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Critters on a Chip

Cheap, flexible biosensors could help out in medical and environmental emergencies
biosensor image

Image: Tom Cerniglio/Oak Ridge National Laboratory
LIVING BIOSENSOR, or "critters on a chip," may have important applications in environmental monitoring and medical diagnositics. The chip (seen magnified on the monitor in the background) is held by its inventor, Mike Simpson of Oak Ridge National Laboratory.

In medicine, information saves lives; ignorance loses them. An accident victim shows up at an emergency ward, unconscious and bleeding, his pulse irregular. He needs a transfusion, but of what blood type? Is he HIV-infected? Is his arrhythmia a sign of a heart attack, or did he just forget to take his medication this morning? The surgeon needs answers fast, but the current tests for determining blood Rh factor, the presence of HIV, the chemical signatures of heart attack and the concentrations of common heart medications are slow--sometimes life-threateningly slow.

The problem is that these biological signals, important as they are, are also extremely faint. Gathering enough of the telltale molecules to make a perceptible mark takes time. In theory, electronic microcircuits attuned to those molecules in solution could be more sensitive and faster than conventional tests. In practice, however, mixing microchips and liquids has been difficult. Since the 1970s, scientists have tried dozens of biosensor designs in search of one that is cheap and flexible enough to use for both viruses and drugs, proteins and enzymes. The biosensors that have reached the market can make simple measurements such as of sugar concentrations in a diabetic's blood, but those designs have been hard to extend. Two designs unveiled in recent months may yield a more general solution.

One sensor, dubbed "critters on a chip" by its inventors at Oak Ridge National Laboratory in Oak Ridge, Tenn., consists of a tiny light-sensitive computer chip coated with bioluminescent bacteria. When the bacteria encounter certain chemicals, they light up, creating an electrical signal that the chip can process or amplify. So far the researchers have used a genetically engineered bacterium called Pseudomonas fluorescens HK44 to create a biochip that is exquisitely sensitive to naphthalene, a common petroleum pollutant.

A naphthalene biosensor could be useful for monitoring hazardous waste sites. But the same principle could be extended to produce cheap (under $1), disposable chips that would "dramatically advance the ability to sense a variety of chemical agents in the environment, such as chemical warfare agents or other toxic substances and things like environmental estrogens that could have detrimental effects on living systems," says Gary Sayler, head of the University of Tennessee's Center for Environmental Biotechnology. Of course, such critter chips have limitations, because they are alive. The bacteria need food, and they can die or mutate. So critter chips will probably carry (literal) expiration dates. Also, it is sufficiently tricky to make the bacteria light up that this design may be impractical for many medical uses.

A more flexible design may soon fill the medical need. After ten years of work, a group of Australian scientists has at last produced a stable bioelectrical switch that can detect minuscule amounts of antibodies, viruses, hormones, drugs and even DNA sequences. The team, led by Bruce A. Cornell at the Cooperative Research Center for Molecular Engineering and Technology in Chatswood, Australia, reported its success in the June 5 issue of Nature.

Unlike the critter chips, the ICS Biosensor, as Cornell calls the device, does not use life itself. Instead it lays an artifical cell membrane atop a gold electrode. The membrane functions like a wall with many gates. Each gate is controlled by a molecule that, like some spiteful doorman, closes the passage when it runs into a particular target molecule. To detect digoxin, a heart medication, Cornell attached to the gates compounds that bind to the drug. When it is present, the gates swing shut, electrical flow from one side of the membrane to the other slows, and the electrode registers a change in impedance. Importantly, the change is proportional to the amount of drug in the sample.

Cornell maintains that his group's design makes it easy to create a wide variety of very sensitive and stable biosensors by simple switching of the doorman molcules. So far they have built chips that can detect viruses, bacteria, drugs, proteins, DNA sequences, and medically important minerals such as potassium and calcium. Cornell's tests show that the sensors can accurately measure levels of target compounds present in blood, serum and urine samples. These biosensors appear to remain stable over a wide range of temperatures. That is important, says Anthony P. F. Turner, head of the Institute of BioScience and Technology at Cranfield University in England, because "stability is a major technical problem for many applications."

Molecular Landscape
Image: R. Pace/P. Cambell/AMBRI

MOLECULAR LANDSCAPE depicts the working of the ICS Biosensor. Compounds of interest (green globs) link up with antigens (orange "arms") which in turn connect to sites in the underlying membrane, disrupting the flow of electricity, thereby indicating the presence of the compounds.

So is cost. Current affinity sensors cost $100,000 or more. The ICS Biosensor, Cornell claims, should be about 10,000-fold cheaper. In fact, manufacturing appears straightforward, he says: "The process is to take a gold-coated electrode and dip it into several solutions. All the layers of chemicals that make it work simply self-assemble." Cornell reckons that the chips should cost just a few dollars each once they go into mass production.

AMBRI, a subsidiary of Pacific Dunlop, is commercializing the device and expects to have the first related products ready for market around 2000. Early applications will include bedside tests for heart attack, drugs of abuse and perhaps a few common genetic mutations. Beyond that, Cornell says, it should be possible to adapt the design of the ICS Biosensor to create sensitive detectors for almost any important biological molecule.

Turner agrees that "the Cornell design, if it is verified in practice, represents a step forward. It promises increased stability of a very sensitive configuration. Being optimistic, I believe we are on the verge of a microsensor revolution which could rival the microprocessor revolution in size, scale and impact." Indeed, Turner adds enthusiastically, "micro-analytical devices could pervade our lives in the next decade or two!"

Then, a medic might take a drop of blood from our hypothetical patient and drop it into a biosensor. Within seconds, the device reveals the patient to be Rh-positive, HIV-negative and suffering not from a heart attack but from an overdose of digoxin. Information like that could save the fellow a very expensive shot of heart attack mediation. Not to mention his life.

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