Will nanotechnology lead to a truly synthetic biology?

This piece was written in response to an invitation from the management consultants McKinsey to contribute to a forthcoming publication discussing the potential impacts of biotechnology in the coming century. This is the unedited version, which is quite a lot longer than the version that will be published.

The discovery of an alien form of life would be discovery of the century, with profound scientific and philosophical implications. Within the next fifty years, there’s a serious chance that we’ll make this discovery, not by finding life on a distant planet or indeed by such aliens visiting us on earth, but by creating this new form of life ourselves. This will be the logical conclusion of using the developing tools of nanotechnology to develop a “bottom-up” version of synthetic biology, which instead of rearranging and redesigning the existing components of “normal” biology, as currently popular visions of synthetic biology propose, uses the inspiration of biology to synthesise entirely novel systems.

Life on earth is characterised by a stupendous variety of external forms and ways of life. To us, it’s the differences between mammals like us and insects, trees and fungi that seem most obvious, while there’s a vast variety of other unfamiliar and invisible organisms that are outside our everyday experience. Yet, underneath all this variety there’s a common set of components that underlies all biology. There’s a common genetic code, based on the molecule DNA, and in the nanoscale machinery that underlies the operation of life, based on proteins, there are remarkable continuities between organisms that on the surface seem utterly different. That all life is based on the same type of molecular biology – with information stored in DNA, transcribed through RNA to be materialised in the form of machines and enzymes made out of proteins – reflects the fact that all the life we know about has evolved from a common ancestor. Alien life is a staple of science fiction, of course, and people have speculated for many years that if life evolved elsewhere it might well be based on an entirely different set of basic components. Do developments of nanotechnology and synthetic biology mean that we can go beyond speculation to experiment?

Certainly, the emerging discipline of synthetic biology is currently attracting excitement and foreboding in equal measure. It’s important to realise, though, that in the most extensively promoted visions of synthetic biology now, what’s proposed isn’t making entirely new kinds of life. Rather than aiming to make a new type of wholly synthetic alien life, what is proposed is to radically re-engineer existing life forms. In one vision, it is proposed to identify in living systems independent parts or modules, that could be reassembled to achieve new, radically modified organisms that can deliver some desired outcome, for example synthesising a particularly complicated molecule. In one important example of this approach, researchers at Lawrence Berkeley National Laboratory developed a strain of E. coli that synthesises a precursor to artmesinin, a potent (and expensive) anti-malarial drug. In a sense, this field is a reaction to the discovery that genetic modification of organisms is more difficult than previously thought; rather than being able to get what one wants from an organism by altering a single gene, one often needs to re-engineer entire regulatory and signalling pathways. In these complex processes, protein molecules – enzymes – essentially function as molecular switches, which respond to the presence of other molecules by initiating further chemical changes. It’s become commonplace to make analogies between these complex chemical networks and electronic circuits, and in this analogy this kind of synthetic biology can be thought of as the wholesale rewiring of the (biochemical) circuits which control the operation of an organism. The well-publicised proposals of Craig Venter are even more radical – their project is to create a single-celled organism that has been slimmed down to have only the minimal functions consistent with life, and then to replace its genetic material with a new, entirely artificial, genome created in the lab from synthetic DNA. The analogy used here is that one is “rebooting” the cell with a new “operating system”. Dramatic as this proposal sounds, though, the artificial life-form that would be created would still be based on the same biochemical components as natural life. It might be synthetic life, but it’s not alien.

So what would it take to make a synthetic life-form that was truly alien? In principle, it seems difficult to argue that this wouldn’t be possible in principle – as we learn more about the details of the way cell biology works, we can see that it is intricate and marvellous, but in no sense miraculous – it’s based on machinery that operates on principles consistent with the way we know physical laws operate on the nano-scale. These principles, it should be said, are very different to the ones that underlie the sorts of engineering we are used to on the macro-scale; nanotechnologists have a huge amount to learn from biology. But we are already seeing very crude examples of synthetic nanostructures and devices that use some of the design principles of biology – designed molecules that self-assemble to make molecular bags that resemble cell membranes; pores that open and close to let molecules in and out of these enclosures, molecules that recognise other molecules and respond by changes in shape. It’s quite conceivable to imagine these components being improved and integrated into systems. One could imagine a proto-cell, with pores controlling traffic of molecules in and out of it, containing an network of molecules and machines that together added up to a metabolism, taking in energy and chemicals from the environment and using them to make the components needed for the system to maintain itself, grow and perhaps reproduce.

