CARLO MONTEMAGNO is planning an invasion of your body. 鈥淲e want to make machines we can insert inside cells,鈥� he says. Once they鈥檙e in there, he aims to make them do things that nature simply can鈥檛, such as make drugs or generate electricity.
This isn鈥檛 just loose speculation or an idle dream: it鈥檚 work-in-progress at Cornell University. Montemagno has already constructed a working biomolecular motor less than one-fifth the size of a red blood cell. The key components are a protein from the bacterium Escherichia coli attached to a nickel spindle and propeller a few nanometres across. Its power comes from ATP, the biological fuel found in every living cell. The motor is just one step on the road to realising an ambitious long-term vision. Next in line is a motor that can self-assemble inside a cell. 鈥淲e want to get seamless integration between machinery and living systems,鈥� Montemagno says.
Advances like these are promising to change the way medicine interacts with living biological matter. Smart implants that deliver drugs precisely when they鈥檙e needed are already near to hitting the market. Also on the way are electronic devices that tell cells to make specific hormones when your body needs them, and electricity generators that assemble themselves inside a cell and then tap into the cell鈥檚 own energy source for the power to run. There is no question that machines are beginning to infiltrate the biological workings of life. 鈥淭hings are incredibly fast-paced at the moment,鈥� says Gary Sayler, a microbiologist at the University of Tennessee, Knoxville. 鈥淚 know some researchers who are talking seriously about micro-robotic surgical techniques,鈥� he says. 鈥淲ith the pace of things now you can go from fiction to reality in 10 years.鈥�
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Machines built on the nanoscale-using parts the size of small molecules-are likely to look very different from everyday devices. 鈥淭hey鈥檙e not going to be small versions of what we make in the microworld- we鈥檙e not going to see levers, tweezers and valves,鈥� says Mauro Ferrari, Director of biomedical engineering at Ohio State University. 鈥淭hey鈥檒l be similar concepts, but entirely different physics because mechanics just doesn鈥檛 work the same at that scale.鈥� Whatever does end up roaming your body, it won鈥檛 be anything like the miniature submarine in the movie Fantastic Voyage.
The first medical application of implantable nanotechnology is currently proving its worth in trials. Tejal Desai at the University of Illinois has developed a nano-engineered implant that could mean people with diabetes would no longer have to inject insulin. Diabetic rats with the implant have now gone for several weeks without needing insulin injections. 鈥淭his is the first we鈥檝e seen of these technologies actually getting past the bench top and being implanted,鈥� Desai says.
Her implant is a silicon box around a tenth of a millimetre across containing a sponge of fibrous collagen tissue. The collagen is seeded with pancreatic cells taken from a pig, a dog or even a mouse. The crucial feature of the box is that the silicon is peppered with holes just 20 nanometres wide-a human hair is about 100,000 nanometres thick. 鈥淭hese pores control what can go in and what comes out of the capsule,鈥� Desai says.
Because glucose molecules are relatively small, they can get into the capsule and wash over the trapped cells. If the cells detect too much glucose in the bloodstream, they start producing insulin. The insulin molecules are small enough to escape into the bloodstream and bring glucose levels down. But bigger molecules-such as antibodies and complement proteins employed by the immune system to attack foreign cells-are too big to get in. This means the body doesn鈥檛 detect the foreign cells, so the implant isn鈥檛 rejected. Simple, but effective.
Even more cunning are the 鈥渄endrimers鈥� designed by James Baker, director of the Center for Biologic Nanotechnology at the University of Michigan in Ann Arbor. These are spherical molecules painstakingly built up layer by layer from a central core. Dendrimers act as multipurpose tools to deal with infection and damage within the body. They can stain diseased tissue with an image-enhancing dye, and give the offending cell a fatal dose of some drug. Doctors can then check this has worked by using a dendrimer that becomes fluorescent in the presence of the enzymes released by a fatally wounded cell. Shining an ultraviolet laser light into the affected area and recording the light emitted reveals how successful the treatment has been.
Each of these tasks is performed by a separate dendrimer, but Baker has now connected some of these dendrimers together to produce the first multifunctional system. 鈥淭he most advanced can deliver a drug inside a cell, document that the drug is in there and report back on the cell鈥檚 response,鈥� he says. Baker can carefully control the structure, size and chemistry of the dendrimers, adding exactly what he wants at each layer. It takes this level of precision to ensure that the dendrimers evade detection by the immune system and slip easily into cells, without causing medical complications (see 鈥淭hanks, but no thanks鈥�).
And once we can interact with individual cells, we should also be able to harness their extraordinary capabilities, says Milan Mrksich, a chemist at the University of Chicago. We might be able to use them as pharmaceuticals factories, for instance. 鈥淐ells are capable of functions we still don鈥檛 know how to engineer,鈥� says Mrksich, who is now attempting to harness these production plants.
