July 17, 2020, by Brigitte Nerlich
Gene writing: Between art and nature
In the past, I have written a bit about genomics, synthetic biology and gene editing, from the perspective of language and culture. So, when Matthew Cobb alerted me to a new thing called ‘gene writing’ at the beginning of July, I pricked up my ears. I told myself that I should write a blog post about this new development, if only just to mark the occasion. However, pandemic despondency set in and I just didn’t find the will to write anything. I finally I told myself that this procrastination should end. So here we go!
When first seeing the phrase ‘gene writing’ together with ‘breakthrough’, I was a bit taken aback, as I had thought that that was what synthetic biology was all about. Weren’t we all told that synthetic biology brought about a revolution from just being able to ‘read’ the genetic code to being able to ‘write’ it? But it seems that ‘gene writing’ or ‘genome writing’, although used as phrases once in a while in the context of synthetic biology, never became a thing, it seems. Whether after this announcement ‘gene writing’ will become a thing still has to be seen. One thing has changed though; it has become trademarked!
Gene writing announcement
On 7 July PR Newswire from Cambridge MA announced that: “Flagship Pioneering today announced the unveiling of Tessera Therapeutics, Inc. a new company with the mission of curing disease by writing in the code of life. Tessera is pioneering Gene WritingTM, a new biotechnology that writes therapeutic messages into the genome to treat diseases at their source.”
That announcement was also tweeted out by Flagship Pioneering and Tessera with an accompanying article. I was surprised not to have heard about this apart from in Matthew’s tweet. So I had a quick look at the news data-base Nexis for all English language news and could not find a single mainstream newspaper covering this advance in genetic engineering! The PR Newswire was picked up a few times by online websites. Only Wired, not covered by Nexis, seems to have written something on this new development in genetics.
I first read the PR Newswire, then the Tessera announcement, and then the Wired article in a sort of desultory way, not expecting much, but then was swamped by a tidal wave of metaphors. In the following I’ll try to pick out some of them but I can’t cover them all. But first a quick look at the announcement in the PR Newswire article.
Correcting nature’s code
The PR article starts with the usual proclamation that gene writing will be a “potentially revolutionary breakthrough for genetic medicine”…. That type of hyperbole is almost inevitable. Gene writing is said to overcome various limitations of both gene therapy and gene editing and to be able to “alter the genome by efficiently inserting genes and exons (parts of genes), introducing small insertions and deletions, or changing single or multiple DNA base pairs”. It might potentially cure monogenetic and perhaps also neurodegenerative diseases.
The key people are: Geoffrey von Maltzahn, a biological engineer, Jacob Rubens, a synthetic biologist, and, mentioned elsewhere, Rob Citorik, and others. Von Maltzahn explains what gene writing does by telling readers that “DNA codes for life. But sometimes our DNA is written improperly”. He goes on to say that they asked themselves “’What if Nature evolved a better solution than CRISPR for inserting curative therapeutic messages into the genome?” But how is this imitation of nature done?
To get to the heart of the matter of gene writing, I’ll now turn to what I assume is a press release from Tessera Therapeutics and the article in Wired and stitch them together randomly like a patchwork by tracing some salient metaphors they use.
Genomes, mosaics and tiling
To convey what gene writing is or does, the articles use old and new metaphors and also appeal to nature and evolution. We have already seen the use, by the scientists involved, of the ubiquitous code metaphor. However, there is also something new going on with regard to framing the genome in particular. It is depicted not as the book of life (sort of the basis for gene editing metaphors), but as a mosaic “that has evolved over millennia”. The ‘building blocks’ out of which this mosaic is made are base pairs, the nucleobases A, C, T, and G (also known in the olden times as ‘letters’ of the genetic alphabet).
Now, what is new about gene writing is that it draws its power from scientists being able to “add and subtract tiles from our genomic mosaic”, like “artists changing individual tiles – known as tessera – of a mosaic to alter the whole”. Using this new power, the scientists can write “therapeutic messages into the genome”. It should perhaps have been called ‘gene tiling’….