Would such a proto-cell truly constitute an artificial alien-life form? The answer to this question, of course, depends on how we define life. But experimental progress in this direction will itself help answer this thorny question, or at least allow us to pose it more precisely. The fundamental problem we have when trying to talk about the properties of life in general, is that we only know about a single example. Only when we have some examples of alien life will it be possible to talk about the general laws, not of biology, but of all possible biologies. The quest to make artificial alien life will teach us much about the origins of our kind of life. Experimental research into the origins of life consists of an attempt to rerun the origins of our kind of life in the early history of earth, and is in effect an attempt to create artificial alien life from those molecules that can plausibly be argued to have been present on the early earth. Using nanotechnology to make a functioning proto-cell should be an easier task than this, as we don’t have to restrict ourselves to the kinds of materials that were naturally occurring on the early earth.

Creating artificial alien life would be a breathtaking piece of science, but it’s natural to ask whether it would have any practical use. The selling point of the most currently popular visions of synthetic biology is that they will permit us to do difficult chemical transformations in much more effective ways – making hydrogen from sunlight and water, for example, or making complex molecules for pharmaceutical uses. Conventional life, including the modifications proposed by synthetic biology, operates only in a restricted range of environments, so it’s possible to imagine that one could make a type of alien life that operated in quite different environments – at high temperatures, in liquid metals, for example – opening up entirely different types of chemistry. These utilitarian considerations, though, pale in comparison to what would be implied more broadly if we made a technology that had a life of its own.

A synthetic, DNA based molecular motor

The molecule DNA has emerged as the building block of choice for making precise, self-assembled nanoscale structures (in the laboratory, at least) – the specificity of the base-pair interaction makes it possible to design DNA sequences which will spontaneously form rather intricate structures. The field was founded by NYU’s Nadrian Seeman; I’ve written here before about DNA nanostructures from Erik Winfree and Paul Rothemund at Caltech, and Andrew Turberfield at Oxford. Now from Turberfield’s group comes a paper showing that DNA has the potential not just to make static structures, but to make functioning machines.

The paper, Coordinated Chemomechanical Cycles: A Mechanism for Autonomous Molecular Motion (abstract, subscription required for full article), by Simon Green, Jonathan Bath and Andrew Turberfield , was published in Physical Review Letters a couple of weeks ago (see also this Physical Review Focus article). The aim of the research was to design a synthetic analogue of the molecular motors that are so important in biology – these convert chemical energy (in biology, typically from a fuel like the energy carrying molecule ATP) into mechanical energy. One important class of biological motors consists of something like a molecular walker which moves along a track – for example, the motor molecule myosin walks along an actin track to make our muscles contract, while kinesin walks along the microtubule network inside a cell to deliver molecules to where they are needed (to see how this works take a look at this video from Ron Vale at UCSF). What Turberfield’s group has demonstrated is a synthetic DNA based motor that walks along a DNA track when fed with a chemical fuel.

The way molecular motors work is very different to any motor we know about in our macroscopic world. They’re the archetypal “soft machines”, whose operation depends on the constant Brownian motion of the wet nanoscale world. The animation below shows a schematic of the motor cycle of the DNA motor. At rest, the motor is stuck down by both feet onto the track, which is also made of DNA. The first step is that a fuel molecule displaces one foot from the track; the foot part of the motor then catalyses the combination of this fuel molecule with another fuel molecule from the solution, releasing some chemical energy in the process. The foot is then free to bind back to the track again. The key point is that all these binding and unbinding events, together with the flexing of the components of the motor that allow it to pick up and put down its feet on the track are driven by the random buffetings of Brownian motion. What makes it work as a motor is the fact that there’s an asymmetry to which foot is more likely to be displaced from the track; when the foot sticks back each of the two possible positions is equally probable. This means that although each step in the motor is probabalistic, not deterministic, there’s a net movement, on average, in one direction. It’s the input of chemical energy of the fuel that breaks the symmetry between forward and backward motion, making this motor a physical realisation of a “Brownian ratchet”.

