tools to evaluate safety and efficacy of regenerative medicine therapies in preclinical models before they can be translated to the clinics. This is why there is an interest in developing new imaging technologies that enable real time cell tracking with improved sensitivity and/or resolution. This work is our contribution to this field.

To distinguish therapeutic cells from the patient’s own cells (or here from the mouse’s own cell),  the therapeutic cells have to be labelled before they are implanted. It is well known, that biological tissue is more transparent to some regions of the light spectrum than others. This fact is very easy to try at home (or at your favourite club): if you put your hand under a green light, no light will go through it, whilst doing the same under a red light the result will be very different. That means that red light is less absorbed by our body. Near infrared light is even less absorbed and this is why this region of the spectrum is ideal for in vivo imaging. Therefore, we made our cells to absorb strongly in the near infrared so we can easily distinguish them.

Gold nanoparticles of different sizes and shapes (synthesis and picture by Joan Comenge).

Gold nanoparticles of different sizes and shapes (synthesis and picture by Joan Comenge).

To do this, we labelled cells with gold nanoparticles. Interestingly, the way gold nanoparticles interact with light depends on how their electrons oscillate. That means that size and shape of the nanoparticles determine their optical properties, and this is one of the reasons why we love to make different shapes of nanoparticles. In particular, gold nanorods strongly absorb in the near infrared and they are ideal contrast agents for in vivo imaging.

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Figure reproduced from: The production of sound by radiant energy; Science 28 May 1881; DOI: 10.1126/science.os-2.49.242

We have now cells that interact with light in a different way than the tissue. The problem is that light is scattered by tissue, so resolution is rapidly lost as soon as you try to image depths beyond 1 mm. Obviously, this is not the best for in vivo imaging. Luckily for us, Alexander Graham Bell realised 130 years ago that matter emits sounds when is irradiated by a pulsed light. This is known as the photoacoustic effect and it has been exploited recently for bioimaging. Photoacoustic imaging combines the advantages of optical imaging (sensitivity, real-time acquisition, molecular imaging) and the good resolution of ultrasound imaging because ultrasounds (or phonons), contrarily to photons, are not scattered by biological tissue.
GNR-35.2Si3 in cells_16

Silica-coated gold nanorods inside cells

To optimise the performance of our gold nanorods, we coated them with silica. Silica is glass and therefore it protects the gold core without interfering with its optical properties. This protection is required to maintain gold nanorods isolated inside cells since nanorods are entrapped in intracellular vesicles, where they are very packed. The absence of a protective coating ultimately would result in a broader and less intense absorbance band, which would be translated to a less intense photoacoustic signal and consequently a lower sensitivity in cell detection. This of special importance in our system, a photoacoustic imaging system developed by iThera Medical which uses a  multiwavelength excitation to later deconvolute the spectral information of the image to find your components of interest. Thus, narrow absorption bands helps to improve the detection sensitivity even further. With this we demonstrated that we were able to monitor a few thousand nanorods labelled-cells with a very good 3D spatial resolution for 15 days. This allowed for example to see how a cell cluster changed with time, see how it grows or which regions of the cell cluster shows the highest cell density. In addition, this work opens the door to new opportunities such as  multilabelling using gold nanorods of different sizes and consequently different optical properties to observe simultaneously different type of cells. We also believe that not only stem cell therapies, but also other fields that are interested in monitoring cells such as cancer biology or immunology can benefit from the advances described in our work.

You can find the original publication here (or here*).
All the datasets are available via Figshare.

This work was supported by the UK Regenerative Medicine Platform Safety and efficacy, focusing on imaging technologies. Joan Comenge was funded by the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme. The in vivo imaging was done in the Centre for Preclinical Imaging, the Electron Microscopy in the Biomedical EM unit and the Optical Microscopy in the Centre for Cell Imaging.

* the alternative link is to 50 free e-prints; the link will be removed once the paper is fully open access (in a couple of days).

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Cluster of gold nanorod-labelled cells imaged by photoacoustic imaging three days after implantation in mice.

Come on England!

Fourteen years ago, we moved from France to England. My partner and I had both found postdoctoral research positions at the University of Liverpool. We arrived with our one and half year old daughter and immediately felt welcome. After our first Christmas holidays on the continent, coming back to what we were not yet calling “home” , we found presents for us from the next flat neighbour, whom we had barely met. The two years became five. We progressed in our respective academic careers and we made the choice to stay here. The five years became fourteen. Two more children, born in Liverpool. Until these last few weeks, I have always felt welcome.

