June 11, 2021, by Brigitte Nerlich
Maps, books and jigsaws: The human genome is back
I was recently messing about on the news database Nexis when I came across this pronouncement from 1982!! “Weissmann appealed directly to the delegates for an international basic-research fund to determine how genes function and their relationship to disease. With current technology, he declared, mapping the entire human genome would require some 50,000 man-years and cost about $5 billion. This is equivalent to about 25 years of government-supported research in Switzerland.” (McGraw-Hill’s Biotechnology Newswatch, 21 June, 1982).
Charles Weissmann was a founding father of the Swiss-based genetic-engineering firm Biogen founded in 1978. What I was actually looking for were newspaper articles about an announcement that the human genome project had now been really completed. I didn’t find a lot!
Metaphors, of course
Scientists began to sequence the human genome in October 1990. In 2001 they published a draft genome, and in 2003 a ‘full’ one. But even that still had bits missing. My mind went back to an article by John Avise, published in 2001 in conjunction with the first draft of the human genome, dealing with ‘evolving genomic metaphors’. It’s FULL of metaphors itself – have a look -, starting with the abstract:
“Recent genome-sequencing efforts have confirmed that traditional ‘good-citizen’ genes (those that encode functional RNA and protein molecules of obvious benefit to the organism) constitute only a small fraction of the genomic populace in humans and other multicellular creatures. The rest of the DNA sequence includes an astonishing collection of noncoding regions, regulatory modules, deadbeat pseudogenes, legions of repetitive elements, and hosts of oft-shifty, self-interested nomads, renegades, and immigrants.”
Sequencing missing bits
I wonder what he would make of the new announcement of the completer than complete sequencing of the human genome – including, I suppose, ‘deadbeat pseudogenes’, ‘self-interested nomads’, and, importantly, it seems, ‘repetitive elements’.
The Telomere-to-Telomore Consortium (T2T) posted their newly minted human reference genome on the BioRxiv preprint website on 27 May 2021. The consortium is an ‘open, community-based effort to generate the first complete assembly of a human genome’. I think Fred Sanger would have approved of that.
This achievement was not discussed in mainstream news, probably because the paper is not yet peer-reviewed. It is a pre-print, itself a novel event in the history of human genome sequencing – the first time such a paper can now be scrutinised openly by the scientific community. This absence of mainstream coverage meant that I only combed through a few blogs and newsletters online.
It was interesting to note that some of this coverage used the old metaphors that I had encountered before when the first drafts of the human genome were published, something that is perhaps not so surprising, given that this is the completion of a completion, so it continues an old story.
The map metaphor was used quite freely, as for example in this article in Popular Mechanics. As the article, which is really worth reading if you want to understand what’s going on, says: “Sequencing godfather George Church, a biologist at Harvard University, told Stat if this work goes through peer review successfully, it will be the first time any vertebrate genome has been fully mapped.”
The map metaphor is quite apt, as the scientists are exploring unexplored regions of the genome. Mapping the human genome is what scientists do. It is a conventional metaphor, also used, for example, for mapping the brain.
The puzzle or jigsaw metaphor was used in a New Scientist article from 2 June which said: “Because the genome had to be read in small chunks and then reassembled, some highly repetitive parts proved impossible to place, a bit like a jigsaw where all the pieces look alike.”
I also found this metaphor in an article in CE Noticias Financieras English (3 June, 2021), a publication added in 2017 to Lexis Nexis. Here it is attributed to one of the lead scientists: “A massive international consortium announced the first draft of the human genome sequence 20 years ago, but that version was still full of holes. The American bioinformatician Adam Phillippy compares the task to a puzzle of a landscape, in which the blue pieces of the sky were missing, too similar to be fitted with the technology of the time.”
The article goes on to say: “Current mass sequencing techniques – used in hospitals to study diseases with a genetic component – are not able to read the very long human genome of the pull [sic!, probably ‘in one go’], but can recognize fragments of a few hundred letters, which are then ordered thanks to a reference genome, which acts as the landscape photo in the puzzle box. […] The members of the T2T Consortium propose to use their new sequence as a world model: the photo of the puzzle box.”
The jigsaw puzzle metaphor is quite apt too, as we are dealing with missing bits or pieces, all be it ill-defined ones. In this article from the Daily Mail published last year, when scientists took a first step towards the current completion, that metaphor is used quite creatively and instructively. Have a look!
The Informant blog in New Zealand reported that “The Book of Life is finally complete and its still-blank pages have been written, about 8% of the volume.” The following sentence also contains the map metaphor: “After 20 years, the map of the human genome has been completed thanks to an unprecedented technological effort”.
The instruction manual
Related to the book (of life) metaphor, so widely used in the early 2000s, is the metaphor of the instruction manual or instruction book*, also used in the article from Noticias Financieras:
“Homo sapiens have taken about 300,000 years to be able to read their entire instruction manual. […] the so-called T2T Consortium, has now published ‘the first truly complete sequence’ of a human genome. […] The cell instruction book is written with combinations of only four chemical letters (ATTGCTGAA…).” (CE Noticias Financieras English, 3 June, 2021)
The book metaphor is steeped in a long history of genetic science, where metaphors of communication, information, code and letters were key to ‘unlocking’ some of the mysteries of genes and genomes. Scientists started to use the phrase ‘book of life’ from the mid-1960s onwards.
But, of course, the book metaphor also has shortcomings, like all metaphors. In this case, there are implications of power and control that the life sciences might have over life itself through being able to read and write the book of life. That power is, indeed, increasing, as recent research removing ‘synonyms‘ in the ‘book of life’ has shown. So it’s good to keep an eye on things.
This brings me back to Avise and what he said, again rather metaphorically, about the risks and benefits of using metaphors:
“Evocative metaphors can distill an ocean of information, whet the imagination, and suggest promising channels for navigating uncharted genetic waters. For example, the metaphor of nucleotide sequences as encrypted language, translatable to the plain text of polypeptides, may have facilitated research in the 1960s that cracked the ‘genetic code.’ In a more recent example, the notion of the genome as a ‘book of life’ helped to focus and sell the human genome sequencing project. However, metaphors can also mislead. The metaphor of the genome as a wellcrafted blueprint or a finely tuned machine may have blinded many biologists to genomic imperfections attributable to phylogenetic constraints and evolutionary-genetic tradeoffs. Clearly, metaphors vary in utility and can influence research paradigms.”
Keeping this sage advice in mind I am now looking forward to the publication of the complete reference human genome in a peer-reviewed journal and the media coverage that will follow, metaphors included. Will they still be the same?
*PS: I wrote this blog post before reading Philip Ball’s article on the human genome which also discusses some of the pros and cons of the metaphors used 20 years ago and still used today! As he says: “Misleading rhetoric has fuelled the belief that our genetic code is an ‘instruction book’ – but it’s far more interesting than that”
Image: In 2003 the Royal Mail issued some stamps to celebrate the ‘completion’ of the sequencing of the human genome – and of course the scientists are all men – I hope that wouldn’t happen nowadays!!