post-publication peer review

Reply from Wolfgang Parak

Regular readers will remember a recent post where I documented the critical peer review of 20 influential (more than a 1000 citations) articles. I reviewed them initially in a Twitter thread and then also reproduced my comments on PubPeer.

Wolfgang Parak, corresponding author of one of these 20 papers (Cytotoxicity of colloidal CdSe and CdSe/ZnS nanoparticles), has kindly responded to my comments. I reproduce his response below (with his authorisation). The full discussion is here. Wolgang is doing the right thing. I hope other authors will follow suit; especially authors of papers where more serious concerns where raised such as here, here here, here, here, here, here and here.

Dear Raphael

thank you very much for your comments about our article.  In general I agree with your points. There were essentially two shortcomings you pointed out.

1) At low nanoparticle concentration there are less adherent cells after incubation than before incubation. In fact, at low nanoparticle concentrations there should be no effect, and thus the number of adherent cells before and after incubation should be equal (R = 1). However, cells proliferate. Thus, in case cells proliferate during incubation, there would be more cells after than before incubation (R > 1). In order to get rid of this effect we incubated the cells in SATO medium, which should stop cell proliferation. However, in fact the use of SATO medium also causes loss of some adherent cells. We pointed this out in our manuscript: “Exchanging the serum-containing cell culture medium to serum-free SATO medium resulted in the detachment of a significant fraction of cells, i.e., R < 1 even for c(Cd) = 0. Therefore, we assume that there are no toxic effects due to Cd in the first region of low Cd concentration and that the value of R < 1 can be simply explained by the effect of the SATO medium”. Thus, we did the control, that there is an effect due to changes of serum supplemented medium to the SATO medium which is supposed to stop cell proliferation. In retro-perspectives the conditions could have been better optimized, in getting culture conditions where there is no cell proliferation, but there is also no loss of cells during the incubation period. In addition, had I to plan the study today again, I would use a different assay which probes cell metabolism, instead of using cell adhesion as quantifier for toxicity. There are a variety of excellent assays, which also have different sensitivity, see for example: ” X. Ma, R. Hartmann, D. Jimenez de Aberasturi, F. Yang, S. J. H. Soenen, B. B. Manshian, J. Franz, D. Valdeperez, B. Pelaz, N. Feliu, N. Hampp, C. Riethmüller, H. Vieker, N. Freese, A. Gölzhäuser, M. Simonich, R. Tanguay, X.-J. Liang, W. J. Parak, “Colloidal Gold Nanoparticles Induce Changes in Cellular and Subcellular Morphology”, ACS Nano 11, 7807−7820 (2017)”. The reason why at that time we used the adhesion assay was that we were afraid that some metal ions may interfere with colorimetric viability assays. In a previous work (C. Kirchner, M. George, B. Stein, W. J. Parak, H. E. Gaub, M. Seitz, “Corrosion protection and long-term chemical functionalization of gallium arsenide in aqueous environment”, Advanced Functional Materials 12, 266-276 (2002)) we had observed that the MTT assay interferes with As ions released from GaAs surfaces and thus at that time we decided against the use of a biochemical assay.

2) The patch clamp experiment, in which ion currents were measured with and without presence of nanoparticles was merely quantitative. We thought at this time that it would be a good add-on to the paper, using one more complementary technique apart from the detachment assay to probe for toxic effects. In literature at that time there were reports suggesting the use of quantum dots for cell labelling. In our detachment assay we had shown, that at high concentration quantum dots are toxic to cells. Our motivation was to show, that one can use low quantum dot concentrations, which are enough to label cells, but which are low enough not to cause acute toxicity. Thus, we chose one concentration of quantum dots, which is enough to label cells, and showed that with this concentration ion channel currents were not affected. In retro-perspectives with some additional work we could have made also a more quantitative investigation, with a variation of quantum dot concentration, to see at which concentration ion channels are affected.

I hope with this I could comment on your two major points.

