Social and economic aspects of nanotechnology

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.

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

 

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
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Conclusion of this exchange?
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Time to reclaim the values of science

This post is dedicated to Paul Picard, my grand dad, who was the oldest reader of my blog. He was 17 (and Jewish) in 1939 so he did not get the chance to go to University. He passed away on the first of October 2016. More on his life here (in French) and some of his paintings (and several that he inspired to his grandchildren and great-grandchildren). The header of my blog is from a painting he did for me

A few recent events of vastly different importance eventually triggered this post.

A  (non-scientist) friend asked my expert opinion about a campaign by a French environmental NGO seeking to  raise money to challenge the use of nanoparticles such as E171 in foods. E171 receives episodic alarmist coverage, some of which were debunked by Andrew Maynard in 2014. The present campaign key dramatic science quote “avec le dioxyde de titane, on se retrouve dans la même situation qu’avec l’amiante il y a 40 ans {with titanium dioxide, we are in the same situation than we were with asbestos 40 years ago}” is from Professor Jürg Tschopp. It comes from an old media interview (2011, RTS) that followed a publication in PNAS. We cannot ask Professor Tschopp what he thinks of the use of this 5 years old quote: unfortunately he died shortly after the PNAS publication. The interpretation of this article has been questioned since: it seems likely that the observed toxicity was due to endotoxin contamination rather than the nanomaterials themselves. There is on the topic of nanoparticles a high level of misinformation and fear that finds its origins (in part) in how the scientific enterprise is run today. Incentives are to publish dramatic results in high impact factor journals which lead many scientists to vastly exaggerate both the risks and the potential of their nanomaterials of choice. The result is that we build myths instead of solid reproducible foundations, we spread disproportionate fears and hopes instead of sharing questions and knowledge. When it comes to E171 additives in foods, the consequences of basing decisions on flawed evidence are limited. After all, even if the campaign is successful, it will only result in M&M’s not being quite as shiny.

I have been worried for some time that the crisis of the scientific enterprise illustrated by this anecdote may affect the confidence of the public in science. In a way, it should; the problems are real, lead to a waste of public money, and, they slow down progress. In another way, technological (including healthcare) progress based on scientific findings has been phenomenal and there are so many critical issues where expertise and evidence are needed to face pressing humanities’ problems that such a loss of confidence would have grave detrimental effects. Last week, in the Spectator, Donna Laframboise published an article entitled “How many scientific papers just aren’t true? Enough that basing government policy on ‘peer-reviewed studies’ isn’t all it’s cracked up to be“. The article starts by a rather typical and justified critique of peer review, citing (peer-reviewed) evidence, and then, moves swiftly to climate change seeking to undermine the enormous solid body of work on man-made climate change. It just happens that Donna Laframboise is working for “a think-tank that has become the UK’s most prominent source of climate-change denial“.

One of the Brexit leaders famously declared that “people in this country have had enough of experts”. A conservative MP declared on Twitter that he”Personally, never thought of academics as ‘experts’. No experience of the real world. Yesterday, Donald Trump, a climate change denier was elected president of the USA: “The stakes for the United States, and the world, are enormous” (Michael Greshko writing for the National Geographic). These are attacks not just on experts, but on knowledge itself, and, the attacks extends to other values dear to science and encapsulated in the “Principle of the Universality of Science“:

