Micro scope

Stalwart of Sunday afternoon TV schedules, 'Fantastic Voyage' is a favourite film of many in the engineering community. Some like the ingenious plot, where a miniaturised submarine is injected into an injured diplomat to remove a lethal blood clot. Others like the still-impressive special effects, the sneeringly sinister performance of Donald Pleasance, or Raquel Welch's skin-tight wetsuit. But for some, it is not just a movie; it's a research outline.

'Marvellous film. Very educational,' said Prof Richard Jones, nanotechnologist at the

and the

senior strategic advisor on nanotechnology. 'Not only is it a fantastically potent image of medical nanotechnology, but the job of thinking through why it is not accurate is actually very fruitful.'

Of course, nobody thinks that miniaturising a submarine full of medics and sailors is a practical model for surgery. But medical nanobots have begun to emerge from the realm of science fiction and into fact, as the goals of research projects. The concept of a man-made device, of a similar scale or smaller than the cellular structures in the body, being guided to a specific location to destroy disease tissues, is one that many researchers believe could be a reality.

'We already have micro-robots, or perhaps mini-robots — things that you swallow, miniaturised cameras or labs-on-chips, which are very neat,' added Jones. 'But you have to realise that when you get down to the cellular scale, the physical world that you have to operate is very unfamiliar. The fluid dynamics are different; attempts to swim under those conditions tend to involve pushing yourself backwards and forwards continually. If you were to try to make a submarine work under those conditions, you would need a very different sort of propulsion system.'

There are other conditions to contend with. In the bloodstream and other fluid-filled cavities in the body, particles are subjected to constant buffeting from the molecules of the fluid, causing Brownian motion. Then there are proteins, which at the nanoscale are fantastically sticky. 'You will recall in "Fantastic Voyage" that when Raquel Welch went out of the submarine she emerged covered in proteins that the rest of the crew had to scrape off her wetsuit,' said Jones. 'It's one of the few scientifically accurate scenes in the film.'

Propulsion is one of the biggest current research focuses in medical nanobots. For example, James Friend of

in Australia, has developed a micromotor, currently around the size of a grain of salt, which uses piezoelectric effects to operate a propeller in the form of whip-like flagella, mimicking the propulsion system of E.coli bacteria. Friend and his team are aiming to reduce the size of the motor to around 250 microns, small enough to fit inside larger blood vessels. The team obviously have similar taste in films to Richard Jones — the motor is called Proteus, after the submarine in 'Fantastic Voyage'.

Jones is also working on bacteria-mimicking propulsion. 'It is very easy to construct a case as to how nanosubmarines will never work, but bacteria are very good at swimming around at the nanoscale,' he said. 'To me, the simple message from this is that nanoscale devices will actually look biological. The only technology we know that works under these conditions is biology, so realistically, we have to study that and if not actually use the biological components, then copy their mechanisms.'

To design a medical nanobot, then, isn't so much a matter of miniaturising existing technologies. The best way seems to be to look at what the device would have to do, and then constructing a new kind of technology that will do the job under the strange conditions of the nanoscale.

In other words, the concept of a robot has to be re-thought. A robot has to be able to do certain things. It has to be able to follow instructions; it has to be capable of movement; it has to withstand the conditions it will face; it has to be able to communicate, and it has to have some kind of processing power.

For medical nanobot, said Jones, think less of a submarine and more of a drug-delivery system. 'Think of a sphere made up from fat molecules, a liposome; or a similar sphere of synthetic materials, a polymersome. That gives you a vessel or container with an outside and an inside, so it can carry a payload. On the outside, you would have a coating on it to prevent protein absorption. You can think of it as stealth coating; in practice it is likely to be something like polyethylene glycol.'

This is pretty much the state of the art in molecular drug delivery, but Jones starts to go further. 'You need to communicate with the outside world, or at least be detectable; so you might add a fluorescent molecule or, more likely an MRI contrast agent.'

In terms of propulsion, the energy source is worth thinking about. 'You're going to want something that takes energy from its surroundings,' Jones said. 'It might use glucose as a fuel, as that would be commonly available. Our propulsion system, which is just demonstrating physical principles, runs on hydrogen peroxide, but we have ideas about how to make them run on glucose. But at the moment, we are just concentrating on making things go faster; we haven't got the hang of steering.'

Steering and targeting are other lessons that biology could teach us; for an example of a nanomachine that moves, navigates and delivers a payload, look at a sperm cell. 'We don't have targeting agents yet, but they could come soon — you would want some kind of ligand or receptor that would detect or bind to compounds on a cell surface.' Finding such agents is the stock-in-trade of medicinal chemistry, where receptor blockers are used to inhibit cell functions that, for example, are part of the processes that increase blood pressure.

The issue of intelligence, or at least information processing, would seem to be the trickiest of all. But again, it is only tricky if you are thinking of electronic information processing. Imagine instead the simple logic steps that make up the process of computing, and the situation starts to look very different.

'You can actually do some pretty complicated logic with networks of interconnected chemicals,' Jones said. 'One example would be a shell that self-destructs when it encounters an acidic environment, and even that very basic intelligence could be useful, because if you have a polymersome that has taken inside a cell by entocytosis, you find that the interior of the cell, the vacuole, is more acidic than the outside.' From this starting point, Jones said, more complicated logic systems could be built, that would release a payload when they encounter a combination of chemical signals. 'This is another form of programming we are talking about here, but it is still programming and processing.' One project to look at such systems is about to start in the UK. Involving Nottingham, Oxford and Glasgow universities, the three-year project aims to evaluate whether the signals that natural cells use can be imitated by synthetic cells in such a way that the natural cells can't tell the difference. This nanoscale Turing test could lead the way towards smart antibiotics, targeted drug carriers and intelligent agents for tissue repair, the research teams say.

The active agents themselves, the part of the nanobot that burns out infection or destroys cancerous tissues, is also likely to be a chemical. 'We have to be talking about highly sophisticated drug delivery here, if we are talking about the true nano-scale,' Jones said. 'You wouldn't physically destroy cells, you would attack them chemically.'

While there are many projects aiming at medical nanobots, Jones believes that the practical technology is still decades away. 'There will be incremental steps, but a system that includes real processing power and propulsion, which we could meaningfully call a robot, is still at least 20 years off.'