Mirkin

Do planes fly and other difficult scientific questions

The Scientist magazine reported on the ACS meeting incident. Here is Chad Mirkin’s response to their questions:

Mirkin disagrees with Levy’s assessment of the endosome entrapment. “Levy’s narcissistic approach is akin to, ‘I bought an airplane, and I can’t make it fly. Therefore, planes don’t fly, despite the fact that I see them all above me,’” he tells The Scientist.

Mirkin stresses the number of studies in which the probes have been used successfully: “There is no controversy . . . There are over 40 papers reporting the successful use of such structures, involving over 100 different researchers, spanning three different continents,” he writes to The Scientist in an email. “I think the data and widespread use of such structures speak to their reliability and utility for measuring RNA content in live cells,” he adds.

After “dishonest Rafael [sic] Levy and his band of trolls“, “scientific terrorist” and “scientific zealot“, I suppose the “narcissistad hominem, could be considered more moderate?

1920px-John_William_Waterhouse_-_Echo_and_Narcissus_-_Google_Art_Project

Echo and Narcissus, John William Waterhouse, 1903, Walker Art Gallery, Liverpool. Narcissus, too busy contemplating his image, cannot see Echo let alone planes flying above him.

As The Scientist notes, I am hardly the only one who cannot make the SmartFlare plane fly. And the plane manufacturer has stopped selling its product and does not answer questions from journalists.

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:

The great answer to people saying that #preprints are not peer-reviewed

That perfect title is courtesy of (see tweet below)

On Monday (25/06), we will publish a preprint about the spherical nucleic acid technology. Our paper was prompted by the publication in Nature Biomedical Engineering of “Abnormal scar identification with spherical-nucleic-acid technology” by Yeo et al.

The great answer is… review them! I issued a call to review our preprint before it comes out and I have now sent the article to a number of colleagues across the world. I am very much looking forward to their comments good or bad. The comments will be posted on PubPeer. If you have some time on your hands this Friday or over the weekend to look at the paper, drop me an email and I will also send you a preview copy.

Yeo et al corresponding authors were provided with a copy of our preprint two weeks ago but unfortunately they have not responded. I hope they will post comments on PubPeer. We are planning to subsequently submit a version (hopefully improved thanks to the comments) to Nature Biomedical Engineering. It is however sometime rather difficult to debate the scientific literature through the official channels of traditional journals so this route via preprint will accelerate this important discussion.

 

Mind-boggling plagiarism of this blog

In January 2015, someone went to the effort of creating a fake raphazlab blog as the stripy nanoparticles controversy was descending from a scientific debate into the gutters of online discussions.

Fast forward three years. The Spherical Nucleic Acids controversy is slowly heating up. Chad Mirkin continues to win prizes after prizes, but he is unseemly asked to comment on the failing SmartFlare technology (the commercial name of the Spherical Nucleic Acids) by Dalmeet Singh writing for Chemistry World.

Dalmeet writes:

But Chad Mirkin, a chemist at Northwestern University in the US, who developed the precursor to SmartFlares, nanoflares, pointed Chemistry World to more than 30 papers, which, he says, have successfully used the technology.

Chemistry World contacted a number of groups that have used SmartFlares. Hirendranath Banerjee, a molecular biologist at Elizabeth City State University in North Carolina, describes SmartFlares as a ‘very novel and effective technique’, noting that it has been helpful in evaluating gene expression experiments in his lab.2

Now comes the mind-boggling part.

The introduction of Hirendranath’s paper (reference 2 above) is largely plagiarized… from this very blog. From the very first SmartFlare post on this blog, entitled How smart are the SmartFlares?

Below, is an excerpt from my post with, in red, the sentences that reference 2 copied.

RNA molecules play crucial roles in cells such as coding, decoding, regulation, and expression of genes, yet they are much more difficult to study. SmartFlares are nanoparticle-based probes for the detection and imaging of RNA in live cells. Could they become the GFP of the RNA world?

