BARELY a millimetre long, Arnd Pralle’s nematodes look much like any other worms. Then he switches on a magnetic field. The slithering, wriggling nematodes halt and, after a moment’s hesitation, go into reverse. He flicks the field off and on again and the creatures dance to his tune, moving back and forth in synchrony.
These are remote-controlled worms. Pralle and his colleagues at the State University of New York in Buffalo have implanted nano-sized receivers in nerve cells in the nematodes’ heads. Whenever the receivers detect the high-frequency magnetic field, the neurons fire and the worms turn.
Pralle’s nematodes are just the beginning. Biologists are now targeting other hosts and implanting receivers in ion channels, DNA strands and antibodies. Their aim is to take charge of living cells using little more than radio waves.
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This emerging field – a confluence of nanotechnology, biology and radio physics – is proving to be a powerful research tool but it is also creating a new kind of science: call it wireless bioengineering or electromagnetic pharmacology, if you will. Whatever the label, researchers are increasingly turning on and tuning in, and the implications are huge.
A new branch of medicine is on the horizon, says physicist Bernardo Barbiellini-Amidei from Northeastern University in Boston, who helped to organise a US National Science Foundation on the subject last year. Any number of treatments – based on the immune system, on gene therapy or even stem cells – could potentially be controlled remotely. Wirelessly activated medication could offer a nearly instantaneous on-off switch, in contrast to conventional drugs that can take hours to act and which linger in the body. “Imagine using radio fields to trigger cells to supply therapeutic proteins that are costly or difficult to deliver by other means,” says Sarah Stanley of Rockefeller University in New York, one of a team that has already developed a way to control the production and release of insulin using radio waves. It is perhaps not even too far-fetched to imagine a generation of drugs that start to work when activated by a smartphone app. “Nanoscale wireless systems have tremendous potential for medical therapeutics,” says Barbiellini-Amidei.
Powerful magnetic fields are already used as therapy for some illnesses. For example, a technique called transcranial magnetic stimulation (TMS) is approved in the US as a treatment for depression. It works by inducing localised electric currents in the brain.
TMS is not overly precise, and now ways of targeting magnetic fields far more specifically are being developed. In 2005, Sylvain Martel at the École Polytechnique in Montreal, Canada, hit on the idea of using magnetically sensitive bacteria to create tiny drug delivery systems.
Martel’s idea was to use a strain of bacteria called MC-1 as tiny tugboats. MC-1 swim along the field lines of Earth’s magnetic field, which they sense using chains of iron oxide particles embedded in structures called magnetosomes. Each magnetosome “acts like a miniature compass or nano-steering system”, Martel says.
In 2007, he and his team linked the bacteria to plastic beads several times their size and used a computer-controlled magnetic field generated by an MRI scanner to prove that the bacteria could and deposit their cargoes on target. Since then, they have replaced the beads with cell-like capsules called liposomes. Loaded with anti-cancer drugs, the liposomes can be steered through the bloodstream . The researchers have already guided a cargo of the anti-cancer drug doxorubicin attached to nanoscale magnets through arteries to tumours in a rabbit’s liver. Such therapies should minimise side effects by reducing the exposure of healthy cells to powerful drugs. Backed by a consortium of Canadian pharmaceutical companies, Martel is now hoping to target colorectal cancer.
But why stop there? Electromagnetic fields might offer a way to intervene directly inside cells by manipulating their biochemistry. Such wireless control would offer a precision that few drugs can match.
This approach was demonstrated in 2002 by Joseph Jacobson and a team at the Massachusetts Institute of Technology. They realised that metal nanoparticles can act as antennas and absorb energy from a magnetic field oscillating at radio frequencies. This energy is converted to heat and Jacobson suspected this could be useful for triggering biochemical changes inside cells.