Best wishes

Wolfgang

(Wolfgang Parak, wolfgang.parak@uni-hamburg.de)

Nanomedicine on Planet F345

Last year, Matthew Faria et al published Minimum information reporting in bio–nano experimental literature, introducing a checklist (MIRIBEL) of experimental characterisations that should accompany any new research paper. 12 months later, the same journal has published 22 (!!!) short opinion pieces. As I feel particularly generous (and a bit facetious) today, I shall summarise those 22 pieces in 2 sentences.

  1. There are authors who feel that MIRIBEL is great and should be implemented although really colleagues should also consider using these other characterization techniques (that they happen to be developing/proposing in their lab/European network [INSERT ACRONYM]).
  2. There are authors who think that there is a risk that MIRIBEL standardisation will stiffle creativity and innovation  (and they also regret that MIRIBEL authors haven’t cited their editorials deploring irreproducible research).

Thankfully, there are more interesting takes from young researchers on Twitter (why do we need journals again?).

Wilson Poon remarks that the sheer amount of acronyms for nano-bio related guidelines & databases is insane;  he remains unconvinced that making new guidelines is the best way to address the current “significant barriers to progress in [nanomedicine],  and, even more damningly, he notes the hypocrisy of many researchers in the field [who] just talk the talk, and not walk the walk

Shrey Sindhwani demands quantification of what is happening to particles at a cellular and sub-cellular level, multiple lines of evidence and the use of appropriate biological controls. He makes two other really important points: 1) he demands critical discussion of what is in the literature; 2) he says we need replications: multiple groups should try to reproduce core concepts of the field for their systems. This involves mechanistic studies of what the body does to your specific formulation. This will define the scope of a broad concept and its applicability.

I largely agree with Wilson and Shrey. MIRIBEL may be well intentioned (and so are most responses), but they are not digging in the right place, and that is because they might otherwise find skeletons that they’d rather not find. This is very explicit in the original MIRIBEL paper:

… our intention is not to criticize existing work or suggest a specific direction for future research. The absence of standards and consistency in experimental reporting is a systemic problem across the field, and our own work is no exception.

God forbids criticizing existing work. If we start there, people might even consider criticising our own work and then where we will it stop? We might have to answer difficult questions at conferences?! That would be scientific terrorism.

Better reporting guidelines is not the solution because it does not address the core of the problems we are facing. In his 2012 paper entitled “Why Science Is Not Necessarily Self-correcting, John P. A. Ioannidis noted that

Checklists for reporting may promote spurious behaviors from authors who may write up spurious methods and design details simply to satisfy the requirements of having done a good study that is reported in full detail; flaws in the design and execution of the study may be buried under such normative responses.

This is exactly what will happen with MIRIBEL. Some will ignore it. Some will talk the talk, i.e. they will burry flaws in the design and execution of the study under a fully checked list of characterizations. Ben Ouyang makes a similar point when he asks what’s the point of reporting standards that might not relate to the problem?:

So, what are the core issues. What needs to be done?

First, we need to look critically at the scientific record. We need to sort out our field. We need to know what are solid concepts we can build on and what are fantasies that have been pushed at some point to get funding but have no underpinnings in the real world. This is important and necessary work. It may impact evaluation of what is worth or not worth funding. It may impact evaluation of risks and public perception of science and technology (badly needed) and even the approval of clinical trials. It may make all the difference for a starting PhD student if she finds a critical analysis of the paper their supervisor is asking them to base their PhD project on.

I have started here with 20 reviews of highly cited papers; we need more people joining in this effort of critically annotating the literature. The tools are available via PubPeer (have you installed their browser plugin that tells you when you are reading a paper which has comments available?). It is not accidental that such tools are not provided by the shiny journals such as Nature Nanotechnology who are happy to publish some buzz about reproducibility but have very little interest in correcting the scientific record.

