October 2, 2017, by Brigitte Nerlich
Base editing, biological complexity and the limits of metaphorical explanation
Gene editing has been in the news since around 2013. Here I want to focus on one of the most recent advances which made me question my own understanding of gene editing.
In 2015 a team of scientists led by Junjiu Huang at Sun Yet-Sen University in Guangzhou, China, used gene editing techniques, in this case CRISPR Cas9, to experiment on human embryos (and I’ll not engage with the ethical and social issues surrounding such work). Now, two years later, the same team has used another gene/genome editing technique, namely ‘base editing’, again on human embryos. In both cases they attempted to correct abnormal genes that lead to a potentially fatal blood disorder called beta thalassemia. Both the 2015 and the 2017 papers were published in the online journal Protein & Cell.
CRISPR Cas9 has been hailed by many as a revolution in genetic manipulation as it enables the relatively precise ‘editing’ of DNA. I have written a few blog posts about gene editing here and here. However, I had never heard about ‘base editing’ before the 23rd of September. Reading and thinking about base editing made me realise how little I understand, really, about how gene editing using CRISPR works, and, of course, how base editing works. In both cases, the little word ‘editing’ hides a lot of complexity!
In the following, I’ll home in on some of the linguistic efforts to communicate ‘gene’/’base’ editing through metaphors and how this might help or hinder understanding.
Gene surgery and chemical surgery
When writing about CRISPR I had come across, and have written about, a certain precision-evoking metaphor, namely ‘gene surgery’. So, I was very interested to find that the inventor of ‘base editing’, Professor David Liu, of Harvard University, called this new technique ‘chemical surgery’.
What is the difference, I wondered, between gene surgery and chemical surgery, metaphorically or otherwise? Put briefly, the difference seems to lie in CRISPR ‘breaking’ (‘chunks’ of) DNA, indeed both strands of DNA, and then letting the break heal itself or using this break to insert new genetic information. By contrast, base editing operates instead on just one ‘letter’ or ‘base’ of a DNA strand at a time.
But what does all this actually mean in terms of the underlying biology (and why is the word ‘chemical’ used)? To answer that question I’ll make a little detour into basic biology (or not so basic, at least for me) and then I’ll look at some of the metaphors used to convey the novelty of base editing, over and above ‘chemical surgery’.
Molecules and mutations
As we have all learned at school: “DNA molecules are found in the nuclei of cells. They carry genetic information. A DNA molecule consists of a backbone polymer of sugar molecules and phosphate groups. Attached to this are the four bases adenine, guanine, cytosine and thymine. The sequence of these bases comprises the genetic code.”
That looks quite complex to me, I have to confess. Adenine (A), for example, is a molecule made of carbon, nitrogen, and hydrogen atoms. Its chemical formula is C5H5N5. Reading about replacing ‘A’ with ‘G’ through base editing or ‘chemical surgery’ now suddenly doesn’t seem to be so easy. But on we go.
As we all know, DNA is a ‘double helix’. Each of its two twisted strands is made up of As, Ts, Cs and Gs. During cell division DNA makes a copy of itself, it replicates itself by unzipping and separating the two strands and putting them back together. In this (complicated!) process, mistakes can happen (for the following see here). The cell repair machinery may, or may not, correct these mistakes. If not corrected, the mistakes can persist in the form of a mutation.
There are various types of mutation: (1) ‘deletion’, where a string of letters is deleted from a DNA sequence as in: …TTGATCA… => …TTTCA; (2) ‘insertion’, where a string of letters is inserted into a DNA sequence, as in …GGCTAG… => …GGTCAACTAG; (3) point mutation, where one base is substituted for another, as in – …ACGGCT… => …ACGCCT…
Base editing deals with correcting the latter type of mistake or mutation. In the case of beta thalassemia, the point mutation means that A has been converted to G. Base editing then converts G back to A.
