The First Automated DNA Sequencer

Credit: Courtesy of Lloyd M. Smith" /> Credit: Courtesy of Lloyd M. Smith Lloyd M. Smith joined Lee Hood?s CalTech laboratory in 1982 with the idea that he would finally get to do ?real biology.? Having come from a chemistry background, people suggested that he learn DNA sequencing to get a handle on molecular biology. ?Although it was really interesting to learn because there were so many new techniques that one had to master ? it turns out once you get those techniques down it was a

Feb 1, 2006
Brendan Maher
<figcaption> Credit: Courtesy of Lloyd M. Smith</figcaption>
Credit: Courtesy of Lloyd M. Smith

Lloyd M. Smith joined Lee Hood?s CalTech laboratory in 1982 with the idea that he would finally get to do ?real biology.? Having come from a chemistry background, people suggested that he learn DNA sequencing to get a handle on molecular biology. ?Although it was really interesting to learn because there were so many new techniques that one had to master ? it turns out once you get those techniques down it was a pretty laborious, repetitive process,? Smith says. Handling huge sequencing gels in the wee hours of the morning indicated a need for automation.

Hood asked him to evaluate a project initiated by a former lab member, Henry Huang, who was looking to automate sequencing using the ultraviolet absorption of DNA. ?I pulled the plug on that project when I did a few calculations that convinced me it wasn?t going to work?. It just wasn?t sensitive enough.? But with the background of that project and nearly a year of late nights in the halls of CalTech, Smith and colleagues came up with the idea of fluorescently labeling DNA in four colors. They were able to publish on the chemistry in 1985,1 and on the automated detection a year later.2

As shown in this photo, taken nearly 20 years ago, the laser originates at the far end of the table and passes through a filter wheel. The light then hits fluorescently tagged nucleic acids as they pass through the thin gel tube that ends in the buffer reservoir, the clear box near the left of the photo. The photomultiplier sits at right angles with the laser?s path, behind a second filter wheel. The inaugural sequence run was the popular cloning vector M13, a short stretch of which is shown in the inset, an image that now sits framed on Smith?s desk at the University­ of Wisconsin, Madison.

bmaher@the-scientist.com

References

1. L.M. Smith et al., ?The synthesis of oligonucleotides containing an aliphatic amino group at the 5' terminus - synthesis of fluorescent DNA primers for use in DNA-sequence analysis,? Nucl Acids Res, 13:2399?412, 1985? 2. L.M. Smith et al., ?Fluorescence detection in automated DNA-sequence analysis,? Nature, 321:674?9, 1986.