Brown University’s mass spectrometry for DNA sequencing

Overview: Brown University’s laboratory-stage technology combines nanopores and mass spectrometry for single-molecule DNA sequencing. Tools and diagnostics companies should monitor one form of the proposed technology, which, if successful, would be a major advance for the sequentially-ordered removal of individual bases from DNA strands.

Background: Derek Stein’s laboratory at Brown University is developing a nanopore-based, electrospray ionization technology to detect cleaved DNA bases by means of mass spectrometry. The group is also developing a further-reaching version of the technology to generate individual bases from intact DNA strands prior to their detection[1]. Brown’s technology transfer office is preparing to file a patent, “Method and apparatus for sequencing biomolecules”[2], which is likely the initial corresponding patent. The application of mass spectrometry to DNA detection is decades old, though has largely been aimed at detecting DNA fragments and SNPs (e.g. Sequenom’s MassARRAY product). Stein has outlined multiple ways in which DNA strands could be precisely broken up, including use of incident electron beams and lasers, while pointing out that the base-to-phosphate backbone bond is the weak link[3].

Analysis: The technology has two main corresponding applications: an alternative detector component to ion current blockade detectors associated with nanopores; and, a stand-alone sequencing instrument. The first application is tractable from a technical standpoint, but faces patent and cost issues. The second application involves a number of experimental unknowns and may require extensive exploration of device parameter space to identify a suitable system. However, a resulting device which can both cleave and detect bases could be competitive in a future market.

Sequenom (SQNM) owns much of the intellectual property on mass spectrometry for DNA detection, including detection of specially-terminated sequences in a modified Sanger method[4], detection of certain DNA fragments[5], and the use of exonucleases to cleave individual bases for subsequent mass measurement[6]. The last of these Sequenom patents is in direct conflict with Stein’s detector-only technology, which would in all likelihood also rely on exonucleases.

Sequencing companies and those considering entering the space should monitor results of Stein’s upcoming experiments on the sequentially-ordered cleavage of DNA bases. Studies on the alternative detector will be of interest to companies like Oxford Nanopore Technologies as a back-up approach to detection, but costs will likely be prohibitively high.

For additional information on this technology or analysis of related technologies and companies, contact: bruce@schiamberggroup.com

Copyright © Bruce A. Schiamberg 2010. All rights reserved.

References:

[1] “Sequencing by Nanopore Mass Spectrometry,” $896,000, The National Human Genome Research Institute’s Advanced Sequencing Technology Awards 2009.
[2] http://www.brown.edu/Departments/Physics/people/facultypage.php?id=1154701503 – see curriculum vitae.
[3] http://www.genomeweb.com/sequencing/qa-derek-stein-marrying-nanopores-and-mass-spec-single-molecule-sequencing
[4] US 5547835
[5] US 6764822
[6] US 5872003

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    • Gabe
    • February 27th, 2010

    Dr. Schiamberg,

    This is quite an excellent review. Could I request your analysis of glycomics, lipidomics, or metabolomic technology in future posts?

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