DNA sequencing: ‘a boring, thankless task’?

Post by James Lowe, who leads the pig strand as part of the TRANSGENE: Medical Translation in the History of Modern Genomics project. His research into the pig genome project is funded by a European Research Council Horizon 2020 Programme Starting Grant. See the TRANSGENE website for more information on the project: www.stis.ed.ac.uk/transgene

Autoradiograph

An autoradiograph showing a DNA sample pattern. Royalty-free image from the MRC Laboratory of Molecular Biology.

When it was first developed, DNA sequencing was dirty, dangerous and extremely time-consuming. It was a long way from the modern image of speed, high-tech banks of sequencing machines, and researchers sitting at their desks managing and analysing the raging torrents of data funnelling into their computers: as dry as a dry lab can be. Its origins were in biochemistry. Biochemists try to extract minute fractions of important molecules from complex squishy organisms, and this involves a lot of mess, fluids and chemicals: as wet as a wet lab can be, perhaps. The very earliest methods were laborious and slow: for instance, sequencing just 24 bases (the building blocks of DNA) took Walter Gilbert and Allan Maxam 2 years from 1971 to 1973. At the time of writing, a whole human genome of about 3 billion bases can be sequenced in less than a day (although it is usually sequenced in a couple of months). The use of radioactive labellers in early techniques added some risk to the procedure as well.

It’s easy to see, therefore, why researchers for whom producing DNA sequences would be useful would want to get around the whole painful process of doing it themselves at a lab bench. This was not the case for everyone though: however painstaking a procedure might be, the execution of a mastered skill brings its own satisfaction and reward. The members of DNA sequencing pioneer Frederick Sanger’s laboratory in particular drew pleasure from this work.

As Miguel Garcia-Sancho points out in his book ‘Biology, Computing, and the History of Molecular Sequencing’, the tedium of sequencing by hand provided some motivation for the development of machines to do it in an ‘automated’ way. Of course, the potentially lucrative business opportunity was also a motivating factor.

Some of the researchers I have interviewed as part of my research into the pig genome project were delighted that those who had driven the sequencing of the pig genome had done so, but felt that the activity and discussion of sequencing was utterly boring to them. One compared the sequence to a tool; to paraphrase, if they wanted to tighten a nut, they just needed a good spanner, they didn’t need or care to know how it was made. The impression given by some researchers is that sequencing is just a service task, a lower-order activity not quite constituting ‘real science’.

Based on a 2001 article in Science published in the same issue as one of the papers heralding the completion of a draft of the human genome, a legend has developed that one of the driving forces behind genome mapping, Nobel Prize-winner Sydney Brenner, believed just that. This has been cited in support of the claim that Brenner indeed thought that sequencing was dull drudge-work.

Sydney Brenner, c. 1960s

Sydney Brenner, c. 1960s. Royalty-free image from the MRC Laboratory of Molecular Biology.

The author of the 2001 piece, Leslie Roberts, relayed supposed criticisms of the human genome project in its early days, reporting that for sceptics, “this was technology development, not experimental biology, and it would be mind-numbingly dull. Sydney Brenner of the MRC [Medical Research Council] facetiously suggested that project leaders parcel out the job to prisoners as punishment—the more heinous the crime, the bigger the chromosome they would have to decipher.” Brenner was not quoted, however, and no reference was given for this reported crack.

It is true that Brenner did not get involved in any of the human genome projects initiated in the late 1980s, and the quip certainly tallies with his puckish humour. Writing in 1990, however, Brenner actually stated that “I am not one who believes that mapping and sequencing the human genome is a boring, thankless task, suitable perhaps only for a penal colony where transgressing molecular biologists might serve sentences of up to 20 megabases. On the contrary, I think that it is the most important, the most interesting and the most challenging scientific project that we have, and that it will come to attract the best minds in scientific research” (Brenner, 1990, p. 6).

As an activity, DNA sequencing is not held in high esteem by all scientists. But the legend of Brenner’s attitude to it is quite the opposite to his actually expressed views.

 

Sources used in the text:

http://genomemag.com/2018/03/from-13-years-to-20-hours-genome-sequencing-breaks-record/

http://www.nature.com.ezproxy.is.ed.ac.uk/articles/nature24286#abstract

Brenner, S. (1990). The human genome: the nature of the enterprise. In: Human Genetic Information: Science, Law and Ethics (Ciba Foundation Synposium 149), pp. 6-12. Chichester, UK: John Wiley and Sons.

García-Sancho M. (2012). Biology, Computing and the History of Molecular Sequencing: From Proteins to DNA, 1945-2000. Basingstoke, UK: Palgrave Macmillan.

Roberts L. (2001). Controversial From the Start. Science, 291, 1182-1188.

 

 

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