history

A History of the Human Genome Project
Credit: A. Barrington Brown/Science Photo Library	1953 (April) James Watson and Francis Crick discover the double helical structure of DNA (Nature).

Credit: Jane Reed/Harvard U.	1972 (October) Paul Berg and co-workers create the first recombinant DNA molecule (PNAS). 1977 Allan Maxam and Walter Gilbert (pictured) at Harvard University and Frederick Sanger at the U.K. Medical Research Council (MRC) independently develop methods for sequencing DNA (PNAS, February; PNAS, December).

Credit: Dennis Normile Credit: Victor McKusick Credit: Cold Spring Harbor Lab Credit: Robert Paz/Caltech Credit: Burke et al. T. J. McMaster/Wellcome Photo Library Credit: Margo Bennet/Cold Spring Harbor Lab	1980 (May) David Botstein of the Massachusetts Institute of Technology, Ronald Davis of Stanford University, and Mark Skolnick and Ray White of the University of Utah propose a method to map the entire human genome based on RFLPs (American Journal of Human Genetics). 1982 Akiyoshi Wada (pictured), now at RIKEN in Japan, proposes automated sequencing and gets support to build robots with help from Hitachi. 1984 (May) Charles Cantor and David Schwartz of Columbia University develop pulsed field electrophoresis (Cell). (July) MRC scientists decipher the complete DNA sequence of the Epstein-Barr virus, 170 kb (Nature). 1985 (May) Robert Sinsheimer (pictured) hosts a meeting at the University of California (UC), Santa Cruz, to discuss the feasibility of sequencing the human genome. (December) Kary Mullis and colleagues at Cetus Corp. develop PCR, a technique to replicate vast amounts of DNA (Science). 1986 (February) Sydney Brenner of MRC urges the European Union to undertake a concerted program to map and sequence the human genome; Brenner also starts a small genome initiative at MRC. (March) The U.S. Department of Energy (DOE) hosts a meeting in Santa Fe, New Mexico, to discuss plans to sequence the human genome. (March) Renato Dulbecco of the Salk Institute promotes sequencing the human genome in a paper (Science). (June) Merits of a human genome project are hotly debated at a meeting at Cold Spring Harbor Laboratory in New York state, "The Molecular Biology of Homo sapiens." (pictured) (June) Leroy Hood (pictured) and Lloyd Smith of the California Institute of Technology (Caltech) and colleagues announce the first automated DNA sequencing machine (Nature). (September) Charles DeLisi begins genome studies at DOE, reallocating $5.3 million from the fiscal year 1987 budget. 1987 (February) Walter Gilbert resigns from the U.S. National Research Council (NRC) genome panel and announces plans to start Genome Corp., with the goal of sequencing and copyrighting the human genome and selling data for profit. (April) An advisory panel suggests that DOE should spend $1 billion on mapping and sequencing the human genome over the next 7 years-and that DOE should lead the U.S. effort. DOE's Human Genome Initiative begins. (May) David Burke, Maynard Olson, and George Carle of Washington University in St. Louis develop YACs (left) for cloning, increasing insert size 10-fold (Science). (October) Helen Donis-Keller and colleagues at Collaborative Research Inc. publish the "first" genetic map with 403 markers, sparking a fight over credit and priority (Cell). (October) DuPont scientists develop a system for rapid DNA sequencing with fluorescent chain-terminating dideoxynucleotides (Science). Applied Biosystems Inc. puts the first automated sequencing machine, based on Hood's technology, on the market. 1988 (February) In a pivotal report, the NRC endorses the Human Genome Project (HGP), calling for a phased approach and a rapid scale-up to $200 million a year of new money. (March) Prompted by advisers at a meeting in Reston, Virginia, James Wyngaarden, then director of the National Institutes of Health (NIH), decides that the agency should be a major player in the HGP, effectively seizing the lead from DOE. (June) The first annual genome meeting is held at Cold Spring Harbor Laboratory. (September) NIH establishes the Office of Human Genome Research and snags Watson (pictured) as its head. Watson declares that 3% of the genome budget should be devoted to studies of social and ethical issues. (October) NIH and DOE sign a memorandum of understanding and agree to collaborate on the HGP. 1989 (January) Norton Zinder of Rockefeller University chairs the first program advisory committee meeting for the HGP. (September) Olson, Hood, Botstein, and Cantor outline a new mapping strategy, using STSs (Science). (September) DOE and NIH start a joint committee on the ethical, legal, and social implications of the HGP. (October) NIH office is elevated to the National Center for Human Genome Research (NCHGR), with grant-awarding authority.