We need clarity and critical thinking. We need to evaluate what we have. Take one of the founding idea of bionano, that nanoparticles are good at crossing biological barriers. Where does this idea comes from? What does it actually mean (i.e. what % of particles do that? which barriers are we talking about? “Good” compared to what?)? What is the evidence? Is it true? Can it be tested? Are we being good scientists when we make such statements in the introduction of our papers, in press releases or in grant applications? I would argue, contrarily to Ben, that the problem is not that things are complex, but rather that we have been blurring simple facts under a ton of mud for about two decades [1].

In his 2012 paper already cited above, Ioannidis describes science on planet Planet F345, Andromeda Galaxy, Year 3045268. It sounds worryingly not exotic. Let’s try not to emulate Planet F345.

Planet F345 in the Andromeda galaxy is inhabited by a highly intelligent humanoid species very similar to Homo sapiens sapiens. Here is the situation of science in the year 3045268 in that planet. Although there is considerable growth and diversity of scientific fields, the lion’s share of the research enterprise is conducted in a relatively limited number of very popular fields, each one of that attracting the efforts of tens of thousands of investigators and including hundreds of thousands of papers. Based on what we know from other civilizations in other galaxies, the majority of these fields are null fields—that is, fields where empirically it has been shown that there are very few or even no genuine nonnull effects to be discovered, thus whatever claims for discovery are made are mostly just the result of random error, bias, or both. The produced discoveries are just estimating the net bias operating in each of these null fields. Examples of such null fields are nutribogus epidemiology, pompompomics, social psychojunkology, and all the multifarious disciplines of brown cockroach research—brown cockroaches are considered to provide adequate models that can be readily extended to humanoids. Unfortunately, F345 scientists do not know that these are null fields and don’t even suspect that they are wasting their effort and their lives in these scientific bubbles.

Young investigators are taught early on that the only thing that matters is making new discoveries and finding statistically significant results at all cost. In a typical research team at any prestigious university in F345, dozens of pre-docs and post-docs sit day and night in front of their powerful computers in a common hall perpetually data dredging through huge databases. Whoever gets an extraordinary enough omega value (a number derived from some sort of statistical selection process) runs to the office of the senior investigator and proposes to write and submit a manuscript. The senior investigator gets all these glaring results and then allows only the manuscripts with the most extravagant results to move forward. The most prestigious journals do the same. Funding agencies do the same. Universities are practically run by financial officers that know nothing about science (and couldn’t care less about it), but are strong at maximizing financial gains. University presidents, provosts, and deans are mostly puppets good enough only for commencement speeches and other boring ceremonies and for making enthusiastic statements about new discoveries of that sort made at their institutions. Most of the financial officers of research institutions are recruited after successful careers as real estate agents, managers in supermarket chains, or employees in other corporate structures where they have proven that they can cut cost and make more money for their companies. Researchers advance if they make more extreme, extravagant claims and thus publish extravagant results, which get more funding even though almost all of them are wrong.

No one is interested in replicating anything in F345. Replication is considered a despicable exercise suitable only for idiots capable only of me-too mimicking, and it is definitely not serious science. The members of the royal and national academies of science are those who are most successful and prolific in the process of producing wrong results. Several types of research are conducted by industry, and in some fields such as clinical medicine this is almost always the case. The main motive is again to get extravagant results, so as to license new medical treatments, tests, and other technology and make more money, even though these treatments don’t really work. Studies are designed in a way so as to make sure that they will produce results with good enough omega values or at least allow some manipulation to produce nice-looking omega values.

Simple citizens are bombarded from the mass media on a daily basis with announcements about new discoveries, although no serious discovery has been made in F345 for many years now. Critical thinking and questioning is generally discredited in most countries in F345.

[1] The example of uptake of nanoparticles in cells is a case in point. Endocytosis was literally discovered and initially characterized using gold colloids as electron microscopy contrast agents in the 1950s and 1960s, yet half a century later, tens of thousands of articles write that the uptake of nanoparticles in cells is a mystery that urgently needs to be investigated.

20 critical reviews of influential articles about nanoparticles and cells

I have commented on the 20 highly cited articles below. They all relate to nanoparticles and cells. They were published between 1998 and 2006 and have received more than 1,000 citations each, over 40,000 citations overall.

