Archive for September, 2007

Towards the $1000 human genome

Friday, September 28th, 2007

It currently costs about a million dollars to sequence an individual human genome. One can expect incremental improvements in current technology to drop this price to around $100,000, but the need that current methods have to amplify the DNA will make it difficult for this price to drop further. So, to meet a widely publicised target of a $1000 genome a fundamentally different technology is needed. One very promising approach uses the idea of threading a single DNA molecule through a nanopore in a membrane, and identifiying each base by changes in the ion current flowing through the pore. I wrote about this a couple of years ago, and a talk I heard yesterday from one of the leaders in the field prompts me to give an update.

The original idea for this came from David Deamer and Dan Branton, who filed a patent for the general scheme in 1998. Hagan Bayley, from Oxford, whose talk I heard yesterday, has been collaborating with Reza Ghadiri from Scripps, to implement this scheme using a naturally occuring pore forming protein, alpha-hemolysin, as the reader.

The key issues are the need to get resolution at a single base level, and the correct identification of the bases. They get extra selectivity by a combination of modification of the pore by genetic engineering, and insertion into the pore of small ring molecules – cyclodextrins. At the moment speed of reading is a problem – when the molecules are pulled through by an electric field they tend to go a little too fast. But, in an alternative scheme in which bases are chopped off the chain one by one and dropped into the pore sequentially, they are able to identify individual bases reliably.

Given that the human genome has about 6 million bases, they estimate that at 1 millisecond reading time per base they’ll need to use 1000 pores in parallel to sequence a genome in under a day (taking into account the need for a certain amount of redundancy for error correction). To prepare the way for commercialisation of this technology, they have a start-up company – Oxford NanoLabs – which is working on making a miniaturised and rugged device, about the size of a palm-top computer, to do this kind of analysis.

Stochastic sensor
Schematic of a DNA reader using the pore forming protein alpha-hemolysin. As the molecule is pulled through the pore, the ionic conduction through the pore varies, giving a readout of the sequence of bases. From the website of the Theoretical and Computational Biophysics group at the University of Illinois at Urbana-Champaign.

Soft Machines in Korean

Tuesday, September 25th, 2007

Soft Machines Korean cover

My book “Soft Machines: nanotechnology and life” is now available in a Korean translation made by Dr Tae-Erk Kim, and published by Kungree, price 18,000 Won.

The publication of the English paperback version is imminent: in the UK, OUP is giving the publication date as October 2007, (OUP catalogue entry) with a price of £9.99. Readers in the USA will have to wait until December 17th, where their version is priced at $17.99.

Three good reasons to do nanotechnology: 2. For healthcare and medical applications

Friday, September 21st, 2007

Part 1 of this series of posts dealt with applications of nanotechnology for sustainable energy. Here I go on to describe why so many people are excited about the possibilities for applying nanotechnology in medicine and healthcare.

It should be no surprise that medical applications of nanotechnology are very prominent in many people’s research agenda. Despite near universal agreement about the desirablility of more medical research, though, there are some tensions in the different visions people have of future nanomedicine. To the general public the driving force is often the very personal experience most people have of illness in themselves or people close to them, and there’s a lot of public support for more work aimed at the well known killers of western world, such as cardiovascular disease, cancer, and degenerative diseases like Alzheimer’s and Parkinson’s. Economic factors, though, are important for those responsible for supplying healthcare, whether that’s the government or a private sector insurer. Maybe it’s a slight exaggeration to say that the policy makers’ ideal would be for people to live in perfect health until they were 85 and then tidily drop dead, but it’s certainly true that the prospect of an ageing population demanding more and more expensive nursing care is one that is exercising policy-makers in a number of prosperous countries. In the developing world, there are many essentially political and economic issues which stand in the way of people being able to enjoy the levels of health we take for granted in Europe and the USA, and matters like the universal provision of clean water are very important. Important though the politics of public health is, the diseases that blight developing world, such as AIDS, tuberculosis and malaria, still present major science challenges. Finally, back in the richest countries of the world, there’s a climate of higher expectations of medicine, where people look to medicine to do more than to fix obvious physical ailments, and to move into the realm of human enhancement and prolonging of life beyond what might formerly be regarded as a “natural” lifespan.

