Since winning the 2007 Foresight Institute Feynman Prize in Nanotechnology, Theory category, Professor David Leigh FRS FRSE FRSC MAE, and since 2012 at the University of Manchester, has continued to achieve major milestones on the road to complex systems of molecular machinery. Contributions we have recently cited here:

The most recent achievement of his team has garnered much well-deserved attention. A hat tip to Nanowerk for pointing to this University of Manchester news release “Scientists create world’s first ‘molecular robot’ capable of building molecules“:

Scientists at The University of Manchester have created the world’s first ‘molecular robot’ that is capable of performing basic tasks including building other molecules.

The tiny robots, which are a millionth of a millimetre [that is, a nanometer] in size, can be programmed to move and build molecular cargo, using a tiny robotic arm.

Each individual robot is capable of manipulating a single molecule and is made up of just 150 carbon, hydrogen, oxygen and nitrogen atoms. To put that size into context, a pile of a billion billion of these robots would still only be the same size (volume/weight) as a few grains of salt.

The robots operate by carrying out chemical reactions in special solutions which can then be controlled and programmed by scientists to perform the basic tasks.

In the future such robots could be used for medical purposes, advanced manufacturing processes and even building molecular factories and assembly lines. The research, which was funded by the Engineering and Physical Sciences Research Council (EPSRC) will be published in Nature today (21st September) [“Stereodivergent synthesis with a programmable molecular machine”, by Kassem et al. Abstract; full text provided on Prof. Leigh’s web site].

Professor David Leigh, who led the research at University’s School of Chemistry, explains: ‘All matter is made up of atoms and these are the basic building blocks that form molecules. Our robot is literally a molecular robot constructed of atoms just like you can build a very simple robot out of Lego bricks. The robot then responds to a series of simple commands that are programmed with chemical inputs by a scientist.’

A schematic of the operation of a molecular robot shows the position of the cargo arm in seven stages of operation

Programmable operation of a molecular machine that synthesizes different products by moving a substrate between different activating sites. Image credit: Leigh group, School of Chemistry, University of Manchester

“Molecular robotics represents the ultimate in the miniaturisation of machinery. Our aim is to design and make the smallest machines possible. This is just the start but we anticipate that within 10 to 20 years molecular robots will begin to be used to build molecules and materials on assembly lines in molecular factories.”
—Professor David Leigh, Sir Samuel Hall Professor of Chemistry

‘It is similar to the way robots are used on a car assembly line. Those robots pick up a panel and position it so that it can be riveted in the correct way to build the bodywork of a car. So, just like the robot in the factory, our molecular version can be programmed to position and rivet components in different ways to build different products, just on a much smaller scale at a molecular level.’

The benefit of having machinery that is so small is it massively reduces demand for materials, can accelerate and improve drug discovery, dramatically reduce power requirements and rapidly increase the miniaturisation of other products. Therefore, the potential applications for molecular robots are extremely varied and exciting.

Prof Leigh says: ‘Molecular robotics represents the ultimate in the miniaturisation of machinery. Our aim is to design and make the smallest machines possible. This is just the start but we anticipate that within 10 to 20 years molecular robots will begin to be used to build molecules and materials on assembly lines in molecular factories.’

Whilst building and operating such tiny machine is extremely complex, the techniques used by the team are based on simple chemical processes.

Prof Leigh added: ‘The robots are assembled and operated using chemistry. This is the science of how atoms and molecules react with each other and how larger molecules are constructed from smaller ones.

‘It is the same sort of process scientists use to make medicines and plastics from simple chemical building blocks. Then, once the nano-robots have been constructed, they are operated by scientists by adding chemical inputs which tell the robots what to do and when, just like a computer program.’

Prof. Leigh’s web site has a page “Building with a Programmable Molecular Robot” that links to the full text of the paper, places this advance in the context of the ‘molecular assembler’ concept originally proposed by K Eric Drexler in 1986 and inspired by Richard Feynman’s 1959 lecture. The molecular machine design used in the recent paper, based upon their previous molecular robot, is illustrated to show how this molecular robot can be programmed to produce one of four possible molecules from a tandem reaction process, including molecules that cannot be made through conventional organic catalysis. The page speculates that “Future generations of programmable molecular machines may play significant roles in chemical synthesis and molecular manufacturing.”

