Computing with molecules

This is a pre-edited version of an essay that was first published in April 2009 issue of Nature Nanotechnology – Nature Nanotechnology 4, 207 (2009) (subscription required for full online text).

The association of nanotechnology with electronics and computers is a long and deep one, so it’s not surprising that a central part of the vision of nanotechnology has been the idea of computers whose basic elements are individual molecules. The individual transistors of conventional integrated circuits are at the nanoscale already, of course, but they’re made top-down by carving them out from layer-cakes of semiconductors, metals and insulators – what if one could make the transistors by joining together individual molecules? This idea – of molecular electronics – is an old one, which actually predates the widespread use of the term nanotechnology. As described in an excellent history of the field by Hyungsub Choi and Cyrus Mody (The Long History of Molecular Electronics, PDF) its origin can be securely dated at least as early as 1973; since then it has had a colourful history of big promises, together with waves of enthusiasm and disillusionment.

Molecular electronics, though, is not the only way of using molecules to compute, as biology shows us. In an influential 1995 review, Protein molecules as computational elements in living cells (PDF), Dennis Bray pointed out that the fundamental purpose of many proteins in cells seems to be more to process information than to effect chemical transformations or make materials. Mechanisms such as allostery permit individual protein molecules to behave as individual logic gates; one or more regulatory molecules bind to the protein, and thereby turn on or off its ability to catalyse a reaction. If the product of that reaction itself regulates the activity of another protein, one can think of the result as an operation which converts an input signal conveyed by one molecule into an output conveyed by another, and by linking together many such reactions into a network one builds a chemical “circuit” which in effect can carry out computational tasks of more or less complexity. The classical example of such a network is the one underlying the ability of bacteria to swim towards food or away from toxins. In bacterial chemotaxis, information from sensors about many different chemical species in the environment is integrated to produce the signals that control a bacterium’s motors, resulting in apparently purposeful behaviour.

The broader notion that much cellular activity can be thought of in terms of the processing of information by the complex networks involved in gene regulation and cell signalling has had a far-reaching impact in biology. The unravelling of these networks is the major concern of systems biology, while synthetic biology seeks to re-engineer them to make desired products. The analogies between electronics and systems thinking and biological systems are made very explicit in much writing about synthetic biology, with its discussion of molecular network diagrams, engineered gene circuits and interchangeable modules.

And yet, this alternative view of molecular computing has yet to make much impact in nanotechnology. Molecular logic gates have been demonstrated in a number of organic compounds, for example by the Belfast based chemist Prasanna de Silva; here ingenious molecular design can allow several input signals, represented by the presence or absence of different ions or other species, to be logically combined to produce outputs represented by optical fluorescence signals at different wavelengths. In one approach, a molecule consists of a fluorescent group is attached by a spacer unit to receptor groups; in the absence of bound species at the receptors, electron transfer from the receptor group to the fluorophore suppresses its fluorescence. Other approaches employ molecular shuttles – rotaxanes – in which physically linked but mobile molecular components move to different positions in response to changes in their chemical environment. These molecular engineering approaches are leading to sensors of increasing sophistication. But because the output is in the form of fluorescence, rather than a molecule, it is not possible to link many such logic gates into a network.

At the moment, it seems the most likely avenue for developing complex networks for information processing based on synthetic components will use nucleic acids, particularly DNA. Like other branches of the field of DNA nanotechnology, progress here is being driven by the growing ease and cheapness with which it is possible to synthesise specified sequences of DNA, together with the relative tractability of design and modelling of molecular interactions based on the base pair interaction. One demonstration from Erik Winfree’s group at Caltech uses this base pair interaction to design logic gates based on DNA molecules. These accept inputs in the form of short RNA strands, and output DNA strands according to the logical operations OR, AND or NOT. The output strands can themselves be used as inputs for further logical operations, and it is this that would make it possible in principle to develop complex information processing networks.

What should we think about using molecular computing for? The molecular electronics approach has a very definite target; to complement or replace conventional CMOS-based electronics, to ensure the continuation of Moore’s law beyond the point when physical limitations prevent any further miniaturisation of silicon-based. The inclusion of molecular electronics in the latest International Technology Roadmap for Semiconductors indicates the seriousness of this challenge, and molecular electronics and other related approaches, such as graphene-based electronics, will undoubtedly continue to be enthusiastically pursued. But these are probably not appropriate goals for molecular computing with chemical inputs and outputs. Instead, the uses of these technologies are likely to be driven by their most compelling unique selling point – the ability to interface directly with the biochemical processes of the cell. It’s been suggested that such molecular logic could be used to control the actions of a sophisticated drug device, for example. An even more powerful possibility is suggested by another paper (abstract, subscription required for full paper) from Christina Smolke (now at Stanford). In this work an RNA construct controls the in-vivo expression of a particular gene in response to this kind of molecular logic. This suggests the creation of what could be called molecular cyborgs – the result of a direct merging of synthetic molecular logic with the cell’s own control systems.