Making life from the bottom up

I wrote below about Craig Venter’s vision of synthetic biology – taking an existing, very simple, organism, reducing its complexity even further by knocking out unneccessary genes, and then inserting new genetic material to accomplish the functions you want. One could think of this as a kind of top-down synthetic biology; one is still using the standard mechanisms and functions of natural biology, but one reprogrammes them as desired. Could there be a bottom-up synthetic biology, in which one designs entirely new structures and systems for metabolism and reproduction?

One approach to this goal has been pioneered by Steven Benner at the University of Florida. He’s been concentrating on creating synthetic genetic systems by analogy with DNA, but he’s not shy about where he wants his research to go: “The ultimate goal of a program in synthetic biology is to develop chemical systems capable of self-reproduction and Darwinian-like evolution.” He’s recently written a review of this kind of approach in Nature Genetics Reviews (subscription only): Synthetic biology.

David Deamer, from UC Santa Cruz, has a slightly different take on the same problem in another recent review, this time in Trends in Biotechnology (again, subscription only, I’m afraid). “A giant step towards artificial life?” concentrates on the idea of creating artificial cells by using self-assembling lipids to make liposomes (the very same creatures that L’Oreal uses in its expensive face creams). Encapsulated within these liposomes are some of the basic elements of metabolism, such as the mechanisms for protein synthesis. How close can this approach get to creating something like a living, reproducing organism? In Deamer’s words: “Everything in the system grows and reproduces except the catalytic macromolecules themselves, the polymerase enzymes or ribosomes. Every other part of the system can grow and reproduce, but the catalysts get left behind. This is the final challenge: to encapsulate a system of macromolecules that can make more of themselves, a molecular version of von Neumann’s replicating machine.” He sees a glimmer of hope in the work of David Bartel at MIT, who has made a RNA enzyme that synthesizes short RNA sequences, pointing the way to RNA-based self-replication.

But all these approaches still follow the pattern set by the life we know about on earth; they depend on the self-assembling properties of a familiar repertoire of lipids and macromolecules, like DNA, RNA and proteins, in watery environments. Could you do without water entirely? Benner is quoted in an article by Philip Ball in this week’s Nature (Water and life: Seeking the solution, subscription required) arguing that you can: “Water is a terrible solvent for life…. We are working to create alternative darwinian systems based on fundamentally different chemistries. We are using different solvent systems as a way to get a precursor for life on Earth.”

A view from the Greenhouse

Here’s another brief report on the Nottingham nanotechnology debate. It’s from Jack Stilgoe, from the thinktank Demos, who was the non-scientist on the panel. He frames the debate in rather nationalistic terms. Is this really just a clash between the habitual rainsoaked pessimism of the British, and sunny American optimism and its associated can-do attitude?

Nanotechnology debate at Nottingham

I don’t know about anybody else, but I enjoyed yesterday’s nanotechnology debate at Nottingham. The whole thing was filmed, and as soon as it’s been edited and tidied up we’ll get the video put up on the web. Given that everyone will soon have the opportunity to judge for themselves how the thing went, I’ll confine myself here to some general observations. There was a big crowd, mostly graduate students attending the surface science summer school, supplemented by a good fraction of the local nanoscientists. The nature of the audience meant that the debate rapidly got quite technical; I don’t think anyone could say that the molecular manufacturing point of view didn’t get a serious hearing. I must say that I was a little apprehensive, given the rancour that has entered previous debates, but I felt the tone was robust but mutually respectful.

My prize for gnomic aphorism of the evening goes to my fellow-panellist Saul Tendler (bionanotechnologist and pharmacy professor). “If a cat had wheels, who would change its tyres?”

Nanotechnology and human enhancement

A session at the British Association’s annual meeting in September, which this year is being held in Dublin, is devoted to a debate on the topic “Should we enhance ourselves: does nanotechnology have limits”. The debate, which is between 7 pm and 9 pm on Tuesday 6 September, has been put together by Donald Bruce, the Director of the Church of Scotland’s Science, Religion and Technology Project. The speakers are myself, Donald, and Paul Galvin, teamleader for Nanobiotechnology at the Tyndall National Institute in Cork.

Under attack

Soft Machines is currently the victim of what amounts to a denial of service attack. This post is by way of warning that the site may need to be taken down (temporarily, I hope) later today if it can’t be sorted out.

Update 20 August. There’s been a bit of improvement, following various measures. Data transfer (normally 20-30 MB a day) is back to about 50 MB a day, from a high of 500 MB a day. I’ve made my peace with the web hosting company. But I do need to move the site onto a different server, which is proving to be a bit of a pain, and means that I’m needing to find out more about mySQL than I really want to know.

22 August. The site is now on the new server. I hope most things have transferred ok; please let me know if you find any glitches. The last four comments – from Kurt, Howard Salis, and replies from me to each – aren’t registered in the “Recent Comments” sidebar, but can be found in the appropriate posts, “commercialising synthetic biology” and “cheap designer genes”.

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: BiologyRNAi 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.