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9 min read

Ethics needs to catch-up with genetic innovation

Are we morally obliged to genetically edit?

John is Professor Emeritus of Cell and Molecular Biology at the University of Exeter.

An artistic visualisation of a DNA strand growing flowers from it.
Artist Nidia Dias visualises how AI could assist genomic studies.
Google Deepmind via Unsplash.

It makes me feel very old when I realise that Louise Brown, the first baby to be born via in vitro fertilisation (IVF), will be 47 years old on July 25th this year. Since her birth in 1978, over 10 million IVF-conceived babies have been born worldwide, of whom about 400,000 have been in the UK. Over that period, success rates have increased such that in some clinics, about 50 per cent of IVF cycles lead to a live birth. At the same time, there have also been significant advances in genetics, genomics and stem cell biology all of which, in relation to human embryos, raise interesting and sometimes challenging ethical issues. 

I start with a question: what is the ‘moral status’ of the early human embryo? Whether the embryo arises by normal fertilisation after sexual intercourse or by IVF, there is a phase of a few days during which the embryo is undergoing the earliest stages of development but has not yet implanted into the wall of the uterus; the prospective mother is not yet pregnant. In UK law, based on the Human Fertilisation and Embryology Act (1990), these early embryos are not regarded as human persons but nevertheless should be treated with some respect. Nevertheless, there are some who oppose this view and believe that from the ‘moment of conception’ (there actually isn’t such a thing – fertilisation takes several hours) embryos should be treated as persons. In ‘conventional’ IVF this debate is especially relevant to the spare embryos that are generated during each IVF cycle and which are stored, deep-frozen, in increasing numbers for possible use in the future.  

A further dimension was added to this area of debate when it became possible to test IVF embryos for the presence of genetic mutations that cause disease. This process is called pre-implantation genetic diagnosis and enables prospective parents who are at known risk of passing on a deleterious mutation to avoid having a child who possesses that mutation. But what about the embryos that are rejected? They are usually discarded or destroyed but some are used in research. However, those who hold a very conservative view of the status of the early embryo will ask what right we have to discard/destroy an embryo because it has the ‘wrong genes’. And even for the many who hold a less conservative view, there are still several questions which remain, including ‘which genetic variants we should be allowed to select against?; should we allow positive selection for genes known to promote health in some way?’; should we allow selection for non-therapeutic reasons, for example, sporting prowess?’ These questions will not go away and there are already indications that non-therapeutic selection is being offered in a small number of countries. 

Genetic modification 

This leads us on to think about altering human genes. Initially, the issue was genetic modification (GM) which in general involves adding genes. GM techniques have been used very successfully in curing several conditions, including congenital severe immune deficiency and as part of treatment programmes for certain very difficult childhood cancers. One key feature of these examples is that the genetic change is not passed on to the next generation – it just involves the body of someone who has already been born. Thus, we call them somatic genetic changes (from the Greek, sōmatikos, meaning ‘of the body’).  

Genetic modification which is passed on to the next generation is called germline GM which means that the genetic change must get into the ‘germ cells’, i.e., the sperm or egg. Currently, the only feasible way of doing this is to carry out the genetic modification on the very early embryo. At present however, with just one very specific exception, GM of human embryos is forbidden in all the countries where it would be possible to do it. There is firstly the question of deciding whether it is right to change the genetic makeup of a future human being in such a way that the change is passed to succeeding generations. Secondly, there are concerns about the long-term safety of the procedure. Although it would involve adding specific genes with known effects, the complexity of genetic regulation and gene interactions during human development means that scientist are concerned about the risks of unforeseen effects. And thirdly, germline GM emphasises dramatically the possibility of using GM for enhancement rather than for medical reasons.  

Genome editing 

This leads us to think about genome editing. In 2011, it was shown that a bacterial system which edits the genomes of invading viruses could also work in other organisms This opened up a large array of applications in research, agriculture and medicine. However, the ethical issues raised by genome editing are, in essence, the same as raised by GM and so there is still a universal prohibition of using the technique with human embryos: germline genome editing is forbidden. Despite this, a Chinese medical scientist, He Jiankui, announced in 2018 that he had edited the genomes of several embryos, making them resistant to HIV; two babies with edited genomes had already been born while several more were on the way. The announcement caused outrage across the world, including in China itself. He Jiankui was removed from his job and then, after a trial, was imprisoned for three years; his two colleagues who collaborated in this work received shorter sentences. 