In this paper the authors don’t directly show the motor in action – rather, they demonstrate experimentally the presence of the various bound and unbound states. But this does allow them to make a good estimate of the forces that the motor can be expected to exert – a few picoNewtons, very much in the ball-park of the forces exerted by biological motors.

dnamotor.gif
Schematic showing the operation of the DNA motor. Animation by Jonathan Bath.

Top US energy role for leading nanoscientist

It’s being reported that US President-Elect Obama will name the physicist Steven Chu as his Energy Secretary. Chu won the Nobel prize in 1997 (with Bill Phillips and Claude Cohen-Tannoudji) for his work on cooling and trapping atoms with laser light. One of the spin-offs from his discovery was the development of the “optical tweezers” technique, by which micron-size particles can be held and manipulated by a highly focused laser beam. Chu himself used this technique to manipulate individual DNA molecules, directly verifying the reptation theory of motion of long, entangled molecules. The technique has since become one of the mainstays of single molecule biophysics, used by a number of groups to characterise the properties of biological molecular motors.

Chu is currently director of the Lawrence Berkeley National Laboratory, where one of his major initiatives has been to launch a major initiative to develop economic methods for harnessing solar energy on a large scale – Helios. One can get some idea of what Chu’s priorities are from looking at recent talks he has given, for example this one: The energy problem and how we might solve it (PDF). This concludes with these words: ‘“We believe that aggressive support of energy science and technology, coupled with incentives that accelerate the concurrent development and deployment of innovative solutions, can transform the entire landscape of energy demand and supply … What the world does in the coming decade will have enormous consequences that will last for centuries; it is imperative that we begin without further delay.”

Overcoming nanophobia-phobia

It’s all too easy to worry about what the public thinks of nanotechnology, while forgetting that the public isn’t at all homogenous, and that their attitude will depend on their existing values and preconceptions. Three papers in the current issue of Nature Nanotechnology explore this issue. Dan Kahan and coworkers test the idea that, if people learn more about nanotechnology, they will tend to become more positive about it. Not so, they say: while people who support free markets and respect the authority of hierarchies find more to like in nanotechnology the more they learn, people with more egalitarian and communitarian views find more to worry about. Nick Pidgeon and his coworkers look for national differences, conducting parallel public engagement exercises in the UK and the USA. They find a somewhat surprising uniformity in views across the Atlantic, with both sets of people optimistic about potential benefits, particularly in the energy area. There are some national differences, with a greater consciousness of the possibility of regulatory failure in the UK (connected to recent history of the GMO debate and the BSE crisis), and a more consumerist attitude to potential medical benefits in the USA. The biggest media interest (see, for example, this BBC piece) has been attracted by Dietram Scheufele’s team’s suggestion that a dismissal of nanotechnology as morally unacceptable is correlated with religiosity, and that as a consequence nanotechnology is more publicly acceptable in the relatively irreligious countries of Europe than in the USA (see also Scheufele’s own blog).

I’ve written at greater length about these findings in this opinion piece on the Nature News website. I think many scientists will agree with Tim Harper that it’s a category error to ask whether “nanotechnology” is morally acceptable or unacceptable. A related question that occurs to me is this: when we compare public responses in the USA and Europe, how much of the difference is due to the religiosity of the members of the public being asked, and how much is due to the way nanotechnology is popularly framed on either side of the Atlantic? It’s notable that Scheufele’s paper illustrates the potential conflict between religion and nanotechnology (and converging technologies more generally) with a couple of papers about human enhancement, and a commentary by a Lutheran on the full Drexlerian vision of nanotechnology, all of which come from the USA. My sense is that this explicit connection of nanotechnology to human enhancement and transhumanism is much less prominent in Europe than the USA. Maybe it’s not so much the religiosity of the public that’s important in determining people’s attitudes, but the fervour of the people who are promoting nanotechnology.