He and his colleagues decided to test the idea with DNA. They made strands of DNA in which base pairs on one half were bound to pairs on the other, forming a loop like a hairpin. Next, they attached a single gold nanoparticle to each strand. When they switched on a high-frequency field, heat from the nanoparticles broke the base-pair bonds and the hairpins sprang open. With the field off, the molecules cooled and the bonds reformed. This cycle can be repeated over and over again, and Jacobson suggests it could be a useful tool for controlling gene function.
Pralle has a different use in mind: to open and close the pores in cell walls. Some of these protein-based pores regulate the passage of ions into and out of the cell – a key process that, if controlled, could have a host of uses.
As a postdoc researcher at the University of California, Berkeley, Pralle had studied an ion channel called TRPV1, usually found in pain-sensing neurons. At normal body temperature of around 37 °C, the channel is closed, but if the temperature rises to 43 °C, TRPV1 opens and calcium ions flood through, triggering a nerve impulse that creates the sensation of heat. In humans, TRPV1 is also responsible for the burning sensation created by “hot” substances such as chilli.
At first, Pralle thought about using an infrared laser to open the channels, but then he came across Jacobson’s work. “I began thinking we could use temperature to directly stimulate the TRPV1,” he says. Calculations told him that a single nanoparticle couldn’t gather sufficient energy to open an ion channel. But he figured that a small cluster of nanoparticles fixed to the membrane in which TRPV1 was embedded would be enough to heat the pore to 43 °C.
To test the idea, Pralle and his colleagues modified a protein that sits alongside TRPV1 in the cell membrane so it binds several magnetic nanoparticles made from manganese ferrite. It worked: they switched on a powerful 40 megahertz magnetic field, and in just 10 seconds the temperature of the channels rose by 6 °C and the pores opened ().
Then Pralle’s team tried the same thing with the nematode worm Caenorhabditis elegans. They added their TRVP1 nano-antenna system to neurons in the worms’ heat-sensitive “noses” and sure enough, when the modified neurons detected the magnetic field, the worms backed away from what felt to them like a heat source.
Zombie cells
A tantalising glimpse of where this wireless switch could lead came just last month (). A team led by Jeffrey Friedman of Rockefeller University created genetically modified cells in which calcium ions released by TRVP1 channels trigger the production of insulin. The researchers then added metal nanoparticles directly to the TRVP1 channels and injected the cells into a mouse. When they switched on a magnetic field oscillating at radio frequency, the animal’s blood sugar levels fell, indicating that insulin had been released.
Friedman’s team even figured out how to get the cells to make their own iron nanoparticles, by giving them the genetic machinery necessary to synthesise ferritin, a protein that gathers iron atoms together into clumps. The researchers say this approach could be modified so processes such as muscle contraction, which depends on calcium ions, could be triggered remotely. It could even offer a way to tackle tumours in sites like the brain, which are difficult to treat because the blood-brain barrier prevents large molecules in blood from entering the brain. Modify a patient’s own stem cells to produce a recombinant antibody in response to a radio signal and we could implant them in the central nervous system to deliver therapeutic antibodies, says Stanley. This is the realisation of some of wireless control’s potential, Pralle says. “It’s pretty cool,” he adds.
If this kind of remote heating is to be useful, it mustn’t destroy proteins in the ion channels or damage nearby molecules. One answer, Pralle believes, is to make the heating process more efficient. If he can cut the time it takes to raise the temperature of the ion channel, it should reduce the amount of heat affecting neighbouring molecules. To this end, he is designing better nano-sized heat absorbers.
There are other ways besides heat to remotely control cells. Don Ingber at Harvard Medical School in Boston has found evidence to suggest that cells use physical tweaks and tugs to communicate. His team found they could alter patterns of gene activity in cells and even trigger cell suicide – apoptosis – simply by stretching cells in specific ways.
