Social and economic aspects of nanotechnology

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.

 

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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 (!).

Capture

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.

How smart are SmartFlares?

This post is co-authored by Raphaël Lévy and Dave Mason.

Note: We contacted Chad Mirkin and EMD Millipore for comments. Chad Mirkin replied but did not allow me to share his comments as he prefers to discuss his work in peer reviewed manuscripts rather than blogs. EMD Millipore has provided a response (reproduced below) and is keen to further engage in the discussion.  They wrote that they “look forward to responding to [the questions you pose at the end of the post] after your blog is posted so other researchers who may have the same questions can follow our discussion online.” [Update: they have gone into silent mode after that comment].

Update: The results of our study have now been published.


To image proteins in cells, biologists have powerful tools based on the Green Fluorescent Protein (GFP) for which Osamu Shimomura, Martin Chalfie and Roger Y. Tsien  obtained the 2008 Nobel Prize in Chemistry. 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. The release is shown at 2:05. Simple and convincing. Gold nanoparticles are indeed excellent fluorescence quenchers (we have used this property in a couple of papers).

But, for a molecular sensor to work, it also needs to reach the molecule it is supposed to detect. The SmartFlares are shown at 1:40 entering the cells via endocytosis, a normal mechanism by which the cell engulfs extracellular material by entrapping them into a bag made of cell membrane. Molecules and particles which enter the cell by endocytosis normally remain trapped in this bag. This entrapping is essential to protect us from viruses and bacteria by preventing them from accessing the cell machinery. Here, however, at 1:45 – 1:46, something truly remarkable happens: the endosome (the bag) suddenly fades away leaving the particles free to diffuse in the cell and meet their RNA targets. This is a promotional video so you might say that the demonstration of, and explanation for, this remarkable endosomal escape is to be found in the primary literature but that is not the case.

SmartFlares_scheme

There is an extensive body of literature (not related to SmartFlare) dealing with endosomal escape. Some bacteria (like Listeria which can cause food poisoning) and viruses (like Influenza or HIV) use proteins to destabilise the endosome, escape and cause disease. Other mechanisms involve altering the ion balance in the endosome to pop it like an over-inflated balloon (you can read more about the ‘Proton Sponge Effect’ in this review). The problem is that none of these scenarios are applicable to gold nanoparticles conjugated to oligonucleotides. The problem is compounded by the choice of techniques used to analyse SmartFlare uptake into cells. Most of the published papers (for examples see here, here and here) characterise “uptake” and do so largely via Flow Cytometry or Mass Spectrometry (to measure the gold content of the cells). These papers certainly support NanoFlares being taken up into endosomes, but don’t offer any evidence for endosomal escape. A systematic unbiased electron microscopy study would enable to gather an estimate of how many nanoparticles have escaped the endosomes. Alternatively, fluorescence microscopy can be used to visualise a diffuse (released) instead of punctate (still in endosomes) distribution of intensity. While there are some images of cells having taken up NanoFlares, the sort of resolution required to discern distribution is not afforded by publication-size figures.

Wouldn’t it be nice if we had access to the original data? Researchers are often left squinting at published figures and all too often have to rely on the author’s interpretation of the data. One solution to this problem is to make supporting data available after publication. This is the idea behind the JCB Dataviewer; allowing authors to upload the original data to support papers published in the Journal of Cell Biology. The other option is to make the data available before publication, in what is called Open Research. This has the huge advantage of opening up a discussion about data, its interpretation and meaning before going through the formal peer-review process.

It is this latter technique that we are currently using to share our study of the use of NanoFlares as VEGF RNA reporters in cells. Our Open Science Notebook gives an overview of the experimental design, results and discussion, while our OMERO server is being used to host all of the original data for anyone to access. The project is still in progress, however our main findings so far are that:

In all conditions where fluorescence is seen, the distribution is consistently punctate (see all of the data here ).

So far these findings have left us with several questions, the most interesting of which are:

  1. Why do we see punctate fluorescence with the VEGF SmartFlares? If the SmartFlares are still in endosomes, they shouldn’t be able to interact with mRNA and thus fluorescence should be quenched.
  2. Why do we see signal at all in the scrambled control?
  3. Why do different cells take up varying amounts of SmartFlares? Fluid phase dextran shows approximately equal uptake in all cells.

We’re presently investigating these and other questions. As we find out more, we will continue to post the data and update the blog.