At present the universal prohibition of human germline genome editing remains in place. However, the discussion has been re-opened in a paper by an Anglo-Australian group.  They suggest that we need to develop heritable (i.e. germline) polygenic genome editing in order to reduce significantly an individual's risk of developing degenerative diseases. These includecoronary artery disease, Alzheimer’s disease, major depressive disorder, diabetes and schizophrenia. I note in passing that one of the authors is Julian Savulescu at Oxford who is already well-known for his view that parents who are able to do so, are ‘morally obliged’ to seek to have genetically enhanced children, whether by PGD, GM or genome editing. The use of polygenic editing, which would, in all likelihood, be available only to the (wealthy) few, fits in well with his overall ethical position. Needless to say, the paper, published in the prestigious journal Nature, attracted a lot of attention in the world of medical genetics. It was not however, universally welcomed – far from it. Another international group of medical scientists and ethicists has stated that ‘Human embryo editing against disease is unsafe and unproven …’ and even go as far as to suggest that the technology is ‘… going to be taken up by people who are pushing a eugenics agenda …’ remain very pertinent. 

Harder still and harder 

I have no doubt that amongst different reader there will be a range of opinions about the topics discussed so far. For anyone who is Christian (or indeed an adherent of almost any religious faith), one of the difficulties is that modern science, technology and medicine have thrown up ethical questions that could not have even been dreamed of by the writers of the Bible (or of other religious texts). We just have to use our wisdom, knowledge and general moral compass (and for some, prayer) to try to reach a decision. And if what I have already written makes that difficult, some recent developments multiply that difficulty still more.  

In the early years of this century, scientists developed methods of transforming a range of human cells into ‘pluripotent’ stem cells, i.e., cells capable of growing into a wide range of cell types. It also became possible to get both induced stem cells and natural stem cells to develop into functional differentiated cells corresponding to specific body tissues. This has huge potential for repairing damaged organs. However, other applications are potentially much more controversial. In 2023, Cambridge scientists reported that they had used stem cells to create synthetic mouse embryos which progressed at least as far as brain and heart formation within the normal pattern of mouse embryo development. 

At about the same time, the Cambridge group used individual human embryonic stem cells (from the blastocyst stage of embryonic development), to ‘grow’ early human embryos in the lab. There is no intention to use these embryos to start a pregnancy – indeed, it would be illegal to do so – but instead to study a period of embryo development which is not permitted with ‘real’ human embryos (research must not continue past 14 days of development). But how should we regard synthetic embryos? What is their moral status? For those who hold a conservative view of the normal human embryo (see earlier), should we regard these synthetic embryos as persons? Neither does the law help us. The legal frameworks covering in vitro fertilisation and early embryos (Human Fertilisation and Embryology Acts, 1990, 2008) do not cover artificial embryos – they were unknown at the times the legislation was drawn up. Indeed, synthetic embryos/embryo models are, in law, not actually embryos, however much they look like/behave like early embryos. Earlier this month, the Human Fertilisation and Embryology Authority (HFEA) discussed these developments with a view to recommending new legislation, but this will not dispel an unease felt by some people, including the science correspondent of The Daily Telegraph, who wrote that this research is irresponsible.  

But there is more. In addition to synthetic embryos, the HFEA also discussed, the possible use of gametes – eggs and sperm – grown from somatic stem cells (e.g., from skin) in the lab. Some authors have suggested that the production of gametes in vitro is the ‘Holy Grail’ of fertility research. I am not so sure about that but it is clear that a lot of effort is going into this research. Success so far is limited to the birth of several baby mice, ‘conceived’ via lab-grown eggs and normal sperm. Nevertheless, it is predicted that lab-grown human eggs and sperm will be available within a decade. Indeed, several clinicians have suggested that these ‘IVGs’ (in vitro gametes) seem destined to become “a routine part of clinical practice”.  

The lab-grown gametes would be used in otherwise normal IVF procedures, the only novelty being the ‘history’ of the eggs and/or sperm. Clinicians have suggested that this could help couples in which one or both were unable to produce the relevant gamete, but who still wanted to have children. In this application, the use of IVGs poses no new ethical questions although we may be concerned about the possibility of the gametes carrying new genetic mutations. However, some of the more wide-ranging scenarios do at the least make us to stop and think. For example, it would be possible for a same-sex couple to have a child with both of them being a genetic parent (obviously for males, this would also involve a surrogate mother). More extremely, a person could have a child of which he or she was actually, in strictly genetic terms, both the ‘father’ and the ‘mother’. What are we to make of this? Where are our limits?  

Dr Christopher Wild, former director of International Agency for Research on Cancer, explores in depth many of the developments and issue I outlined above. His article on why a theology of embryos is needed, is clear, well-written, helpful and thought-provoking. 

 

This article is based on a longer blog post with full footnotes.  

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Article
Belief
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5 min read

Waiting for George: why I am yearning for an ending in Game of Thrones

Why does it matter so much that the series is unfinished?

James is a writer of sit coms for TV and radio.

Two people sit at a table strewen with old books lit by candle light.
Looking for the next chapter.
HBO.

