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


References for my talk at Gold 2018

Update: the slides are available (here: gold2018-Levy2) and there is a recording of a few minutes here.

Slide 1:

Slide 2: Nanotech is bs Tweet.

Slide 3: Calling Bullshit.

Slide 4:  Dinosaur. (from here)

Slide 5: Electron microscopy of Hela cells after the ingestion of colloidal gold; C.G. Harford, A. Hamlin, and E. Parker; 1957

Slide 6: The entry and distribution of herpes virus and colloidal gold in Hela cells after contact in suspension; M. A. Epstein, K. Hummeler, and A. Berkaloff; 1963

Slide 7:

Slide 8: The spherical nucleic acid paradox; D. Mason, G. Carolan, M. Held, J. Comenge, S. Cowman, and R. Lévy; 2015

Slide 9: Excerpt from email (shared with permission).

Slide 10:  Evaluation of SmartFlare probe applicability for verification of RNAs in early equine conceptuses, equine dermal fibroblast cells and trophoblastic vesicles;  S. Budik, W. Tschulenk, S. Kummer, I. Walter, and C. Aurich; 2017

Slide 11: SmartFlares fail to reflect their target transcripts levels; M. Czarnek and J. Bereta; 2017

Slide 12: Calcium-Binding Proteins S100A8 and S100A9: Investigation of Their Immune Regulatory Effect in Myeloid Cells; J. Yang, J. Anholts, U. Kolbe, J.A. Stegehuis-Kamp, F.H.J. Claas and M. Eikmans

Slide 13: SmartFlare catalog.

Slide 14:

Drug Discovery 2017

This is a guest post by Marie Held reporting from the ELRIG conference held last week.

On 3rd-4th October I attended ELRIG’s flagship event, Drug Discovery 2017, in Liverpool. With around 250 participants, it was the largest of the ELRIG conferences yet. The spacious arrangement of the vendors and posters in the exhibition hall was a refreshing change. There was ample space to mingle, chat and discuss equipment on show.

On day one, I attended the Advances in Imaging stream (one of three parallel streams). The keynote lecture by Tony Ng covered a broad range of the spatial scale, stressing the importance of whole body imaging in cancer in combination with investigating the tumour microenvironment down to super resolution imaging of individual molecules. He outlined their attempts in predicting tumour metastasis enabled via immune system hijacking by the cancer cells. An important conclusion was that with the wealth of imaging methods and tracers being developed, we need standardisation and validation across facilities to bring them closer to the clinic, ultimately improving the lives of patients. The imaging methods discussed in the following six talks ranged from man to molecule, focussing on ever smaller features as the day went on. A transpiring theme was the generation of large amounts of data from different techniques and the associated challenge of deriving meaningful information. Machine learning and artificial intelligence were mentioned time and again as being part of that quest. The last scientific presentation, by Charlotte Dodson, focussed on twinkling enzymes, studying the conformational changes of kinases in disease and after treatment via single molecule spectroscopy. Throughout the imaging stream, twelve men contributed to the presentations, vendor snapshots and poster tasters and three women contributed to the stream. The other streams were a bit more gender balanced but only the workshop on Tuesday achieved a 50/50 split.

On the second day, I attended the Lab of the Future workshop presented by SiLA and ELRIG. The general consensus was that the lab of the future (whether you call it Lab 4.0, Industry 4.0 or something else) is an interconnected space in which smart machines are communicating with each other, running fully automated cycles of fabrication, screening and/or testing. Machinery that can be monitored if not controlled remotely via mobile device apps was mentioned multiple times. Smart products are uniquely identifiable, may be located at any time and “know” their own history, current status and alternative routes to achieving their target state. It left some of the audience wondering where innovation is going to come from. A lot of innovation is not based on a “Eureka” moment but rather lucky accidents or not quite sticking to the protocol and making mistakes. These instances are near on excluded in an automated lab. Another doubt that was raised was: Where is the space, if not need, for the scientist is in this fully automated lab? “He” has more time to think about the science and efficiency gains rather than processing the work. Unfortunately, the scientist was exclusively referred to as a “he” throughout the whole workshop, which irritated myself and another female member of the audience to the extent that it seemed appropriate to clarify that the scientist can be a female scientist. Unconscious discrimination is one of the reasons why there are still so few leading women in science. There was a conspicuous lack of women, both in the audience and in particular in the selection of session leaders, which were all male. It would be nice to see some female panel members in the future. Also, this year only one out of 12 session chairs throughout the whole conference were female.

