Looking back to the publication of the first draft human genome in Nature and the official declaration of the completion of the Human Genome Project (HGP) 15 years ago, it is easy to overlook, based on the power of today’s sequencing technology, how monumental a task the project was when it was formally launched in 1990. Today, we take the prodigious power of next-gen sequencing for granted, but the human genome was assembled using trusty Sanger sequencing.
“In graduate school lectures I ask the students to imagine that there was no Internet or computers, or cells phones when we started,” said Richard Gibbs, Ph.D., founder and director of the Human Genome Sequencing Center (HGSC), established at Baylor College of Medicine, and one of the five sequencings sites worldwide funded for the HGP. “Then I show them pictures of some of the old sequencing machines where we could run 16 samples and have them divide 16 into 60 million, or however many [bases] it was we had to do, and they begin to understand.”
Jane Rogers, Ph.D., who rose to be head of sequencing at the Wellcome Trust Sanger Institute in Cambridge, U.K.—the single largest contributor to the HGP—put it a different way: “Nowadays, you assume you can sequence all four bases at a time. At that time, we were sequencing with primers and we were only essentially doing a reaction for one base at a time.” In the mid 1990s, many of the chemistries were also still being perfected. “When the terminators first came out, the chemistry and the enzymes weren’t particularly great. So we were doing all the separations on gels that separated 250 bases. We could run 36 lanes of 250 bases, in 12 hours,” she added. “It was slow.”
With roughly 3 billion bases to sequence over the projected 15-year timeline, the sequencing centers of the HGP needed to adopt a production mindset—essentially turning their research facilities and campuses into genome sequencing factories. That’s how Elaine Mardis, Ph.D., currently co-executive director, Institute for Genomic Medicine at Nationwide Children’s Hospital in Ohio, became involved with the work at HGP consortium member Washington University, St. Louis.
After working in industry for four years with Bio-Rad Laboratories, leveraging her experience in enzymology and DNA sequencing automation, Mardis was lured back to academia by Bob Waterston at Washington University in 1993. Waterston was just beginning his work to sequence the Caenorhabditis elegans genome and Mardis’ background in molecular biology and automation made her a top choice to scale up the university’s sequencing operation.
“Those were interesting days just because sequencing wasn’t a big industry like it is today. Mundane things that needed automation, like the ability to harvest plaques or colonies off plates, weren’t available as things you could buy, we had to build them,” Mardis said. “So, my early technology development group included engineers as well as molecular biologists who worked together to develop robotics and automation that were highly customized.”
Mardis’ activities in the U.S. mirrored the work Rogers was performing at the Sanger, whose founding director, the late Sir John Sulston, was collaborating with Waterston on C. elegans (work that earned Sulston a share of the Nobel Prize in 2002). For both institutions sequencing the model organism provided the ultimate springboard to working on the human genome.
“We had a sense of how important this work was—how having a completed C. elegans sequence gave a huge boost to researchers who now had a template to research their own specific [C. elegans] phenotype,” Mardis said. “We understood we were moving to a much more complicated organism, but that these same type of biological inquiries were going to be greatly accelerated through the human genome.”
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