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 biologyresearchers to develop a highly efficient system of generating nucleic acidmolecules, called aptamers, as part of its Roadmap program, designed to providea framework of priorities that the NIH is addressing to optimize its researchportfolio.

If successful, the technology will provide an entirely newmethod of discovering and mass-producing new high-performance aptamers for abroad range of applications, including next-generation disease diagnosis at thepoint of care, or "theranostics."

The researchers, based at UC Santa Barbara, are working toreplace one-at-a-time development, typical of antibodies, with high-throughputsequencing (HTS) of affinity reagents for molecular diagnostics. Their system,dubbed Quantitative Parallel Aptamer Selection System (QPASS), is an HTSprocess that will pave the way to develop "instant diagnosis" devices, such asthose that detect infectious disease or genetically test a person's response tocancer drugs.

One of the team's leaders, Dr. H. Tom Soh, professor ofmechanical engineering and materials and co-director of the Center for StemCell Biology and Engineering at UC Santa Barbara, cautions that the process hasjust begun.

"Our technology is the first step toward devices that couldinstantly test for HIV or H1N1 in the field or at the bedside, instead ofwasting critical time and money waiting for results," says Soh.

According to the research team, QPASS solves aptamerdiscovery problems that have plagued the field for more than 20 years, such asan expensive and lengthy process, and stability of the molecules at roomtemperature that obviates the necessity of maintaining a cold chain in thefield where doing so is problematic.

"We are developing innovative new technologies that makeeach step of our process several orders of magnitude more efficient," adds Soh."QPASS will generate high-performance synthetic affinity reagents in amassively parallel manner to meet a growing need in labs and clinics."

Biomedical researchers James Thomson and Lloyd Smith arecollaborating with Soh to develop the three novel technologies that compriseQPASS—aptamer selection, sequencing and validation. Soh notes that validationis the most resource- and time-intensive, and that "massively parallel"processing will address this issue.

Soh is engineering a screening tool that uses microfluidicstechnology to find the best aptamer sequences among trillions. Thomson, who iswell-known for his stem cell research, has designed a way to integratesequencing with selection using computer algorithms to quickly identify themost promising sequences. Smith's microarray research uses surface plasmonresonance imaging (SPRi) in combination with a microscopic DNA chip that canvalidate 10,000 times more sequences than current practices, identifying themost effective aptamers instantly.

"I am delighted to have the opportunity to work with thisoutstanding team of scientists," sais Thomson, co-director of the Center forStem Cell Biology and Engineering at UC Santa Barbara and director ofregenerative biology at the Morgridge Institute for Research in Wisconsin, in astatement. "This grant will strengthen the continuing collaborative effortsbetween UC Santa Barbara, the Morgridge Institute and the University ofWisconsin-Madison, bringing together leading edge technologies and experts fromdifferent disciplines."

"This is an exciting project to address a major barrier toprogress in biological research: the lack of effective reagents to specificallybind to target proteins that play central roles in cell biology," says LloydSmith, professor of chemistry at University of Wisconsin-Madison and directorof the Genome Center of Wisconsin.

"There is a new paradigm in medicine called theranostics, orpoint-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 greateffect. I believe our integrated technology will someday allow a technician ina small clinic to make a quick diagnosis. Making it affordable for everyone touse is really the value that engineers can provide."

All about aptamers

Aptamers are molecules that have been engineered throughrepeated rounds of in-vitro selection tobind to various molecular targets such as small molecules, proteins, nucleicacids and even cells, tissues and organisms. Aptamers are useful inbiotechnological and therapeutic applications as they offer molecularrecognition properties that rival that of the commonly used biomoleculeantibodies. In addition to their discriminate recognition, aptamers offeradvantages over antibodies as they can be engineered completely in a test tube,are readily produced by chemical synthesis, possess desirable storage propertiesand elicit little or no immunogenicity in therapeutic applications.