Near on every panel member in the lab of the future workshop voiced that the interconnectivity should be down scalable to medium and small labs. As a member of the academic research community and a small lab, I felt somewhat left out though. We do not generally use automated machinery, never mind machinery connected to the internet of things. Often enough there is a piece of equipment, that has to be taken off the net entirely because the software is so outdated (and not supplier maintained anymore) that it has to run on an obsolete operating system posing a risk to the University network. That means we are in fact taking a step away from the lab of the future. The audience saw the responsibility with the industrial sector to come up with a solution and I am looking forward to seeing a change in the future. Also, electronic notebooks (find the same presentation here with audio comment) are already a standard in the industrial sector but the academic sector is severely lagging behind. Not all universities have specific guidelines on how to keep a paper lab book, never mind having a system of electronic lab books in place. The responsibility here lies in the academic sector to catch up but it might have to be a bottom up approach to induce a change.

The high point of the second day and probably the conference as a whole was the plenary keynote by Dr Nessa Carey asking whether we can fix big pharma. Her keynote was eloquent, inspiring and also entertaining. We can all do our bit to help fix big pharma. It is not the evil it is often made out to be. Millions of lives have been saved by pharmacological advances and still are being saved, however it does suffer from the worst PR there is.

Overall, I enjoyed the ELRIG Drug Discovery 2017 and am looking forward to the next instalments in London in 2018 and back in Liverpool in 2019.


At the 254th ACS conference in Washington DC

This is a guest post by Sumaira Ashraf.

Last month, I got the opportunity to attend and present my work at the 254th ACS conference held in Washington DC. The session was organized by Raphaël Lévy, Niveen Khashab, and Zhihong Nie. I presented preliminary data regarding my work on multimodal imaging probes for stem cell tracking. I enjoyed the conference but was disappointed by some of the talks. Many speakers  exaggerate their results to impress their audience and hype the worth of their work. I did wonder if it is productive to point out mistakes as no one seems interested in correcting them, but, instead, they might become your lifelong rivals. Here is an example. I know from practical experience that liposomes loaded with small molecule dyes cannot be used as long-term imaging modality because within 24 hrs of loading ~99% signal intensity is lost due to leakage from the liposomal cavity. But speakers presented quantitative imaging data based on these approaches. I wanted to point this problem out but I did not want to get involved in never ending discussion where no one will be ready to admit their errors. Eventually, I did not say anything.

Of course, my own work with polylelectrolyte capsules has some limitations as well: while they are good candidates for protecting imaging probes from intracellular degradation and intracellular species from potentially toxic probes, the limit of detection depends on the amount of contrast agent delivered which still remain low. In my current experiments, I need to overcome this limitation by modifying or choosing an alternate approach.

The Kavli lectures were really very informative… but I could not attend the full talk of the 2nd speaker because the air conditioning was set at a temperature so low that I could not tolerate it: I was forced to leave this interesting lecture. The industry exhibition downstairs the convention centre was massive and fun. I particularly liked the Bruker stall which had good explanation of NMR, mass spectrometers, etc., (covering theoretical and experimental data evaluation). There were other advantages to the visit of the exhibition: chocolates, bags, T- shirts, ice cream (prepared in liquid nitrogen within 3 minutes), lunch, free L’Oréal products, and lucky draw (especially when you win; I won a Swag Bag of merchandise from the ACS Store worth USD$75.00). I was lucky to see the solar eclipse through the cover glasses provided by the conference.

I missed the opportunity to visit the reflecting pool near Lincoln memorial and some interesting museums due to time limitation. I am looking forward to some forthcoming opportunity to see them.

I came back with some thoughts to work with new nanocomposites (recent work presented in one of the talk by Amit Joshi; based on doping materials rather than combining them inside big capsules or attaching via linkers) for multimodal imaging which might have potential to overcome the flaws associated with above mentioned materials. But I need to try… without trying one cannot be sure of anything.

Time-resolved Microscopy and Correlation Spectroscopy

This is a guest post from Jennifer Francis, PhD Student in the group. When group members go to conferences or courses, they have to write a travel blog post.

