Exploring the Third Human Genome Editing Summit

The third human genome editing summit, which I was an organiser of, has finished and it was very interesting; a blend of science, ethics, law and patients. Consenus summary here: https://t.co/CR4DS5CgK2 My thoughts, as an informed genomics expert below:

— Ewan Birney (@ewanbirney) March 9, 2023

First off some background, definitions and history. We can now "edit" DNA in a cell's genome - change some bases (letters of DNA) to others. When the cell is a cell in our body, eg, the cells which make red blood cells this is called "somatic genome editing".

— Ewan Birney (@ewanbirney) March 9, 2023

When the edits are on the cells in a very early embryo or in the in vitro cells which we could become sperm or eggs this is called germline editing, and there is precise distinction between these edits *only for legally defined research* compared to implanting an embryo

— Ewan Birney (@ewanbirney) March 9, 2023

Heritable human genome editing is the definition for edits which aim to make a embryo that one would bring to term and make a human from.

— Ewan Birney (@ewanbirney) March 9, 2023

Broadly; somatic genome editing to cure disease is credible, has been done, and the potential is huge. Germline editing for resesarch should continue. Heritable human genome editing is not safe nor effective and has complex unresolved ethics, but these discussions should continue

— Ewan Birney (@ewanbirney) March 9, 2023

Before I unpack this, two other bits of history. Firstly this field - and the summit - has the shadow of 3 girls who did undergo heritable human genome editing administered by a chinese scientist in 2018. He was put in jail and china has strengthened its legal +ethical framework

— Ewan Birney (@ewanbirney) March 9, 2023

The second is that the "early" gene therapy - the introduction usually of complete healthy genes into the genome in another location (technically often called transgene) has been going since 1990s and this field provide a key enabling technology - delivery systems

— Ewan Birney (@ewanbirney) March 9, 2023

Although the interest is around editing at this summit and in biotech etc, this "classic" gene therapy now works in some cases and one can imagine more coming. This should be seen as another modality - some now call it gene addition - alongside gene editing.

— Ewan Birney (@ewanbirney) March 9, 2023

A highlight of the summit was the talk from Victoria Grey, an individual who has been cured of her sickle cell disease via somatic gene therapy. Sickle cell disease is due to a faulty version of haemoglobin when the red blood cells change shape and block blood vessels.

— Ewan Birney (@ewanbirney) March 9, 2023

It is extremely painful and dangerous. Victoria spoke movingly of her life growing up and her young family knowing that their mother may well suddenly have weeks in hospital in pain. She accepted to be the first clinical trial patient for a somatic gene therapy trial

— Ewan Birney (@ewanbirney) March 9, 2023

This was a risky, painful and complex procedure of her blood cells extracted, modified in the lab - she called those cells her "super cells" - then her full blood system was ablated by radiation and repopulated by these super-cells. She had a tough month in hospital recovering

— Ewan Birney (@ewanbirney) March 9, 2023

But after that she had no more sickle cell episodes - no emergency trips to the hospital and extreme pain. She ended drawing her faith and her interaction with science together - "I stand before you today that miracles do happen and that God and science can coexist".

— Ewan Birney (@ewanbirney) March 9, 2023

There are millions of people in the world with sickle cell disease; at least 100,000 in the US, very often African Americans as the sickle cell mutation confers resistance to malaria when hetreozygote, so is far higher frequency in sub saharan african, in particular west africa

— Ewan Birney (@ewanbirney) March 9, 2023

Victoria is not the only person who has had somatic genome editing cure for sickle cell; there are more on the same trial + other trials happening. The preliminary data behind these is very strong, as expected. Sickle cell is a genetic disease; fix the gene, prevent the disease.

— Ewan Birney (@ewanbirney) March 9, 2023

Much of the summit therefore also moved to equitable access of these therapies. The current ex-vivo cell modification followed by blood cell ablation and repopulation is ... not going to scale well. One needs in vivo solutions.

— Ewan Birney (@ewanbirney) March 9, 2023

Here the experience of "classic" gene therapy comes in with their 20 years experience of how to get transgenes into cells with triggering an immune response. This is now successful - in particular Luxturna, a gene addition scheme to cure blindness due to defects in RPE65

— Ewan Birney (@ewanbirney) March 9, 2023

This is getting to routine; around 30 children a year in the UK, and far more worldwide, are not going blind due to this treatment. This is getting less press perhaps somatic genome editing but another genetic disease falling to genetic therapy.

