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Springs to Life

one reason for vettiger’s enthusiasm is that mechanical devices can do things electronics can’t. Electronics are great for moving information, but with mechanics you can detect physical forces and material properties-such as mass-possibly down to the level of individual molecules. Down the hall from Vettiger, Christoph Gerber, one of the inventors of the AFM, is turning loose his nanomechanical skills on biology in order to do just that.

An AFM’s tiny imaging tip is suspended from an ultrathin cantilever; as the tip rides over an atomic or molecular surface, minuscule deflections in the cantilever are measured optically with the help of ultrasmall lasers. These cantilevers are essentially small springs, sensitive enough to measure the nano force from individual atoms. Gerber’s idea is to use an array of these cantilevers as simple but extremely sensitive sensors. If you coat one of the cantilevers in the array with, say, a particular sequence of DNA, the complementary strand of DNA will selectively bind to that cantilever. You can then detect the deflection of that cantilever and use the information to measure the presence of that specific sequence of DNA-something that is of enormous value in medical research, disease detection and genetic screening.

Gerber and his co-workers have recently built such a sensor. Consisting of eight cantilevers that are each 500 micrometers long but less than one micrometer thick, the device is sensitive enough to measure deflections of only a few nanometers. In recent tests, the sensor differentiated DNA sequences differing by a single base pair (the smallest unit of DNA information); the ability to detect individual base-pair differences without radioactive or fluorescence tags is a remarkable accomplishment. Existing technology for DNA screening-DNA chips-has found wide applications in everything from disease diagnostics to biomedical research; but these commercial chips require the DNA to be fluorescently tagged and read by a bulky optical reader. Gerber believes his biosensors, which don’t require tagging of DNA, are potentially far simpler and easier to use.

The cantilever technology could also prove to be a simple way to detect specific proteins, a feat that Gerber says is difficult for current technology. “If we can fully develop this for proteins, we see a great potential,” says Gerber. For example, he says, the onset of a heart attack produces in the body a signature set of proteins. However, it often takes hours for physicians to sort out the welter of proteins and determine definitively whether a person is actually having a heart attack. Gerber believes his sensors could quickly and cheaply solve the problem. “We could have a device that says yes or no,” predicts Gerber.

Like Vettiger, however, Gerber gets most excited by the longer-term implications of his work. Demonstrating that DNA and protein molecules can actually move a tiny cantilever suggests it might be possible to build nanomachines that act independently. Imagine, Gerber suggests, implanted microcapsules for drug delivery that have a nanoscale valve able to detect a signature protein from a cancer cell; the binding of the protein to the cantilever would trigger the opening of the valve, releasing just the right amount of an anti-cancer drug from the microcapsule in the exact location needed.

At MIT’s Media Lab, Assistant Professor Scott Manalis is using some of the same tools-tiny cantilevers and AFM probes-to tackle similar biological problems. But Manalis is using a completely different strategy: probes that detect electrical signals. Many biological molecules, including DNA and proteins, are electrically charged. But from a materials point of view, the world of biomolecules, which normally exist in a watery environment, is largely incompatible with conventional microelectronics. (Spill water on your Palm Pilot, and you’ll get the point.) By altering the makeup of the electronic materials, however, Manalis has fabricated in essence a small transistor at the end of an AFM cantilever that works just fine under water.

The result is a microscopic detector that operates in the environment where DNA, proteins and cells flourish. So far, Manalis and his co-workers are using it as a sensitive probe that can be placed at the end of a microfluidic channel, for example, to detect the electrical signals of-and hence analyze–the DNA flowing out. Like the biosensors being developed at IBM, the tiny device detects DNA without tagging or bulky optical readers. Eventually, Manalis hopes the biosensor could help make possible one of biomedicine’s grander visions: a simple wireless device with a few electrodes that could be implanted in a patient with, say, kidney disease to act as an early warning signal detecting when a troublesome protein is being released.

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