Congratulations Dr Baradji

Congratulations to Aiseta!

On Monday 4 December Aiseta Baradji successfully defended her thesis. A long journey and a hard one as ever with its ups and downs, surprises and a certain amount of head scratching over data that push us in new directions. In the end a great thesis that will be consulted in the labs of her supervisors for a long time. Now onto the next phase.

 

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Not one, but two papers on fibroblast growth factors and glycosaminoglycans

Changye Sun and Yong Li, who successfully defended their PhD theses in November have published a paper each in Open Biology on the interactions of fibroblast growth factors (FGFs) with glycosaminoglycans:

Heparin binding preference and structures in the fibroblast growth factor family parallel their evolutionary diversification

and

Selectivity in glycosaminoglycan binding dictates the distribution and diffusion of fibroblast growth factors in the pericellular matrix.

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Responding to questions raised on PubPeer

I am a fan of PubPeer, as it provides a forum for discussion between authors and the wider community, something I have discussed in a number of posts (two examples being here and here). Two days ago, My colleague Mike Cross came by my office, having just delivered a pile of exam scripts for second marking (it’s exam and marking season), asking if I had seen a comment on our paper on PubPeer. I had not – too many e-mails and too busy to look at incoming!
So I looked at the question, which relates to panels in two figures being identical in our paper on neuropilin-1 and vascular endothelial growth factor A (VEGFA) – indeed they are labelled as being identical.

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Why gel splicing is not OK

Gel (see footnote at end for a brief description of gels aimed at non-biologists) splicing is a term that describes the cutting and pasting of images of lanes (where 1 lane = 1 sample) and placing the images of the lanes in a different order or even combining lanes from different gels. A more extreme form is to simply shift the subsection of the lane, corresponding to the probed molecule, from one lane to the next.
This is wrong and it always has been. However, in post publication peer review on PubPeer, it is often defended, particularly for “older” papers, from a decade or more ago. This then raises arguments about what was acceptable then and are we shifting the goalposts of scientific integrity? The matter has even been a “Topic” on PubPeer.

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An accidental discovery

Changye and Yong’s first paper, up as a preprint at PeerJ
in accord with my 2015 and 2014 New Year resolutions describes an accidental discovery. One of their co-authors, Sarah Taylor, was exploring HaloTag as an alternative means of labelling protein to green fluorescent protein, and I thought it would be good to be able to have a pure in vitro system to validate labelling. So Changye and Yong made some recombinant HaloTag fibroblast growth factor-2 (HT-FGF2). When they showed me the gel, they noted that HT-FGF2 did not seem terribly promising, because there was quite a lot of protein in the bacterial pellet.

It is at this point that the professor earns his keep,

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Self-righting or sinking?

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.

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Reproducing science: there are no stripes, but FGF-1 IS the universal ligand

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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When rigour deserts science we are left with quackery

Update June 5
Standards, who needs them? I am just back from the E-MRS spring meeting in Strasbourg, which was most enjoyable, though someone seems to have forgotten about the “Spring” bit. Meanwhile, out in the world of science we continue to witness ridiculous decisions regarding manipulated and falsified data by journals and a quite stunning self-justification by a materials scientist who looks to be the next serial fraudster.

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PhD position available on “Short- and long-range structure of the extracellular matrix

http://www.intelliagence.fr/Page/Offer/ShowOffer.aspx?popup=1&OfferId=47887&rwndrnd=0.9729958744719625.

either go through the ABG website, the University of Liverpool website or contact Dave Fernig directly.

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Still no stripes: debate spreads to the Times Higher Education

There was an article on “Stripy Nanoparticles” in the Times Higher (THE) by Paul Jump on Jan 10. It was followed by a series of comments. Most of the comments (a substantial number from anonymous commentators) reckon that there is no evidence for stripes on nanoparticles.

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