The Soft Machines blog is getting some visitors referred from a page on the new Foresight Institute website discussing the various debates there have been on the feasibility of Drexler’s version of a radical nanotechnology. For their convenience, and for anyone else who is interested, here is a quick summary of some the relevant posts on Soft Machines. When I get a moment, I will move a version of this summary to a more permanent home.
Archive for June, 2005
This is a draft of a piece I’ve been invited to write for the special edition of Journal of Polymer Science: Polymer Physics Edition that is associated with the March meeting of the American Physical Society. The editors invited views from a few people about where they saw the future of polymer science. Here’s my contribution, with themes that will be familiar to readers of Soft Machines. Since the intended audience consists of active researchers in polymer science, the piece has more unexplained technical language than I usually use here.
In the first half of the twentieth century, polymer science and biochemistry developed together. With synthetic polymer chemistry in its infancy, most laboratory examples of macromolecules were of natural origin, and the conceptual foundations of polymer science, such as Staudinger’s macromolecular hypothesis, were as important for biology as for chemistry. Techniques for the physical characterisation of macromolecules, like Svedberg’s ultracentrifuge, were applied as much to biological macromolecules as synthetic ones. But with the tremendous development of the field of structural biology that x-ray protein crystallography made possible, the preoccupations of polymer science increasingly diverged from those of what was now being termed molecular biology. The issues that are so central to protein structure – secondary and tertiary structural motifs, ligand-receptor interactions and allostery, had no real analogue in synthetic polymer science. Meanwhile, the issues that exercised polymer scientists – crystallisation, melt dynamics and rheology – had little relevance to biology. Of course there were exceptions, but conceptually and culturally the two disciplines had become worlds apart.
I believe that the next fifty years we need to see much more interaction between polymer science and cell biology. In polymer science, we’ve seen the focus shift away from the properties of bulk materials to the search for new functionality by design at the molecular level. In cell biology, the new methods of single molecule biophysics permit us to study the behaviour of biological macromolecules in their natural habitat, rather than in a protein crystal, allowing us to see how these molecular machines actually work. Meanwhile synthetic polymer chemistry has started to give us access to control over molecular architecture. This is not yet at the precision that we obtain from biology, but we are already seeing the exploitation of non-trivial macromolecular architectures to achieve control over structure and function. The next stage is surely to take the insights from single molecule biophysics about how biological molecular machines work and design synthetic molecules to perform similar tasks.
We could call this field biomimetic nanotechnology. Biomimetics, of course, is a well-known field in material science; what we are talking about here is biomimetics at the level of single molecules, at the level of cell biology. Can we make synthetic analogues of molecular motors and other energy conversion devices? Can we learn from membrane biophysics to make selective pumps and valves, which would allow the easy and energy-efficient separation and sorting of molecules? Will it be possible to create any synthetic analogue of the systems of molecular sensing, communication and computation that systems biology is just starting to unravel? It’s surely only by achieving this degree of nanoscale control that the promise of molecular medicine could be fulfilled, to give just one example of a potential application.
What are the areas of polymer science that need to be advanced to enable these developments? Obviously, in polymer chemistry, synthesis with precise architectural control is key, and achieving this goal in water-soluble systems is going to be important if this technology is going to find wide use, particularly in medical applications. Polymer physicists are still much less comfortable dealing with systems involving water and charges than with polymer solutions in simple non-polar solvents, and we’ll need more work to ensure that we have a good understanding of the physical environment in which our devices will be operating.
The importance of self-assembly as a central theme will continue to grow. This way of creating intricate nanostructures by programmed interactions in macromolecules is well known to polymer science; the richness of the morphologies that can be obtained in block copolymer systems is well-known. But in comparison with the sophistication of biological self-assembly, synthetic self-assembly still operates at a very crude level. One new element that we should import from biology is the exploitation of secondary structure and its coupling to nanoscale morphology. Another important idea is to exploit the single chain folding of a sequenced copolymer in an analogue of protein folding. This, of course, would require considerable precision in synthesis, but theoretical developments are also necessary. We have learnt from the theory of protein folding theory that only a small fraction of possible sequences are foldable, so we will need to learn how to design foldable sequences.
Another important principle will be exploiting molecular shape change. In biology, this principle underlies the operation of most sophisticated nanoscale machines, including molecular motors, ion channel proteins and signalling molecules. In polymer physics the phenomenon of the coil-globule transition in response to changing solvent conditions is well known and has its macroscopic counterpart in thermoresponsive gels. To be widely useful, we need to engineer responsive systems with much more specific triggers and with a more highly amplified response. One promising way of doing this uses the coupling between transitions in secondary structure and global conformation; however we’re still a long way from the remarkable lever arms of biological motor proteins, in which rather subtle changes at a binding site produce a large overall mechanical response.