Talking nanotechnology on the street

The BBC’s Radio 4 has been running a series of short programs – Street Science – featuring scientists being sent out onto the streets to engage random members of the public about controversial bits of science. The latest program dealt with nanotechnology, with my friend and colleague Tony Ryan getting a good hearing in the centre of Sheffield. The programme (RealPlayer file) is well worth a listen, as he talks about applications in medicine and novel photovoltaics, how 2-in-1 shampoo works, Fantastic Voyage, Prince Charles and grey goo, the potential dangers of carbon nanotubes, and why nanosilver-based odour resistant socks may not be a good idea.

Metamodern

Eric Drexler, the author of Nanosystems and Engines of Creation, launches his own blog today – Metamodern. The topics he’s covered so far include DNA nanotechnology and nanoplasmonics; these, to my mind, are a couple of the most exciting areas of modern nanoscience.

In the various debates about nanotechnology that have taken place over the years, not least on this blog, one sometimes has the sense that some of the people who presume to speak on behalf of Drexler and his ideas aren’t necessarily doing him any favours, so I’m looking forward to reading about what Drexler is thinking about now, directly from the source.

A shadow biosphere?

Where are we most likely to find truly alien life? The obvious (though difficult) place to look is on another planet or moon, whether that’s under the icy crust of Europa, near the poles of Mars, or, perhaps, on one of the planets we’re starting to discover orbiting distant stars. Alternatively, we might be able to make alien life for ourselves, through the emerging discipline of bottom-up synthetic biology. But what if alien life is to be found right under our noses, right here on earth, forming a kind of shadow biosphere? This provocative and fascinating hypothesis has been suggested by philosopher Carol Cleland and biologist Shelley Copley, both from the University of Colorado, Boulder, in their article “The possibility of alternative microbial life on Earth” (PDF, International Journal of Astrobiology 4, pp. 165-173, 2005).

The obvious objection to this suggestion is that if such alien life existed, we’d have noticed it by now. But, if it did exist, how would we know? We’d be hard pressed to find it simply by looking under a microscope – alien microbial life, if its basic units were structured on the micro- or nano- scale, would be impossible to distinguish just by appearance from the many forms of normal microbial life, or for that matter from all sorts of structures formed by inorganic processes. One of the surprises of modern biology is the huge number of new kinds of microbes that are discovered when, instead on relying on culturing microbes to identify them, one directly amplifies and sequences their nucleic acids. But suppose there exists a class of life-forms whose biochemistry fundamentally differs from the system based on nucleic acids and proteins that all “normal” life depends on – life-forms whose genetic information is coded in a fundamentally different way. There’s a strong assumption that early in the ancestry of our current form of biology, before the evolution of the current DNA based genetic code, a simpler form of life must have existed. So if descendants of this earlier form of life still exist on the earth, or if life on earth emerged more than once and some of the alternative versions still exist, detection methods that assume that life must involve nucleic acids will not help us at all. Just as, until the development of the polymerase chain reaction as a tool for detecting unculturable microbes, we have been able to detect only a tiny fraction of the microbes that surround us, it’s all too plausible that if alien life did exist around us we would not currently be able to detect it.

To find such alien life would be the scientific discovery of the century. We’d like to be able to make general statements about life in general – how it is to be defined, what are the general laws, not of biology but of all possible biologies, and, perhaps, how can one design and build new types of life. But we find it difficult to do this at the moment, as we only know about one type of life and it’s hard to generalise from a single example. Even if it didn’t succeed, the effort of seriously looking for alien life on earth would be hugely rewarding in forcing us to broaden our notions of the various, very different, manifestations that life might take.

Deja vu all over again?

Today the UK’s Royal Commission on Environmental Pollution released a new report on the potential risks of new nanomaterials and the implications of this for regulation and the governance of innovation. The report – Novel Materials in the Environment: The case of nanotechnology is well-written and thoughtful, and will undoubtedly have considerable impact. Nonetheless, four years after the Royal Society report on nanotechnology, nearly two years after the Council of Science and Technology’s critical verdict on the government’s response to that report, some of the messages are depressingly familiar. There are real uncertainties about the potential impact of nanoparticles on human health and the environment; to reduce these uncertainties some targeted research is required; this research isn’t going to appear by itself and some co-ordinated programs are needed. So what’s new this time around?