I have used Twitter to document my reviewing process.

I have copied all of my reviews to PubPeer ; see the link below each papers in the bibliography at the bottom of this post. The orange colour indicates serious problems; the blue colour indicates that important old relevant papers have been overlooked.

You can also find the tweets via the ThreadReaderApp:

 

1             Bruchez, M., Moronne, M., Gin, P., Weiss, S. & Alivisatos, A. P. Semiconductor nanocrystals as fluorescent biological labels. Science 281, 2013-2016, doi:10.1126/science.281.5385.2013 (1998).

=> Comment on PubPeer.

2             Gref, R. et al. ‘Stealth’ corona-core nanoparticles surface modified by polyethylene glycol (PEG): influences of the corona (PEG chain length and surface density) and of the core composition on phagocytic uptake and plasma protein adsorption. Colloids and Surfaces B-Biointerfaces 18, 301-313, doi:10.1016/s0927-7765(99)00156-3 (2000).

=> Comment on PubPeer.

3             Lewin, M. et al. Tat peptide-derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells. Nature Biotechnology 18, 410-414, doi:10.1038/74464 (2000).

=> Comment on PubPeer.

4             Akerman, M. E., Chan, W. C. W., Laakkonen, P., Bhatia, S. N. & Ruoslahti, E. Nanocrystal targeting in vivo. Proceedings of the National Academy of Sciences of the United States of America 99, 12617-12621, doi:10.1073/pnas.152463399 (2002).

=> Comment on PubPeer.

5             Hirsch, L. R. et al. Nanoshell-mediated near-infrared thermal therapy of tumors under magnetic resonance guidance. Proceedings of the National Academy of Sciences of the United States of America 100, 13549-13554, doi:10.1073/pnas.2232479100 (2003).

=> Comment on PubPeer.

6             Lai, C. Y. et al. A mesoporous silica nanosphere-based carrier system with chemically removable CdS nanoparticle caps for stimuli-responsive controlled release of neurotransmitters and drug molecules. Journal of the American Chemical Society 125, 4451-4459, doi:10.1021/ja028650l (2003).

=> Comment on PubPeer.

7             Wu, X. Y. et al. Immunofluorescent labeling of cancer marker Her2 and other cellular targets with semiconductor quantum dots. Nature Biotechnology 21, 41-46, doi:10.1038/nbt764 (2003).

=> Comment on PubPeer.

8             Gao, X. H., Cui, Y. Y., Levenson, R. M., Chung, L. W. K. & Nie, S. M. In vivo cancer targeting and imaging with semiconductor quantum dots. Nature Biotechnology 22, 969-976, doi:10.1038/nbt994 (2004).

=> Comment on PubPeer.

9             Sondi, I. & Salopek-Sondi, B. Silver nanoparticles as antimicrobial agent: a case study on E-coli as a model for Gram-negative bacteria. Journal of Colloid and Interface Science 275, 177-182, doi:10.1016/j.jcis.2004.02.012 (2004).

=> Comment on PubPeer.

10           Connor, E. E., Mwamuka, J., Gole, A., Murphy, C. J. & Wyatt, M. D. Gold nanoparticles are taken up by human cells but do not cause acute cytotoxicity. Small 1, 325-327, doi:10.1002/smll.200400093 (2005).

=> Comment on PubPeer.

11           El-Sayed, I. H., Huang, X. H. & El-Sayed, M. A. Surface plasmon resonance scattering and absorption of anti-EGFR antibody conjugated gold nanoparticles in cancer diagnostics: Applications in oral cancer. Nano Letters 5, 829-834, doi:10.1021/nl050074e (2005).

=> Comment on PubPeer.

12           Hussain, S. M., Hess, K. L., Gearhart, J. M., Geiss, K. T. & Schlager, J. J. In vitro toxicity of nanoparticles in BRL 3A rat liver cells. Toxicology in Vitro 19, 975-983, doi:10.1016/j.tiv.2005.06.034 (2005).