Credit: James King-Holmes/Science Photo Library Credit: K.G. Murti/Visuals Unlimited Credit: James Holmes-King/Visuals Unlimited Credit: Photo Researchers, Inc. Credit: Sanger Centre Wellcome Photo Library Credit: David Sieren/Visuals Unlimited Credit: Sam Ogden Credit: Wellcome Trust Photo Library Credit: The Institute For Genomic Research Credit: Schena et al. Credit: Blattner et al. Phil Green Credit: Joanna Green	1990 Three groups develop capillary electrophoresis (left), one team led by Lloyd Smith (Nucleic Acids Research, August), the second by Barry Karger (Analytical Chemistry, January), and the third by Norman Dovichi (Journal of Chromatography, September). (April) NIH and DOE publish a 5-year plan. Goals include a complete genetic map, a physical map with markers every 100 kb, and sequencing of an aggregate of 20 Mb of DNA in model organisms by 2005. (August) NIH begins large-scale sequencing trials on four model organisms: Mycoplasma capricolum, Escherichia coli (left, pink), Caenorhabditis elegans (left, rainbow), and Saccharomyces cerevisiae (left, ovals). Each research group agrees to sequence 3 Mb at 75 cents a base within 3 years. (October) NIH and DOE restart the clock, declaring 1 October the official beginning of the HGP. (October) David Lipman, Eugene Myers, and colleagues at the National Center for Biotechnology Information (NCBI) publish the BLAST algorithm for aligning sequences (Journal of Molecular Biology). 1991 (June) NIH biologist J. Craig Venter announces a strategy to find expressed genes, using ESTs (Science). A fight erupts at a congressional hearing 1 month later, when Venter reveals that NIH is filing patent applications on thousands of these partial genes. (October) The Japanese rice genome sequencing effort begins. (December) Edward Uberbacher of Oak Ridge National Laboratory in Tennessee develops GRAIL, the first of many gene-finding programs (PNAS). 1992 (April) After a dispute with then-NIH director Bernadine Healy over patenting partial genes, Watson resigns as head of NCHGR. (June) Venter leaves NIH to set up The Institute for Genomic Research (TIGR), a nonprofit in Rockville, Maryland. William Haseltine heads its sister company, Human Genome Sciences, to commercialize TIGR products. (July) Britain's Wellcome Trust enters the HGP with $95 million. (September) Mel Simon of Caltech and colleagues develop BACs for cloning (PNAS). (October) U.S. and French teams complete the first physical maps of chromosomes: David Page of the Whitehead Institute and colleagues (pictured) map the Y chromosome (Science); Daniel Cohen of the Centre d'Etude du Polymorphisme Humain (CEPH) and Généthon and colleagues map chromosome 21 (Nature). (December) After lengthy debate, NIH and DOE release guidelines on sharing data and resources, encouraging rapid sharing and enabling researchers to keep data private for 6 months. U.S. and French teams complete genetic maps of mouse and human: mouse, average marker spacing 4.3 cM, Eric Lander and colleagues at Whitehead (Genetics, June); human, average marker spacing 5 cM, Jean Weissenbach and colleagues at CEPH (Nature, October). 1993 (April) Francis Collins of the University of Michigan is named director of NCHGR. (October) NIH and DOE publish a revised plan for 1993-98. The goals include sequencing 80 Mb of DNA by the end of 1998 and completing the human genome by 2005. (October) The Wellcome Trust and MRC open the Sanger Centre at Hinxton Hall, south of Cambridge, U.K. Led by John Sulston (pictured), the center becomes one of the major sequencing labs in the international consortium. (October) The GenBank database officially moves from Los Alamos to NCBI, ending NIH's and DOE's tussle over control. 1994 (September) Jeffrey Murray of the University of Iowa, Cohen of Généthon, and colleagues publish a complete genetic linkage map of the human genome, with an average marker spacing of 0.7 cM (Science). 1995 (May to August) Richard Mathies and colleagues at UC Berkeley and Amersham develop improved sequencing dyes (PNAS, May); Michael Reeve and Carl Fuller at Amersham develop thermostable polymerase (Nature, August). (July) Venter and Claire Fraser of TIGR and Hamilton Smith of Johns Hopkins publish the first sequence of a free-living organism, Haemophilus influenzae, 1.8 Mb (Science). (September) The Japanese government funds several sequencing groups for a total of $15.9 million over 5 years: Tokai University, University of Tokyo, and Keio University. (October) Patrick Brown of Stanford and colleagues publish first paper using a printed glass microarray of complementary DNA (cDNA) probes (Science). (December) Researchers at Whitehead and Généthon (led by Lander and Thomas Hudson at Whitehead) publish a physical map of the human genome containing 15,000 markers (Science). 