Posts Tagged ‘Nanotechnology’


Today was the culmination of Zaid’s PhD journey, when he successfully defended his thesis on the use of gold nanoparticles to probe the mechanism of action of a peptide that inhibits ‘flu virus infectivity. Though he approached his viva with trepidation, his beaming face afterwards told a different story. The usual smattering of corrections, a paper already up on Bioarxiv ready to submit for peer review and another to put up on Bioarxiv, and in a few weeks he will be truly done, with a CV to match.


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Of nanoparticles, cells and polyanions

It is the end of semester 2 so it’s marking season. Since we double mark (a good thing), the final year research projects are marked by both supervisor and an assessor, a member of staff who is not involved in the project. One of the projects I marked was Gemma Carolan’s on “How do SmartFlares RNA detection probes reach the cytosol? Available are the PDF of report, and posts here and here.

I had a sense of déjà vu while reading the project – the clear endosomal location of the SmartFlares, regardless of the DNA sequences brought me back to the days when antisense was the technology of the future for medicine.

While evaluating new technology it is useful to go back and look at other high flying technology. The reality is that it takes decades before we know whether the promise (and hype) were justified; this is true for any hot topic from stem cells to nanoparticles and graphene.

Antisense effects can be mediated by RNAse H, an enzyme that specifically cleaves RNA-DNA duplexes and which protects our cells from RNA viruses. There are other mechanisms, e.g., interference with splicing or translation, but the RNAse-H mediated transcript degradation should be central to many antisense effects. There were many papers reporting specific effects (evidenced by differences between sense, antisense and scrambled oligonucleotides sequences). These certainly contributed to success of individuals and of institutions, e.g., in UK Research Assessment Exercise and grant awards.

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David Paramelle’s paper on using gold nanoparticles stoichiometrically functionalised with a peptide that recognises sphingolipids has just been published in Advanced Healthcare Materials (Publisher’s site; Pubmed)

The paper is the classic “Sunday afternoon” project, which arose through discussions with Rachel Kraut at NTU.

As ever, a lot more than Sunday afternoons ended up being put into the paper, because David had to develop some new approaches. Particularly nice was the purification of nanoparticles functionalised with the sphingomyelin-binding peptide (called “SBD”) from non-functionalised nanoparticles. This is a key step for the preparation of nanoparticles carrying just one functional peptide or group. Hitherto, we have happily had affinity tags as the functional group, which allows for affinity chromatography (examples here, here and here). (more…)

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The question relates to what Langmuir termed “Pathological Science”, simply put “people are tricked into false results … by subjective effects, wishful thinking or threshold interactions“. There is a lot of pathological science and I only use the examples below, because I am most familiar with them; for nanoparticles, I have a personal interest in understanding these materials, since I use them to try to make biological measurements, e.g., here.

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Dan Nieves’ paper on an easy and accessible method to covalently conjugate proteins, sugars and indeed pretty much any biomoleucle onto nanoparticles has just come out in Chem. Commun. (more…)

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On December 31 2013 I posted my New Year’s resolution: to only review manuscripts from open access or learned society journals.

My reasoning was that open access will only be the norm if we stop giving that which is most precious, our time, to closed access journals. I really think the wider community needs to start to be selective in reviewing. It is far easier to implement than the radical re-alignment of library journal subscriptions. (more…)

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The sadly predictable hyping of things nano reached a nadir recently with the promotion of silver nanoparticles (aka “silver bullet”) as a treatment for ebola virus. There has been a great discussion of this and other aspects of silver nanoparticles by Andrew Maynard (here, here for ebola and here for the essential Risk Bites video).

It may surprise some, but until a few weeks ago, there was no simple, direct published method to quantify non-destructively silver nanoparticles. Yet, the non-destructive quantification of silver nanoparticles is essential to any experiment that aims to prepare and use these in a biological context. Without it any experimental work is likely to be qualitative and simple things, such as determining the stoichiometry of functonalisation, become difficult. Indeed, so important is simple quantification of nanoparticles that we validated and published a method for gold nanoparticles in 2007 that has been very well received by the community and which we use daily in the lab. (more…)

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This post has been stimulated by a post on PubPeer entitled “A crisis of trust
This post should be required reading for all engaged in research and in the management of the institutions involved in research, including funders and journal editors. I made a brief comment, relating to a sentence that is some way down the post:

“This could be done if together we invert the burden of proof. It should be your responsibility as a researcher to convince your peers, not theirs to prove you wrong”. (more…)

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Inspiration for this post comes from various sources, including Arjun Raj’s posts on the STAP papers (here and here) and that by The Spectroscope (here)
and my previous posts on the question of whether science does self-right.