Implementation of the Principle of the Universality of Science is fundamental to scientific progress. This Principle embodies freedom of movement, association, expression and communication for scientists, as well as equitable access to data, information and research materials. These freedoms are highly valued by the scientific community and generally well accepted by governments and policy makers. Hence, scientists are normally able to travel to international meetings, associate with colleagues and freely express their opinions regardless of factors such as ethnic origin, religion, citizenship, language, political stance, gender, sex or age. However, this is not always the case and so it is important to have mechanisms in place at the local, national and international levels to monitor compliance with this principle and intervene when breaches occur. The International Council for Science (ICSU) and its global network of Members provide one such mechanism to which individual scientists can turn for assistance. The Principle of the Universality of Science focuses on scientific rights and freedoms but implicit in these are a number of responsibilities. Individual scientists have a responsibility to conduct their work with honesty, integrity, openness and respect, and a collective responsibility to maximize the benefit and minimize the misuse of science for society as a whole. Balancing freedoms and responsibilities is not always a straightforward process. For example, openness and sharing of data and materials may be in conflict with a scientist’s desire to maintain a competitive edge or an employer’s requirements for protecting intellectual property. In some situations, for example during wars, or in specific areas of research, such as development of global surveillance technologies, the appropriate balance between freedoms and responsibilities can be extremely difficult to define and maintain. The benefits of science for human well-being and development are widely accepted. The increased average human lifespan in most parts of the world over the past century can be attributed, more or less directly, to scientific progress. At the same time, it has to be acknowledged that technologies arising from science can inadvertently have adverse effects on people and the environment. Moreover, the deliberate misuse of science can potentially have catastrophic effects. There is an increasing recognition by the scientific community that it needs to more fully engage societal stakeholders in explaining, developing and implementing research agendas. A central aspect of ensuring the freedoms of scientists and the longer term future of science is not only conducting science responsibly but being able to publicly demonstrate that science is being conducted responsibly. Individual scientists, their associated institutions, employers, funders and representative bodies, such as ICSU, have a shared role in both protecting the freedoms and propagating the responsibilities of scientists. This is a role that needs to be explicitly acknowledged and embraced. It is likely to be an increasingly demanding role in the future.

It is urgent that we, scientists, reclaim these values of humanity, integrity and openness and make them central (and visibly so) in our Universities. To ensure this transformation occurs, we must act individually and as groups so that scientists are evaluated on their application of these principles. The absurd publication system where we (the taxpayer) pay millions of £$€ to commercial publishers to share hide results that we (scientists) have acquired, evaluated and edited must end. There are some very encouraging and inspiring open science moves coming from the EU which aim explicitely at making “research more open, global, collaborative, creative and closer to society“. We must embrace and amplify these moves in our Universities. And, as many, e.g. @sazzels19 and @Stephen_curry have said, now more than ever, we need to do public engagement work, not with an advertising aim, but with a truly humanist agenda of encouraging curiosity, critical thinking, debates around technological progress and the wonders of the world.

 

The Internet of NanoThings

Nanosensors and the Internet of Nanothings” ranks 1st in a list of ten “technological innovations of 2016” established by no less than the World Economic Forum Meta-Council on Emerging Technologies [sic].

The World Economic Forum, best known for its meetings in Davos, is establishing this list because:

New technology is arriving faster than ever and holds the promise of solving many of the world’s most pressing challenges, such as food and water security, energy sustainability and personalized medicine. In the past year alone, 3D printing has been used for medical purposes; lighter, cheaper and flexible electronics made from organic materials have found practical applications; and drugs that use nanotechnology and can be delivered at the molecular level have been developed in medical labs.

However, uninformed public opinion, outdated government and intergovernmental regulations, and inadequate existing funding models for research and development are the greatest challenges in effectively moving new technologies from the research lab to people’s lives. At the same time, it has been observed that most of the global challenges of the 21st century are a direct consequence of the most important technological innovations of the 20st century.

Understanding the implications of new technologies are crucial both for the timely use of new and powerful tools and for their safe integration in our everyday lives. The objective of the Meta-council on Emerging Technologies is to create a structure that will be key in advising decision-makers, regulators, business leaders and the public globally on what to look forward to (and out for) when it comes to breakthrough developments in robotics, artificial intelligence, smart devices, neuroscience, nanotechnology and biotechnology.

Given the global reach and influence of the WEF, it is indeed perfectly believable that decision-makers, regulators, business leaders and the public could be influenced by this list.

