While there is one short section on the problem of sample preparation, the heart of the paper can be found in the other headings:
- surface chemistry
- fluorescent labels
- the enzyme-substrate system
- throughput versus accuracy
- read-length and phasing limitations
Each section is tightly written and well-balanced, with no obvious playing of favorites or bashing of anti-favorites present. Trade-offs are explored & the dreaded term (at least amongst scientists) "cost models" shows up; indeed there is more than a little bit of a nod to accounting -- but if sequencing is really going to be $1K/person on an ongoing basis the beans must be counted correctly!
I won't try to summarize much in detail; it really is hard to distill such a concentrated draught any further. Most of the ideas presented as possible solutions can be viewed as evolutionary relative to the current platforms, though a few exotic concepts are floated as well (such as synthetic aperture optics. It is noteworthy that an explicit goal of the paper is to summarize the problem areas so that new minds can approach the problem; as implied by the section title list above this is clearly a multi-discipline problem. It does somewhat suggest the question whether Nature Biotechnology, a journal I am quite fond of, was the best place for this. If new minds are desired, perhaps Physical Review Letters would have been better. But that's a very minor quibble.
Fuller CW, Middendorf LR, Benner SA, Church GM, Harris T, Huang X, Jovanovich SB, Nelson JR, Schloss JA, Schwartz DC, & Vezenov DV (2009). The challenges of sequencing by synthesis. Nature biotechnology, 27 (11), 1013-23 PMID: 19898456