1996 (February) At a meeting in Bermuda funded by the Wellcome Trust, international HGP partners agree to release sequence data into public databases within 24 hours. (April) NIH funds six groups to attempt large-scale sequencing of the human genome. (April) Affymetrix makes DNA chips commercially available. (September) DOE initiates six pilot projects, funded at $5 million total, to sequence the ends of BAC clones. (October) An international consortium publicly releases the complete genome sequence of the yeast S. cerevisiae (Science). (November) Yoshihide Hayashizaki's group at RIKEN completes the first set of full-length mouse cDNAs. 1997 (January) NCHGR is promoted to the National Human Genome Research Institute; DOE creates the Joint Genome Institute. (September) Fred Blattner, Guy Plunkett, and University of Wisconsin, Madison, colleagues complete the DNA sequence of E. coli, 5 Mb (Science). (September) Molecular Dynamics introduces the MegaBACE, a capillary sequencing machine. 1998 (January) NIH announces a new project to find SNPs. (February) Representatives of Japan, the U.S., the E.U., China, and South Korea meet in Tsukuba, Japan, to establish guidelines for an international collaboration to sequence the rice genome. (March) Phil Green (pictured) and Brent Ewing of Washington University and colleagues publish a program called phred for automatically interpreting sequencer data (Genetic Research). Both phred and its sister program phrap (used for assembling sequences) had been in wide use since 1995. (May) PE Biosystems Inc. introduces the PE Prism 3700 capillary sequencing machine. (May) Venter announces a new company named Celera and declares that it will sequence the human genome within 3 years for $300 million. (May) In response, the Wellcome Trust doubles its support for the HGP to $330 million, taking on responsibility for one-third of the sequencing. (October) NIH and DOE throw HGP into overdrive with a new goal of creating a "working draft" of the human genome by 2001, and they move the completion date for the finished draft from 2005 to 2003. (December) Sulston of the Sanger Centre and Robert Waterston of Washington University and colleagues complete the genomic sequence of C. elegans (Science). 1999 (March) NIH again moves up the completion date for the rough draft, to spring 2000. Large-scale sequencing efforts are concentrated in centers at Whitehead, Washington University, Baylor, Sanger, and DOE's Joint Genome Institute. (April) Ten companies and the Wellcome Trust launch the SNP consortium, with plans to publicly release data quarterly. (September) NIH launches a project to sequence the mouse genome, devoting $130 million over 3 years. (December) British, Japanese, and U.S. researchers complete the first sequence of a human chromosome, number 22 (Nature).

Credit: Adams et al. Credit: Dwight Kuhn Photography Credit: Doug Wechsler Credit: Joshua Mylne Credit: Ann Elliott Cutting	2000 (March) Celera and academic collaborators sequence the 180-Mb genome of the fruit fly Drosophila melanogaster (left), the largest genome yet sequenced and a validation of Venter's controversial whole-genome shotgun method (Science). (March) Because of disagreement over a data-release policy, plans for HGP and Celera to collaborate disintegrate amid considerable sniping. (May) HGP consortium led by German and Japanese researchers publishes the complete sequence of chromosome 21 (Nature). (June) At a White House ceremony, HGP and Celera jointly announce working drafts of the human genome sequence, declare their feud at an end, and promise simultaneous publication. (October) DOE and MRC launch a collaborative project to sequence the genome of the puffer fish, Fugu rubripes (left), by March 2001. (December) An international consortium completes the sequencing of the first plant, Arabidopsis thaliana (left), 125 Mb. (December) HGP and Celera's plans for joint publication in Science collapse; HGP sends its paper to Nature. 2001 (February) The HGP consortium publishes its working draft in Nature (15 February), and Celera publishes its draft in Science (16 February).