Understanding Genome Editing

Next couple of days is the 3rd international summit on human genome editting, at the @TheCrick, where I am attending with my "genotype to phenotype" hat on, aka, "do you know what you are doing when you are making that edit?". A primer:

— Ewan Birney (@ewanbirney) March 5, 2023

Genome editing as a technology was created by the discovery and exploitation of a bacterial anti-virus immune system, where a DNA cutting enzyme can be directed to cut a piece a DNA via a RNA segment; this is called (clunkily) CRISPR-Cas9

— Ewan Birney (@ewanbirney) March 5, 2023

This discovery rightly was awarded the Nobel Prize to Emmanuel Charpentier and Jennifer Doudna, and is a great example of serendipity in research.

— Ewan Birney (@ewanbirney) March 5, 2023

Early genome editing was more "targeted genome local messing around" as the targeted cut point of DNA healed up in a somewhat random way. More modern genome editing is precise with all sorts of different ways to cut, fix and edit and flip bases

— Ewan Birney (@ewanbirney) March 5, 2023

This means we can move to the real precise "genome surgery" as suggested. So - what can we do with a human genome and what should we (and this is a societal we) allow?

— Ewan Birney (@ewanbirney) March 5, 2023

Let's do the easy ones; we should - and do - use this technology for research in human cells - long lived cell lines in the lab and fresh from a blood draw white blood cells - to work out how the human system works in more detail.

— Ewan Birney (@ewanbirney) March 5, 2023

This is ... awesome ... and there are so many papers and techniques exploiting this technology. One particularly powerful scheme is one can make lots of different edits in a single "test tube" (scientists say "eppendorf" as this is the more common type of tube in use in the lab)

— Ewan Birney (@ewanbirney) March 5, 2023

These libraries allow scientists in a single experiment to simultaneously knock out (delete) every gene in the human genome; if you can work out how to read out enough lines with a record of what you knocked out, bingo, you've just performed a systematic screen

— Ewan Birney (@ewanbirney) March 5, 2023

Moving beyond research, what can - and what should we - do for therapies? One thing we can do is fix bits of genome where we know its definitely the wrong form in people's bodies. This is called somatic genome editing (or somatic therapeutic genome editing).

— Ewan Birney (@ewanbirney) March 5, 2023

This looks feasible - the hardest bit is getting the editting machinery into the right cell type at scale - and lots of people expect a lot of progress here.

— Ewan Birney (@ewanbirney) March 5, 2023

In some sense this is "just" a very complex drug that works through a complex mechanism, and there are some well established rules about safety and trials to follow. There is plenty of detail here (eg, editing the wrong place inadvertently - so called off target effects) but ...

— Ewan Birney (@ewanbirney) March 5, 2023

broadly people are not too spooked about fixing things in live children or adults so that they don't get a disease. It needs good, appropriate regulation, knowing how to get the edit machinery to the right cell and knowing what to edit

— Ewan Birney (@ewanbirney) March 5, 2023

(this latter point is where geneticists/genomicists like myself get involved)

— Ewan Birney (@ewanbirney) March 5, 2023

Finally we could - and one question is if we should - edit embryos (potentially at the single cell stage but plenty of details) to make all the cells of someone's body, including their sperm or egg, different.

— Ewan Birney (@ewanbirney) March 5, 2023

This is doable; we can we do it in mice (and regularly do it for research) and in highly regulated research settings on embryos scientists can show they can do the first stages of this. So - this is feasible.

— Ewan Birney (@ewanbirney) March 5, 2023

Now - should we do it? This is a question for society to answer not "just" scientists because it gets into changing the relationship between parents and their children in the fundamental make up of genomes.

— Ewan Birney (@ewanbirney) March 5, 2023

As well as this big picture ethics question, a simpler question is what scenarios might we want to do this. For the most obvious scenarios - fixing something in the genome that is broken - there is a simpler scheme in selecting the non-broken embryos in IVF

— Ewan Birney (@ewanbirney) March 5, 2023

This is already allowed in many societies now and works well. One has to come up with pretty rare scenarios (but it is feasible) for when one can't do it via selection but can do it via edits.

— Ewan Birney (@ewanbirney) March 5, 2023

But I worry now; there is a big confluence of misunderstanding potential. We know a lot about genetics broadly in terms of segments of DNA that change traits (eg height, risk of type II diabetes, results of standardised test scores in a particular exam setting)

— Ewan Birney (@ewanbirney) March 5, 2023

Although this knowledge is firm+robust, it is does not mean we know which *edits* to make, nor do we know whether the edit made for this person would have the effect we see on average across a population. Its all far murkier than the glib "we can do human genetics+we can edit"

— Ewan Birney (@ewanbirney) March 5, 2023

(and I say this as an enthusiast for genetics, genomics, genome editing and therapeutic applications of genetics and genome editing - the latter here somatic genome editing).

— Ewan Birney (@ewanbirney) March 5, 2023

Somewhat concerningly a Chinese scientist, He Jiankui, has actually made germline edits in 2018 to two chinese girls. He was tried and imprisoned, and is now released.

— Ewan Birney (@ewanbirney) March 5, 2023

As well as China (though China's regulation has become more strict on this) I also get concerned by the largely self-regulation by clinicians in the US of IVF clinics - in a country with a lot of parental choice, technology confidence and money this I think is concerning

— Ewan Birney (@ewanbirney) March 5, 2023

I am looking forward to the talks at the summit, and also looking forward to explaining at least my perspective on this exciting technology - in short the fact we *can* do things does not mean we *should* do things.

— Ewan Birney (@ewanbirney) March 5, 2023