It should be noted, however, that there is nothing in this report that points toward using molecular machines or systems of molecular machines to apply sufficient mechanical force to break strong covalent bonds, or to precisely manuever extremely reactive free radicals or similar fragments to form strong covalent bonds. Rather, larger, less reactive molecules are being used as building blocks:

This first generation machine augurs well for the development of small-molecule robots that can be programmed to manipulate substrates to control synthesis in a form of mechanosynthesis (that is, the use of mechanical constraints to direct reactive molecules to specific molecular sites), in a manner reminiscent of the way that molecular construction is carried out in biology.

A News & Views technical review of the paper published in the same issue of Nature presents much the same picture. “A molecular assembler,” by T. Ross Kelly and Marc L. Snapper, recalls both K. Eric Drexler’s 1986 vision of “molecular assemblers,” published in Engines of Creation: The Coming Era of Nanotechnology, which formed the Foresight Institute’s founding vision, and the censure the concept attracted, and positions the Kassem et al. paper as reporting “a non-biological example of what could be regarded as a molecular assembler”.

The review illustrates how this latest molecular robot from David Leigh’s group can be reversibly switched between a left-handed and a right handed assembly mode by the addition or removal of a proton. A process of typically seven steps begins with the attachment of a substrate to the assembler, followed by activation, then the attachment of two chemical groups to the substrate in separate steps, with the outcome dependent on whether the assembler has been switched to left- or right-handed mode. Four different products can be made, dependent on the sequence of reactions and switching steps. The reviewers see the chief appeal of the molecular assembler as “the long-term prospect of streamlining organic synthesis.” Since conventional organic synthesis commonly requires 10-30 reactions, the process is time-consuming, inefficient, and expensive, often taking months to years. By contrast, each product of the molecular assembler can be made in one flask without purification between steps. The reviewers speculate that this molecular assembler could bring to general organic synthesis, choosing from up to 100 million molecular building blocks, benefits comparable to the benefits that solid-phase synthesis brought to peptide (20 building blocks) and DNA synthesis (4 building blocks). It is too soon to tell whether this molecular assembler holds advantages compared to automated solid-phase organic synthesis. While acknowledging the limitations of this first generation molecular assembler, the reviewers caution:

… those who dismiss the concept of molecular assemblers should heed the lesson of Lord Kelvin’s infamous 1895 pronouncement that “heavier-than-air flying machines are impossible”. We look forward to seeing what other impossibilities take flight in the future.

Derek Lowe’s blog on drug discovery and the pharma industry presents a similar take on the Kassem et al. paper “Building Our Own Molecular Machines“:

Let’s talk about enzyme envy. That’s what we organic chemists experience when we stop to think about how every complex natural product in the world is synthesized so much more quickly and efficiently than we can do it. All those crazy multiple rings systems, those bizarre heterocycles, huge macrolides, and dense arrays of stereochemistry are cranked out at ambient temperature, under aqueous conditions, on a time scale of minutes to hours. Oh, and they’re made offhand, in the background, as time permits, while the cells and organisms themselves are otherwise occupied with the even more startling business of being living chemical systems. …

Now let’s talk about nanotechnology. … The dream of assembling molecules and materials to order, atom by atom, has been around for some years now, and it largely remains just that: a dream. Eric Drexler and others have taken a lot of grief for maintaining that such things are possible, and to be sure, I have trouble myself with the real atomic scale this-carbon-goes-right-here level of the idea. But what about “this acetyl group goes right here?” That is, small-molecular scale versus atomic scale? That is exactly what every living cell on the planet is doing right now — that’s enzymatic chemistry, and I see no reason why we can’t get smart and capable enough to do the same sorts of things ourselves, and more. That leads up to this new paper … which is basically a molecular-sized stereoselective synthesis machine. …

… this thing has been designed to give you such chiral products, in a programmable fashion, and that it can indeed switch states on command to give them to you. It’s a machine – a very small machine, with limited inputs, but the first computer circuits were also very small machines with limited inputs, too.