Some of the most powerful ideas from biology still remain essentially unexploited. An obvious one is, of course, evolution. At the molecular level, evolution offers a spectacularly powerful way of searching multidimensional parameter spaces to find efficient design solutions. It’s arguable that, given the combinatorial complexity that arises with even modest degrees of architectural control and our unfamiliarity with the design rules that are appropriate for the nanoscale environment, that significant progress will positively require some kind of evolutionary approach, whether that is executed in computer simulation or with real molecules.
Perhaps the most fundamental difference between the operating environments of biology and polymer science is the question of thermodynamic equilibrium. Polymer scientists are used to systems at, or perturbed slightly away from, equilibrium, while biological systems are driven far from equilibrium by a continuous energy input. How can we incorporate this most basic feature of life into our synthetic devices? What will be our synthetic analogue of life’s universal energy currency, adenosine triphosphate?
Ultimately, what we are talking about here is the reverse engineering of biology. It’s obvious that the gulf between the crudities of synthetic polymer science and the intricacies of cell biology is currently immense (certainly quite big enough to mean that the undoubted ethical issues that would arise if we could make any kind of reasonable facsimile of life are still very distant). Nonetheless, even rudimentary devices inspired by cell biology would be of huge practical benefit. Potentially even more significant a benefit than this, though, would be the deep understanding of the workings of biology that would arise from trying to copy it.
The operation of most living organisms, from bacteria like E. Coli to multi-cellular organisms like ourselves, depends on molecular motors. These are protein-based machines which convert chemical energy to mechanical energy; the work our muscles do depends on many billions of these nanoscale machines all operating together, while individual motors propel bacteria or move materials around inside our cells. Molecular motors work in a very different way to the motors we are familiar with on the macroscopic scale, as has been revealed by some stunning experiments combining structural biology with single molecule biophysics. A good place to start getting a feel for how they work is with these movies of biological motors from Ronald Vale at UCSF.
The motors we use at the macroscopic scale to convert chemical energy to mechanical energy are heat engines, like petrol engines and steam turbines. The fuel is first burnt to convert chemical energy to heat energy, and this heat energy is then converted to useful work. Heat engines rely on the fact that you can maintain part of the engine at a higher temperature than the general environment. For example, in a petrol engine you burn the fuel in a cylinder, and then you extract work by allowing the hot gases expand against a piston. If you made a nanoscale petrol engine, it wouldn’t work, because the heat would diffuse out of the cylinder walls, cooling the gas down before it had a chance to expand. This is because the time taken for a hot body to cool down to ambient temperature depends on the square of its size. At the nanoscale, you can’t maintain significant temperature gradients for any useful length of time, so nanoscale motors have to work at constant temperature. The way biological molecular motors do this is by exploiting molecular shape change – the power stroke is provided by a molecule changing shape in response to the binding and unbinding of the fuel molecules and their products.
In our research at Sheffield we’ve been trying to learn from nature to make crude synthetic molecular motors that operate in the same way, by using molecular shape changes. The molecule we use is a polymer with weak acidic or basic groups along the backbone. For a polyacid, for example, in acidic conditions the molecule is uncharged and hydrophobic; it takes up a collapsed, compact shape. But when the acid is neutralised, the molecule ionises and becomes much more hydrophilic, substantially expanding in size. So, in principle we could use the expansion of a single molecule to do work.
How can we clock the motor, so that rather than just expanding a single time, our molecule will repeatedly cycle between the expanded and the compact shape? In biology, this happens because the reaction of the fuel molecule is actually catalysed by the the motor molecule. Our chemistry isn’t good enough to do this yet, so we use a much cruder approach.
We use a class of chemical reactions in which the chemical conditions spontaneously oscillate, despite the fact that the reactants are added completely steadily. The most famous of these reactions is the Belousov-Zhabotinksy reaction (see here for an explanation and a video of the experiment). With the help of Steve Scott from the University of Leeds, we’ve developed an oscillating reaction in which the acidity spontaneously oscillates over a range that is sufficient to trigger a shape change in our polyacid molecules.
You can see a progress report on our efforts in a paper in Faraday Discussions 128; the abstract is here and you can download the full paper as a PDF here (this is available under the author rights policy of the Royal Society of Chemistry, who own the copyright). We’ve been able to demonstrate the molecular shape change in response to the oscillating chemical reaction at both macroscopic and single chain level in a self-assembled structure. What we’ve not yet been able to do is directly measure the force generated by a single molecule; in principle we should be able to do this with an atomic force microscope whose tip is connected to a single molecule, the other end of which is grafted to a firm surface, but this has proved rather difficult to do in practise. This is high on our list of priorities for the future, together with some ideas about how we can use this motor to do interesting things, like propel a nanoscale object or pump chemicals across a membrane.
