This article mentions NGEN, AFFX, HYSQ.
Biochips: from sci-fi to critical tech
by Margaret Quan
Once relegated to science fiction, chips that analyze biological material to diagnose disease, aid in drug discovery and deliver medicine inside the body will provide the basis for major research and commercial breakthroughs in the 21st century. In 2010, a patient may go to a doctor's office for a blood test with a lab-on-a-chip device that tells the doctor in real-time if a patient's illness will respond well to a drug based on his DNA. The chip could also confirm the patient's identity, diagnose disease and even be used to establish paternity. Indeed, these are heady times for electronics engineers and researchers marrying semiconductor technologies and techniques with biology, chemistry and genetics.
John Santini Jr., PhD, a former Massachusetts Institute of Technology researcher, heads MicroChips, a Cambridge, Mass., startup developing controlled-release microchips that deliver drugs inside or outside the body. The company is in the early stage of developing technology, but its goal is to develop a silicon chip with tiny wells filled with drug compounds that can be released in the body in a controlled manner via a pre-programmed microchip.
Although the field of biochips is lucrative today, the path to the biochip was not always clear.
Santini admits the idea of such a device was science fiction years ago-especially a microchip device that could operate on its own in the body.
"It's kind of the way people felt about tissue engineering many years ago," said Santini. (Tissue engineering involves growing an entire organ from a few living cells.)
"But with the advances that have been made to date, we can envision using chips to replace faulty systems in the body," he added.
Researchers say there is no single individual, advance or invention responsible for the biochip-it is the result of work completed by researchers who achieved parallel advances in microelectronics, biology, genetics and other fields.
Some point to early biosensors, such as the Clark-style oxygen electrode, as a predecessor to biosensors-simple biochips. The Clark electrode measures oxygen levels in a living system. The sensor was conceived in the '50s. At that time, L.C. Clark Jr., one of the electrode's developers, probably did not envision biochips that would one day read and identify DNA.
"It wasn't so much that the scientific and engineering communities misunderstood the technology but a misunderstanding of just where the technology could go," said H. Frederick Bowman, PhD, formerly of MIT. Bowman developed microfabbed transducers to measure temperature, radiation, blood flow, etc. and used them to determine how much heat it would take to kill a cancerous tumor.
"The measurements that were possible with such devices [like the Clark oxygen electrode] were always important, but it was not always clear whether results were reproducible and accurate," Bowman added.
Several decades later, bioelectronic sensors are being developed at Massachusetts Institute of Technology's Lincoln Laboratory (Lexington, Mass.) to help combat the threat of biological warfare by detecting and identifying biological agents.
The lab is collaborating with MIT's Biology Department on a bioelectronic sensor that uses living cells that are genetically engineering so that the cell emits light when a particular bioagent touches a cell. The light is then detected by a miniature imager similar to a camcorder and used to identify individual bioagents.
In addition to government interest in the technology-MIT's Lincoln Laboratory research is funded by Darpa (Defense Advanced Research Projects Agency)-semiconductor companies like Motorola Inc. (Schaumburg, Ill.) consider it critical to have a biochip-devoted research group.
Nicolas Naclerio, head of Motorola's Biochip Systems Unit, said he receives 100 or more resumes a week from scientists and engineers who want to work with the research group.
"It's a hot new field, and it's generating a lot of excitement," said Naclerio.
Naclerio credits the long-term vision of Motorola's executive committee chairman Robert Galvin, and his son Christopher, Motorola's chief executive officer, who several years ago urged Motorola executives to consider the next big thing-the convergence of biology and electronics.
Naclerio was skeptical about the idea when he joined Motorola in 1996 as director of strategy for the New Enterprises unit. A former executive at Darpa who was charged with looking for opportunities outside Motorola's core businesses, Naclerio originally didn't expect the small group of employees scouting out biotechnology to unearth an opportunity for the company.
Naclerio said the company chose to focus on the next-generation technology, the understanding of human variation and the ability to measure it.
Motorola's biochip technology will use the results of the Human Genome Project. The project is a 13-year research effort coordinated by the U.S. Department of Energy and the National Institutes of Health to identify more than 100,000 genes in human DNA, determine the sequences of the 3 billion chemical base pairs that make up human DNA, store this information in databases, develop tools for data analysis, and address the ethical, legal and social issues that may arise.
"Once the results of the Human Genome Project are available (estimated to be around 2002), we need to understand human variation and be able to measure it in order to develop better drugs," explained Naclerio.
He said Motorola believes biochips will play "a key role in allowing researchers to look at different places of the genome and analyze them much in the same way parallel processing works to achieve economies of scale and carry many processes at once."
Motorola has focused on three areas of development: microarray chips, which resemble DRAMs and use fluorescent reporters, lasers and optical scanners to read reactions; microfluidic chips, which resemble microprocessors and carry out chemical processes; and electronic chips that influence and detect chemical reactions.
Motorola plans to make its microarray chips available for research applications next year. Other companies working in this area are Nanogen of San Diego, Calif., Affymetrix Inc. of Santa Clara, Calif., and Hyseq Inc., of Sunnyvale, Calif.
Eventually, Motorola plans to integrate microarrays, microfluidics and electronic chips into a single cartridge so doctors can test a blood sample for drug reactivity with one chip. Naclerio envisions the entire medical lab moving on-chip so doctors could take a sample and analyze its DNA in real time.
There are companies marrying the power of molecular biology and microelectronics. Nanogen incorporates a semiconductor chip into an automated molecular analysis system.
The system analyzes molecules by taking advantage of the naturally occurring positive and negative charges associated with most biological molecules. The chip contains test sites arranged in an array that can be individually manipulated electronically from the instrument controls. Each chip is coated with a layer that functions as the interface between the electrochemical surface of the microchip and the biological test environment.
The system is used for medical diagnostics, genetic testing, genomic research and drug discovery. For research applications, Nanogen delivered a bench-top instrument system based on its NanoChip cartridge in 1999 and expects to follow with a PC-sized instrument and a handheld device in five years.
Nanogen co-founder and chief technical officer Michael J. Heller, PhD-whose own work in co-founding the company derived from his background in biochemistry-credits MEMS (microelectro-mechanical systems) as an enabling technology for such biochips as DNA chips, microfluidics and lab-on-a-chip devices. He mentioned precursors to biochips MEMS as the gas chromatograph-on-n-a-chip and early patents on electrophoresis on a silicon wafer by a scientist at Dupont, Sal Pacce.
Heller also credits the advancing field of biochips to the achievements in materials science and lithography, atomic force microscopy, nanotechnology, and closer interaction than ever before among engineers, biologists and chemists.
Orchid BioComputer Inc. (Princeton, N.J.) applies technology from the semiconductor industry to provide high-throughput drug discovery and diagnostic tests, a field called pharmacogenomics. Pharmacogenomics is a branch of genetic research in which scientists correlate minute variations in a person's DNA ( known as snps for single nucleotide polymorphism) with response to prescription drugs.
Dale R. Pfost, Orchid BioComputer's chairman and chief executive officer, is an electronics engineer who worked with semiconductors and describes his job now as "applying Moore's Law and microfluidics to build systems that take drug discovery to the next stage."
His belief is that "as the function of molecules and materials become more understood, the role they can play in electronics becomes possible."
Pfost projects that electronics and biology will come closer together in the future and "we will see biological materials used in the fabric of electronic devices. But one should remember that the underlying motives developed from the engineering sense need to be weighed with the needs of drug discovery."
In other words, developing biochips for DNA testing is a medical advancement that should be a driving force for engineers |