His plan is to hook the cells up to electronic circuitry by sitting them on a bristling carpet of molecular arms. He can then persuade them to do what he wants. Carbon chains between 10 and 20 atoms long are attached to a gold-plated glass plate with sulphur atoms, with the strands packed so densely that they are forced to stand upright on the surface. That creates a forest of free ends which Mrksich can use to manipulate cells. 鈥淲e can put anything on the end of these molecules that we want to,鈥� he says.
Before he can tell the cells what to do, Mrksich has to grab hold of them. He can do this by tagging the exposed ends of the molecular chain with a ligand-a molecule that usually acts to anchor cells within tissue. 鈥淚f we apply a potential to the gold layer, when it gets high enough, electrons jump from the gold onto the molecule,鈥� Mrksich says. Electrons shift along the chain and alter the chemistry of the ligand, activating it so that it will bind to a cell. Mrksich can grab hold of passing cells at the flick of a switch.
Switch on the genes
Though impressive, this is just the start. 鈥淭here are all kinds of different receptors on cell surfaces,鈥� he says. 鈥淭hese trigger the cells to express different genes.鈥� Mrksich believes he鈥檒l be able to coerce cells to switch on the appropriate genes to make whatever the body needs. 鈥淵ou could have them producing different products, depending on how you stimulate them,鈥� he says. Integrating electronics with biological cells would mean that diagnosis, drug production and treatment could all be automated within the body.
Montemagno believes that when cells can be engineered and instructed to produce drugs, his nanomotors could be used to collect and store the drug molecules. 鈥淟et鈥檚 suppose you take a cell, strip out everything you don鈥檛 need and put in genetic information to produce a drug like taxol,鈥� he says. 鈥淚f the taxol is released in the cell, it鈥檒l kill it immediately, so you need a machine that grabs individual molecules as they鈥檙e made and sequesters them.鈥�
So Montemagno is working on what he calls a 鈥減harmacy in a cell鈥�, designed to grab the crucial molecules and drop them into a storage compartment. He made a nickel drum 100 nanometres in diameter and attached it to a biological motor. Either side of the drum are two chambers-one containing a drug, the other empty. The drum is coated with antibodies that bind to the drug, so it picks up molecules from the drug-filled chamber as it rotates. An electric field across the empty chamber pulls the drug molecules off the drum and holds them there.
This device even runs on an energy source readily available within the body. Because the motor is essentially biological, it can exploit the fundamental energy-producing reaction that powers life-the breakdown of ATP, or adenosine triphosphate. Wedged within cell membranes is a protein called F1-ATPase which both makes and breaks down ATP. A current of hydrogen ions into this protein makes a part of it rotate clockwise, churning out molecules of ATP. Reverse the proton flow, and the protein rotates anti-clockwise, breaking down ATP. The exact mechanism remains a mystery to researchers, but that hasn鈥檛 stopped Montemagno making use of it. He has genetically modified the protein to give it a 鈥渉andle鈥�, which can then be locked onto nanoengineered parts such as a propeller shaft, bridging the gap between biological and mechanical systems.
Montemagno believes that if several of these motors could be coupled together, they could generate useful amounts of electricity from biological fuel. 鈥淚 don鈥檛 know how to do this, but it鈥檚 theoretically possible,鈥� he says. This electricity could be used to power the moving parts of implanted machinery, or microelectronic implants that diagnose problems inside the body.
Adam Heller, a biochemical engineer at the University of Texas, Austin, is also looking at harnessing biology in order to produce electricity within the body. He has developed a biological fuel cell comprising two carbon fibres coated with the enzymes, glucose oxidase and laccase. The plan is to produce electricity from glucose and oxygen in the bloodstream, but there are still significant hurdles to overcome. For a start, the two enzymes he uses prefer different environments.
鈥淎t the moment we have two enzymes which have conflicting optimal conditions,鈥� Heller says. Because of that, his fuel cell only operates in a solution more acidic than the conditions found in the body, and he is not yet claiming to have a fuel cell ready for implantation. 鈥淲e鈥檙e working on finding enzymes that will work in physiological conditions,鈥� he says. Heller published his initial results in the Journal of the American Chemical Society last month, but he is not willing to guess whether all the problems can be solved.
Heller believes overexaggerated claims have been a big problem for nanotech. 鈥淭here鈥檚 been a formidable amount of talking and not doing,鈥� he says. Ferrari agrees that this hype isn鈥檛 harmless. 鈥淥ver-promise can lead to a rapid drying up of wells when people think it鈥檚 not delivering,鈥� he says.
