Grey Goo won’t get you across the Valley of Death

The UK’s main funder of academic nanoscience and nanotechnology – the Engineering and Physical Science Research Council (EPSRC) – has published a report of a review of its nanotechnology portfolio held last summer. The report – released in a very low key way last November – is rather critical of the UK’s nanotechnology performance, noting that it falls below what the UK would hope for both in quality and in quantity, and recommends an urgent review of the EPSRC’s strategy in this area. This review is just getting under way (and I’m one of the academics on the working party).

Unlike many other countries, there is no dedicated nanotechnology program in the UK (the Department of Trade and Industry does have a program in micro- and nano- technology, but this is very near-term and focused on current markets and applications) . With the exception of two (small scale, by international comparisons) nanotechnology centres, at Oxford and Cambridge, nanoscience and nanotechnology proposals are judged in competition with other proposals in physics, chemistry and materials science. There’s no earmarked funding for nanotechnology, and the amount of funding given to the area is simply the aggregate of lots of decisions on individual proposals. This means, of course, that even estimating the total size of the UK’s nanotechnology spend is a difficult task that depends on a grant-by-grant judgement of what is nanotechnology and what is not.

This situation isn’t entirely bad; it probably means that the UK has been less affected by the worst excesses of academic nanohype than countries in which funding has been much more directly tied to the nanotechnology brand. But it does mean that the UK’s research in this area has lacked focus, it’s been developed without any long term strategy, and there’s been very little attempt to build research capacity in the area. Now is probably not a bad time to look ahead at where the interesting opportunities in nanotechnology will be, not next year, but in ten to fifteen years time, and try refocus academic nanoscience in a way that will create those longer term opportunities.

One of the perceptions mentioned in the report was that the quality of work was rather patchy, particularly in areas like nanomaterials, with some work of very moderate quality being done. One panelist on the theme day review memorably called this sort of research “grey goo” – work that is neither particularly exciting scientifically, but which, despite its apparent applied quality, isn’t particularly likely to be commercialised either. Everyone in government is concerned about the so-called “valley of death” – that trough in the cycle of commercialisation of a good idea which comes after the basic research has been done, but when products and revenues still seem a long way off. Much government intervention aims to get good ideas across this melodramatically named rift, but this carries a real danger. Clearly, funding high quality basic science doesn’t help you here, but there’s a horribly tempting false syllogism – that if a proposal isn’t interesting fundamental science, then it might be just the sort of innovative applied research that gets the good ideas closer to market. Well, it might be, but it’s probably more likely simply to be mediocre “sort-of-applied” work that will never yield a commercial product – it might be “grey goo”. I don’t think this is solely a UK problem – in my view every funding agency should ask themselves: ‘are we funding “grey goo” in a doomed attempt to get across the “valley of death”?’

On Nanohype

David Berube’s new book on nanotechnology, Nanohype, is reviewed in this week’s Nature (subscription required). The review is, in truth, not very favourable, but I’m not going to comment on that until my own copy of Nanohype makes it from the Amazon warehouse across the Atlantic. As is often the case, though, the major message of the review is that this is not the book that the reviewer would have written, which in this case is rather interesting, as the reviewer was Harry Collins, one of the foremost exponents of the discipline of the sociology of science.

Collins’s research method is in-depth studies of scientific communities, in which he attempts to uncover the often tacit shared values that underly the scientific enterprise. As such, he is rather sceptical about the value of written material: “science is an oral culture. Although science’s spokespersons rattle on endlessly about peer review, the vast majority of published papers, peer reviewed or not, are largely ignored by scientists in the field. The problem that would face an alien from another planet who wanted to make a digest of terrestrial science from the literature alone would be about as bad as that facing a lay person who tries to understand it by reading everything on the Internet.”

Here’s why nanotechnology is interesting – as a scientific culture it barely exists yet. In contrast to the fields that Collins has studied – most recently, the search for gravitational waves – the idea of nanotechnology as a field has been imposed from the outside the scientific community, by the forces which I imagine Berube’s book documents, rather than emerging from within it. So the community shared values that Collins’s work aims to uncover are not yet even agreed upon.

