Commercialising synthetic biology

What’s going to be the quickest way of achieving some kind of radical nanotechnology, in which sophisticated nanoscale machines carry out complex chemical tasks? Since nature has evolved sophisticated and effective nanomachines that are optimised for the nanoscale environment, an obvious approach is to take components from living systems and reassemble them to do the tasks you want. This is the approach of bionanotechnology. But we could take this logic further. Rather than rebuilding systems from individual biological components, we could take a complete organism, strip out the functions we don’t want, and patch in the genetic code for the components we need. This top-down approach to bionanotechnology is exactly what is being proposed by a new company, Synthetic Genomics Inc, founded in June by Craig Venter. Venter is, of course, the scientist behind the private sector venture to sequence the human genome. The initial focus will be on the use of these partly synthetic organisms to make alternative fuels such as hydrogen and ethanol.

The vehicle for these strange hybrids is likely to be the parasitic bacteria Mycoplasma genitalium, an unwelcome inhabitant of some people’s urinary tracts, which currently has the distinction of having the smallest known genome. This is contained on a mere 580,000 base pairs of DNA, coding for about 480 proteins and 40 RNA molecules. Venter’s group systematically knocked out genes from this organism in an attempt to find a so-called minimal genome. One can think of this as the simplest possible fully functioning life-form (of course, such an organism would be very restricted in the environment it can live in). In Venter’s 1999 paper in Science, Global transposon mutagenesis and a minimal mycoplasma genome, a further 100 proteins were eliminated without fatally compromising the organisms’ existence. Having stripped the organism down to a minimal level of complexity, the idea would be to reinsert synthetic genes coding for whatever machinery you require.

There are two questions to ask about this: will it work, and should it be done? It’s certainly a very bold commitment to a very reductionist view of life: in their words “using the genome as a bio-factory, a custom designed, modular cassette system will be developed so that the organism executes specific molecular functions”. As for the ethics of the enterprise, I’m sure even the most enthusiastic technophile would at least pause to think about the implications of attempting to re-engineer life on this scale. Indeed, Venter’s group commissioned their own bioethicists to think about the issues, and this ethical commentary accompanied their original Science article. This is just the beginning of a very big story.

Cheap designer genes

The kind of DNA-based nanotechnology pioneered by New York University’s Ned Seeman is currently the closest thing we have to the radical aim of making nanoscale structures and machines with atomic precision, but the development of the technology is limited by cost. DNA is an expensive molecule – currently it costs about $5000 a gram to make short, synthetic DNA sequences.

The cost of synthetic DNA has been dropping, but a new company is promising orders of magnitude drops in cost for much longer sequences of DNA. The company, Codon Devices, is commercialising methods developed in George Church’s group at Harvard Medical School – the method is describe in this Nature paper (subscription required for full paper): Accurate multiplex gene synthesis from programmable DNA microchips.

It’s not DNA nanotechnology that the company cites as its major potential market, though. Their ambition is to make synthetic genes for synthetic organisms, in the emerging field of synthetic biology.

The big picture on nanoscience

The Wellcome Foundation – one of the world’s largest biomedical research charities – has released a 16 page briefing document on nanoscience and nanotechnology intended for science teachers and post-16 students. It can be downloaded as a PDF from the associated web-pages – The Big Picture on Nanoscience – which are well-supplied with additional web-based resources and also have instructions for ordering the print version.

The document seems pretty exemplary to me – well and punchily written by some excellent science writers, well-illustrated and covering most of the points in a pretty balanced way. It’s particularly good on the debate about risks and potential downsides of nanotechnology.

The highlight for me is this nanointerview with two people from different sides of the debate – Doug Parr, Chief Scientist of Greenpeace, and Mark Welland, director of the Cambridge Nanoscience Centre. It’s a model of thoughtful debate with each protagonist looking cooly at both sides of the argument. Many people will welcome this statement from Doug Parr: “There isn’t big public opposition to nanotechnologies. Greenpeace isn’t opposed to them either: I hope some good things will come out of them. But we do have some scepticism about how they will be shaped.”

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: Biology – RNAi 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.

Public engagement in nanotechnology – the UK government publishes its outline programme

The UK government has taken another step forward towards implementing some of the recommendations of the Royal Society Report on nanotechnology. Its initial response was published in February to not entirely universal acclaim (see here for my analysis). Today it published its outline programme for public engagement on nanotechnologies, available as a PDF here. This mostly brings together a number of existing elements. The major new development is the establishment of the Nanotechnology Engagement Group – “The Nanotechnology Engagement Group (NEG) is being established to support public bodies in developing a wider programme of social and ethical research and public dialogue around nanotechnology. It will also draw more general lessons for the governance of other emerging science and technology areas.” The NEG will be run by a new NGO called Involve. I see that Richard Wilson, the director of Involve, is getting off to a good start in asserting his independence of Government; he writes on his blog “The Involve Group … already has real concerns as to whether the programme outlined is up to the challenges posed.” I’ll get a chance to judge for myself, as I’ve accepted the role of chair of the NEG.

Nanotube composites – deja vu all over again?

Carbon nanotubes are, in principle, about the strongest and stiffest materials we know about. The obvious way to exploit the strength and stiffness of fibrous materials like nanotubes is to use them to make a composite material, like the carbon fibre composites that are currently some of the strongest and lightest materials available for advanced applications like the aerospace industry. But the development of nanotube composites has been disappointingly slow. To quote from a recent review in Current Opinion in Solid State and Materials Science (subscription required) – Carbon nanotube polymer composites – by Andrews and Weisenberger (University of Kentucky), “after nearly a decade of research, their potential as reinforcement for polymers has not been fully realized; the mechanical properties of derived composites have fallen short of predicted values”. One of the major problems has been the tendency of nanotubes to agrregate in bundles – for a composite to work well, the reinforcing fibres need to be evenly distributed through the matrix material.

