in a DNA molecule. Grouped under the heading of nanopore sequencing, these methods focus on the physical differences between the four base types to produce a readable signal. When a single strand of DNA passes through a 1.5-nanometer pore, it causes fluctuations in the pore’s electrical conductance. Each base type produces a slightly different conductance change that can be used to identify it [see box above]. Devised by Dan Branton of Harvard, Dave Deamer of the University of California, Santa Cruz, and me, this method is in development now by Agilent Technologies and others with interesting variations, such as fluorescent signal detection. Lowering Cost evaluating these next-generation sequencing systems against one another and against the Sanger method illustrates some of the factors that will influence their usefulness. For example, two research groups, my own at Harvard and one from 454 Life Sciences, recently published peer- reviewed descriptions of genome-scale sequencing projects that allow for a direct comparison. My colleagues and I described a sequencing-by-ligation system that used polony bead amplification of the template DNA and a common digital microscope to read fluorescent signals. The 454 group used a similar oil-emulsion PCR for