Last month, when Professor Charles Lieber and his students made wires whose thinness is measured in atoms instead of fractions of an inch, he boasted excitedly that “there are so many potential uses for this technology that we feel like kids in a candy shop.”
In the past week, Lieber’s team has developed what is likely to be an important piece of scientific candy, a coated wire capable of detecting low levels of a protein that marks the presence or recurrence of prostate cancer. “The device immediately senses levels of PSA (prostate-specific antigen) four times smaller than is now possible with blood tests that often take days,” says Lieber, Hyman Professor of Chemistry at Harvard University.
He believes it will be possible to expand the use of such unimaginably small wires to sense the presence of malignancies, such as breast and ovarian cancers, as well as other types of diseases, and pathogens used in biological warfare. The sensor is so small it opens up the possibility of detectors implanted in the body to continuously monitor levels of insulin and other critical molecules.
The nanowire, as it’s known, is a scant 10-billionths of a meter (10 nanometers) in diameter, or about five times smaller than a virus. Its length stretches to approximately 1,000 nanometers. Proteins called antibodies, placed along the wire, bind to antigen proteins like PSA in a blood sample. The antigens carry an electric charge that changes the conductivity of the wire when they stick to the antibodies. That change can be measured by an ordinary voltmeter.
The technology exists for making antibodies to any protein specific to a disease, or to proteins present in viruses, bacteria, or other pathogens. This capability leads Lieber to envision an inexpensive generic device that would quickly detect many different disease markers and biowarfare agents such as anthrax spores. Chips that carry such detectors could be made small and cheaply enough to equip soldiers, firefighters, and other individuals with one.
Harvard has applied for a patent on the device, and a company called Nanosys, which was founded by Lieber, has licensed the technology. “Our goal is to have testable prototypes of a PSA detector within a year,” Lieber says. “Depending on the necessary FDA [Food and Drug Administration] approval, and tests with cancer patients, a couple more years of work could lead to a commercial product.” This process could be accelerated if the chip can fill a unique gap, such as providing a disease or biowarfare test where none now exists.
Pushing the limit
Prostate cancer survivors, like myself, live with the fear that tumor cells will regrow and spread to our bones. We undergo regular checks of PSA. A rise in blood levels of that protein signals recurrence may have begun. In such cases, you want to detect any rise in PSA as soon as possible.
At present, it takes a couple of days to get the results of a blood test, with a detectibility limit of 0.02 nanograms per milliliter. Lieber’s students Yi Cui and Wayne Wang tested a nanowire detector that pushes this limit down to 0.005. What’s more, the result is obtained immediately. With a commercial version, a physician could do the test in one office visit, or a patient might monitor his PSA at home, the way diabetics now track their blood sugar levels.
Cui and Wang did their tests on PSA samples of known concentration sent by collaborators at the University of California Medical School, San Francisco. “We’re now attempting to get certification to test blood samples from people who had or have prostate cancer and those who don’t have the disease,” notes Lieber. “We need to prove that we can detect PSA in a fluid full of other charged proteins. Tests we’ve done so far make us reasonably confident that we can.”
Detecting malignant changes
When a cell becomes transformed from normal to cancerous, PSA is not the only thing that changes. A sick cell has at least six other proteins not present in a well cell. A capability to detect all these changes could conceivably give scientists a better understanding of how this cancer develops in the first place.
“We can make a chip with 10 wires holding 10 different antibodies as easily as you can do it with one,” Lieber comments. “It takes up only nanospace.”
Keener insight into how a normal cell progresses to a malignant one may solve the biggest dilemma facing every prostate cancer patient: which treatment he should choose. Choices include surgery, two types of radiation, hormones, and doing nothing. The last has appeal because many tumors grow so slowly that the chances of an older man dying from the disease are lower than dying from some other cause. On the other hand, more aggressive tumors can kill a patient if he doesn’t choose a treatment in time.
Being able to test for the complex of proteins associated with development of the tumor holds the potential for determining both how aggressive a malignancy is and what might be the best course of treatment.
“We’ve also begun to look past prostate cancer to other cancers and diseases, especially breast cancer,” Lieber notes. “Breast cancer will be more difficult because we don’t have a robust marker like PSA. Markers for breast and ovarian cancer are not as positive. We would probably need a combination of antibodies on several wires.”
Taking another step into the future, Lieber and his students, in collaboration with Xiaowei Zhuang, assistant professor of chemistry, are setting up a capability to detect low levels of viruses. They will start with a flu virus. These experiments should be easier than working with PSA because viruses are larger than the PSA protein and carry a higher electrical charge.
“The natural charge is what gives us the detection signal,” Lieber explains. “We should be able to easily detect a single virus.”
Small, cheap, simple detectors could warn people about the presence of pathogens that cause natural epidemics, or that have been introduced by terrorists. Lieber believes they would be more effective than any system now in place.
He also thinks that, once developed, nanowire devices could become a valuable tool for use at Harvard’s new research center, the Molecular Target Laboratory. The center, just funded by a $40 million grant from the National Cancer Institute, has a goal of determining the role of proteins in disease and investigating which natural or synthetic molecules might be used in drug treatments.
Gently scan your fellow man. – Burns