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Genetics and Genomics Timeline
Leroy Hood (1938-) develops the automated sequencer

The techniques for sequencing DNA, developed independently by Walter Gilbert and Frederick Sanger in the late 1970s, represented dramatic advances for research in molecular biology. But they were labor intensive and costly. Automation was always a goal, and just about the time that scientists began to confront the prospect of sequencing the human genome, it became a reality. In 1986, Applied Biosystems Incorporated (API) announced the first automatic sequencer, invented by Leroy Hood.

A biologist at the California Institute of Technology and a founder of API, Hood improved the existing Sanger' method of enzymatic sequencing, which was becoming the laboratory standard. In this method, DNA to be sequenced is cut apart, and a single strand serves as a template for the synthesis of complementary strands. The nucleotides used to build these strands are randomly mixed with a radioactively labeled and modified nucleotide that terminates the synthesis. Fragments of all different lengths result. The resulting array, sent through a separation gel, reveals the order of the bases. Transferred to film, an "autoradiograph" provides a readable sequence from raw data. This data could be transferred to a computer by a human reader.

In automating the process, Hood modified both the chemistry and the data-gathering processes. In the sequencing reaction itself, he sought to replace the use of radioactive labels, which were unstable, posed a health hazard, and required separate gels for each of the four DNA bases.

• In place of radioisotopes, Hood developed chemistry that used fluorescent dyes of different colors—one for each of the four DNA bases. This system of "color-coding" eliminated the need to run several reactions in overlapping gels.

The fluorescent labels were also aspects of the larger system that revolutionized the end stage of the process—the way in which sequence data was gathered. Hood integrated laser and computer technology, eliminating the tedious process of information-gathering by hand.

• As the fragments of DNA percolated through the gel, a laser beam stimulated the fluorescent labels, causing them to glow. The light they emitted was picked up by a lens and photomultiplier, and transmitted as digital information directly into a computer.

In conjunction with a team that included Lloyd Smith and Michael and Tim Hunkapiller, Hood conceived the automated sequencer in 1985 and Applied Biosystems brought it to market in June 1986. A handful of other companies, including du Pont de Nemours and Hitachi, soon brought out similar machines, although ABI's four-dye technology remained unique. During the next thirteen years, the machine was constantly improved, and by 1999 a fully automated instrument could sequence up to 150,000,000 base pairs per year.

Automated sequencing was essential for the development of genomics. Together with the advances in biochemistry that included the discovery of restriction enzymes and the cascade of techniques for recombinant DNA, it made sequencing genes and whole genomes—including the human genome—feasible enterprises that could open the way to new horizons in medicine and the biological sciences.

Leroy Hood winner of the
1987 Albert Lasker Award for Basic Medical Research

Lloyd M. Smith et al. Fluorescence detection in automated DNA sequence analysis. Nature 321, 674-679 (June 12, 1986).
T. Hunkapiller, R. J. Kaiser, B. F. Koop, L. Hood. Large-Scale and automated DNA sequence determination. Science 254, 59-67 (October 4, 1991).

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