Metaphors and molecules
The use of base editing to correct the beta thalassemia base in a human embryo was reported by the BBC and many newspapers. They all told the story using the metaphor of ‘chemical surgery’, a deliberate metaphor introduced, it seems, by Professor Liu. Ian Sample, writing for The Guardian for example, writes about “’chemical surgery’ to mend harmful mutations in human embryos for the first time” and points out that base editing “is an adaptation [of CRISPR] that chemically alters the DNA bases themselves” (but he doesn’t explain what that means). The BBC talks about “precise ‘chemical surgery’”, that is, the use of base editing “to correct a single error out of the three billion ‘letters’ of our genetic code”. However, only Gizmodo, in an article by George Dvorsky, went all out in trying to explain base editing using a variety of analogies and metaphors.
Let’s first see how Dvorsky describes CRISPR gene editing: He talks about “snapping and replacing strands of faulty DNA” (one almost winces reading about this). He also says that CRISPR “slashes sloppily through DNA like an unsharpened knife”. That really changed my view of CRISPR as a new ‘precision’ instrument (molecular scissors, scalpel etc.) used in genetic manipulation!
What about base editing? Here we are not dealing with crude snapping, slashing and breaking of things. Instead, Dvorsky says that it involves “rewriting errors in the genetic code” (‘real’ writing and editing then, it seems, not just slashing) and that base editing goes “into the code of DNA itself”, “flipping misspelled letters, or bases, into their correct form” (other articles talk about ‘swapping’) (As in this article by David Cyranoski by for Nature: “In the latest study, Huang’s team used ‘base editing’, a modification of CRISPR–Cas9. It guides an enzyme to specific gene sequences, but does not cut the DNA. Instead, the Cas9 enzyme is disabled and tethered to another enzyme that can swap out individual DNA base pairs. So far, this technique can convert guanine (‘G’) to adenine (‘A’), and cytosine (‘C’) to thymine (‘T’).” (Italics mine)
Back to Dvorsky: He further elaborates the difference between (crude) CRISPR and (brilliant) base editing through a rather eye-catching metaphor, namely Brazilian Jiu-Jitsu, a form of martial art – but a subtle and elegant one: … “rather than coming out all guns-a-blazing with fists, knees and elbows”, practitioners of that art, “use their opponents’ weight and strength against them” – and base editing does, its seems, just that. We are not just dealing with “clumsy karate chops”.
CRISPR is portrayed as brutal and clumsy, as it cuts and breaks and snaps through the two strands of DNA, while base editing is represented as cunningly manipulating a single base/letter of DNA, or flipping and replacing it. When reading this I thought: So, CRISPR, which sounded so crisp and neat only a little while ago, now evokes what one may call the work of a barber surgeon, while base editing now conjures up the image of advanced key-hole surgery! Is that the difference between gene editing and base editing, between gene surgery and chemical surgery?
After having explained the differences between gene editing and base editing in colourful ways, Dvorsky goes on to say: “Direct chemical surgery is an appropriate analogy because base editors actually catalyze the rearrangement of atoms on the target DNA base to transform that DNA base from a C to something that looks like a T (for example).”
Metaphors and mysteries
When I looked back at the pictures of the A, C, T and G molecules above, I realised that ‘swapping’ or ‘flipping’ base A to/with base G, for example, involves rearranging quite a lot of chemical/atomic furniture, so to speak. How THAT is done is still quite a mystery to me!
I’d love to hear from those who can explain this to me. It sure is different to ‘editing’ this post.
Metaphors and analogies are great, but they only go so far before they hit the bedrock of biological complexity and/or the limits of my rather limited biological understanding.
PS: I didn’t want to talk about ethics in this post, but it just occurred to me that base editing might be easier to ‘sell’, as, on the face of it, it can only be used to ‘cure’ diseases, while CRISPR can also be used for enhancement (I might be wrong). However, in both cases the use for germline modification is controversial.