Ingber’s trick is to bind magnetic nanobeads to integrins, proteins that are found in the outer membrane of cells and which anchor them to the extracellular matrix. Turning on a magnetic field puts a force on the beads. This tugs on the integrins and pulls the cell out of shape. In 2007, Ingber showed he could pull cells into a flattened form and when the field was turned off, the cells died. In other words, he says, “we were switching cell fates from living to dying”. Similarly, he and his team have found that deforming a stem cell can determine which type of tissue it turns into. “Mechanical forces are as important in development as genes,” he says.
could also influence our immune systems. In another set of experiments, Ingber’s team attached magnetic nanoparticles to antibody receptors on the surface of mast cells, which produce allergic immune responses to particular antigens. In a magnetic field, the nanoparticles formed a cluster, pulling the receptors together in much the same way that occurs when an antigen binds. Normally, this clustering triggers a series of biochemical events that leads to the release of histamine – the immune response. Sure enough, the magnetic field made that happen (). “It worked unbelievably well,” Ingber says.
Such wirelessly triggered histamine release could allow control of inflammation and much more besides, says Ingber. Histamine affects blood-vessel dilation, muscle contraction and secretion of gastric acid in the gut. It also functions as a neurotransmitter that influences wakefulness and vigilance. And the clustering effect could be used with other molecules on cell surfaces to create cancer therapies, perhaps triggering apoptosis of tumour cells, for example.
“Wirelessly triggered histamine release allows control of inflammation and much more besides”
Pralle is now planning to see if his remote heating technique can be used to stimulate the sense of smell in mice by activating specific neurons in the animals’ olfactory bulb – the part of the brain involved in processing smells. In effect, the mice will “smell” substances that aren’t present. Last year, his group received $1.3m from the US National Institutes of Health to develop the technique. “Olfaction provides a great testing ground, because the olfactory bulb can be reached from the outside and so delivery of nanoparticles is relatively easy,” he says.
Yet there are still plenty of questions. A key challenge is to get all the functions – sensing a wireless signal and converting it into a useful response – into a single, safe integrated system. Some researchers also suggest that electromagnetic signals like those from cellphones have dangerous effects on cells, altering gene expression or even triggering cancer. So far this idea remains .
Then there is the question of security. In February, Barnaby Jack, from web security company McAfee, revealed he had found a way to use wireless signals to carried by diabetics and to take control of them. This followed earlier work showing how insulin delivery systems, pacemakers and defibrillators that rely on wireless connections can be hacked. In response, the US Government Accountability Office is now investigating whether the medical-device industry’s security rules should be tightened. The report is due in July.
Clearly any such interference – by accident or design – raises alarming possibilities. “This opens up questions of computer and communications security in the nano world,” says Barbiellini-Amidei. “Future wireless nanodevices for medicine must contain safety mechanisms.” But solving these challenges should be worth the struggle: with remarkable prospects on offer if we can tune in to wireless medicine, why switch off now?
DNA calling
Tiny magnets may not be the best receivers for wireless cell control. Physicist Alex Zettl at the University of California, Berkeley, has shown that carbon nanotubes can act as : as an antenna plus amplifier and tuner combined.
To make a nanotube responsive to radio waves, Zettl and his team applied an electric charge to its tip. In the presence of radio waves, the charge creates vibrations in the tube that can be converted back into an oscillating electromagnetic signal. By altering the nanotube’s resonant frequency – by changing its length – he found he could tune the nanotube to a particular radio frequency. Zettl even showed that his nanotube radio could reproduce the transmission, by broadcasting the Beach Boys song Good Vibrations. The tune was easily recognisable in the from the nanotube receiver.
Yet even nano-radios might not be needed, if there is anything in controversial claims that cells might actually have their own wireless machinery. In 2009, immunologist and Nobel laureate Luc Montagnier asserted that to transmit information. This was based on claims that he picked up radio signals from water enriched with bacteria, and that the signals persisted when the cells were killed as long as their DNA was intact. Few researchers accepted these ideas. Then, last year, physicist Allan Widom at Northeastern University in Boston calculated that such signals could originate from in bacterial chromosomes: circulating charges are predicted to generate electromagnetic waves. He points out that some ancient bacteria are known to link themselves up into electrical networks through conductive nanowires. “More modern bacteria may use wireless,” Widom proposes.