Many researchers put the blame for this on Eric Drexler. In 1986 Drexler, a space-systems researcher at the Massachusetts Institute of Technology, published Engines of Creation, which claimed that our ever-improving ability to manipulate matter would lead to the creation of machine parts the size of small molecules. These could be assembled into machines much smaller than biological cells, enabling us to interact directly with the machinery of biology, he said. After all, Drexler argued, biology is nothing more than a bunch of molecular machines created and honed by evolution. Man-made 鈥渃ell-repair machines鈥�, directed by nano-engineered computers, could do better than nature鈥檚 efforts, repairing damage atom by atom, correcting mistakes in DNA and servicing and maintaining all the components of individual cells. This, he claimed, could spell the end of ageing, and ultimately even defeat death.
Drexler never said his nanotechnology dream would come easy, and he still defends the book as a scientific work (see 鈥淚 started it鈥�). But many researchers feel it may have done more harm than good. Subsequent speculation about the potential of nanotechnology has given people unreasonable expectations, they say. Time and again they have been asked to measure their progress against technological fantasies inspired by Engines of Creation. Back on one cold Sunday in February, for example, Montemagno鈥檚 phone started ringing at 3 o鈥檆lock in the morning. 鈥淚t was a radio station in Portugal,鈥� he recalls. 鈥淭hey had me live on air and wanted to know about 鈥榥anocopters鈥� that would fly around the body, dive-bombing cancer cells.鈥� In the wake of his nanomotors, this wasn鈥檛 unusual. 鈥淧eople just wanted to do this Fantastic Voyage thing.鈥�
Despite the hype, it seems that nanotechnology really is going to deliver on some of its promises. 鈥淔inding good ways to deliver drugs is a huge problem,鈥� says Ferrari. 鈥淭hat鈥檚 the one place I think nanotech is actually going to open up new horizons and have a big impact on healthcare.鈥�
Pills with surfaces crafted on the nanoscale could make treatments possible for people who鈥檝e previously had to go without, says Ferrari. Drugs that are vulnerable to digestive enzymes and need to be injected into veins, for instance, are difficult for people to self-administer. 鈥淭here鈥檚 a great drug for anaemia called erythropoietin, or EPO,鈥� says Ferrari, 鈥渂ut we only give it to people who are already in hospital for something else, like cancer. Because you need to inject it intravascularly, it鈥檚 inconvenient and expensive. People just end up living with it.鈥� Ferrari has developed a nano-engineered pill that allows people to take drugs like EPO orally. Its surface prevents digestive enzymes breaking down the drug in the stomach and enables it to latch onto the intestinal wall and pass through into the bloodstream.
Useful nanoscale machines will be altogether more difficult to make. Although Montemagno believes he will demonstrate uses for the biological motor within two years, he also admits there are enormous engineering problems to solve. 鈥淩ight now I can make devices with an efficiency of between 1 and 4 per cent,鈥� Montemagno says. To make the motors commercially viable, he needs an assembly technique where 99.9 per cent of them work. And the jump from these prototypes to machines that can actually do something useful is an even bigger challenge. Montemagno doesn鈥檛 believe he or any of his contemporaries will solve the problems themselves: he thinks it鈥檚 a job for the scientists of the future. 鈥淪ome smart kid who鈥檚 at school right now will figure this out,鈥� he says.
That鈥檚 assuming the funding frenzy lasts long enough. Last year, Europe, Japan and the US together poured $624 million of public money into nanotechnology-an increase of almost 80 per cent on four years ago. The US is now committing even more money, announcing a massive $497 million of funding for this year. And the biggest research companies-Hewlett-Packard, IBM and 3M, for instance-are allocating up to a third of their research money to nanotechnology.
However, the number of hands begging for nanotech money is also increasing. As all research ultimately involves atoms, scientists are finding it hard to resist the temptation to stake a claim on nanotech funding. 鈥淓veryone is requalifying themselves as a nanoscientist,鈥� says Ferrari. 鈥淚鈥檓 a nanoscientist even if I鈥檓 a railroad engineer.鈥� It鈥檚 not just individual researchers: companies too are queuing up to change their names to include 鈥渘ano鈥�, says James Chilcott of Evolution Capital, a London-based investment bank. 鈥淭he nano prefix could become as dangerous as the dotcom suffix,鈥� he warns.
But the researchers are confident that they are going to turn healthcare inside out. Montemagno believes that, despite the hype which Drexler鈥檚 initial speculations caused, they can at least be seen as an essential catalyst for nanotechnology. 鈥淚 am very reluctant to talk about people鈥檚 ideas and visions as being ridiculous,鈥� Montemagno says. 鈥淪o often they鈥檝e been proven to be not so stupid.鈥� So what if we don鈥檛 learn how to live forever? It doesn鈥檛 mean we won鈥檛 benefit from trying.
