For the first time, researchers have demonstrated a means of controlling cell functions with a physical, rather than chemical, signal. Using a magnetic field to pull together tiny beads targeted to particular cell receptors, Harvard researchers made cells take up calcium, and then stop, then take it up again. Their work is the first to prove that such a level of control over cells is possible. If the approach can be used with many cell types and cell functions, it could lead to a totally new class of therapies that rely on cells themselves to make and release drugs.
The research was led by Donald Ingber, professor of pathology at Harvard Medical School and co-chair of the Harvard Institute for Biologically Inspired Engineering. Ingber's group demonstrated its method for biomagnetic control using a type of immune-system cell that mediates allergic reactions. Targeted nanoparticles with iron oxide cores were used to mimic antigens in vitro. Each is attached to a molecule that in turn can attach to a single receptor on an immune cell. When Ingber exposes cells bound with these particles to a weak magnetic field, the nanoparticles become magnetic and draw together, pulling the attached cell receptors into clusters. This causes the cells to take in calcium. (In the body, this would initiate a chain of events that leads the cells to release histamine.) When the magnetic field is turned off, the particles are no longer attracted to each other, the receptors move apart, and the influx of calcium stops.
"It's not the chemistry; it's the proximity" that activates such receptors, says Ingber.
The approach could have a far-reaching impact, as many important cell receptors are activated in a similar way and might be controlled using Ingber's method.
"In recent years, there has been a realization that physical events, not just chemical events, are important" to cell function, says Shu Chien, a bioengineer at the University of California, San Diego. Researchers have probed the effects of physical forces on cells by, for example, squishing them between plates or pulling probes across their surfaces. But none of these techniques work at as fine a level of control as Ingber's magnetic beads, which act on single biomolecules.
"Up to now, there hasn't been much control [over cells] at this scale," says Larry Nagahara, project manager in the National Cancer Institute's Alliance for Nanotechnology in Cancer and a physics professor at Arizona State University.
Many drugs, from anticancer antibodies to hormones, work by activating cell receptors. Once a hormone is in the blood, however, there's no turning it on or off. "This shows that you can turn on and off the signal, and that you can do it instantly," says Christopher Chen, a bioengineer at the University of Pennsylvania. "That's something that's hard to do, for example, with an antibody."
Ingber has many ideas for devices that might integrate his method of cellular control. Magnetic pacemakers could use cells instead of electrodes to send electrical pulses to the heart. Implantable drug factories might contain many groups of cells, each of which makes a different drug when activated by a magnetic signal. Biomagnetic control might lead to computers that can take advantage of cells' processing power. "Cells do complex things like image processing so much better than computers," says Ingber. Ingber, who began the project in response to a call by the Defense Advanced Research Projects Agency for new cell-machine interfaces, acknowledges that his work is in its early stages. In 50 years, however, he expects that there will be devices that "seamlessly interface between living cells and machines."
Other researchers agree. Ingber's biomagnetic control "may represent a new mechanism for man-machine interfaces," says UC San Diego's Chien. But before such interfaces can be developed, says University of Pennsylvania engineer Chen, researchers need to learn a lot more about cells.
"Say we have cells on a chip and we know what behavior we want to elicit," such as getting a stem cell to enter a wound site and initiate repairs, says Chen. "We don't know what signaling events have to happen to put the cell into the right state" so that it will take the desired action.
In the short term, Chen says that Ingber's method could help biologists gain crucial knowledge about cell signaling, such as how these signals are processed chemically and physically by the cell, and how they lead to particular outcomes, from calcium uptake to changes in gene expression. "It provides a tool that lets us tweak the cell and see what happens," says Chen.
Illustration: Immune cells coated with nanoparticles take up calcium in the presence of a magnetic field. –Donald Ingber, Harvard Medical School.
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Abstract (Nature Nanotechnology 3, 36 – 40, 2008)