For those readers who are sceptical about the very idea of the sociology of science, the BBC is currently broadcasting a pair of very interesting documentaries about how science works, called Under Laboratory Conditions; the first one, broadcast last Wednesday on the BBCs digital service BBC4, rang very true to me (and I say this not just because I made a brief appearance in the program myself).

China not, after all, #2 in nanotechnology – Lux Research

My post on Wednesday about the reported claim that China was now #2 in nanotechnology in the world, as measured by output of nanoscience publications, brought a detailed and useful response by email from Matthew Nordan from Lux Research. He pointed out that the study that the Small Times report was based on aggregated a total of 17 metrics, of which the publications count I was referring to was only one. Taking the overall picture, China was still weak both in nanotechnology activity and in its capacity to use nanotechnology to drive economic growth. The only two measures on which it is currently strong is in the publications count that I was discussing, whose shortcomings Matthew acknowledges, and in total spending. There are some pertinent comments about the difficulty of ranking expenditure measures over on TNTlog. Nonethless, China’s capability is growing fast.

The way this story has been reported is an interesting case study in how commentators look for the story they want to see. “China rising” is a powerful narrative at the moment, and any evidence that can be beaten into a form that supports this narrative will be newsworthy. The four page summary of the complete report, which Matthew Nordan kindly forwarded to me, divides nations into Dominant (USA, Japan, Germany and South Korea) – strong both in basic research and commercialisation, Ivory Tower (UK and France), strong in basic research but weaker in commercialisation, Niche Players (Israel, Singapore and Taiwan), weaker in basic research but strong in commercialisation of selected regions. China falls into the Minor League category, weak on both measures, and so not even in the top nine of nanotech powers. The report does suggest that China is moving strongly forward but there is no suggestion that it will overtake the current leaders. Nonetheless, it’s the China story that Lux’s public relations people chose to highlight, heading their press release “CHINA: MOVING FROM LAGGARD TO POWER PLAYER IN NANOTECHNOLOGY” (PDF). The story was obligingly picked up by Small Times, who headlined their story “CHINA MOVING UP IN NANO WORLD” and picked out the two measures on which China took second place (publications and government spend at purchasing power parity). This allowed Nanodot to headline its story “Claim: China is now #2 in nanotech”, which, as we now see, wasn’t the claim at all.

Radical innovation in nanomaterials

Wednesday found me, yet again, in London, this time for a one-day meeting organised by the Royal Academy of Engineering called Radical Innovation in Nanomaterials (PDF link). The speakers were a mix of industrialists and innovation theorists, if I can put it that way, with me thrown in for light entertainment. I must say I find the idea of finding or creating a theory of radical innovation which would allow one to manage it predictably a bit hard to accept. But that’s presumably why I’m a humble academic rather than a high-flying business leader (or perhaps more pertinently, the multi-millionaire author of airport business books).

The talks from the industrialists were perhaps more interesting, not least because the underlying message coming out from all of them was so similar. On the face of it, the companies represented couldn’t have been more different. There were two global giants, the US based chemical company du Pont, and the Europe based pharmaceutical major, GlaxoSmithKline, and one relative minnow – the recently floated UK nanomaterials company Oxonica (whose CEO’s proud boast was that they are the only European pure nanotech company with products generating significant revenue). But the changing environment they were talking about was the same, and one that very much resonates with my comments earlier this week. It’s an atomised world in which innovation and intellectual property is generated by many different organisations – in universities and research institutions, in small start-up companies, but less and less in big corporate R&D labs. Core functions like production are increasingly outsourced, and companies like Oxonica flourish best as brokers, identifying useful intellectual property whereever they can, working with contract manufacturers to realise physical products, and then finding other partners – typically large consumer oriented companies – to develop markets for them.