I recently attended the 8th European Short Course on “Time-resolved Microscopy and Correlation Spectroscopy” at PicoQuant headquarters in Aldershof-Berlin; specifically to learn about the principles and application of FRET, FLIM, and FCS to the Life Sciences. A day prior to this microscopy course, I also attended the 14th SymPhoTime Training Day. As well as discussing problems and applications of the SymPhoTime64 software with other users, I also had the opportunity to speak with a programmer of the software, who demonstrated many new features and assisted with analysis of my own FCS measurements at a computer station. My mornings generally started with passing an incredible sculpture of two heads, before arriving at the Max Born Institute for lectures delivered by scientists in the field of time-resolved microscopy, including Professor Jörg Enderlein.

two heads

Landmark of Berlin-Aldershof: Kopfbewegung – heads, shifting.


After a Flammkuchen, I participated in afternoon practical microscopy sessions, where I got the chance to experience the commercially available super-resolution microscope: MicroTime 200 STED, which was awesome. Not only did we see this cutting-edge instrument in action, resolving structures below the diffraction limit, but we also had a peek inside the operating laser boxes! Whilst at the STED station, members of GATTAquant informed us about nanorulers, which are new standards for super-resolution microscopy. Another highlight of this workshop was the demonstration of the Zeiss LSM 880 with Airyscan, which boasts 32 detectors. There were a total of 42 participants on this course, both from academia and industry, including microscope representatives from Olympus, Zeiss, Leica, and Nikon. The consensus take home tip from all participating microscope companies was to always match the refractive index of the objective with that of the sample and to adjust the correction collar to take into account coverslip thickness.


A postcard from Israel

Originally published on the University of Liverpool news website.

“I sat next to the taxi driver. We started talking. The ride from my hotel on Ben Yehuda Street in down town Tel Aviv to the Bar Ilan campus takes about 45 minutes. ‘Liverpool’, the taxi driver said, ‘I was there several times in the 1950s; I was a sailor.’

I was sufficiently intrigued to ask him his age. ’80 in six months,’ was his reply. He, who was older than his country, had no shortage of stories and the 45 minutes went quickly. When the Suez crisis broke in 1956, he was in Odessa, Soviet Union, on a tanker ship supposed to bring coal to Israel. I also learnt that Russia is 800 times larger than Israel.

I had spent the previous three days at Tel Aviv University, closer to the city centre, starting the week (on Sunday, of course) by giving a seminar in the Centre for Nanoscience and Nanotechnology. In Bar Ilan, I visited and gave a seminar at BINA, the Institute for Nanotechnology and Advanced Materials. The aim of my 10 days visit, funded by the British Council, is to develop scientific collaborations with Israeli colleagues and so, beyond taxi drivers, I met biologists, physicists and chemists working on areas more or less related to my own research interests, i.e. the preparation of nanoparticles and their applications in biology, especially for imaging of biomolecules and tracking of cells.

The discussions, prompted by my somewhat provocative, or ‘iconoclastic’ as one distinguished Israeli colleague put it, seminar were not limited to nanoscience but extended to the reproducibility crisis, changes in the scientific publishing landscape, and the opportunities that the internet offers to improve the way we do science by increasing the sharing of ideas (including critiques) and the sharing of data.

The tree of knowledge and electronics, and, Ouri’s corner by Asaf Lifshitz.

The tree of knowledge and electronics, and, Ouri’s corner (detail), by Asaf Lifshitz. Picture by Raphaël Lévy.

This week, I complete my journey by visiting a third major Israeli institution, and giving two more seminars, at the Technion, situated in Haifa, also on the coast, an hour by train North of Tel Aviv. The stunning campus is decorated by a number of sculptures. The first seminar takes place in the Institute of Biomedical Engineering and the second in Chemical Engineering.

During these ten days I will have met over 50 scientists at different stages of their careers and I hope that there will be some lasting links; maybe one of the younger ones will join my lab in Liverpool, or, an international collaborative project will take shape with more established colleagues? Whatever happens, if I go again, I’ll send you another postcard from Israel.”

How do I know if an article is good? an #ACSBoston tale

This week I attended the fall meeting of the American Chemical Society in Boston. A little meeting of about 14,000 attendees. I was speaking in a symposium with an impossibly long title but which turned out to be good fun and interesting; big thanks to the organisers: Kimberly Hamad-Schifferli, Clemens Burda and Wolfgang Parak.