— Ewan Birney (@ewanbirney) March 9, 2023

The other bright spot here has been the success of the lipid nanoparticle delivery by BioNTech and Moderna for two of the SARS-CoV-2 vaccines - although gene therapy/editing is a different ask from vaccine, the engineering control being gained is very positive

— Ewan Birney (@ewanbirney) March 9, 2023

At the summit we also heard about improvements to the editing machinery - the first editing schemes were more "targetted disruption" but now there is an increasing number of precise edits or micro cut-and-paste schemes working better and better.

— Ewan Birney (@ewanbirney) March 9, 2023

Research also has progressed in understanding the impact of edits in the embryo of the DNA - early embryo DNA is very fragile (more than other cells) - and potentially editing gamete producing cells - cells which would make sperm and eggs, something we can do in the mouse

— Ewan Birney (@ewanbirney) March 9, 2023

A host of questions therefore around the far more fraught heritable genome editing, where one edits either embryos or gamete producing cells to make a systematic change to all cells of a person and their descdants. Is it safe? would it work? should society allow it?

— Ewan Birney (@ewanbirney) March 9, 2023

Many of these questions have been discussed for a decade or so - in the abstract even further back - but it is becoming more and more feasible to do and to responsibly think about assessing, potentially answering, the safety concerns (eg, off target effects) with these new tools.

— Ewan Birney (@ewanbirney) March 9, 2023

My opinion did shift during the summit. Before the summit I could not see many, if any, scenarios which one could not solve with pre-implanation genetic diagnosis but one could solve with heritable genome editing. This changed for me.

— Ewan Birney (@ewanbirney) March 9, 2023

There are now rare cases of double homozygous parents for a disease (most obviously sickle cell) and parents who are homozygous for a dominant disorder (like huntington's). As we develop better somatic treatments for genetic disease, this double homozygous parent number will rise

— Ewan Birney (@ewanbirney) March 9, 2023

It would be very strange to be in the situation where society has essentially cured a genetic disease for some individuals but say to a couple who have been cured that all their children must have a risky and extremely painful life until they are strong enough for a cure.

— Ewan Birney (@ewanbirney) March 9, 2023

Another practical issue is that for pre implanation diagnosis there are often many cycles of ovulation and IVF to get to even a single embryo without a disease; this will also get more complex in more consangieous situations where one might have two loci to worry about

— Ewan Birney (@ewanbirney) March 9, 2023

I remain skeptical that there is a *large* number of cases which can be cured/alleviated by heritable genome editing but not by pre-implantation diagnosis, but I no longer think this is so rare to be effectively zero.

— Ewan Birney (@ewanbirney) March 9, 2023

Nevertheless clearly patients and citizens need a voice and a discussion about, given safety and efficacy criteria are met, what scenarios should be allowed and although my opinion has changed, a consensus societal position might be still "never".

— Ewan Birney (@ewanbirney) March 9, 2023

(very obviously, society gets to set the rules, usually via legislation and regulation, and if there is one consistent call it is for countries - the place of action for this - to think about this and deliver).

— Ewan Birney (@ewanbirney) March 9, 2023

At the start of summit we heard from three Chinese speakers (one an academic in the UK on China) about the more explicit tightening in China - no longer a pragmatic, post-hoc regulation but more up front about the need to meet ethical standards

— Ewan Birney (@ewanbirney) March 9, 2023

(though the legislation presented was silent on how those ethical standards are determined).

— Ewan Birney (@ewanbirney) March 9, 2023

This area is not new ground - bioethicists have been discussing the ethics of heritable genetic therapies for a while, and two ethicists presented some contrasting views.

— Ewan Birney (@ewanbirney) March 9, 2023

This clear "red light but continue discussion" on heritable genome editing should not though detract from the promise and enthusiasm around somatic genome editing, and even broader to somatic genetic therapy (bringing in RPE65 as another success story)

— Ewan Birney (@ewanbirney) March 9, 2023