=> Comment on Pubpeer.

13           Kirchner, C. et al. Cytotoxicity of colloidal CdSe and CdSe/ZnS nanoparticles. Nano Letters 5, 331-338, doi:10.1021/nl047996m (2005).

=> Comment on PubPeer.

14           Loo, C., Lowery, A., Halas, N. J., West, J. & Drezek, R. Immunotargeted nanoshells for integrated cancer imaging and therapy. Nano Letters 5, 709-711, doi:10.1021/nl050127s (2005).

=> Comment on PubPeer.

15           Morones, J. R. et al. The bactericidal effect of silver nanoparticles. Nanotechnology 16, 2346-2353, doi:10.1088/0957-4484/16/10/059 (2005).

=> Comment on PubPeer.

16           Chithrani, B. D., Ghazani, A. A. & Chan, W. C. W. Determining the size and shape dependence of gold nanoparticle uptake into mammalian cells. Nano Letters 6, 662-668, doi:10.1021/nl052396o (2006).

=> Comment on PubPeer.

17           Huang, X. H., El-Sayed, I. H., Qian, W. & El-Sayed, M. A. Cancer cell imaging and photothermal therapy in the near-infrared region by using gold nanorods. Journal of the American Chemical Society 128, 2115-2120, doi:10.1021/ja057254a (2006).

=> Comment on PubPeer.

18           Panacek, A. et al. Silver colloid nanoparticles: Synthesis, characterization, and their antibacterial activity. Journal of Physical Chemistry B 110, 16248-16253, doi:10.1021/jp063826h (2006).

=> Comment on PubPeer.

19           Rosi, N. L. et al. Oligonucleotide-modified gold nanoparticles for intracellular gene regulation. Science 312, 1027-1030, doi:10.1126/science.1125559 (2006).

=> Comment on PubPeer.

20           Xia, T. et al. Comparison of the abilities of ambient and manufactured nanoparticles to induce cellular toxicity according to an oxidative stress paradigm. Nano Letters 6, 1794-1807, doi:10.1021/nl061025k (2006).

=> Comment on PubPeer.

 

 

Open peer review of (not so) controversial articles

Publishing articles that are critical of previously published work is notoriously difficult but the secrecy of peer review makes it hard to explain the kind of biases and tricks that one faces in this enterprise. Opening peer review, i.e. sharing reports and responses, would certainly help. Here is an interesting exemple related to an article (nicely discussed by Philip Moriarty in a previous post) which is not even critical of prior literature but touches on the stripy nanoparticles controversy. That was too much for Reviewer #1 (hyperlinks added by me; they point to relevant blog posts here or at PubPeer):

Reviewer #1 (Remarks to the Author):
This paper describes the scanning tunnelling microscopy imaging (STM) of a silver cluster (Ag374). To the best of my knowledge there is no report of such things to date. As such I think this paper should be published but in a specialised journal or a broad journal with reporting functions as Scientific Reports.

The significance of this paper as such is minimal. The STM does not add anything to what X-ray crystallography has shown so far also on the same cluster. In fact it requires strong support from calculation.

The STM itself has been widely published on nanoparticles by the group of Stellacci. The authors do reference a controversy there but do not comment on it an neither add to it.

The approach used is almost identical to the one described by such group in Ong et al ACS Nano (non cited), and the results achieved are similar to the ones described in the same paper and in Moglianetti et al. (not cited). Their minimal difference is that they achieved these results in liquid nitrogen and helium temperature, but low temperature results were described in Biscarini et al. (not cited).

Given the scant discussion in the paper (lacks any point) and the two major objections report, I suggest rejection.

The other, more supportive reports, and the response from the authors, can be downloaded from Nature Communications.

Probes, Patterns, and (nano)Particles

philipmoriarty

Philip Moriarty

This is a guest post by Philip Moriarty, Professor of Physics at the University of Nottingham (and blogger).

“We shape our tools, and thereafter our tools shape us.”