 Many certainly believe this to be the case. SmartFlare ranked second in TheScientist top ten 2013 innovations, with one of the judges, Kevin Lustig, commenting “These new RNA detection probes can be used to visualize RNA expression in live cells at the single-cell level.”  The following year, SmartFlare won an R&D100 award. The technology comes from Chad Mirkin’s lab at Northwestern University. Chad Mirkin is the winner of numerous prestigious prizes and a science adviser to the President of the United States. The scientific articles introducing the SmartFlare concept (under the name of Nano-Flare) were published in the Journal of the American Chemical Society in 2007, ACS Nano in 2009, etc. In 2013, the SmartFlare technology was licensed to EMD Millipore. Here is one of their promotional video:

For a molecular sensor to work, it needs a detection mechanism. The principle of the SmartFlare is explained from 0:45. A capture oligonucleotide (i.e. DNA) is bound to the gold nanoparticles. A reporter strand is bound to the capture strand. The reporter strand carries a fluorophore but that fluorophore does not emit light because it is too close to the gold (the fluorescence is “quenched”). In the presence of the target RNA, the reporter strand is replaced by the target RNA and therefore released, quenching stops, and fluorescence is detected.

This is plagiarism, with, in addition, a clear intent to deceive: whilst the article entire point appears to be the celebration of the SmartFlare technology, e.g concluding sentence (Thus Smart Flare novel gold nanoparticles could revolutionize the field of differential gene expression studies and drug discovery), the 2015 blog post was already doubting the validity of the technology.
I wrote to the Editor of the Journal who said that they would evaluate the claims and take some form of action. I contacted Hirendra Banerjee who declined to provide a statement; instead he issued a legal threat against the publication of this post.
Meanwhile, on Twitter
Capture
Capture
Capture
Conclusion of this exchange?
Capture

Guest post: SmartFlares fail to reflect their target transcripts levels

Czarnek&BeretaThis is a guest post by Maria Czarnek and Joanna Bereta, who have just published the following article in Scientific Reports entitled SmartFlares fail to reflect their target transcripts levels

We got the idea of using SmartFlare probes when working on generating knockout cells. In the era of CRISPR-Cas9 genome editing, the possibility of sorting out knockout cells based on their low target transcript content (mRNAs that contain premature stop codons are removed in a process called nonsense-mediated decay) instead of time-consuming testing of dozens or thousands of clones would be a great step forward. SmartFlare probes seemed to be just the ticket: no transfection, lysis or fixation needed; moreover, the probes were supposed to eventually leave the cells. We were full of hope as the first probes arrived. (more…)

A RESPONSE FROM CHAD MIRKIN’S GROUP [follow up #1/n]

Some readers might wonder why I am going on about this, so let me tell you: this is a considerably more important story than Stripy Nanoparticles Revisited. If, as I am arguing, some of this science is shaky, then it is not only the way we evaluate scientists and spend public money which are put into question, but the foundation of ongoing clinical trials.

Back to basics: in the section of Mirkin’s group PhD dissertation (previous post) that respond to our critique of their work on Spherical Nucleic Acid / SmartFlare / StickyFlare, they wrote the following:

Additionally, since the commercialization and sale of the nanoflare platform under the trade name Smartflare (Millipore), dozens of researchers around the world have participated in successful sequence-specific gene detection.[80]

Reference [80] correspond to six (half a dozen) articles, 80a to 80f (see below for details and links). Out of these six, only two are actual research papers, and, for both, the SmartFlares are a very minor addition to the work. Out of these two, only one is completely independent of Mirkin/EMD Millipore (the other one comes from Northwestern).

80a) is not primary research; it is an advertorial produced by EMD Millipore.

80b) is not primary research: it is a 300 words congress abstract (no figure). A follow up paper by the same group is discussed here.

80c) is a review and it is a collaboration between Northwestern (Mirkin’s University) and EMD Millipore. CoI statement from the paper: “D. Weldon is the R&D Manager at EMD Millipore responsible for the production of SmartFlares. Patents related to therapeutically targeting Nodal in tumor cells have been awarded to E.A. Seftor, R.E.B. Seftor, and M.J.C. Hendrix.

80d) is a research paper. It does not show in any way that SmartFlares work. It assumes it does. The SmartFlare is a minor part of the article.

80e) is not primary research: it is an advertorial in a magazine funded by company advertising (including EMD Millipore in that very issue). The author is a journalist working for the magazine, not a practicing scientist.

80f) is a research paper. It does not show in any way that SmartFlares work. It assumes it does. SmartFlares are a very minor part of the article. The authors are from Northwestern, i.e. Mirkin’s University.