But now things are different because there is a nationwide debate about getting rid of us, European immigrants. Some will object and say that Brexit is not really about that, but whatever their objections, this is most definitely how it feels. This is how it feels not just because of the xenophobia which is rife through most of the Brexit campaign, but also because for us, the 3M of EU nationals who live in the UK (and probably the 1.2M UK nationals living in the EU), Europe is not an undemocratic and distant abstraction, it is us: we are European. As EU nationals, we vote in local elections in the UK. As EU nationals, we have the right to work and live here. We are Europeans. Therefore, as Europe is under attack in the country where we live our happy lives and where we have made so many wonderful friends, we feel under attack.

On Friday, I received the following message from a German colleague at another University:

Hi Raphael
I wonder what you are doing in ‘preparation’ to the seemingly increasing likelihood that there will be a Brexit?
Have you or Violaine applied for permanent residency? What about UK citizenship?
I am getting a bit nervous…
Best wishes
XXX

In truth, we have done nothing, partly because if the worse comes to the worse, there will hopefully still be some time to get our affairs in order, and partly because we don’t want to believe that this will really happen. On Twitter, François Guesnet who is teaching Jewish history in London puts it this way, in an hommage to the British sense of humour,

but, humour apart,

Like him, I am very concerned but also, rightly, powerless. I do not have (and do not claim) the right to vote. This is a decision for you, my UK friends, to make. I – and many others – will be cheering from the tribunes, and, like the supporters of the EURO 2016, we will be waiting anxiously for the final score.

 

Leading on research assessment

The University of Liverpool, my University, is currently developing a Code of Practice for the Annual Assessment of Individual Research and Impact Performance. There is an internal consultation and this post is my open contribution to this consultation process following a short presentation  (this morning) of the draft code to staff of my Institute by The Faculty APVC for Research and Impact, Prof Malcolm Jackson.

A draft document is available on the intranet for University of Liverpool staff. Whilst I cannot share the draft code (an internal University document currently under consultation), I can reveal that the motivation, spirit, and managerial consequences of the code are entirely dictated by the concepts of “excellence” and “increasing the number of 4* papers” ahead of the next Research Excellence Framework (REF). For non UK readers, REF is a national exercise of evaluation of the research carried in Universities which happens every few years and which has important implications in term of core funding (more via Wikipedia here).

The point I made in the meeting this morning, and which I now reiterate, is that this attitude to management of research, focusing on excellence and 4* papers, is not visionary and not world leading. It is what everyone else is doing with disastrous consequences. It is not setting the scene and it is not ambitious.

We, as a scientific community, are facing serious challenges since a very large portion of the research we produce is not reproducible. This is now so regularly in the news that a specific link becomes unnecessary. In an excellent (SIC) and timely paper published yesterday and entitled “Excellence R Us: University Research and the Fetishisation of Excellence”, Samuel Moore and colleagues write (abstract):

 We trace the roots of issues in reproducibility, fraud, as well as diversity to the stories we tell ourselves as researchers and offer an alternative rhetoric based on soundness. “Excellence” is not excellent, it is a pernicious and dangerous rhetoric that undermines the very foundations of good research and scholarship.

An Institution of the size of the University of Liverpool could be leading by advocating and adopting a scientific culture [1] that promotes soundness. John Ioannidis explains both the problems with our research practices and potential solutions in his Berlin Institute of Health Annual Special Lecture  given a few weeks ago. In particular, from 1:11:37, he discusses the “future re-engineering of our reward system”:


As a very minimum requirement, the University should adopt the San Francisco Declaration on Research Assessment, and the principles of that declaration should be reaffirmed in the draft code.

In considering a new code of evaluation, it is essential to consider the impact of assessment on research practices. We need to change the incentives to improve research and this consultation could be an opportunity to do that: let’s the University of Liverpool be part of those that shape the future of how we do research.

UPDATE: Stephen Curry has kindly pointed to this very relevant document from Imperial College: Application and Consistency of Approach in the Use of Performance Metrics, A report by the Associate Provost [Institutional Affairs] December 2015

[1] see also, The Culture of Scientific Research, Nuffield Council on Bioethics, 2014