IMG_0117I spent most of my time in that symposium but also went to a few other sessions which tackled questions surrounding the ways we do and communicate science. I learnt a bit more about the activities of the Center for Open Science and the platform they offer to researchers to organise, plan, record and share their work (and I was even offered a T-shirt). Probably the best lecture I heard – and certainly the most entertaining – was in a science communication session “The poisoner’s guide to communicating chemistry” by Deborah Blum (now I really need to read her book).

I joined a session with the promising title of “Scientific Integrity: Can We Rely on the Published Scientific Literature?“. Judith Currano (Head of the Chemistry Library, University of Pennsylvania) discussed how to help students evaluate the quality of scientific articles; I reproduce the abstract below (italics and bold mine):

This paper, by a chemistry librarian and a professor who edits an online journal, frames the challenges facing scientists at all levels as a result of the highly variable quality of the scientific literature resulting from the introduction of a deluge of new open-access online journals, many from previously unknown publishers with highly variable standards of peer review. The problems are so pervasive that even papers submitted to well-established, legitimate journals may include citations to questionable or even frankly plagiarized sources. The authors will suggest ways in which science librarians can work with students and researchers to increase their awareness of these new threats to the integrity of the scientific literature and to increase their ability to evaluate the reliability of journals and individual articles. Traditional rules of thumb for assessing the reliability of scientific publications (peer review, publication in a journal with an established Thomson-Reuters Impact Factor, credible publisher) are more challenging to apply given the highly variable quality of many of the new open access journals, the appearance of new publishers, and the introduction of new impact metrics, some of which are interesting and useful, but others of which are based on citation patterns found in poorly described data sets or nonselective databases of articles. The authors suggest that instruction of research students in Responsible Conduct of Research be extended to include ways to evaluate the reliability of scientific information.

Now the problem of (rapidly) evaluating the reliability of an article, especially for new researchers in a particular field is a serious and acute one, so I fully approve the author’s suggestions.

However the entire paper is based largely on a false premise: the idea that it is the “introduction of a deluge of new open-access online journals” which creates this reliability problem. This is hardly the case. The difficulty in identifying poor articles is not the deluge of open access journals nor is it predatory publishing. The growth in the volume of publications is not particularly related to open access and predatory publishing can be easily identified (with a little bit of common sense and a few pointers). The abstract (and to a lesser extent the talk) also conflates the evaluation of the reliability of a journal (an impossible task if you ask me) and the reliability of an article (an extremely onerous task if you ask me, but more on this later). Do I need to comment on the “rule of thumbs“?

I do teach third year undergraduate students on a similar topic. I ask them this same question: “how can you evaluate the validity of a scientific article?”. I write their answers on the white board; in whatever order, I get: the prestige of the University/Authors/Journal, the impact factor, the quality (?) of the references… I then cross it all. I show the Arsenate DNA paper published in Science, the STAP papers published in Nature. I try to convince them that no measure of prestige can help them evaluate the quality and reliability of a paper, that the only solution they have is to read the paper carefully and critically analyse the data. If necessary, discuss it with others. If necessary ask questions to the authors.

Of course, reading carefully takes time, but there is (currently) no alternative. There is absolutely no reason to think that a paper is reliable because it is in an high impact factor journal. The Scottish philosopher David Hume (1771-1776) wrote that “A wise man proportions his belief to the evidence”…and should “always reject the greater miracle.” Many articles in high impact journals resemble such miracles and eventually turn out to be irreproducible.

The second part of my own scientific presentation focused on our ongoing SmartFlare project. On the last slide, it featured the David Hume quote as well as an updated 21st version (see below).


With the PubPeer browser extension, you can immediately see, on the journal page (or anywhere else the article is cited) if there is an existing discussion at PubPeer

There is however something simple that we can do immediately to make it easier for every body to evaluate the reliability of individual articles: sharing our critiques (positive or negative) of articles we read. If we all commit to use PubPeer and start sharing at least one review per month, this will go a very long way towards generating open discussions around articles. It will obviously not alleviate the need to read the articles and the reviews critically, but it will crowd source the evaluation and this can be very powerful (it is the model of SJS, ScienceOpen, F1000).