So how can nanotechnology help? There are three broad areas.

1. Therapeutic applications of nanotechnology. An important area of focus for medical applications of nanotechnology has been in the area of drug delivery. This begins from the observation that when a patient takes a conventionally delivered drug, an overwhelmingly large proportion of the administered drug molecules don’t end up acting on the biological systems that they are designed to affect. This is a serious problem if the drug has side effects; the larger the dose that has to be administered to be sure that some of the molecule actually gets to the place where it is needed, the worse these side-effects will be. This is particularly obvious, and harrowing, for the intrinsically toxic molecules the drugs used for cancer chemotherapy. Another important driving force for improving delivery mechanisms is the fact that, rather than the simple and relatively robust small molecules that have been the main active ingredients in drugs to date, we are turning increasingly to biological molecules like proteins (such as monoclonal antibodies) and nucleic acids (for example, DNA for gene therapy and small interfering RNAs). These allow very specific interventions into biological processes, but the molecules are delicate, and are easily recognised and destroyed in the body. To deliver a drug, current approaches include attaching it to a large water soluble polymer molecule which is essentially invisible to the body, or wrapping it up in a self-assembled nanoscale bag – a liposome – formed from soap like molecules like phospholipids or block copolymers. Attaching the drug to a dendrimer – a nanoscale treelike structure which may have a cavity in its centre – is conceptually midway between these two approaches. The current examples of drug delivery devices that have made it into clinical use are fairly crude, but future generations of drug delivery vehicles can be expected to include “stealth” coatings to make them less visible to the body, mechanisms for targeting them to their destination tissue or organ and mechanisms for releasing their payload when they get there. They may also incorporate systems for reporting their progress back to the outside world, even if this is only the passive device of containing some agent that shows up strongly in a medical scanner.

Another area of therapeutics in which nanotechnology can make an impact is in tissue engineering and regenerative medicine. Here it’s not so much a question of making artificial substitutes for tissues or organs; ideally it would be in providing the environment in which a patient’s own cells would develop in such a way as to generate new tissue. This is a question of persuading those cells to differentiate to take up the specialised form of a particular organ. Our cells are social organisms, which respond to chemical and physical signals as they develop and differentiate to produce tissues and organs, and the role of nanotechnology here is to provide an environment (or scaffold) which gives the cells the right physical and chemical signals. Once again, self-assembly is one way forward here, providing soft gels which can be tagged with the right chemical signals to persuade the cells to do the right thing.

2. Diagnostics. Many disease states manifest themselves by the presence of specific molecules, so the ability to detect and identify these molecules quickly and reliably, even when they are present at very low concentrations, would be very helpful for the rapid diagnosis of many different conditions. The relevance of nanotechnology is that many of the most sensitive ways of detecting molecules rely on interactions between the molecule and a specially prepared surface; the much greater importance of the surface relative to the bulk for nanostructured materials makes it possible to make sensors of great sensitivity. Sensors for the levels of relatively simple chemicals, such as glucose or thyroxine, could be integrated with devices that release the chemicals needed to rectify any imbalances (these integrated devices go by the dreadful neologism of “theranostics”); recognising pathogens by recognising stretches of DNA would give a powerful way of identifying infectious diseases without the necessity for time-consuming and expensive culturing steps. One obvious and much pursued goal would be to find a way of reading, at a single molecule level, a whole DNA sequence, making it possible cheaply to obtain an individual’s whole genome.

3. Innovation and biomedical research. A contrarian point of view, which I’ve heard frequently and forcibly expressed by a senior figure from the UK’s pharmaceutical industry, is that the emphasis in nanomedicine on drug delivery is misguided, because fundamentally what it represents is an attempt to rescue bad drug candidates. In this view the place to apply nanotechnology is the drug discovery process itself. It’s a cause for concern for the industry that it seems to be getting harder and more expensive to find new drug candidates, and the hopes that were pinned a few years ago on the use of large scale combinatorial methods don’t seem to be working out. In this view, there should be a move away from these brute force approaches to more rational methods, but this time informed by the very detailed insights into cell biology offered by the single molecule methods of bionanotechnology.

