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A Bioassay with a Heart of Gold

EXQUISITE SENSITIVITY:In the new assay system used at the Mirkin lab, the protein to be detected (in this case, prostate specific antigen, PSA) is sandwiched between a magnetic microparticle (MMP) and a gold nanoparticle (NP). The system detects the bio-bar-codes present on the NPs with sensitivity five orders of magnitude greater than that of ELISA. (Reprinted with permission, Science, 301:1884–6, 2003.)As any 5-year-old child will tell you, magnets are great for lifting things off the fl

Sam Jaffe
<p>EXQUISITE SENSITIVITY:</p>

In the new assay system used at the Mirkin lab, the protein to be detected (in this case, prostate specific antigen, PSA) is sandwiched between a magnetic microparticle (MMP) and a gold nanoparticle (NP). The system detects the bio-bar-codes present on the NPs with sensitivity five orders of magnitude greater than that of ELISA. (Reprinted with permission, Science, 301:1884–6, 2003.)

As any 5-year-old child will tell you, magnets are great for lifting things off the floor, but they don't help to get your room cleaned any faster. They can, however, be extremely helpful in identifying proteins and nucleic acids, according to new research from Northwestern University.

Chemistry professor and nanotech entrepreneur Chad Mirkin's "bio-barcode"-based system12 equals PCR in its sensitivity while promising to vastly undercut the cost and improve the accuracy of traditional PCR or ELISA-based tests. "It's the first demonstration of a system with the...

TO PCR OR NOT

Users can quantify these barcodes via standard PCR, but Mirkin's team has developed an alternative, non-PCR approach. Using the Verigene ID system (developed by Northbrook, Ill.-based Nanosphere, a company Mirkin cofounded), users quantify the barcodes using the kind of technology found in a flatbed scanner, providing results as clear as an at-home pregnancy strip test.

"It reaches the sensitivity of PCR but without having to deal with enzymes or the threat of easy contamination," says Mirkin. "And when it comes to protein detection, it far surpasses the sensitivity of any other system out there." Mirkin pegs the system's sensitivity at 30 attomolar, five orders of magnitude more sensitive than is ELISA (peak sensitivity of around 3 picomolar). As for DNA, the system can detect as little as 10 molecules in minutes.

That's not to say it is perfect. For protein detection, the Achilles heel is the same as with every other antibody-based assay: the antibodies themselves. Antibodies can distort, fall apart, or cling to the wrong analyte. Phil Belgrader, the founder and chief scientific officer of MFSI, a Pleasanton, Calif.-based microfluidics startup, says the technology shows promise in proteomics, but "the fundamental issues with antibodies, such as cross-reactivity, nonspecific binding, and lot-to-lot variability remain."

MEGA-MULTIPLEXING

Mirkin agrees that his system for protein detection is only as good as the antibodies it uses. But the same is true for almost all other protein detection assays, he says. "The point is that if one has good antibodies, you'll always win the sensitivity game with the barcode assay, by up to six orders of magnitude!"

In addition, the system has enormous potential for multiplexing. Mirkin points out that the system could hypothetically test for 415 different analytes simultaneously by tagging the different gold beads with different barcode sequences. Right now, however, the technology is at such an early stage of development that Mirkin's lab hasn't even begun testing it for its multiplexing capabilities.

That hasn't stopped many scientists from salivating at the prospect of getting to use it, though most want to see validation of the technique in the literature first. "If the technique is shown to work with microbial pathogens and human specimens, I would be very interested in using it," says Andrew Onderdonk, a microbiologist at Harvard Medical School.

Others are more wary. Nick Cirino, director of the Bioterrorism Response Laboratory at the New York Department of Health's Wadsworth Center in Albany, worries that the system might be too good for some biodefense applications. Its extreme sensitivity "could also be a detriment since many real-world pathogen isolates might have SNPs or secondary structure in the probe region of interest." Nevertheless, Cirino looks forward to the development of the system into a mature technology. Mirkin expects to have a commercial product ready in 12 to 18 months.

- Sam Jaffe

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