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ORNL researchers are developing two types of miniaturized devices for diagnosing diseases. These devices are based on cantilevers and biochips.

Disease Detectives

Cantilever Devices

Take a silicon chip as small as a grain of rice and carve out barely visible diving-board–like projections at one edge. Coat these cantilevers with gold. Attach thiolated single-stranded DNA to the gold-coated cantilevers. Allow single-stranded DNA of different sequences to come in contact with the DNA attached to the cantilevers. If a DNA sequence complements the DNA on a cantilever, they will bind together, or hybridize, to form double-stranded DNA. Thomas Thundat and Karolyn Hansen, both of ORNL's Life Sciences Division, use this recipe to distinguish between numbers of base pairs in DNA sequences on cantilevers.

"We immobilized single strands of DNA containing 20 bases on a series of cantilevers," Thundat says. "The DNA bases on these cantilevers paired with 20, 15, 10, and 9 bases of single-stranded DNA introduced to the cantilevers. We found that the cantilevers all bend because of the changes in surface tension as a result of DNA hybridization." The more bases a cantilever holds, the more it bends, changing the angle of deflection of laser light bounced off the cantilever, as recorded in a detector.

A cantilever beam on which an antibody for prostate-specific antigen is attached
A cantilever beam on which an antibody for prostate-specific antigen is attached.

Thundat believes that this technology could be used for DNA sequencing and that the approach would cost less and take less time than conventional techniques because it would avoid the step of adding fluorescent dyes to label the DNA bases. This technology has been licensed to Graviton, Inc.

Thundat believes that cantilevers can be used to detect defective genes that cause breast cancer, colorectal cancer, and cystic fibrosis. These mutant genes have one incorrect DNA base. ORNL experiments have shown that a DNA sequence in a liquid sample will hybridize with a complementary DNA sequence bound to a cantilever, even if the sample sequence has one wrong base, or a mismatch.

Thomas Thundat examines a cantilever beam on which an antibody for prostate-specific antigen is attached
Thomas Thundat examines a cantilever beam on which an antibody for prostate-specific antigen is attached. By bending when PSA binds to the probe antibody molecule, this device detects early signs of prostate cancer in serum samples with unusually high sensitivity.

"We found that a mismatch causes the cantilever to bend up instead of down," Thundat says. "This change in bending direction could be used to detect defective genes that cause disease."

The cantilever technology could also be used to detect prostate cancer. ORNL researchers have immobilized on a cantilever the antibody for prostate-specific antigen (PSA), the chemical signal for the disease. An ORNL collaboration with the University of California's Professor Arun Majumdar has shown that the cantilever bends when its antibody matches PSA in serum samples supplied by Majumdar. The sensitivity of this technology is 10 times higher than that of conventional techniques.

Biochip Devices

By detecting a mutant breast cancer gene, a doctor can predict that a patient will get breast cancer. By detecting a certain protein, a doctor can determine that the patient has adult-onset diabetes. Someday, physicians will be able to rapidly analyze both genes and proteins from a single drop of a patient's blood, using a palm-size device. At least that's the goal of Tuan Vo-Dinh and his co-workers David Stokes, Minoo Askari, and Guy Griffin, all of the Life Sciences Division, and Alan Wintenberg of ORNL's Instrumentation and Controls Division.

A miniaturized laser diode illuminates the array of sites
To make a multifunctional biochip work in the doctor's office, a patient's blood sample would be processed to separate DNA sequences and proteins, which are then labeled with a fluorescent dye. The chip would then be exposed to these blood fragments. Disease-related DNA and proteins will bind to the chip's complementary DNA and antibody probes. A miniaturized laser diode illuminates the array of sites, causing fluorescence at the sites of hybridization. The signals are collected and sent to a microprocessor chip, which stores the identity of the probes at each location. By matching signal locations to the probes known to be there, the microprocessor detects disease-related genes and proteins in the patient's blood and relays the diagnosis to the physician.

"We can do genomics and proteomics on a single platform using our multifunctional biochip," says Vo-Dinh. "The biochip is being designed to process up to 100 samples in 30 minutes." The multifunctional biochip is an advanced version of the group's DNA biochip, which contains only DNA probes. This technology has been licensed to HealthSpex, Inc., in Oak Ridge.

To sample a patient's blood for a DNA sequence that is a red flag for a genetic disease, the multifunctional biochip has a complementary DNA sequence to which this mutant sequence will bind. To sample for a specific disease-related protein, the biochip has a probe (e.g., an antibody or protein receptor) that will bind with this particular protein.

ORNL experiments have shown that the biochip can detect the tuberculosis bacterium, the HIV gene, a cancer suppressor gene, the anthrax bacterium used in biological warfare, and Escherichia coli found in contaminated food. Thus, the biochip could be used for medical diagnosis, defense, and food safety applications.

Small though they are, both the cantilever device and biochip could make a big contribution to health care.

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ORNL Life Sciences Division
ORNL Instrumentation and Controls Division

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