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Roadmap to theranostics
SANTA BARBARA, Calif.—The U.S. National Institutes of Health (NIH) has awarded $3.2 million to a team of engineering, chemistry and biology researchers to develop a highly efficient system of generating nucleic acid molecules, called aptamers, as part of its Roadmap program, designed to provide a framework of priorities that the NIH is addressing to optimize its research portfolio.
If successful, the technology will provide an entirely new method of discovering and mass-producing new high-performance aptamers for a broad range of applications, including next-generation disease diagnosis at the point of care, or "theranostics."
The researchers, based at UC Santa Barbara, are working to replace one-at-a-time development, typical of antibodies, with high-throughput sequencing (HTS) of affinity reagents for molecular diagnostics. Their system, dubbed Quantitative Parallel Aptamer Selection System (QPASS), is an HTS process that will pave the way to develop "instant diagnosis" devices, such as those that detect infectious disease or genetically test a person's response to cancer drugs.
One of the team's leaders, Dr. H. Tom Soh, professor of mechanical engineering and materials and co-director of the Center for Stem Cell Biology and Engineering at UC Santa Barbara, cautions that the process has just begun.
"Our technology is the first step toward devices that could instantly test for HIV or H1N1 in the field or at the bedside, instead of wasting critical time and money waiting for results," says Soh.
According to the research team, QPASS solves aptamer discovery problems that have plagued the field for more than 20 years, such as an expensive and lengthy process, and stability of the molecules at room temperature that obviates the necessity of maintaining a cold chain in the field where doing so is problematic.
"We are developing innovative new technologies that make each step of our process several orders of magnitude more efficient," adds Soh. "QPASS will generate high- performance synthetic affinity reagents in a massively parallel manner to meet a growing need in labs and clinics."
Biomedical researchers James Thomson and Lloyd Smith are collaborating with Soh to develop the three novel technologies that comprise QPASS—aptamer selection, sequencing and validation. Soh notes that validation is the most resource- and time-intensive, and that "massively parallel" processing will address this issue.
Soh is engineering a screening tool that uses microfluidics technology to find the best aptamer sequences among trillions. Thomson, who is well-known for his stem cell research, has designed a way to integrate sequencing with selection using computer algorithms to quickly identify the most promising sequences. Smith's microarray research uses surface plasmon resonance imaging (SPRi) in combination with a microscopic DNA chip that can validate 10,000 times more sequences than current practices, identifying the most effective aptamers instantly.
"I am delighted to have the opportunity to work with this outstanding team of scientists," sais Thomson, co-director of the Center for Stem Cell Biology and Engineering at UC Santa Barbara and director of regenerative biology at the Morgridge Institute for Research in Wisconsin, in a statement. "This grant will strengthen the continuing collaborative efforts between UC Santa Barbara, the Morgridge Institute and the University of Wisconsin-Madison, bringing together leading edge technologies and experts from different disciplines."
"This is an exciting project to address a major barrier to progress in biological research: the lack of effective reagents to specifically bind to target proteins that play central roles in cell biology," says Lloyd Smith, professor of chemistry at University of Wisconsin-Madison and director of the Genome Center of Wisconsin.
"There is a new paradigm in medicine called theranostics, or point-of-care testing of a patient's reaction to a medication," Soh observes. "They've just started doing this in larger research hospitals, and to great effect. I believe our integrated technology will someday allow a technician in a small clinic to make a quick diagnosis. Making it affordable for everyone to use is really the value that engineers can provide."
All about aptamers
Aptamers are molecules that have been engineered through repeated rounds of in-vitro selection to bind to various molecular targets such as small molecules, proteins, nucleic acids and even cells, tissues and organisms. Aptamers are useful in biotechnological and therapeutic applications as they offer molecular recognition properties that rival that of the commonly used biomolecule antibodies. In addition to their discriminate recognition, aptamers offer advantages over antibodies as they can be engineered completely in a test tube, are readily produced by chemical synthesis, possess desirable storage properties and elicit little or no immunogenicity in therapeutic applications.