Measuring proteins in the blood can help doctors determine patients’ cancer risk and monitor the health of the elderly and people with chronic diseases. But current methods for testing these proteins are too expensive and require too much blood to be performed regularly. A microfluidic chip in clinical trials does on a single chip in 10 minutes what normally takes multiple technicians hours to do–and with just a single drop of blood. Researchers hope to make bedside diagnostics based on blood proteins a reality by bringing down the cost of such tests by at least an order of magnitude.
The diagnostic chip is being developed by Caltech chemistry professor James Heath and by Leroy Hood, the president and founder of the Institute for Systems Biology, in Seattle. Heath and Hood have founded a company called Integrated Diagnostics to commercialize the blood chip.
“Serum proteins provide an incredible window into the biology of disease,” says Paul Mischel, a professor of pathology at the University of California, Los Angeles. But today, it costs about $500 to test for one blood protein, and these tests require 10 to 15 milliliters of blood and multiple visits to the doctor.
“We decided to make things dirt cheap: it costs a nickel a protein,” Heath says of the current device. Such rapid and cheap tests requiring only a drop of blood should allow doctors to monitor more proteins more frequently, enabling earlier detection of diseases like cancer and better preventive care for the elderly. The new diagnostics should also be more accurate, says Heath. Traditional blood samples sit for hours or even days before the measurement process is completed, allowing plenty of time for them to degrade.
Heath and Hood’s device, described in this week’s issue of Nature Biotechnology, starts the analysis process with some simple microfluidics. A drop of blood is pulled down a microscale channel by the application of a small external pressure. This first channel branches off into narrower ones, which exclude blood cells and admit the protein-rich blood serum. In typical blood tests, this separation step requires a centrifuge.
The narrower channels are patterned with what Heath calls a protein bar code–lines of DNA bound to antibodies that capture proteins of interest from the serum. After the serum and cells are flushed out, antibodies bound to red fluorescent proteins are flushed in, lighting up captured blood proteins. The protein bar codes can be read under a fluorescent microscope or a gene-chip scanner. The identity of the captured blood proteins can be determined by the location of red lines in the bar code relative to a green fluorescent reference line.
By measuring how much light radiates from a particular protein’s spot in the bar code, Heath and Hood can quantify its concentration in the blood. Heath notes that the chip can measure blood proteins present over a wide concentration range, making it possible to measure not only plentiful blood proteins created by the immune system, but also rarer proteins originating in organs such as the brain. The device is as sensitive as conventional protein tests, and Heath and Hood can measure any proteins they’re interested in by making custom chips with the right antibodies.
While other groups have focused on proteins that are created by many organs, making the results difficult to interpret, Hood says, “We’re developing a strategy to identify blood proteins that are organ-specific.” Hood says his group is currently using mass spectrometry to discover proteins specific to the liver and brain.
In their published paper, the researchers describe using the blood test to determine the risk level of people with breast and prostate cancer. Heath says that the chip is being tested in clinical trials involving both cancer patients and healthy individuals. The studies of healthy patients that the group is currently undertaking would be impractical using technologies that require a large blood draw, but using the chips, Heath says that it’s possible to measure blood proteins several times a day. The researchers are using the blood chips to monitor how diet and exercise influence blood-protein composition.
“These devices should lead to a decrease in cost and an incredible benefit to patients,” says Emil Kartalov, a professor of pathology at the University of Southern California’s Keck School of Medicine. Kartalov, who’s not collaborating with Heath and Hood, is developing similar chips, and he developed some of the separation methods used on the blood chip. Kartalov says that Heath and Hood’s work is a major step forward, but that for these chips to truly go out into the field, they’ll need to move beyond fluorescent proteins. Fluorescent microscopes are too expensive and too bulky to be carried onto the battlefield or into patients’ homes. Kartalov says that future diagnostics will probably replace the fluorescent proteins with charged proteins, since measuring changes in electrical current is much simpler and more practical.
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