July 3, 2000 WEST LAFAYETTE, Ind. – Scientists at Purdue University have created the first protein "biochips," mating silicon computer chips with biological proteins.
The research coordinator says chips containing thousands of proteins could be organized into a device about the size of a handheld computer that could quickly and cheaply detect specific microbes, disease cells and harmful or therapeutic chemicals.
Michael Ladisch, professor of agricultural and biological engineering and biomedical engineering at Purdue, says that if the first real-world tests of the biochips are successful, the protein-encrusted silicon chips could appear in dozens of applications in a few years: Physicians could use devices containing biochips to quickly diagnose common diseases or to test the efficacy of chemotherapy. Soldiers might rely on sensors on the battlefield to sound the alarm in the event of a biological or chemical attack. Farmers could place sensors in their fields to alert them to crop diseases. Medical scientists could use the biochips to investigate whether certain plants popular as folk remedies actually contain biochemicals that have beneficial biological activity, and from the findings could develop new pharmaceutical products.
Although biochips containing DNA already are used to automate the sequencing of genes, including the human genome, many scientists have been interested in mating proteins with computer chips because proteins are very specific about which other proteins or biochemicals they will interact with.
Scientists often compare the binding of proteins to a key matching with a lock. By attaching these biological "keys" to computer chips, scientists believe they will be able to detect specific microbes, disease cells and harmful or therapeutic chemicals quickly and cheaply.
Take, for example, a protein that binds to the cell wall of a particular bacterium. That protein could be attached to the biochip. If the bacterium were present in a sample passed over the chip, it would bind to the protein, causing a detectable change in the electrical signal passing through the chip. This change in the electrical signal would be registered by the device, confirming the presence of the bacterium in the sample. Other bacteria or molecules in the sample would not bind to the chip.
The base computer chips were first fabricated by Rashid Bashir, assistant professor of electrical and computer engineering, working with graduate student Rafael Gomez, in Purdue's microelectronics fabrication facilities. Then, working with Ladisch and his graduate students, the group successfully attached the protein avidin to the chip. Avidin binds to a vitamin called biotin, and fluorescently labeled biotin molecules did attach to the avidin embedded on the biochip.
A key element of this research was verifying that the chips actually held the proteins, Ladisch says. J. Paul Robinson, professor of biomedical engineering and immunopharmacology, used advanced microscopic techniques to detect interactions at the surface of these chips and verify the attachment of the proteins.
Bashir and his graduate students attached the two proteins to the chip by first applying an overlay onto the chips using a process known as photolithography, which is similar to lithography printing. This helped to define the channels and metal surface regions on the chip. Then the proteins were attached by using the electrical charges naturally occurring within the proteins.
A patent application for the new Purdue biochip is pending.
A paper on the biochip, "Micro-Scale Detection of Biological Species in Micro-Fluidic Chips," was presented at the Nanoscience and Nanotechnology: Shaping Biomedical Research conference at the National Institutes of Health in Bethesda, Md., on June 25.
The first non-laboratory application of the new biochips will be to develop sensors to detect the deadly pathogen Listeria monocytogenes in foods.
According to 1999 statistics from the Centers for Disease Control and Prevention, there are an estimated 2,500 cases of Listeria monocytogenes infections annually. Unlike other foodborne pathogens, a high number – one out of five – of the cases of Listeria are fatal.
Better detection of this fatal food pathogen is a high priority for the food industry, according to Arun Bhunia, associate professor of food science at Purdue. "The problem is, however, that at the present time we can only detect the pathogen if we have a large sample. To get a large number, you have to let the bacterium grow in a laboratory. You typically don't see levels that high in a food system," he says. "It can take as much as five to seven days to grow, test and confirm the presence of a specific pathogen."
The biochip could speed this process dramatically. It would contain antibodies to Listeria monocytogenes obtained from rabbits or mice. Antibodies are natural defense proteins that organisms use to recognize and disable harmful proteins.
Because only Listeria monocytogenes could interact with the antibodies on the chip, a definite determination of the absence or presence of the bacterium could be made within minutes.
The work to develop a biochip sensor for the food industry is being financed by the Purdue Food Safety Engineering Project with funds from the U. S. Department of Agriculture.
"This is a good first use of this technology," Ladisch says. "To detect Listeria monocytogenes, speed is needed, and the combination of biotechnology with computer chips is a possible answer."
The biochips would require approval of the Food and Drug Administration before they could be used in food production.
Researchers from several schools and disciplines at Purdue played key roles in the development of the biochip.
"Microelectronic technology and life sciences have historically been separate areas of research," Bashir says. "But applying micro- or even nano-electronic technologies and devices, such as these biochips, to life science problems will result in solutions that are low cost compared to current testing methods, and will significantly reduce the time needed for the detection of organisms and specific biological materials."
Expertise on processing samples and interpreting their interactions is being contributed by Rakesh Singh, professor of food science, and Mike McElfresch, associate professor of physics and materials engineering.
Ladisch and Dr. Stephen Badylak, a senior research scientist in Purdue's Department of Biomedical Engineering, originally proposed the concept as a way to probe natural materials for therapeutic molecules.
"The real bottleneck in biological research is the lack of a way to quickly interrogate the chemistry of various organisms to find out if they contain any beneficial or harmful compounds," Ladisch says.
Scientists have long known that each species of plant or animal produces unique chemical compounds, and that some of these compounds can, like penicillin, become miracle drugs.
"There are estimates that there are about a million species of organisms on earth, and through human history tens of thousands of these have been used for medicinal purposes," Ladisch says. "Up to now, we've been uncovering the actual proteins or molecules at the rate of just a few a year. This research has the potential to increase that number several fold.
"What we would have would be a high-tech litmus paper. It would tell us the presence of molecules with specific properties and the concentrations. There are a lot of secrets still being held by Mother Nature. Maybe this will allow us to probe for some of the more obvious ones."
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