I take issue with the trivialisation of data fabrication. (more…)

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Gradually, the structural problems in sciences are making their way to the surface. There have been articles in newspapers, The Economist and other magazines around the world on the subject. These are stimulated by the constant dripping of information and studies that sit awkwardly with the perceived notion of how science functions.

The high profile controversies tend to catch our attention, simply because of a sense of outrage amongst the wider community that nothing has been done to fix the problem, or that the fixes have been inadequate. Despite the outrage, it remains the case that only a very few are willing to put their head above the parapet and say something. There has been an interesting discussion of this on Athene Donald’s blog here.

Not surprisingly, the “reproducibility question” has gained quite a lot of traction( e.g., here and here). This leads to a simple question: what qualifies as a reproduction?

I argue that an important aspect of reproduction is that it is not necessarily actual reproduction, but a re-examination of observations made with better methods, which includes analytical tools. I have two examples of how scientists deal with the changing landscape of data and their interpretation in these circumstances. The first example is an instance of good practice and is common (or should be). The second seems to ignore the past and the clear message provided by the new data.

Example 1
This is from an excellent 2012 paper in Journal of Biological Chemistry that we discussed (again) in a recent lab meeting. It deals with the molecular basis for one member of the fibroblast growth factor family, FGF-1, being a universal ligand. That is, FGF-1 can bind all FGF receptor isoforms, whereas other FGFs show clear restriction in their specificity. These differences must lie in the structural basis of the recognition of the FGF ligand, the FGF receptor and the heparan suflate co-receptor. The first model put forward by Moosa Mohamadi was superseded in his 2012 paper, when he and his group obtained higher resolution structures of the complexes. This is a great step forward, as FGFs are not just important to basic biology, but they also impact on a wide range of diseases, as well as tissue homeostasis and regeneration. I highlight the following from the paper:
To quote (page 3073, top right column)
“Based on our new FGF1-FGFR2b and FGF1-FGFR1c structures, we can conclude that the promiscuity of FGF1 toward FGFR isoforms cannot be attributed to the fact that FGF1 does not rely on the alternatively spliced betaC’-betaE loop of FGFR for binding as we initially proposed (31).”

This paper provides a great example of how science progresses and is how we should all deal with the normal refinement of data and the implications of such refinements.

Example 2
This is from the continued discussions on whether the ligands on the surface of gold nanoparticles can phase separate into stripes. This has been the subject of a good many posts on Raphael Lévy’s blog (from here to here), following his publication a year ago of his paper entitled “Stripy nanoparticles revisited“, as well as commentary here and elsewhere.

Some more papers from Stellacci and collaborators have been published in 2013. The entire oeuvre has been examined in detail by others, with guest posts on Raphael Lévy’s blog (most recent here) and comments on PubPeer relating to a paper on ArXiv that takes apart the entire body of evidence for stripes.

What is quite clear, even to a non-specialist, is that the basics of experimental science had not been followed in the Stellacci papers on the organisation of ligands on nanoparticles published from 2004 to 2012. These basics include the importance of signal being greater than noise and ensuring that experimental data sample at sufficient depth to avoid interpolation; note that in no cases did instrumentation limitation require interpolation. This might happen to any of us, we are, after all “enthusiasts”.

To conclude, I refer to my quote from Seneca “Errare humanum est sed perseverare diabolicum

This excellent advice is clearly being followed by one FGF lab. It would be good if this advice was adopted more generally across science. When we see real data and analysis (the hard stuff) that challenges our previous data and interpretations, we should all be happy to change these. This is how science (should) move forward. If everyone did this, then there would be no discussion regarding reproducibility. When we see more of the same stuff, without a clear hypothesis testing experiment, we are veering towards metaphysics.

Metaphysics is not science. I note that when data are hidden, so that analysis is restricted, we again enter the realm of metaphysics – hence, for example, the call for open access to clinical trials data.

Links with some relevance to the Seneca’s advice, reproducibility and so on:
There is an excellent post at The Curious Wavefunction’s Sci Am blog
PubPeer: here and here
Neuroskeptic’s post at Discover
Chembark’s post in response to an ACS Nano editorial on reporting misconduct.

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