Marshall McLuhan (1911-1980)

My previous posts for Raphael’s blog have focussed on critiquing poor methodology and over-enthusiastic data interpretation when it comes to imaging the surface structure of functionalised nanoparticles. This time round, however, I’m in the much happier position of being able to highlight an example of good practice in resolving (sub-)molecular structure where the authors have carefully and systematically used scanning probe microscopy (SPM), alongside image recognition techniques, to determine the molecular termination of Ag nanoparticles.

For those unfamiliar with SPM, the concept underpinning the operation of the technique is relatively straight-forward. (The experimental implementation rather less so…) Unlike a conventional microscope, there are no lenses, no mirrors, indeed, no optics of any sort [1]. Instead, an atomically or molecularly sharp probe is scanned back and forth across a sample surface (which is preferably atomically flat), interacting with the atoms and molecules below. The probe-sample interaction can arise from the formation of a chemical bond between the atom terminating the probe and its counterpart on the sample surface, or an electrostatic or magnetic force, or dispersion (van der Waals) forces, or, as in scanning tunnelling microscopy (STM), the quantum mechanical tunnelling of electrons. Or, as is generally the case, a combination of a variety of those interactions. (And that’s certainly not an exhaustive list.)

Here’s an example of an STM in action, filmed in our lab at Nottingham for Brady Haran’s Sixty Symbols channel a few years back…

Scanning probe microscopy is my first love in research. The technique’s ability to image and manipulate matter at the single atom/molecule level (and now with individual chemical bond precision) is seen by many as representing the ‘genesis’ of nanoscience and nanotechnology back in the early eighties. But with all of that power to probe the nanoscopic, molecular, and quantum regimes come tremendous pitfalls. It is very easy to acquire artefact-ridden images that look convincing to a scientist with little or no SPM experience but that instead arise from a number of common failings in setting up the instrument, from noise sources, or from a hasty or poorly informed choice of imaging parameters. What’s worse is that even relatively seasoned SPM practitioners (including yours truly) can often be fooled. With SPM, it can look like a duck, waddle like a duck, and quack like a duck. But it can too often be a goose…

That’s why I was delighted when Raphael forwarded me a link to “Real-space imaging with pattern recognition of a ligand-protected Ag374 nanocluster at sub-molecular resolution”, a paper published a few months ago by Qin Zhou and colleagues at Xiamen University (China), the Chinese Academy of Science, Dalian (China), the University of Jyväskylä (Finland), and the Southern University of Science and Technology, Guandong (China). The authors have convincingly imaged the structure of the layer of thiol molecules (specifically, tert-butyl benzene thiol) terminating 5 nm diameter silver nanoparticles.

What distinguishes this work from the stripy nanoparticle oeuvre that has been discussed and dissected at length here at Raphael’s blog (and elsewhere) is the degree of care taken by the authors and, importantly, their focus on image reproducibility. Instead of using offline zooms to “post hoc” select individual particles for analysis (a significant issue with the ‘stripy’ nanoparticle work), Zhou et al. have zoomed in on individual particles in real time and have made certain that the features they see are stable and reproducible from image to image. The images below are taken from the supplementary information for their paper and shows the same nanoparticle imaged four times over, with negligible changes in the sub-particle structure from image to image.

This is SPM 101

This is SPM 101. Actually, it’s Experimental Science 101. If features are not repeatable — or, worse, disappear when a number of consecutive images/spectra are averaged – then we should not make inflated claims (or, indeed, any claims at all) on the basis of a single measurement. Moreover, the data are free of the type of feedback artefacts that plagued the ‘classic’ stripy nanoparticle images and Zhou et al. have worked hard to ensure that the influence of the tip was kept to a minimum.

Given the complexity of the tip-sample interactions, however, I don’t quite share the authors’ confidence in the Tersoff-Hamann approach they use for STM image simulation [2]. I’m also not entirely convinced by their comparison with images of isolated molecular adsorption on single crystal (i.e. planar) gold surfaces because of exactly the convolution effects they point towards elsewhere in their paper. But these are relatively minor points. The imaging and associated analysis are carried out to a very high standard, and their (sub)molecular resolution images are compelling.

