Park Ridge, Ill. - Biochip development, which peaked two years ago during the national anthrax scare, has begun paying unexpected dividends, as research work in the area yields a new breed of "protein chips" that could aid in the early detection of cancer, Alzheimer's disease and HIV.
Researchers at a nanotechnology startup have taken a step toward commercializing the technology by licensing a protein-chip-based detection system from Northwestern University. Nanosphere Inc. (Northbrook, Ill.), which hopes to integrate the system into desktop products within a year, said the technology exhibits about 1 million times more sensitivity than conventional methods in the detection of prostate-specific antigen, a protein linked to prostate cancer. Last week's announcement followed the publication of a company co-founder's description of the technology in the Sept. 26 issue of Science.
Nanosphere's announcements put the company in lockstep with other players that have been accelerating their development of protein chips. "Protein chips are the next generation of biochip technology," said Darrell Chandler, technical-group leader for Argonne National Laboratory's Biochip Technology Center (Argonne, Ill.). "DNA chips were the first generation, and now a lot of people are working very hard on protein chips because they provide the ability to diagnose diseases based on certain protein signatures."
Looking for proteins
Researchers at Argonne said last week that their Biochip Technology Center has developed protein chips that can be connected to a charge-coupled device camera or CMOS chip, and could one day serve in handheld protein-chip-based diagnostic devices. "Ultimately, we can foresee putting the chip into a cartridge, and having the cartridge fit into a Palm Pilot or a similar device," Chandler said.
Similarly, scientists at Pacific Northwest National Laboratory (Richland, Wash.) are developing protein chips that allow researchers to screen for multiple proteins simultaneously. They plan to use the technology to identify new protein markers that could serve as a screen for the presence of breast cancer.
Some researchers, such as those at Argonne, are developing systems that work with optical detection techniques and don't need to be directly connected to electronics. Argonne's chips are not conventional integrated circuits, but are essentially glass slides that employ an array of tiny gel elements, or "nano test tubes," onto which researchers cram tens of thousands of proteins in a square area measuring a half-centimeter on a side. Argonne has demonstrated the technology in portable biochip readers that optically examine the slides as a means of detecting biological agents or chemicals.
Argonne's approach differs from that of Nanosphere, which plans to employ an electrical technique that uses silicon protein chips containing gold nanoparticles. The technology, invented by a Northwestern University professor who is also a company founder, is already being used to detect strands of DNA. The company now intends to use it to locate protein markers as well.
Nanosphere uses the technique to measure bonding between DNA strands in, for example, a drop of blood. DNA strands in the sample combine with similar strands in the silicon substrate and in the gold nanoparticles, which measure about 15 nanometers wide. To check for bonding, researchers measure the electrical resistance across two gold particles, located microns from each another. The chip has no memory or processing capability, but engineers can measure inductance, capacitance, impedance or resistance across the device.
When no bonding is present, resistance is high and electrical current barely conducts across the gap between the particles. But by laying a capture strand of DNA across the gap and then applying a blood sample, researchers can create an electrical bridge. The resulting change in conduction signals the presence of the DNA or protein for which they're looking.
The company's engineers said the electronic technique shows promise for high-volume production of handheld detection devices. Nanosphere said that when it gets to volume production, it will contract out the construction of the chip to an electronics company, but will do its own DNA or protein "spotting." Spotting refers to the placement of the DNA or protein strands on the chip, which shares such standard semiconductor technology as inlaid circuitry and contact pads.
"Electronics allow you to put gold electrodes onto a silicon base, which can be manufactured in high quantities," said William Cork, the chief technical officer for Nanosphere. "With electronics, the costs go down because the complexity goes down."
The startup company said it has used the silicon-and-gold configuration in its Verigene ID desktop system, which was unveiled over the summer and is currently undergoing clinical trials. Nanosphere's engineers designed the system using an off-the-shelf single-board computer from Ampro Computers Inc. (San Jose, Calif.) and an in-house-developed "glue logic" board that integrates all the I/O, including touchscreen drivers, along with FPGAs and software interfaces.
Nanosphere's biochips, like those made by other researchers, can also be used for identification of DNA from such pathogens as anthrax, smallpox and tuberculosis. Many researchers are working with government agencies on biochips that can be used to detect the deadly contaminants in military and civilian settings.
Nanosphere engineers said they plan to initially sell their Verigene ID desktop system for $30,000, and their Verigene Mobile system for approximately $5,000 when it reaches the market.
"But if we get an order for 10,000 units from the Defense Department, the prices would drop fast," CTO Cork said.
In medical settings, Cork maintained that the protein chips offer vastly greater sensitivity than existing protein-detection methods that are being used by today's medical community.
Tests using the protein chip may be more expensive than those using conventional methods, said Vijaya Vasista, chief operating officer of Nanosphere, but would have other cost benefits for cancer treatment, for example. "By detecting the cancer earlier, you're actually saving on health care costs as well as reducing grief for the patient," Vasista said. "That's where the value proposition of this technology becomes really compelling."
CTO Cork said that the detection of proteins is "fairly routine" in many applications today, but that Nanosphere's protein chip "offers far greater sensitivity than those tests, and it gives more diagnostic information than has ever been available before."
For cancer victims, or for those with the potential of contracting certain cancers, the new technology reportedly could detect the disease as much as 10 times sooner than it is found today.
"There is concurrence [within the research community] that we could detect it earlier," Cork said. "How much earlier we still don't know for sure."
Researchers said that the protein chip techniques could also be used for earlier detection of Alzheimer's disease and HIV, the virus that causes AIDS.
"The real value of the protein chips will definitely be in life-science research," said Chandler of Argonne. "Discovery of the proteins will come first, and then we'll create tools to do the diagnostics."