My friend and colleague from Cambridge, Athene Donald, reminds us that we’ve been here before. In an opinion piece (PDF) in the May issue of Nano Today, she recalls the enthusiasm in the early ’80s for so-called molecular composites. The idea was to take the strong, rigid polymers that were being developed at the time (of which Kevlar is the most famous), and make a composite in which dispersed, individual molecules of the rigid polymer played the role of the fibre reinforcement. Despite the expenditure of large sums of money, notably by the US Air Force, this idea didn’t go anywhere, because the forces that make rod-like molecules tend to want to bunch together are very strong and very difficult to overcome. It’s exactly the same physics that’s making it so hard to make good nanotube based composites.

Athene’s piece is about self-assembly. When so many people (including me) are writing about the huge potential for the use of self-assembly as a scalable manufacturing method in nanotechnology, it’s salutory to remember that the tendency to self-assemble can have unwelcome, as well as beneficial, effects. Matter doesn’t always do what you want it to do, particularly at the nanoscale.

One year of Soft Machines

It’s just over a year since I became the proud owner of the domain softmachines.org and managed a basic WordPress installation. At the time I thought to myself “I’ll just get this working, and then make it pretty later”, but of course I never actually got around to much in the way of cosmetic improvement. Let me say to the various people who have emailed me with very sensible suggestions about how to make the site better, thank you for your input, and I still hope to get around to implementing some of them one day…

Looking back on the expectations I had starting out, it’s clear that things haven’t unfolded the way I planned. I’ve certainly spent much less time than I thought I would talking about my own research. I’ve certainly not filled the blog with details of my day-to-day life (maybe that’s a pity – one of my colleagues, when I announced last year that I was starting a blog, said rather caustically “Good – maybe now your graduate students might have some idea where you are when they try in vain to find you”). I’ve probably spent more time than I anticipated discussing MNT, and issues around public engagement and public acceptance seem to have loomed larger than I would have predicted. But I’m happy that the blog has developed a steadily growing readership of a very worthwhile size, and I am continually surprised at the number of people I meet who say they look at it.

Soft machines site statistics

I have some ideas about how the site might develop next year. One thing I hope to do is increase visual impact of the site by including more images; another long overdue task is to go over the archives and arrange some of the more durable entries in a more logical and accessible way. In terms of the balance of the subject matter (or anything else, for that matter), any suggestions are welcome. Ultimately, though, perhaps the best I can hope for is just to try to follow this fascinating and unpredictable subject in whichever direction the advancing science and unfolding debate takes it.

Anti-cancer nanotechnology – a two-pronged attack

Drug delivery – and in particular the delivery of anti-cancer therapeutics – has emerged as one of the major applications of nanotechnology in medicine. There’s a nice brief review of the subject by Ruth Duncan in this month’s issue of Nano Today: – Nanomedicine gets clinical . An interesting paper in this week’s Nature reports a significant new development from Sasisekharan’s group at MIT, in which two drugs are combined in a single delivery system. This nanovector first selectively targets tumour tissue, then releases a drug which cuts off the blood supply to the tumour, isolating and starving it, and then releases a second drug which directly attacks the tumour cells.

The full article can be found here, and there’s a commentary about it here. A subscription to Nature may be required for these articles, but you can also look at the Nature’s editor’s summary and the press release from MIT.

What’s interesting about this work is the way it brings together quite a lot of different tricks to make something that is starting to look like a piece of integrated nanoengineering. You have the coupling of a drug to a polymer which slowly breaks down in water; then this drug-polymer conjugate is prepared in the form of nanoparticles. These nanoparticles are, together with a second drug, encapsulated in a liposome, a self-assembled hollow shell formed by a phospholipid sheet which has folded round on itself to form an enclosed surface. The size of these liposomes is controlled so they selectively find their way into the tumour tissue and their surfaces are decorated with hairy layers of water soluble polymers to hide them from the immune system. Individually, none of these features is novel, but their combination in an integrated nanosystem is very impressive.

Nanojury UK – finalising its conclusions

The Guardian today ran a piece about the Citizen’s Jury on Nanotechnology that I’ve been involved in, which has now had its final meeting. I’ve reported on the way the project has unfolded here (the launch), here (week 1), and here (week 3). The Guardian’s piece does a good job of conveying the diversity of points of view that are represented amongst the members of the jury. I’m looking forward to the publication of the jury’s conclusions and recommendations in September.

A better alligator clip for molecular electronics

The dream of molecular electronics is to wire up circuits using individual molecules as the basic components. A basic problem is how you connect your (typically semiconducting) molecules to the metallic connectors; the leading candidate at the moment is to use molecules with a terminal thiol (-S-H) group. Thiols stick very effectively to the surface of gold; this thiol-gold chemistry has quietly become one of the most widely used tools of today’s nanotechnologists, and has been referred to as a molecular alligator clip. But it’s not without its drawbacks; rather than bonding to a single metal ion the thiol group complexes with a group of neighbouring gold atoms, and the electrical properties of the bond through the single linking sulphur atom aren’t ideal. Two papers in this week’s Science magazine suggest an alternative.

The two papers – by Siaj and McBreen (Université Laval, Québec) and Nuckolls and coworkers (Columbia University) (subscription required for access to the full articles) both describe ways of getting a molecule linked to a metal surface by a double bond (i.e. M=C- where M is a metal atom and C is the terminal carbon of an organic molecule). The surface bonded organic molecule can then be used to initiate polymerisation by a method known as ring opening metathesis polymerisation (ROMP). This is vey interesting because ROMP provides a way of growing organic semiconducting molecules with great precision. In short, we have here a better alligator clip for wiring up molecular electronics.