The Evolution of Sequencing Technology

From July 16 to 19, 2015, Cold Spring Harbor Laboratory hosted a meeting on “The Evolution of Sequencing Technology: A Half-Century of Progress” as part of a meeting series on the history of science. The meeting brought together the major researchers involved in DNA sequencing since its inception in the 1960s. Prominent guest speakers examined the history of sequencing and how the technology has transformed the biological sciences over the past five decades.

Sequencing began with the British biochemist Fred Sanger, two-time winner of the Nobel Prize in Chemistry. While studying nucleic acids in the early 1960s, Sanger figured out a way to sequence small sections of RNA. This work evolved into methods of sequencing DNA, giving geneticists the tools to usher in yet a new era in biology.

The Cold Spring Harbor meeting began with a memorial session honoring Sanger and his work. The meeting was a unique chance to see science and history merge in a single event. A focus on the evolution of sequencing technology meant framing contemporary knowledge in terms of the field’s history. The meeting was international in scope, featuring world-recognized scientists who worked or continue to work in the area of sequencing technology. Scientists from major centers of genomics research in the United States, United Kingdom, Germany, and China convened to give and hear lectures. Among the speakers were Nobel Laureates and titans of molecular biology including Walter Gilbert and James Watson, as well as several students of Sanger himself.

The opening session covered the early efforts in protein, RNA and DNA sequencing. Other sessions covered advances over the years in the capture of raw sequence information; the hurdles that had to be overcome to scale these methods to generate the millions of reads required for complex genomes; and the development of strategies and software that converted these millions of reads into larger segments and, ultimately, whole genomes. Also covered was the adaptation of DNA sequencing to measure a variety of biological functions and how the dramatic decrease of the cost of DNA sequencing has led to an increasing appreciation of the significance of human variation in health and disease and to improved undertanding of our evolution as a species.


  • Early Days of Sequencing
  • Capturing Sequences
  • Access to Sequence
  • Scaling to Genomes
  • Going from Sequences to Genomes
  • Human Variation and Disease
  • Panel Discussion
  • Poster Session

The meeting was the fifth in a series of CSHL Genentech Center Conferences on the History of Molecular Biology and Biotechnology. These conferences aim to explore important themes of discovery in the biological sciences, bringing together scientists who made seminal discoveries with others whose interests include: the current status of the field, the historical progress of the field, and/or the application of the techniques and approaches in biotechnology and medicine. Previous meetings in the series have included:


  • Mark Adams, J. Craig Venter Institute
  • Nigel Brown, University of Edinburgh, UK
  • Mila Pollock, Cold Spring Harbor Laboratory
  • Robert Waterston, University of Washington


  • Mark Adams, J. Craig Venter Institute
  • Gillian Air, University of Oklahoma
  • Shankar Balasubramanian, University of Cambridge, UK
  • Hagan Bayley, University of Oxford, UK
  • David Bentley, Illumina, Inc., UK
  • George Brownlee, University of Oxford, UK
  • Graham Cameron, Founder and ex-Director, EMBL-EBI
  • Piero Carninci, RIKEN, Japan
  • Norman Dovichi, University of Notre Dame
  • William Efcavitch, Molecular Assemblies, Inc.
  • Miguel Garcia-Sancho, University of Edinburgh
  • Mark Gerstein, Yale University
  • Jack Gilbert, University of Chicago
  • Walter Gilbert, Harvard University
  • Philip Green, University of Washington
  • Cheryl Heiner, Pacific Biosciences
  • Lee Hood, Institute of Systems Biology
  • Clyde Hutchison, J. Craig Venter Institute
  • James Kent, University of California, Santa Cruz
  • Jonas Korlach, Pacific Biosciences
  • Suzanna Lewis, Lawrence Berkeley National Laboratory
  • Victor Ling, BC Cancer Agency, Canada
  • David Lipman, NCBL/NLM National Institutes of Health
  • Jim Lupski, Baylor College of Medicine
  • Tom Maniatis, Columbia University Medical Center
  • Richard McCombie, Cold Spring Harbor Laboratory
  • Joachim Messing, Waksman Institute, Rutgers University
  • Gene Myers, Max Planck Institute, Germany
  • Richard Myers, HudsonAlpha Institute for Biotechnology
  • Debbie Nickerson, University of Washington
  • Jim Ostell, NCBL/National Center for Biotechnology Information
  • Mila Pollock, Cold Spring Harbor Laboratory
  • Richard Roberts, New England BioLabs
  • Jane Rogers, International Wheat Genome Sequencing Consortium, UK
  • Mostafa Ronaghi, Illumina, Inc.
  • Yoshiyuki Sakaki, University of Tokyo, Japan
  • Jay Shendure, University of Washington
  • Melvin Simon, CalTech
  • Hamilton Smith, J. Craig Venter Institute
  • Llyod Smith, University of Wisconsin, Madison
  • Stanley Tabor, Harvard Medical School
  • J. Craig Venter, J. Craig Venter Institute
  • Robert Waterston, University of Washington
  • James D. Watson, Cold Spring Harbor Laboratory
  • Jean Weissenbach, Genoscope—CNRG, France
  • Barbara Wold, CalTech
  • Huanming Yang, Beijing Genomics Institute, China

What is Sequencing?

“Sequencing” refers to the methods used to determine the order of chemical bases in a strand of DNA. Sequencing is essential to unraveling the information contained in our genetic material. Apart from the pure scientific knowledge derived from sequencing, scientists have been attempting to use these methods to better understand the genetic origins of human disease.

By figuring out which areas of the genome are associated with which diseases, researchers are working toward making clinical medicine a more personalized practice. Genomic medicine, the ability to tailor treatments to individual patients, is the hoped-for endpoint of many years of sequencing research. As the cost of sequencing continues to fall dramatically—researchers can now sequence an entire human genome for about $1,000—this is slowly becoming a reality.

Sequencing Technology

Scientists today use automated machines to sequence large amounts of DNA. During the early years of sequencing, however, all the work was done manually. The first generation of DNA sequencing refers to the earliest methods developed in the mid-1970s. There were two such methods: the Maxam-Gilbert method, pioneered by Allan Maxam and Walter Gilbert, and the Sanger method (a.k.a. dideoxy sequencing), developed by Frederick Sanger.

Due to its relative ease, the Sanger method became the most popular way to sequence DNA. It involves figuring out the sequence of bases in a DNA strand by manipulating the natural DNA replication process. Using a single template DNA and gel electrophoresis, manual Sanger sequencing could process upwards of 700 bases at a time. Sanger sequencing formed the basis of the technology behind the first automated DNA sequencers, which were eventually used in the Human Genome Project. The first commercially available DNA sequencing machine was the model 370A, released by Applied Biosystems in 1986.

Since the completion of the Human Genome Project in 2003, DNA sequencing machines have become much more powerful. Machines today are capable of doing in a single day what the earliest manual sequencing methods would have required many decades to accomplish.

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Copyright © 2015 Cold Spring Harbor Laboratory   Image attribution: Abizar Lakdawalla, Wikimedia