Nanomandala

Monday, September 17th, 2007

Martin Kemp’s “science in culture” column in this week’s Nature – Heaven in grains of sand (subscription required) – brings our attention to a collaboration between nanoscientists at UCLA and some Tibetan monks. This installation – Nanomandala – is based on a Tibetan mandala – a symbolic representation of the cosmos built up from individual grains of sand; nanoscientist Jim Gimzewski responds to the mandala by using optical and scanning electron microscopy to reveal its features on finer and finer scales, culminating in the molecular. In the resulting video installation by Victoria Vesna “visitors watch as images of a grain of sand are projected in evolving scale from the molecular structure of a single grain to the recognizable image of a pile of sand. On the atomic scale the sand particles are like atoms, but a thousand of times smaller. From a bottom-up method of visual image building, a sand mandala slowly emerges.”

Monks in nano-lab
Tibetan monks working with UCLA nanoscientist Jim Gimzewski

My own knowledge of Tibetan Buddhism (or indeed any other kind) is of the very superficial kind that came from growing up as a would-be bohemian teenager in provincial Britain – in Van Morrison’s words, “I went home and read my Christmas Humphreys book on Zen”. But I rather agree with Martin Kemp’s conclusion: “There is something very beautiful and moving in this holy alliance of Buddhist spiritual patience, founded on minute care and untiring repetition, and the unholy processes of iteration of which modern computers are capable. The mandala-makers and the nanoscientists share the wonder of scale, involving countless parts to compose the ordered whole.” The allusion to Blake that Kemp makes in the title of his piece makes the connection to Western mysticism too:

“To see a world in a grain of sand and heaven in a wild flower, Hold infinity in the palms of your hand and eternity in an hour”

Mandala
An 8ft sand mandala created at the Los Angeles County Museum of Art as part of the Nanomandala project.

Nanotechnology, water and development

Friday, September 14th, 2007

What impact will nanotechnology make on the developing world? Some point to the possibility that nanotechnology might help solve pressing problems, such as the availability of clean water and more abundant renewable energy through cheap, nano-enabled solar cells. Others concede that these developments might be possible in principle, but that the political and economic barriers to development are more pressing than the technical ones.

An open meeting, to be held in London on November 7, will consider the issue. It’s organised by the thinktank Demos, and will involve NGOs, scientists and government representatives. Confirmed speakers include two scientists, Mark Welland, head of the Cambridge Nanoscience Centre, and me, as well as David Grimshaw, from the international development charity Practical Action, which was founded by E.F. Schumacher, the author of the famous book “Small is beautiful”.

In the meantime, a couple of interesting publications on the topic have appeared. The Demos project Nanodialogues had a section describing the results of a public engagement exercise carried out in Zimbabwe which explored the gulf between the reality of the water problems people face there and the more glib assurances that technical solutions will be easy. A much more detailed report, Nanotechnology, water and development, has been commissioned by the Meridian Institute, and written by Thembela Hillie and Mbhuti Hlope from South Africa, and Mohan Munasinghe and Yvani Deraniyagala from Sri Lanka. This explores a pair of case studies, and actually is quite positive in tone, concluding that “Developing countries are – on their own initiative – pursuing these technologies for both economic and humanitarian reasons.As the South African case study illustrates, developing countries are using existing nanotechnology products and are initiating nanotechnology projects to remove pollutants from water; the use of these technologies is not limited to developed countries.

The new geography of innovation

Thursday, September 6th, 2007

One of the many interesting features of nanotechnology is that its development is taking place at a time when more and more research is being carried out in the fast developing countries of Asia. The extent of this shift is underlined by a recent piece of research publicised with the headline Western knowledge gap widens with shift to the East. The research, by Robert Huggins and Hiro Izushi, from the Universities of Sheffield and Aston, analysed the destination of the $50 billion invested in R&D by multinationals between 2002 and 2005. They found that 58% of this money was spent in Asia (concentrated in a few locations, such as Bangalore, Hyderabad, and Mumbai in India and Beijing, Guangzhou, Hangzhou and Shanghai in China), 22% in Europe and only 14% in North America. Since North America was the origin of 50% of this money, this prompts the authors to talk about a ” net R&D investment deficit of US$18 billion” for North America (by the same definition, Europe has a smaller deficit of US$3 billion).