As Zhou et al. point out in their paper, STM (or atomic force microscopy) of nanoparticles, as compared to imaging a single crystal metal, semiconductor, or insulator surface, is not at all easy due to the challenging non-planar topography. A number of years back we worked with Marie-Paule Pileni’s group on dynamic force microscopy imaging (and force-distance analysis) of dodecanethiol-passivated Au nanoparticles. We found somewhat similar image instabilities as those observed by Zhou et al…

A-C above are STM data

A-C above are STM data, while D-F are constant height atomic force microscope images [3], of thiol-passivated nanoparticles (synthesised by Nicolas Goubet of Pileni’s group) and acquired at 78 K. (Zhou et al. similarly acquired data at 77K but they also went down to liquid helium temperatures). Note that while we could acquire sub-nanoparticle resolution in D-F (which is a sequence of images where the tip height is systematically lowered), the images lacked the impressive reproducibility achieved by Zhou et al. In fact, we found that even though we were ostensibly in scanning tunnelling microscopy mode for images such as those shown in A-C (and thus, supposedly, not in direct contact with the nanoparticle), the tip was actually penetrating into the terminating molecular layer, as revealed by force-distance spectroscopy in atomic force microscopy mode.

The other exciting aspect of Zhou et al.’s paper is that they use pattern recognition to ‘cross-correlate’ experimental and simulated data. There’s increasingly an exciting overlap between computer science and scanning probe microscopy in the area of image classification/recognition and Zhou and co-workers have helped nudge nanoscience a little more in this direction. Here at Nottingham we’re particularly keen on the machine learning/AI-scanning probe interface, as discussed in a recent Computerphile video…

Given the number of posts over the years at Raphael’s blog regarding a lack of rigour in scanning probe work, I am pleased, and very grateful, to have been invited to write this post to redress the balance just a little. SPM, when applied correctly, is an exceptionally powerful technique. It’s a cornerstone of nanoscience, and the only tool we have that allows both real space imaging and controlled modification right down to the single chemical bond limit. But every tool has its limitations. And the tool shouldn’t be held responsible if it’s misapplied…

[1] Unless we’re talking about scanning near field optical microscopy (SNOM). That’s a whole new universe of experimental pain…

[2] This is the “zeroth” order approach to simulating STM images from a calculated density of states. It’s a good starting point (and for complicated systems like a thiol-terminated Ag374 particle probably also the end point due to computational resource limitations) but it is certainly a major approximation.

[3] Technically, dynamic force microscopy using a qPlus sensor. See this Sixty Symbols video for more information about this technique.

 

Scientific terrorist

At the 2018 American Chemical Society National Meeting in Boston, I asked a question to Chad Mirkin after his talk on Spherical Nucleic Acids. This is what I said:

In science, we need to share the bad news as well as the good news. In your introduction you mentioned four clinical trials. One of them has reported. It showed no efficacy and Purdue Pharma which was supposed to develop the drug decided not to pursue further. You also said that 1600 forms of NanoFlares were commercially available. This is not true anymore as the distributor has pulled the product because it does not work. Finally, I have a question: what is the percentage of nanoparticles that escape the endosome.

I had written my question and I asked exactly this although not in one block as he started answering before I had made all my points. He became very angry. The exchange lasted maybe 5 minutes. Towards the end he said that no one is reading my blog (who cares), that no one agrees with me, he called me a “scientific zealot” and a “scientific terrorist”. The packed room was shell shocked. We then moved swiftly to the next talk.

Two group leaders, one from North America and the other one from Europe, came to me afterwards.