Andrew Maynard picks out some key messages. The Commission is very insistent on the need to move beyond considering nanomaterials as a single class; attempts to regulate solely on the basis of size are misguided and instead one needs to ask what the materials do and how they behave. In terms of the regulatory framework, the Commission was surprisingly (to some observers, I suspect) sanguine about the suitability and adaptability of the EU’s regulatory framework for chemicals, REACH, which, it believes, can readily be modified to meet the special challenges of nanomaterials, as long as the research needed to fill the knowledge gaps gets done.

Where the report does depart from some previous reports is in a rather subtle and wide-ranging discussion of the conceptual basis of regulation for fast-moving new technologies. It identifies three contrasting positions, none of which it finds satisfactory. The “pro-innovation” position calls for regulators to step back and let the technology develop unhindered, pausing only when positive evidence of harm emerges. “Risk-based” approaches allow for controls to be imposed, but only when clear scientific grounds for concern can be stated, and with a balance between the cost of regulating and the probability and severity of the danger. The “precautionary” approach puts the burden of proof on the promoters of new technology to show that it is, beyond any reasonable doubt, safe, before it is permitted. The long history of unanticipated consequences of new technology warn us against the first stance, while the second position assumes that the state of knowledge is sufficient to do these risk/benefit analyses with confidence, which isn’t likely to be the case for most fast moving new technologies. But the precautionary approach falls down, too, if, as the Commission accepts, the new technologies have the potential to yield significant benefits that would be lost if they were to be rejected on the grounds of inevitably incomplete information. To resolve this dilemma, the Commission seeks an adaptive system of regulation that seeks, above all, to avoid technological inflexibility. The key, in their view, is to innovate in a way that doesn’t lead society down paths from which it is difficult to reverse, if new information should arise about unanticipated threats to health or the environment.

The report has generated a substantial degree of interest in the press, and, needless to say, the coverage doesn’t generally reflect these subtle discussions. At one end, the coverage is relatively sober, for example Action urged over nanomaterials, from the BBC, and Tight regulation urged on nanotechnology, from the Financial Times. In the Daily Mail, on the other hand, we have Tiny but toxic: Nanoparticles with asbestos-like properties found in everyday goods. Notwithstanding Tim Harper’s suggestion that some will welcome this sort of coverage if it injects some urgency into the government’s response, this is not a good place for nanotechnology to be finding itself.

Nanocosmetics in the news

Uncertainties surrounding the use of nanoparticles in cosmetics made the news in the UK yesterday; this followed a press release from the consumer group Which? – Beauty must face up to nano. This is related to a forthcoming report in their magazine, in which a variety of cosmetic companies were asked about their use of nanotechnologies (I was one of the experts consulted for commentary on the results of these inquiries).

The two issues that concern Which? are some continuing uncertainties about nanoparticle safety and the fact that it hasn’t generally been made clear to consumers that nanoparticles are being used. Their head of policy, Sue Davies, emphasizes that their position isn’t blanket opposition: “We’re not saying the use of nanotechnology in cosmetics is a bad thing, far from it. Many of its applications could lead to exciting and revolutionary developments in a wide range of products, but until all the necessary safety tests are carried out, the simple fact is we just don’t know enough.” Of 67 companies approached for information about their use of nanotechnologies, only 8 replied with useful information, prompting Sue to comment: “It was concerning that so few companies came forward to be involved in our report and we are grateful for those that were responsible enough to do so. The cosmetics industry needs to stop burying its head in the sand and come clean about how it is using nanotechnology.”

On the other hand, the companies that did supply information include many of the biggest names – L’Oreal, Unilever, Nivea, Avon, Boots, Body Shop, Korres and Green People – all of whom use nanoparticulate titanium dioxide (and, in some cases, nanoparticulate zinc oxide). This makes clear just how widespread the use of these materials is (and goes someway to explaining where the estimated 130 tonnes of nanoscale titanium dioxide being consumed annually in the UK is going).

