NanoBarcodes for Single Biomolecules

December 29^th, 2009 marked the fiftieth anniversary of Richard Feynman asking the famous question¹: Why cannot we write the entire 24 volumes of the Encyclopedia Brittanica on the head of a pin? The legendary physicist from Caltech figured that regular type would need to be shrunk by 1/25,000 to achieve the feat. He offered a $1,000 price for the first experimental demonstration, which was done in 1985 by Tome Newman, a grad student from Stanford.

Fifty years post Feynman's lecture, and 25 years after Newman's demonstration, there is one area where our ability to shrink the physical embodiment of encoded information to such nanodimensions is proving to be critical: in barcoding and tagging of individual biomolecules.

Biomolecules – proteins, DNA's, RNAs, lipids, sugars - are the physical carriers of biological information in every living organism. The ability to detect and inventorize these molecules is necessary if we are to crack the algorithms by which biological systems operate, and perhaps more importantly, they ways in which these algorithms are broken at time of illness.

Tagging of individual biomolecules with easily detectable nanobarcodes enables their direct digital counting and quantification. This is a fundamentally different concept from using functionalized "barcoded" particles as miniature test tubes, on the surface of which a standard analogue-based detection assay can be performed. In contrast to such analogue methods, direct digital counting offers all of the advantages associated with other digital technologies: accuracy at low cost, sensitivity, and (at least in theory) infinitely expandable dynamic range.

It was in 2000 in Seattle when I invented the "nanostring",² a fluorescent nanobarcode for single biomolecules, which since has resulted in a commercial product³ finding diverse applications in systems biology. For example, scientists from the Broad Institute and M.I.T. have used the NanoString barcodes to ask detailed questions about how our immune system responds to pathogenic challenges⁴ for it is the detection method that dictates what nanostructures would need to be synthesized as barcodes.

Using fluorescence labels to encode information in a nanobarcode has multiple advantages and one substantial limitation: Raleigh's diffraction limit. In 1959 Feynman envisioned that an electron microscope would be used to read-out information encoded in nanostructures, with resolution exceeding that of optical detection. Yet, electron microscopy is still an expensive and sophisticated technique, unsuitable for clinical laboratories and physician's offices.

Dr Krassen Dimitrov and his colleagues at the Single Molecule Nanotechnology group is now working on new methods for electronic detection of nanobarcodes, which will offer higher resolution than fluorescence, yet at very low costs.

References

1. http://www.zyvex.com/nanotech/feynman.html
2. Methods for detection and quantification of analytes in complex mixtures. United States Patent 7473767
3. Geiss G.K., Bumgarner R.E., et. al., Direct multiplexed measurement of gene expression with color-coded probe pairs. Nature Biotechnology 26, 317 - 325 (2008).
4. Amit I., Garber M., et. al., Unbiased Reconstruction of a Mammalian Transcriptional Network Mediating Pathogen Responses. 2009 Oct 9; Vol. 326. no. 5950, pp. 257 - 263