Group leader 1:

Science is ever evolving and evidenced based. The evidence is gathered by first starting to ask questions. I witnessed an interaction between two scientists. One asks his questions gracefully and one responding in a manner unbecoming of a Linus Pauling Medalist. It took courage to stand in front of a packed room of scientists and peers to ask those questions that deserved an answer in a non-aggressive manner. It took even more courage to not become reactive when the respondent is aggressive and belittling. I certainly commended Raphael Levy for how he handled the aggressive response from Chad Mirkin. Even in disagreements, you can respond in a more professional manner. Not only is name calling not appropriate, revealing the outcomes of reviewers opinions from a confidential peer-review process is unprofessional and unethical.*

Lesson learned: Hold your self to a high standard and integrity.

Group leader 2:

Many conferences suffer from interesting discussions after a talk in such way that there are questions and there are answers. So far so good. Only in rare cases, a critical mind starts a discussion, or ask questions which imply some disagreement with the presented facts. Here I was surprised how a renowned expert like Chad Mirkin got in rage by such questions of Raphael Levy and how unprofessional his reaction was. It was not science any longer, it was a personal aggression, and this raises the question why Chad Mirkin acted like this? I do not think that this strategy helps to get more acceptance by the audience. I tribute to Raphael Levy afterwards, because I think science needs critical minds, and one should not be calm because of the fear to get attacked by a speaker. Science is full of statements how well everything works, and optimism is the fuel to keep research running. There is nothing wrong with this, but definitely one also need critical questions to make progress, and what we don’t need is unprofessional behavior and discreditation.

* Group leader 1 refers here to the outcome of the reviews of this article which you can read on ChemrXiv and which was (predictably) rejected by Nature Biomedical Engineering. During the incident Chad Mirkin used these reviews to attack me.

Update: some reactions on Twitter:

“re. your exchange at if being a critical thinker is a I think this is something we should all aspire to be. Good for you.” @wilkinglab

“Do you know Rapha’s blog? Not true that no one is reading it! It is the true gem and a rare truth island!” @zk_nano

“Wow, that’s shockingly uncool.” @sean_t_barry

“What an unprofessional guy.”  @SLapointeChem

“Calling a fellow researcher a “scientific terrorist” for raising concerns and asking a question (even if you disagree with them) is shocking. Sorry to hear that there wasn’t any real discussion instead, would’ve been interesting.” @bearore

“Surprised this isn’t getting more pub. One must wonder at what point does one’s ego/reputation become more important than the science, which ABSOLUTELY must include the bad with the good.” @Ben_Jimi440

“Keep fighting the good fight tenaciously, Raphael. Like the detectives in those old film noir shows… 🤜🏼🤛🏽”  @drheaddamage

 

The conference dinner chatter way of (not) correcting the scientific record

One of the common responses of senior colleagues to my attempts to correct the scientific record goes somewhat like this:

You are giving X [leading figure in the field] too much credit anyway. We all know that there are problems with their papers. We discussed it at the latest conference with Y and Z. We just ignore this stuff and move along. Though of course X is my friend etc.

This approach is unfair, elitist and contributes to the degradation of the scientific record.

First, it is very fundamentally unfair to the many scientists who are not present at these dinner table chatters and who may believe that the accumulation of grants, prizes, and high profile papers somewhat correlate with good science. That group of scientists will include pretty much all young scientists as well as most scientists from less advantadged countries who cannot get so easily to these conferences where the truth about scientific achievements is discussed between drinks at the end of a play-acting day (for inquisitive questions at the end of talks are of course also not the right way to act).

Second, it devalues fundamentally the role of the scientific record. We are basically accepting that it does not matter whether what gets published is right or wrong.  Here, I’ll insert an anecdote. I reviewed, a couple of years ago, a high profile review authored by a senior colleague in the field of nanoparticles. One of the figures highlighted a paper which I knew to be fundamentally wrong. In my review, I pointed that fact. The senior colleague did not dispute that the paper was flawed but he opted for keeping the figure, not discussing the fact the paper was wrong. His (post-modern) argument was that the  “concept” was important.

Dinner chatter is fine. But please also share your criticisms, e.g. via PubPeer.

(and by the way, if you could comment on our preprint on Spherical Nucleic Acids, that would be much appreciated)