It’s a model that fits well with prevailing neo-liberal orthodoxies about taking the globalised division of labour to the extreme. Of course it’s a model that must take for granted the absolute integrity and fungibility of intellectual property. I can’t help feeling that this leads to some major potential fragilities, given the difficulties that international patent law is currently going through. The other question that it seems to leave unanswered is this: if production is outsourced and essentially commoditised, who is going to drive the radical innovations, not in the products themselves, but in ways of making things? The orthodox answer, of course, is that competition by itself will do the job. Maybe.

Nanomedicine gets clinical

Everyone agrees that some of the key applications of nanotechnology will be in medicine. Within medicine, drug delivery is an obvious target. So when can we expect to see nano-enabled medicines on the pharmacy shelves? The answer, as usual, depends on what you mean by nanotechnology. Many people have welcomed Abraxane™, which received FDA approval for use for breast cancer earlier this year, as the first nano-drug. But a number of other drugs already in clinical use have just as much right to the nano- label.

Ruth Duncan gives a useful list of nano-medicines in current clinical use in an article in Nano TodayNanomedicine gets clinical (I’ve already referred to this article here). We can summarise the key functions that nano-engineering confers on these products as packaging and targeting – the active drug molecules need to be protected from the body’s systems for repelling foreign materials, and if possible they need to be actively targetted to the parts of the body at which the therapy is directed. For the anti-cancer therapeutics that dominate this list, this target is the tumour.

One approach to targetting is to wrap the molecule up in a liposome – a nanoscale container that is formed, by self-assembly, when soap-like lipid molecules form a bilayer sheet which folds over on itself to make a bag. These are the same structures that are already incorporated in some cosmetics. DaunoXome® consists of the anti-cancer drug daunorubicin encapsulated in liposomes, and is used for the treatment of HIV–related Kaposi’s sarcoma. Doxil® and Caelyx® are liposomal preparations of the related drug doxorubicin, and are used for advanced ovarian cancers. Simple liposomes have quite a short lifetime in the body; in Doxil the surfaces of the liposome are modified by being coated by the water soluble polymer polyethylene glycol.

Rather than putting the drug in a liposome, and then coating the liposome with polymer, it is possible simply to attach polyethylene glycol directly to the drug. This is the basis of “polymer therapeutics” (this is Ruth Duncan’s own field). Examples in clinical use include Oncaspar®, for acute lymphoblastic leukemia, and Neulasta®, used to decrease infection in patients receiving chemotherapy. Both these drugs consist of a protein drug molecule which is disguised from the body by being coated in a diffuse cloud of polyethylene glycol (PEG). How PEG works is still not entirely clear, but the basis of the effect is that it forms a diffuse layer which resists protein adsorption.

Mylotarg®, a drug licensed in the USA for acute myeloid leukemia, is a (currently rather rare) example of a targetted drug. The drug itself – a potent anti-tumor antibiotic – is chemically linked to an antibody – a protein molecule which specifically binds to chemical groups on the outside of the target cells. In Abraxane™, it is the drug molecule itself, paclitaxel, that is nanoengineered – it is prepared in a nanoparticulate form to improve its solubility; the nanoparticles are coated with the blood protein albumin.

So what we see now are a number of products which use individual tricks of nanoengineering to improve their effectiveness. What we will probably see in the future is the combination of more than one of these functions in a single product – moving beyond clever formulation to integrated nanodevices.

Delivering interfering RNA

RNA interference is one of the most fascinating biological discoveries of the last few years, and there’s excitement that it could lead to a new class of powerful drugs which would be an absolutely specific treatment both for viral diseases and cancers. But these drugs, based on short lengths of RNA, need to be introduced into the target cell. A recent paper in Nature Biotechnology – Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs by Morissey et al (subscription required) – suggests that encapsulating the RNA in a liposome can do the job.

In the normal process of gene expression, the genetic code for is transferred from the cell’s DNA, where the information is stored, to the ribosome where the corresponding protein is made in the form of a molecule of RNA – messenger RNA. It turns out that there’s a naturally occurring cellular process that destroys messenger RNA when it’s been marked with a short piece of RNA which binds to it. This RNA interference process was named Science Magazine’s breakthrough of the year in 2002 (needs free registration). These short interfering RNA molecules can thus be used to inactivate one individual gene. To quote from a January 2004 article by Richard Robinson in Public Library of Science: BiologyRNAi Therapeutics: How Likely, How Soon?“The clinical applications appear endless: any gene whose expression contributes to disease is a potential target, from viral genes to oncogenes to genes responsible for heart disease, Alzheimer’s disease, diabetes, and more.”