RESPONSE from EMD Millipore:

In their response, EMD Millipore pointed to a number of relevant publications suggesting that we should revise the post after having considered this evidence. We had already seen those references and we have not altered the post, but we reproduce EMD Millipore’s response below:

 Oligo-modified nanoparticle internalization and endosomal release:

·         Oligonucleotide modified nanostructures are taken in through an endocytotic mechanism.  http://www.pnas.org/content/110/19/7625.long

·         These highly anionic structures attract a counterbalancing salt cloud.  http://pubs.acs.org/doi/pdf/10.1021/jp205583j

·         This is thought to be the mechanism of release from endosomes (via osmotic pressure) 

 Observation of punctate fluorescence:

·         At short time points, when these structures are indeed in the endosomes,  or at low detection gains on a microscope (where you are adjusting for the brightest points) the staining appears punctate.  (For example- the light in a room comes from the bulb, which is the brightest, but the room is still lit.  Keeping only the brightest point in a picture would only show you the bulb.)

·         Therefore, with regards to the experiment you’ve already performed, our first suggestion would be to turn up the gain to see cytoplasmic fluorescence.

·         Here for example are some pictures showing nice cytoplasmic stain  http://www.pnas.org/content/109/30/11975/F1.expansion.html

 

Also may be of interest: 

http://www.nature.com/mt/journal/v22/n6/full/mt201430a.html

It may be worth noting some of our more recent examples of SmartFlare in the literature, spanning across cancer and stem cell research on a variety of detection platforms (flow & microscopy).  Here the punctate fluorescence is also observed, but you can also see nice cytoplasmic staining.

·         Seftor et al. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4026856/

 

·         Mehta et al.  http://www.ncbi.nlm.nih.gov/pubmed/24623279
 

We are doomed…

not because of the risks of nanotechnology but because of a broken scientific system.

Last week, I had the privilege of opening, as the first invited speaker, a symposium on ‘Converging technology for nanobio applications’. This was my first slide:

Collage of various images. See links in the paragraph below for reference and credits.

Collage of various images. Credits: top left “Shutterstock”, top right “Cathy Wilcox”, bottom left “Jeremy M. Lange for The New York Times, A scientist at Duke University measures silver nanoparticles”, bottom center “Terminator 3: Rise of the Machines – a vision surely now only decades away. Photograph: Observer”, bottom right “image courtesy of Oregon State University”. See links in the paragraph below for original publication.

I started my talk by asking the audience what these images had in common (I did point out that the one in the top right corner was, in my experience, scientifically accurate).   The answer? These pictures had all been used to illustrate nanoparticle news in the previous week.

Exotic Nanomaterials Claimed Their First Major Workplace Injury said Stephen Leahy, writing for Motherboard on Tuesday about a worker injured by nanonickel while working without protection. The same day, Andrew Maynard, in Slate, published a more reasonable viewpoint on this same event. On Thursday, the Sydney Herald Tribune reported that a ‘Green group [had] called for ban of nano-materials in food’. This has been amplified in various outlets and, Andrew Maynard (again!) attempted to correct the record in the Conversation. On Friday, Deborah Blum, writing on the New York Times blog said that “Silver [is] Too Small to See, but Everywhere You Look”. The same day, Ben Baumont-Thomas informed us in  the Guardian blog that scientists had created bionic particles ‘inspired by Terminator’. Apparently, the latter piece was tongue in cheek, but it is rather difficult to differentiate the satire from the real thing these days (see for example Salon‘s coverage of the same story here).

While these stories are very different, they all originate in peer reviewed scientific research.

The “inspired by Terminator” piece originally comes from a press release by the University of Michigan. The authors of the article and their PR department were seeking this kind of publicity: the original article (very interesting BTW) uses the word “bionic” and the press release starts with “Inspired by fictional cyborgs like Terminator…”. Good to get coverage but it is highly debatable whether this kind of analogies really help improve the general understanding of science.

Deborah Blum article is measured and well researched – as we would expect from this award-winning science journalist – and based on multiple interviews with scientists. Yet in some ways, it also reflects the deep problems we are facing with establishing solid evidence in support of scientific understanding, and, eventually, policy making.

Deborah Blum article quotes Elisabeth Loboa as saying that “There’s evidence that the particles penetrate into plasma membranes, and they can disrupt cell function” [link in the original article, which is excellent practice!]. The idea that nanoparticles can go through the membrane of cells is so often repeated that it must be true, right? Scientists making those sorts of claim should provide a very high level of proof (unfortunately, this does not happen during peer review) because there are at least two fundamental reasons to be highly skeptical of such claims, one related to evolution, and another one related to physical chemistry and thermodynamics.