Should you start something if you can’t be sure it’s going to finish? More specifically, should I read A Dance with Dragons by George RR Martin? It’s book five in the Game of Thrones series. The author is 76. Fans have been waiting fourteen years for book six, The Winds of Winter. And many are doubting the book will ever arrive, let alone book seven, A Dream of Spring. If current trends continue, HS2 will be completed faster than the Game of Thrones book series. 

There are plenty of other reasons not to read A Dance with Dragons. I’ve seen the adaptation for HBO which hit our screens in 2011. The plots have been already spoiled. I already know what’s going to happen. 

Yet over the last couple of years, I’ve read the first four books in the series and enjoyed them. A Storm of Swords, the third book in the series, was stunning, even though the plot had been thoroughly spoiled. I already knew about the Red Wedding, and the fate of King Joffrey and what happened to Jamie Lannister’s hand. Nonetheless, A Storm of Swords was enthralling and relentless. Just when I thought my jaw could not drop any further, it would drop again. The fact that A Dance with Dragons has already been on TV is not a consideration. 

A stronger reason against reading A Dance with Dragons is this: book four in the series, A Feast for Crows is, frankly, for the birds. Following on from the scintillating Storm of Swords, George RR Martin decided to focus on all of the least interesting characters who wander around Westeros desperately seeking a plot. But A Dance with Dragons, I’m told, returns to the best characters, like Tyrion Lannister, Varys and John Snow. What’s not to like? 

Here’s what: I end up being captivated by the world of Westeros all over again and left in the lurch. It could happen. In fact, I would expect it to happen. I might find myself primed and ready for the sixth book in the series, The Winds of Winter, which may never come. It’s been fourteen years. Say it comes next year. Book seven may takes another five. He’ll be 82. He might not make it. Heck, I’ll be 56. I might not make it! 

George RR Martin is aware of this fan fury. He often refers to it in interviews or on his blog. In 2019 he wrote: 

“…if I don’t have THE WINDS OF WINTER in hand when I arrive in New Zealand for worldcon, you have here my formal written permission to imprison me in a small cabin on White Island, overlooking that lake of sulfuric acid, until I’m done.” 

The lake has been prepared, George. You’ll need to do better than ‘direwolves ate my homework.’ Martin explains he’s been working on related projects which now includes opening a pub called Milk of the Poppy. He doesn’t work the bar or change the barrels but fans now suspect that Martin is avoiding finishing the books on purpose. Why? 

Some say he knows he can’t finish the book because he’s an existentialist. After all, he wrote the books to show the sprawling messiness of the real world by using the anarchy of the Seven Kingdoms of Westeros. For George RR Martin, life is not full of heroes and villains like Gandalf and Saruman. He has a point. The most interesting characters in Lord of the Rings are Gollum and Boromir. 

Game of Thrones is an intentionally complex mess of compromise and chaos. There are no good guys, except John Snow. And there are no real villains except King Joffrey. And Cersei, Melisandre, Little Finger, The Mountain and, wow, that’s already quite a long list, isn’t it? 

The moral complexity was highlighted by the end of the TV series, which had to invent its own finale, as none was provided by the author. Many fans were appalled at the last series, outraged that the resolution was jarringly neat. Others were just happy there was an ending – which made that first group of fans even angrier. 

Here’s the real question. Why does it matter? So the series is unfinished. Big deal. 

You know what else is unfinished? Your life. And the lives of everyone around us. We live with not knowing how our story will end. We are finite beings. We are born. We live with the limitations. 

And then the biggest limitation of all hits us: death. So why not just enjoy the moment? If we enjoyed the characters and the stories, what’s the problem? Storm of Swords was incredible. Maybe A Dance with Dragons will be brilliant too. Can’t I just enjoy that and move on? 

No. We yearn for an ending. Life is not one perpetual cliffhanger. Let us not confuse limited knowledge with suspense. The fact is that we are eternal beings. The Lord has set eternity in our hearts. Even the characters of Westeros believe in something beyond themselves – although all the talk of the old gods and the new is entirely unconvincing. I don’t really believe they believe in those gods. 

But they do believe in something outside of themselves. In Game of Thrones, a few good men are prepared to die with honour. Some awful men die in agony. Others are wrestling with doing the right thing when all around seem not to care. Some characters are yearning for home; some vindication; others love and acceptance. 

Our desire for an ending merely matches the desires of the characters that George RR Martin has created. They are so lifelike precisely because they believe in providence, fate, destiny or some divine standard to which they are held to account. In that, George RR Martin has made characters in God’s image, not his own.  

What I do know is this: my favourite character in Game of Thrones, Tyrion Lannister, would read A Dance with Dragons, curious to know what happens next. And that’s good enough for me. I’m in. 

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