Believable and therefore rather worrying for – at least the first item – is, to stay polite, complete utter nonsense backed by zero evidence. The argument is so weak, disjointed and illogical that it is hard to challenge. Here are some of the claims made to support the idea that “Nanosensors and the Internet of Nanothings” is a transformative  technological innovations of 2016.

Scientists have started shrinking sensors from millimeters or microns in size to the nanometer scale, small enough to circulate within living bodies and to mix directly into construction materials. This is a crucial first step toward an Internet of Nano Things (IoNT) that could take medicine, energy efficiency, and many other sectors to a whole new dimension.

Except that there is no nanoscale sensor that can circulate through the body and communicate with internet (anyone knows why sensors would have to be nanoscale to be mixed into construction materials?).

The next paragraph seize on synthetic biology:

Some of the most advanced nanosensors to date have been crafted by using the tools of synthetic biology to modify single-celled organisms, such as bacteria. The goal here is to fashion simple biocomputers [Scientific American paywall] that use DNA and proteins to recognize specific chemical targets, store a few bits of information, and then report their status by changing color or emitting some other easily detectable signal. Synlogic, a start-up in Cambridge, Mass., is working to commercialize computationally enabled strains of probiotic bacteria to treat rare metabolic disorders.

What is the link between engineered bacteria and the internet? None. Zero. I am sorry to inform the experts of the WEF that bacteria, even genetically engineered ones, do not have iPhones: they won’t tweet how they do from inside your gut.

I could go on but will stop. Why is such nonsense presented as expert opinion?

Nanoparticles & cell membranes: history of a (science) fiction?

One of the reason scientists, journalists and the general public are excited about nanoparticles is their supposed ability to cross biological barriers, including, the cell membrane. This could do wonders for drug delivery by bringing active molecules to the interior of the cell where they could interact with key components of the cell machinery to restore function or kill cancer cells. On the opposite side of the coin, if nanoparticles can do this, then there are enormous implications in terms of their potential toxicity and it is very urgent to investigate. But is it true? What is the evidence? How did this idea come into the scientific literature in the first place? I have been intrigued by this question for some time. It is the publication of an article about stripy nanoparticles magically crossing the cell membrane that led me to engage in what became the stripy nanoparticles controversy. It is this same vexing question that led me to question Merck/Mirkin claims about smartflare/nanoflare/stickyflare.

In the introduction of our article “The spherical nucleic acids mRNA detection paradox“, we describe the long history of the use of gold nanoparticles (“gold colloids”) in cell biology and conclude that

…, more than five decades of work has clearly established that nanoparticles enter cells by endocytotic mechanisms that result in their entrapment inside intracellular vesicles unless those nanoparticles are biological in nature and have acquired through evolution, advanced molecular tools which enable them to escape.

In the paragraph that followed, we were trying to make the point, in part using citation data of one of these 1950s pioneering articles, that this solid knowledge has been ignored in some of the thousands of recent articles on interactions of nanoparticles with membranes and cells that have appeared in the past 15 years. In his review of the first version of our article, Steve Royle criticises that latter paragraph (in his word, a “very minor” point):

I’m not a big fan of using number of Web of Science search results as an argument (Introduction). The number of papers on Gold Nanoparticles may be increasing since 2007, but then so are the number of papers on anything. It needs to be normalised to be meaningful. It’s also a shame that only 5 papers have cited Harford et al., but it’s an old paper, maybe people are citing reviews that cover this paper instead?

This is a fair point. While normalisation as well as more detailed and systematic searches might shed some light, it is rather difficult to quantify an absence of citation. Instead, I have tried to discover where the idea that nanoparticles can diffuse through membranes comes from. Here are my prime suspects (but I would be more than happy to update this post to better reflect the history of science and ideas so please leave comment, tweet, email), Andre Nel and colleagues, in Science, 3rd of February 2006, “Toxic Potential of Materials at the Nanolevel” :

“ Moreover, some nanoparticles readily travel throughout the body, deposit in target organs, penetrate cell membranes, lodge in mitochondria, and may trigger injurious responses.”

