Introduction

THE SOURCE OF THE NEW MACHINE 73
thousands of proposals. Over the next decade, DOE granted nearly
$1 billion to hundreds of scientists working on improving instrumentation
technologies, about one dollar for every two spent by NIH on
sequencing. 20
Smith, who left CalTech for the University of Wisconsin in 1987,
remained a central figure as the technology evolved. In 1990, he published
papers outlining what would become the core concept behind the
next generation of machines. He resuscitated the original idea of using
ultra-thin capillaries for transporting the DNA fragments. This concept
would eventually allow scientists to run ninety-six samples at a time (up
from forty-eight on the slab-gel machines) and cut the cycle time (the
amount of time it took the DNA fragments to run down the tubes) to
two to three hours from the previous twelve hours. It was a tenfold
improvement in the number of bases that a single machine could read in
a day. The capillaries would also eliminate a major source of errors in the
slab-gel system. In the old machines, the DNA fragments had a tendency
to wander outside their lanes as they scampered down the glass plates,
thus corrupting the readouts at the end of the line.
Several problems needed solving before the capillary technology could
be made practical. “The capillary work we did was not cost effective the
way we did it,” Smith said. “We used a gel in the capillaries that was difficult
to pour and left bubbles in the capillaries. What were you going to
do Throw them away every time That was too expensive. So a lot of
money from DOE and NIH went into creating polymer liquids to pump
into the capillaries.” Barry Karger, a chemist at Northeastern University,
eventually solved the problem. He came up with a liquid that could carry
the microscopic genetic material through the tiny capillaries without
ruining them. 21
Reading the fluorescent tags in this miniaturized environment was
another major hurdle. That problem was solved by several scientists,
including Richard Mathies of the University of California at Berkeley. He
developed a new set of fluorescent dyes that when attached to the end of
the molecules could be read by a laser that focused its beam on the inside
of the capillaries. Norman Dovichi, a Canadian chemist at the University
of Alberta, developed an alternative laser optics system that read the
fluorescent tags the moment the molecules emerged from the capillaries.
Publicly funded scientists weren’t the only ones working on the problem.
Hitachi, the Japanese electronics giant that also had a biology instrumentation
division, developed a laser-reading system that was identical
to Dovichi’s. Applied Biosystems eventually licensed both.