Continuing with the computer circuit analogy, Lowe suggest’s that a key step in improving molecular synthesis machines is to reduce the key steps to binary ones.

If we develop these and other spatiotemporal switches to be faster, more responsive, more reliable, and more orthogonal to other functional groups, we can adapt them (as this paper does) to do some fairly complicated chemistry by positioning our other reagents in the appropriate places. …

Referring to Lord Kelvin’s infamous 1895 pronouncement that “heavier-than-air flying machines are impossible”:

The attempt to make molecular assemblers — which is, after all, the attempt to make our own enzymes, when we know that enzymes exist — is the same sort of problem. The molecular-machine folks (last year’s Nobel!), who care about rendering fundamental ideas and processes into molecular form, and the more traditional synthetic organic chemists, who care about what products any new reaction or machine can produce for them, can find common ground in building such things. Bring on the molecular machines!

In contrast to the controversy that greeted Drexler’s original conceptual proposal for a molecular assembler, the report of Prof. Leigh’s implementation of an actual molecular assembler, albeit of a more limited type than Drexler’s proposal, has been well received, as exemplified by the coverage cited here. Additional links to news coverage of the paper are available on Prof. Leigh’s publications page (at the top of the page as accessed Sept.28, 2017).

This paper adds a substantial milestone to the general impression, confirmed by the award of the 2016 Nobel Prize in Chemistry to three scientists who pioneered the development of molecular machines, that systems of molecular machines will be developed to perform a wide range of useful tasks. The consensus of the comments cited here is that the most exciting application will be the synthesis of a wide arrange of organic molecules difficult or impossible to synthesize by conventional methods, including pharmaceuticals and medical devices. The challenge for future molecular machine work will be to build increasingly complex arrays of molecular machines, to exert increasingly strong forces on individual atoms and small clusters of very reactive atoms, to build increasingly complex, atomically precise products.

In addition to mechanically interlocked architectures of small organic molecules exemplified by the work cited here, other paths toward complex systems of molecular machines are being explored, also with substantial success, including structural DNA nanotechnology, protein design, and scanning probe microscopy. These paths featured prominently in a first roadmap of the paths from current nanotechnology to advanced systems published ten years ago by Foresight Institute and Battelle. During the past ten years there has been much progress along all of these paths, but it remains to be seen which paths or combinations of paths will lead to systems for general purpose, high throughput atomically precise manufacturing, capable of inexpensively fabricating any useful arrangement of atoms allowed by physical law, as originally proposed by Drexler. The issue raised in comments cited above as to whether systems of molecular machines will be able eventually to break strong covalent bonds and precisely manipulate very reactive groups of atoms has a long history. At a 1989 nanotechnology conference at which Nadrian C. Seeman introduced DNA nanotechnology as his approach to nanoscale construction, he added the following caveat:

I’d like to emphasize something about the interactions of these segments of DNA and of the slide that Eric showed last night of a protein bound to a stretch of DNA. This DNA-protein complex involved several thousand atoms and several thousand bonds. Moving the big protein off the DNA would take about 20 kcal/mol. I think that it is important to emphasize that that is a weak interaction. To break any one of the thousands of covalent bonds in the DNA or protein would take much more energy than to move the whole protein “blob” off the DNA. It is important when thinking about what can be made and what can’t be made to realize that there are two stages of what Eric is talking about as nanotechnology. In one case, he is talking about moving molecules away from or toward other molecules where you are making weak intermolecular contacts. Whereas making particular molecules (like the crankshaft) involves an order of magnitude more energy. I don’t see this second phase as coming during the remainder of my scientific career (which I hope will go on another third of a century), while the first phase should be feasible soon because we are talking about lower energies.

Eric Drexler was in the audience when Prof. Seeman made the above comment. His response: “I agree entirely.” How far can we go, with which varieties of molecular machine systems? We can hope the answer will be clear within another decade or two.
—James Lewis, PhD

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