Nanoparticles are of similar size to viruses. If viruses could so easily penetrate cells, we would not be here discussing the risk of nanoparticles. Thankfully, during evolution, cells have developed very advanced mechanisms to protect themselves from foreign objects. Viruses too have developed very advanced mechanisms to get in there. Quite simply none of the nanomaterials made in the lab today seriously approach the level of sophistication that viruses use to get access to the interior of the cell (see this movie for an example). The linked article by AshaRani et al provides no evidence of particles penetrating through the plasma membrane (apart from the table of content cartoon). The dose used in this particular study is huge: 200 micrograms of nanomaterials per mL of medium (the equivalent of 10 grams of silver for a 50 kg person). In line with many other studies (including our own work), AshaRani et al show nanoparticles overwhelmingly in endosomes, i.e. in bags inside cells where they are isolated from the cell machinery. Endosomal trapping also remains a major limiting factor to siRNA delivery (even using nanoparticles).

Ignoring now the biology, at the simplest level, the membrane of cells is made of a bilayer of lipids. It has an hydrophobic interior and two hydrophilic surfaces. For an object to diffuse through the membrane, it would need to have no significant repulsive or attractive interactions with any of these components (otherwise it would be repelled and not go through, or attracted and then get stuck). It is hard to imagine any nanoparticle that would fulfill such criteria (see also post and comments here for more details). While it is unclear that any nanoparticle can diffuse through the membrane, many small molecules can. We therefore have this strange situation where the supposed capability of nanoparticles to go through the cell membrane is presented as a reason to be particularly worried even though this is unproven, unlikely for nanomaterials, and common for many smaller compounds (e.g. DAPI).

I am not blaming Deborah Blum nor  Elisabeth Loboa for this confusion. Such statements have become the norm. Although a more detailed investigation would be necessary (and I am not qualified to do it though I’d be happy to collaborate), my hypothesis is that the confusion results from a combination of nano hype (both in terms of risks and potential applications – see the Terminator for one striking example), bias towards the publication of positive findings, absence of post-publication peer review and debate, and poor scientific standards in an interdisciplinary area where editors and referees often lack some of the skills to properly evaluate the work (e.g. material scientists with very little understanding of biology, etc).

The situation is however now extremely serious since it has reached the point where it affects understanding of science for both basic scientists and the general public. It is our responsibility to try to fix the system.

Geoffrey A. Ozin: Artificial Photosynthesis – Solar Fuels from the Sun not Fossil Fuels from the Earth

THIS LECTURE HAS BEEN CANCELLED
Brunner Lecture Theatre, Wednesday, January 22, 3:00 pm
Artificial Photosynthesis – Solar Fuels from the Sun not Fossil Fuels from the Earth

Geoffrey A. Ozin, Chemistry Department, University of Toronto

The Intergovernmental Panel on Climate Change reported in October 2013 that it is 95% certain humans are the cause of anthropogenic climate change from carbon dioxide greenhouse gas emitted into the atmosphere. It is now more urgent than ever before that government, industry and business stakeholders around the world invest in long-term research on artificial photosynthesis the aim of which is to discover materials that can harness solar energy and transform carbon dioxide into an energy rich fuel, mimicking the way photosynthetic organisms harvest sunlight and capture carbon dioxide to drive life-sustaining biochemical processes. This paradigm of utilizing carbon dioxide as a source of fuel rather than treating it as a waste product, promises a new era of sustainability by gifting humanity with an unlimited supply of carbon neutral solar fuels from the sun rather than depleting the finite source of legacy fossil fuels from the earth and replacing them with increasing amounts of greenhouse gas in the atmosphere.

Geoffrey OzinGeoffrey Ozin studied at King’s College London and Oriel College Oxford University, before completing an ICI Postdoctoral Fellowship at Southampton University. Currently he is the Tier 1 Canada Research Chair in Materials Chemistry and Nanochemistry and Distinguished University Professor at the University of Toronto. Internationally he is Distinguished Research Professor at Karlsruhe Institute of Technology (KIT) and Global Chair at the University of Bath. He is renowned for pioneering research and teaching accomplishments in nanochemistry that defined, established and popularized this rapidly expanding trans-disciplinary field, a cornerstone of modern chemistry and a foundation for innovative nanotechnology in materials science, engineering and medicine