This claim is not supported by a reference, but later in the article Nel et al refer to an earlier paper entitled “Ultrafine particles cross cellular membranes by nonphagocytic mechanisms in lungs and in cultured cells” by Marianne Geiser and colleagues. These two papers, Nel et al, and, Geiser et al, have been cited respectively 5000 times and 850 times according to PubMed.

As early as 2007, Shayla Banerji and Mark Hayes had already challenged this idea of transport of nanoparticles across membranes in an elegant experimental and theoretical study which was a direct response to the two papers cited above “Examination of Nonendocytotic Bulk Transport of Nanoparticles Across Phospholipid Membranes“:

In accordance with these health concerns, Nel et al. have described some phenomena that can only potentiate fear of the negative health risks associated with nanotechnology.

[…]

Non-endocytotic transmembrane transport of large macromolecules is a significant exception to what is presently known about cell membrane permeability. Most early studies show that lipid bilayers are essentially impenetrable by molecules larger than water under physiological conditions: transport of most molecules across cell membranes is specifically cell-mediated by endocytosis.34 Endocytosis, unlike proposed passive, non-endocytotic transport, is an active cell-mediated process by which a substance gains entry into a cell. Specifically, a cell’s plasma membrane continuously invaginates to form vesicles around materials that originated outside the membrane: as the invagination continuously folds inward, the cell membrane constituents simultaneously reorganize in such a way that the material being transported into the cell is completely enclosed in a lipid bilayer, forming an endosome.35,36

[…]

The results suggest that a diffusive process of transport is not likely.

Figure 8 is particularly telling (!).

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The article by Shayla Banerji and Mark Hayes has been cited 44 times.

 

#Chemophobia and #Nanophobia

In an excellent post entitled “How to recognize (and talk to) a chemophobe” (that I encourage you to read in full), Ash Jogalekar writes:

Chemophobes fear a technically nebulous entity called “chemicals” that’s all too real to them. The problem is that in the jargon of chemistry, “chemicals” essentially means everything in the material world, from fuels and plastics to human bodies and baby oil.

There is a strong parallel between the fear of chemicals and the fear of nanoparticles. If anything, the “nanoparticle” entity is an even broader, and therefore more nebulous, category than “chemicals”. Nanophobia, the fear of nanoparticles is just as irrational as chemophobia, not because all nanoparticles are benign (they are not), but because they constitute a category so broad that thinking in terms of the risks of nanoparticles does not help anyone asking the right scientific and epidemiological questions.

There is however a strong difference between chemophobia and nanophobia.

In the case of chemophobia, most of the scare comes from outside the scientific community, e.g. the Food Babe, and there is a challenge mounted within the scientific community with an attempt to bridge the gap, e.g. Chemistry blog, sense about science, etc.

In the case of nanophobia, many of the scare originate within the community, often with comments about the dangers of those highly nebulous entities called “nanoparticles” from studies that consider one particular material at one particular dose in one particular biological model. Those can take the form of press release, of reports or even be included in scientific articles. They are then build up in blogs and media by various organisations.

Instead of challenging the fear of this nebulous entity, we hear again and again that “more research is needed to understand the toxicological properties of nanomaterials”. We need toxicological research on new molecules and materials which are – or will be – in mass production. The reasearch focus needs to be on a reasonable scientifically sound evaluation of risks, not led by the irrational fear of a “trigger word” [see Ash again for introduction to this term].

To conclude, here is the key message of sense about science “Making sense of chemical storiesguide, adapted (minor changes) to nanoparticles:

The reality boils down to six points:

  • You can’t lead a nanoparticle-free life.
  • Natural isn’t always good for you and man-made nanoparticles are not inherently dangerous.
  • Synthetic nanoparticles are not causing many cancers and other diseases.
  • We need man-made nanoparticles.
  • We are not just subjects in an unregulated, uncontrolled environment, there are checks in place.