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Codebreakers: Makers of Modern Genetics

The Alan Coulson Papers

Alan Coulson helped to establish techniques that laid the foundations for the science of genomics.

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Alan Coulson played a critical role in several of the developments that ultimately led to the sequencing of the human genome. The archive of his scientific papers covers 1967-2000, and is comprised mostly of handwritten notes in loose-leaf files, with illustrative graphs and photographs, along with correspondence from 1983 onwards. It provides an unrivalled opportunity to follow the practical progress of a bench scientist.

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Alan Coulson with worm mapping data at the C. elegans meeting held at Cold Spring Harbor Laboratory, May 1989. Credit: Professor Barry Honda.
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In 1967 Coulson left Leicester Polytechnic and joined the Nobel Prize winner Fred Sanger at the MRC Laboratory of Molecular Biology (LMB) in Cambridge as a lab technician. Sanger was attempting to sequence the nucleotides in the nucleic acids, RNA and DNA, from bacteriophages (viruses that infect bacteria). Coulson's tasks included growing the cultures of bacteria in which the bacteriophages would multiply, before extracting the genetic material and using enzyme chemistry to break it into labelled fragments. He would then run the radioactively labelled fragments through a gel that acted as a sieve to sort them by size, giving a 'barcode' photograph from which the sequence could be deduced.

Coulson's contribution was to find ways both to speed up the sequencing process and to make it more accurate. Sanger's first technique was known as the 'plus and minus' method, and it led to the first complete sequence of an organism: the bacteriophage X174, which has approximately 5375 DNA nucleotides. He and Coulson then developed a related technique known as the chain-termination, or dideoxy, method. This method was adopted by the makers of the automated sequencing machines that made the Human Genome Project possible; it and its predecessor won Sanger a second Nobel Prize in 1980.

The development of these techniques was recorded in his laboratory notebooks. While Coulson's notes are for the most part strictly objective, he occasionally adds a comment: 'basically quite easy', 'pretty poor but not hopeless', 'This won't work!'. He and Sanger went on to publish the first human sequence, the 16 569 nucleotides of the mitochondrion, a cell organelle, in 1981.

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C. elegans cosmid fingerprinting autoradiograph
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The final phase of Coulson's work with Sanger was the complete sequencing of phage ╬╗, which has approximately 48 000 nucleotides. Records of the 'contigs', or contiguous DNA fragments, begin on hand-drawn index cards and evolve into some of the earliest computer printouts of gene sequences, dating from around 1980.

Sanger retired in 1983, and Coulson moved within the LMB to join John Sulston, who was working on the nematode worm C. elegans. With 100 million nucleotides in its genome it seemed impossibly large to sequence. But as a first step Sulston wanted to make a physical map, assembled in the right order from overlapping clones of DNA fragments. Coulson was just the partner he needed to speed up the 'fingerprinting' technique he was using to match the clones. In handwritten notes for a talk in 1985, Coulson, with typical self-deprecation, describes the mapping project as 'nutty'. But by 1989 they were able to display a complete physical map, aligned with a genetic map for C.elegans, on the wall at the Cold Spring Harbor Laboratory worm meeting.

This period is well-documented in the archive through correspondence - in the form of both letters and printed emails. The vast majority of items are requests for clones of worm DNA fragments. But others convey the excitement felt as the project moved from mapping to becoming the first whole-animal sequencing project to be funded. 'The cat is definitely out of the bag', writes Bob Waterston of Washington University in St Louis, an equal partner from 1985. Letters are often addressed to 'John and Alan', though in the early days all emails came via Sulston's address. The archive contains very few copies of Coulson's replies, although there are a number from Sulston.

Rapid progress on the worm genome raised expectations about human sequencing. In 1993 John Sulston moved to head the Wellcome Trust Sanger Centre (now the Sanger Institute), designed for high-throughput sequencing of human DNA. Coulson moved with him, joining the Board of Management and continuing to work on the worm genome. The complete worm sequence appeared in 1998. It took a combination of improved technology and a worldwide collaborative effort; the huge volume of correspondence is a testament to the leadership of the Sanger Centre team.

A later section of the archive covers requests for the research tools - gene knockouts and RNA interference (RNAi) - that Coulson developed to explore the biology of the worm. The most recent items date from 2000, although Coulson continued to work at the Sanger Centre until 2003, returning to the LMB before retiring there in 2007.

A 'nutty project' to... completely map c.elegans genome.

Alan Coulson, 1985 research notes (PP/COU/B/1/5)

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1981: Human mitochondrial DNA sequenced

Human mitochondrial DNA sequenced

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