But bits of free RNA floating around the body are soon identified and destroyed – after all, they are most likely to originate in viruses. And the highly charged RNA molecule can’t penetrate the lipid bilayer that separates a cell from its surroundings. To quote from the Robinson article again: “stability and delivery are also the major obstacles to successful RNAi therapy, obstacles that are intrinsic to the biochemical nature of RNA itself, as well as the body’s defenses against infection with foreign nucleotides.” The Nature Biotechnology article describes the work of scientists from a pharmaceutical company trying to bring this technology to the clinic – Sirna therapeutics. They have shown that by using a lipid-based nanoparticle delivery system they can get good results treating hepatitis B virus in an animals. The delivery system is essentially a liposome, a self-assembled hollow shell formed by a phospholipid sheet which has folded round on itself to form an enclosed surface, but I suspect there’s quite a lot of art to selecting the mixture of lipids to use. This includes charged lipids which probably bind to the RNA, lipids to promote uptake of the delivery device by the cell, and lipids bound to protective polyethylene glycol hairs to disguise the liposomes from the body’s defenses.

Nano cosmetics make the headlines

This week’s Sunday Times ran a story headlined “Safety fears over ‘nano’ anti-ageing cosmetics”. The story highlights the company L’Oreal, which, it says, is “marketing a range of skin treatments containing tiny nano- particles, despite concerns about their possible long-term effects on the human body “, and singles out the product Revitalift, which apparently contains “nanosomes” of pro-retinol A. The article quotes both the FDA and the Royal Society on potential unknown health effects, quoting the latter as saying “We don’t know whether these particles are taken down through the skin and what the long-term effects might be in the bloodstream.” There’s an important point that needs clarifying here.

We need to distinguish between manufactured nanoparticles, like the zinc oxide particles mentioned as being used in some sunscreens, and self-assembled nanostructures, like nanosomes, which are the major subject of the article. It’s the manufactured nanoparticles that have given rise to the health anxieties; nanosomes are quite different. Nanosomes are formed from soap like molecules which self-assemble into water into sheets. If you can persuade these sheets to curve round and make a closed surface you have a liposome; a bag in which you can trap useful molecules like the various vitamins and vitamin precursors that companies like L’Oreal like to put in their products (see here for L’Oreal’s own description of this technology). A nanosome is simply a small liposome. The idea is that these molecular delivery bags will both protect the active molecules and help them penetrate the skin. Should we worry that these nanoparticles will enter the human body and lead to long-term adverse effects? Probably not, because the molecules that make up the bag are identical to or very similar to naturally occuring lipids (in fact, the starting point for most liposomes is lecithin, a naturally occurring mixture of phospholipids that’s very commonly used as food emulsifier), and the structures they form are held together by rather weak forces. Liposomes have been much studied as possible drug delivery agents, and this research shows that most liposomes have a rather short life-time in the body. In fact, from the point of view of drug delivery, the lifetimes are rather too short and special tricks are needed – such as the so-called stealth lipsome technology – to prevent the body recognizing and destroying them.

I’m not sure where this piece has come from – it’s written, not by a science correspondent or an environment correspondent, but by the “Social Affairs” editor. I think “Social Affairs” is a rather pretentious categorisation for all those lifestyle pieces that Sunday newspapers are plagued by, and sure enough the “Style” supplement has a consumer review of non-surgical anti-ageing treatments. Perhaps someone in the lifestyle department saw the nano- word, dimly remembered that nanotechnology had been “derided by the Prince of Wales as ‘grey goo’ “, and saw the chance to get a serious story in the paper for a change.

Will the association of these cosmetics with scare stories about the dangers of nanotechnology be bad for their sales? Somehow I doubt it. Given the popularity of botox, it seems that a combination of outrageous expense and the suggestion of danger is exactly what sells an anti-ageing treatment.