This strongly underlines the comment I made below in my article Nanotechnology and visions of the future (part 2): “Even the remaining large companies have embraced the concept of “open innovation”, in which research and development is regarded as a commodity to be purchased on the open market (and, indeed, outsourced to low cost countries) rather than a core function of the corporation.”

Three good reasons to do nanotechnology: 1. For a sustainable energy economy

Tuesday, September 4th, 2007

When I was in Norway a few months ago, I was talking to an official from their research council about the Norwegian national nanotechnology strategy. He explained how they were going to focus on a few appplication areas for nanotechnology, starting with nanotechnology for energy, nanotechnology for medicine, and nanotechnology for information technology. Thus far his list was very similar to lists being compiled by just about everybody else in the world. Then he went on to explain that the fourth area would be nanotechnology for fish and I had to admit to myself that the latter focus probably would be nationally distinctive. Fish apart, there does seem to be a widespread consensus that the other three areas are the ones in which nanotechnology is likely to make the biggest global impact, at least on the short to medium term. It’s worth summarising some of the arguments for this order of priority.

1. Nanotechnology for a sustainable energy economy. This comes first because our current way of life is utterly dependent on cheap and abundant energy, and there are no easy ways of significantly lessening this dependence. Yet the cheap energy that we’ve come to rely on is threatened in multiple ways. The need to reduce CO2 emissions to combat climate change is growing in urgency, the geopolitical implications of such a vital commodity being in the control of people and nations whose interests may not be the same as ours are becoming more and more obvious, and the prospect of the exhaustion of the most convenient forms of fossil fuel – gas and oil – is appearing on the horizon. It’s no surprise, the, that both private sector investments and government funded research in nanotechnology is increasingly being directed in applications to energy.

So, how could nanotechnology make an impact on our evolving energy economy? Let’s look at this in three categories:

1. Primary energy sources. At the moment, the ultimate sources of most of our energy are oil and gas, either used directly or converted into electricity, and electricity made by burning coal or by harnessing nuclear fission. Renewables – primarily hydroelectric at the moment, with wind power growing, make a small contribution. Nanotechnology’s most significant potential contribution is in the area of solar energy, where alternative photovoltaics capable of being produced cheaply in the very large areas needed to supply significant amounts of power are on the horizon.

2. Energy for transportation. Our societies are dependent on large scale mobility, both personal and for the movement of goods across the world. Liquid hydrocarbons – in the form of petrol, diesel and aviation kerosene – are convenient, high energy density fuels, and a massive infrastructure exists to distribute them. The “hydrogen economy” offers an alternative, in which the transport fuel would be hydrogen, made using primary energy sources like solar energy, nuclear energy, or a combination of fossil fuel use with CO2 sequestration. Nanotechnology could help overcome some of the formidable technical barriers to this scheme, by making possible safe, high density storage for energy and by improving the performance and price of fuel cells. On the other hand, as the recognition of the economic and technical barriers to a hydrogen economy grows, the alternative of a “methanol economy” grows more attractive in some people’s eyes. Using methanol as a transportation fuel has the great advantage that one can use the existing infrastructure for distributing liquid fuels, and continue to use internal combustion engines. An ideal would be to make methanol directly using solar energy to combine water and carbon dioxide – photocatalytic reduction of carbon dioxide. This is something we know ought to be possible in principle, but we don’t know how to do it yet.

3. Lowering the energy intensity of the economy. There are a host of possible incremental improvements in materials and processes to reduce the amount of primary energy needed to produce a given amount of economic output. Individually these may not look spectacular, but together the effect may be very significant. This ranges from more efficient light sources such as light emitting diodes, better materials for building insulation to better materials and coatings allowing turbine blades to be operated hotter, leading to higher energy conversion efficiencies in power stations.

Next – nanotechnology for medicine and health