The story is surprisingly widely covered by the media (considering that yesterday was not exactly a slow news day). Many focus on the angle of lack of consumer information, including the BBC, which reports that “consumers cannot tell which products use nanomaterials as many fail to mention it”, and the Guardian, which highlights the poor response rate. The story is also covered in the Daily Telegraph, while the Daily Mail, predictably, takes a less nuanced view. Under the headline The beauty creams with nanoparticles that could poison your body, the Mail explains that “the size of the particles may allow them to permeate protective barriers in the body, such as those surrounding the brain or a developing baby in the womb.”

What are the issues here? There is, if I can put it this way, a cosmetic problem, in that there are some products on the market making claims that seem at best unwise – I’m thinking here of the claimed use of fullerenes as antioxidants in face creams. It may well be that these ingredients are present in such small quantities that there is no possibility of danger, but given the uncertainties surrounding fullerene toxicology putting products like this on the market doesn’t seem very smart, and is likely to cause reputational damage to the whole industry. There is a lot more data about nanoscale titanium dioxide, and the evidence that these particular nanoparticles aren’t able to penetrate healthy skin looks reasonably convincing. They deliver an unquestionable consumer benefit, in terms of screening out harmful UV rays, and the alternatives – organic small molecule sunscreens – are far from being above suspicion. But, as pointed out by the EU’s Scientific Committee on Consumer Products, there does remain uncertainty about the effect of titanium dioxide nanoparticles on damaged and sun-burned skin. Another issue recently highlighted by Andrew Maynard is the issue of the degree to which the action of light on TiO2 nanoparticles causes reactive and potentially damaging free radicals to be generated. This photocatalytic activity can be suppressed by the choice of crystalline structure (the rutile form of titanium dioxide should be used, rather than anatase), the introduction of dopants, and coating the surface of the nanoparticles. The research cited by Maynard makes it clear that not all sunscreens use grades of titanium dioxide that do completely suppress photocatalytic activity.

This poses a problem. Consumers don’t at present have ready access to information as to whether nanoscale titanium dioxide is used at all, let alone whether the nanoparticles in question are in the rutile or anatase form. Here, surely, is a case where if the companies following best practise provided more information, they might avoid their reputation being damaged by less careful operators.

Books that inspired me

I’ve just done a brief interview with a journalist for the BBC’s Focus magazine, about the three popular science books on nanotechnology that have most inspired me. I’ve already written about my nanotechnology bookshelf, but this time when I came to choose my three favourite books to talk about it turns out that they weren’t directly about nanotechnology at all. So here’s my alternative list of three non-nanotechnology books that I think all nanotechnologists could benefit from reading.

The New Science of Strong Materials by J.E. Gordon. To say that this is the best book ever written about materials science might not sound like that high praise, but I was hugely inspired by this book when I read it as a teenager, and every time I re-read it I find in it another insight. It was first published in 1968, long before anyone was talking about nanotechnology, but it beautifully lays out the principles by which one might design materials from first principles, relating macroscopic properties to the ways in which their atoms and molecules are arranged, principles which even now are not always as well known as they should be to people who write about nanotechnology. It’s a forward looking book, but it’s also full of incidental detail about the history of technology and the science that has underlain the skills of craftsmen using materials through the ages. It also looks to the natural world, discussing what makes materials of biological origin, like wood, so good.

The Self-Made Tapestry by Philip Ball. Part of the appeal of this is the beauty of the pictures, depicting the familiar natural patterns of clouds and sand-dunes, as well as the intricate nanoscale structure of self-assembled block copolymer phases and the shells of diatoms. But alongside the illustrations there is an accurate and clear account of the principles of self-assembly and self-organisation, that cause these intricate patterns to emerge, not through the execution of any centralised plan, but as a result of the application of simple rules describing the interactions of the components of these systems.

Out of Control by Kevin Kelly. This is also about emergence, but it casts its net much more widely, to consider swarm behaviour in insects, economics and industrial ecologies, and flocks of insect-like robots. The common theme is the idea that one can gain power by relinquishing control, harnessing the power of adaptation and evolution in complex systems in which non-trivial behaviour arises from the collective actions of many interacting objects or agents. The style is evangelical, perhaps to the extent of overselling some of these ideas, and some may, like me, not be wholly comfortable with the libertarian outlook that underlies the extension of these ideas into political directions, but I still find it hugely provocative and exciting.