This work is a joint effort of my group in the physics department and Tony Ryan’s group in chemistry. In physics, Mark Geoghegan, Andy Parnell, Jon Howse, Simon Martin and Lorena Ruiz-Perez have all been involved in various aspects of the project, while the chemistry has been driven by Colin Crook and Paul Topham.
The UK’s funding agency for the physical sciences – the Engineering and Physical Science Research Council (EPSRC) – has been holding a theme day to review the nanotechnology it supports. All holders of grants in the nanotechnology area were invited to present their work. A panel of academic and industrial scientists and engineers, with international representation from the USA and Korea, reviewed the work presented on the day, as well as reports on recently finished grants and other evidence in an attempt to assess the health of the subject, to judge the UK’s position in relation to the rest of the world and to make recommendations.
Unlike most other countries, the UK doesn’t have a coordinated nanotechnology program. There are two interdisciplinary research collaborations, based at Oxford and Cambridge respectively, but most funding is provided in response to individual grant applications which are made, not to a single nanotechnology program, but to panels dealing with chemistry, physics, materials or information technology. The last time that nanotechnology was reviewed in this way was in 1999, and at that time it was felt that a single nanotechnology program was not needed.
I was on the panel; the report will be made public when it is finalised, so it’s probably premature to go into details about the conclusions we reached. As they say in diplomatic communiques, the discussions were full and frank, but we finished in remarkable agreement.
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.”
We’re having a visit today, here at the University of Sheffield, from Sir Harry Kroto. Sir Harry, who shared the 1996 Nobel Prize in chemistry with Robert Curl and Richard Smalley is a graduate of Sheffield University and is here to open a new multidisciplinary research building which is going to be named after him.
Sir Harry gave a public lecture about nanoscience, which was an impassioned statement of his belief that nanoscience and technology (which he believes to be essentially synonymous with chemistry) offers the only way towards achieving a sustainable way of life for the whole of the world’s population.
I’ve just finished my talk on nanotechnology here at the Guardian Hay Festival; I was speaking to a nearly full tent, competing only with the sound of the Welsh rain beating on the canvas. There were plenty of questions and afterwards I signed a dozen or so copies of Soft Machines. I have to admit to being more than usually nervous; the audience here gives the impression of being absolutely the epitome of the stereotypical Guardian reader; liberal, left-leaning (this I infer from the wild applause and cheering from the tent in which Tony Benn was talking), and not, perhaps, naturally uncritical supporters of science and technology. They also seem to have implausibly well-behaved and bookish children. Nonetheless it seemed to go well and the comments afterwards were very appreciative, with one exception.
Hay-on-Wye is an odd sort of place at the best of times; a sleepy small market town on the border of England and Wales which by some quirk has become the centre of the UK’s second hand book trade, to support which there’s grown up an infrastructure of organic wholefood outlets, expensive, yet tasteful and understated, guest houses, and shops selling arts and crafts of all kinds. Some tensions result from this collision of the rural and metropolitan cultures; some of these are conveyed in Iain Sinclair’s novel Landor’s Tower, which like all his work manages to impart an unlikely seedy, dangerous glamour to the world of second-hand books. But none of this takes away from the beauty of the landscape here; it’s where the rich orchards and half-timbered houses of Herefordshire meet the harder hills and moors of Wales, with its scrawny sheep and struggling hill-farms. This liminal quality is reflected in the strange place-names, neither Welsh nor English – “Evenjobb”, “Burfa”, “the Begwns”, and a surprising number of places called “Worlds End”. The area has a deep personal resonance for me, because as a boy it’s the first place that I was let out into on my own for a few days without adult supervision. In 1975 a school-friend and I, both just turned 14, walked and camped from near Shrewsbury to Hay-on-Wye. At the time it felt to us like a bigger adventure than going to the Himalayas. The friend, Mark Miller, later became a mountaineer of some notoriety (there are some good anecdotes about him in Joe Simpson’s memoir “This Game of Ghosts”) before a tragically early death in the 1993 Katmandu air crash.
I’m veering into literature and autobiography, clearly intoxicated by my adventure past the “Artists only” sign into the famous Hay Festival Green Room. The people around me are undoubtedly famous authors and literary figures, but I’m too unworldly to recognise them. Time for me to pick up my payment (a case of champagne) and return to my usual rather less literary surroundings.