Beyond cutting and pasting
The real novelty of gene writing is said to lie in overcoming some shortcomings of gene editing. The most important one seems to be something that formerly was hailed as a breakthrough, namely gene editing’s or Crispr’s ability to ‘cut’ DNA – remember those molecular ‘scissors’! But cutting is quite close to breaking and destroying DNA and that’s obviously not good. Fortunately, “nature evolved a better way to alter genomes than cutting DNA”. So, it was time to take lessons from nature (although it should be stressed that gene editing too had taken lessons from nature!).
Junk DNA turns into genomic architects
The above-mentioned scientific artists rearranging genomic tiles began to harness “evolution’s greatest genomic architect: mobile genetic elements” (MGEs), a type of genetic material that can move around within a genome. Some of these were once known as “junk DNA”, but turned out not to be junk after all. To understand the genius of MGEs we have to dig a bit deeper…
Gene villages and jumping genes
Tessera mentions Richard Dawkins’ 1976 book The Selfish Gene to point out that evolution may act not only at the level of genomes but also “at the level of genes”. So, genomes are “not only unitary evolutionary entities but are also like villages composed of thousands of inhabitants called genes, each vying for its own survival”. In this evolutionary context “some genes evolved the ability to replicate independently of the rest of the genome” – and these are MGEs. Barbara McClintock who was the first to research ‘jumping genes’ or transposons.
Cutting, hopping and shuttling
As Wired points out, “MGEs come in a few flavours”: “There are transposons, which can cut themselves out of the genome and hop into a different neighorhood” and there are retrotransposons who “make a copy and shuttle that replica to its new home, expanding the size of the genome with each duplication”. It seems that, so far, Tessara has “identified about 6,000 retrotransposons (what Tessera calls RNA writers) and 2,000 transposons (DNA writers) that show potential” to being harnessed for gene writing.
Battling and stealing
These MGEs are busy little buggers, to put it bluntly. They do not only hop around, move house, etc., there is more. Peters, Koonin and others found in 2017 that there was a type of transposon that “had stolen some Crispr genes to help it move between bacterial hosts”. (Now I leave out a whole lot of battle-stained metaphors employed to explain what bacteria, viruses and phages do, from viral invaders to arms race; something that would deserve further analysis) The researchers realised “that these molecular tools for cutting, copying, and pasting were constantly being shuttled between MGEs, phages, and bacteria to be used alternative as means of offense or defense.” That’s what gene writing tries to imitate.
Mining and prospecting
In order to find good MGEs to work with, bioinformaticians have been mining databases and are “prospecting for MGEs that might be best suited for making these kinds of therapeutic DNA changes”. They have found many candidates.
Plugging and shooting
As I said above, gene writing is supposed to go beyond the cutting and pasting feats of gene editing. Tessera aims to use the characteristics of MGEs to develop “a new class of gene editors capable of precisely plugging in long stretches of DNA – something that Crispr can’t do”. Crispr was, apparently only good at breaking DNA, and only short bits at that. By using MGEs in novel ways, gene writing can, it seems, write “therapeutic messages into the genome to treat diseases at their source”. This is supposed to work through giving the genome one ‘shot’ or ‘injection’ of RNA, something that hasn’t been done before, but something that, apparently is also being explored in the making of COVID-19 vaccines!
Nature, art and science
One tweet announced the gene writing breakthrough by quoting: “This is us standing on the shoulders of Mother Nature”. This quote brings together nature and science, just as the name Tessera brings together art and biology or biology and design in order to indicate that those working with Tessera engineer and create “synthetic mobile genetic elements”.
This brings us back to synthetic biology which can be defined as “the design and construction of novel biologically based parts, devices and systems, as well as the redesign of existing natural biological systems, for useful purposes.” Gene writing in Tessera’s sense exploits the evolutionary design capabilities of nature. This is why people writing about gene writing focused on ‘architecture’, ‘art’, ‘mosaics’ and ’tiling’, rather than on scissors and cutting and pasting. However, ‘writing’ harks back to the cutting and pasting days of gene editing, which is a bit confusing. But ‘gene tiling’ might have been too novel a metaphor to use!