Nanobiotechnology and the communications industry

One of the UK’s two flagship nanotechnology centres, the Interdisciplinary Research Collaboration in Bionanotechnology at Oxford University, was having its mid-term review yesterday; I was there in my role as a member of the external steering committee. One thing I learnt that had previously passed me by was that one of the largest industrial collaborations they have is not, as one might think, with a pharmaceutical or biomedical company, but with the Japanese telecoms company NTT.

The linkup was announced last October; the $2 million project is concentrated in the area of the study of the function of membrane proteins. Why would they be interested in this? Membrane proteins provide the mechanisms by which living cells sense their surroundings and communicate with the outside world. As the leader of the NTT side of the project, Dr Keiichi Torimitsu, is quoted as saying, “We are especially interested in this field because of the possibility of future applications in the area of human – electronic interfaces.”

Politics in the UK

Some readers may have noticed that we are in the middle of an election campaign here in the UK. Unsurprisingly, science and technology have barely been mentioned at all by any of the parties, and I don’t suppose many people will be basing their voting decisions on science policy. It’s nonetheless worth commenting on the parties’ plans for science and technology.

I discussed the Labour Party’s plans for science for the next three years here – this foresees significant real-terms increases in science funding. The Conservative Party has promised to “at least match the current administration’s spending on science, innovation and R&D”. However, the Conservative’s spending plans are predicated on finding ��35 billion in “efficiency savings”, of which ��500 million is going to come from reforming the Department of Trade and Industry’s business support programmes. I believe it is under this heading that the ��200 million support for nanotechnology discussed here comes from, so I think the status of these programmes in a Conservative administration would be far from assured. The Liberal Democrats take a simpler view of the DTI – they just plan to abolish it, and move science to the Department for Education.

So, on fundamental science support, there seems to be a remarkable degree of consensus, with no-one seeking to roll back the substantial increases in science spending that the Labour Party has delivered. The arguments really are on the margins, about the role of government in promoting applied and near-market research in collaboration with industry. I have many very serious misgivings about the way in which the DTI has handled its support for micro- and nano- technology. In principle, though, I do think it is essential that the UK government does provide such support to businesses, if only because all other governments around the world (including, indeed perhaps especially, the USA) practise exactly this sort of interventionist policy.

Nanotechnology and the developing world

There’s a rather sceptical commentary from Howard Lovy about a BBC report on a study from Peter Singer and coworkers. At the centre of the report is a list of areas in which the authors feel that nanotechnology can make positive contributions to the developing world. Howard’s piece attracted some very sceptical comments from Jim Thomas, of the ETC Group. Jim is very suspicious of high-tech “solutions” to the problems of the developing world which don’t take account of local cultures and conditions. In particular, he sees the role of multinational companies as being particularly problematic, especially with regard to issues of ownership, control and intellectual property.

I see the problem of multinational companies in rather different terms. To take a concrete example, I’d cited the case of insecticide-treated mosquito nets for the control of malaria as a place where nanoscale technology could make a direct impact (and Jim did seem to agree, with some reservations, that this in could, in some circumstances, be an appropriate solution). The technical problem with insecticide treated mosquito nets is that the layer of active material isn’t very robustly attached, and the effectiveness of the nets falls away too rapidly with time, and even more rapidly when the nets are washed. One solution is to use micro- or nano-encapsulation of the insecticide to achieve long-lasting controlled release. The necessary technology to do this is being developed in agrochemical multinationals. The problem, though, is that their R&D efforts are steered by the monetary size of the markets they project. They’d much rather develop termite defenses for wealthy suburbanites in Florida than mosquito nets. The problem, then, isn’t that these multinationals will impose technical fixes on the developing world, it’s that they’ll just ignore the developing world entirely and potentially valuable technologies simply won’t reach the places where they could do some good.

To overcome this market failure needs intervention from governments, foundations and NGOs, as well as some active and informed technology brokering. Looking at it in this light, it seems to me that the Singer paper is a useful contribution.