Genome editing: a lot to think about

Tanya Brigden discusses the ethical implications and regulatory challenges that should be considered in the innovative area of genome editing. In recent years, the potential of somatic genome editing has elicited both excitement and caution among researchers, clinicians, patients, and ethicists.

Welcome back to Making science work for health, the PHG Foundation podcast that explains the most promising developments in science and their implications for healthcare.
 
In each episode, host Ofori Canacoo discusses with a PHG Foundation policy analyst, the underpinning science, the ambitions for improving population health and the impact it could have on patients, on society and on the people delivering your healthcare.
 
If you would like to find out more about what was discussed in this episode, you can find additional information on our website, phgfoundation.org.

Make sure to read our briefing on advanced therapy medicinal products as mentioned in the episode.

If you have any questions about the topic then you can email us at intelligence@phgfoundation.org. 

Transcript

Ofori: Welcome to Making science work for health, the PHG Foundation's podcast exploring developments in genomics and related emerging health technologies. The progress being made by teams of scientists and researchers around the world is gaining more interest and attention. Many of the latest advances feature genomics and omics related technologies.

The field in which the PHG Foundation has more than 25 years of experience helping policy makers get to grips with practical on the ground delivery. Making science work for health aims to look behind the hype and explain what new science means for patients, health professionals, and members of society.

My name is Ofori Canacoo, part of the communications team at the PHG Foundation and host of Making science work for health. For this episode, we are talking about human genome editing. In recent years, the potential of somatic genome editing has elicited both excitement and caution among researchers, clinicians, patients, and ethicists.

We discussed with Tanya Brigden, Senior Policy Analyst in biomedical ethics at the PHG Foundation, the ethical implications and regulatory challenges that should be considered in this innovative area. 

Hello, Tanya. 

Tanya: Hi. 

Ofori: How are you? 

Tanya: I'm well, thank you. How are you? 

Ofori: Yes, good, thank you. So thank you for joining me.

We are gonna be talking about genome editing. So to kick us off, I would like to ask you, could you explain what genome editing is? 

Tanya: Yes, of course. So the term genome editing refers to a group of technologies that let us make precise targeted changes to the DNA of a living organism. And that could be for a human or a plant or an animal.

And sometimes you'll hear it referred to as gene editing, but the term genome editing is more accurate. Because editing can happen in parts of the genome, which aren't protein coding regions. And in the context of human health, which I think is the focus of this podcast today, I think it's really exciting because of its potential to treat or cure genetic diseases.

Ofori: So when we talk about genome editing, we aren't just talking about one technology? 

Tanya: No, that's a, that's a really good point. We're not, there's lots of different genome editing technologies. And some of the older methods date back to the 1980s, so it's not really new, but the use of genome editing tools has really grown and accelerated since 2012 with the development of a technology called CRISPR-Cas9 genome editing, which is now the best known and most widely used tool. 

Ofori: What has made CRISPR-Cas9 more popular than other genome editing tools?

Tanya: So it is generated a lot of excitement in the community because it's faster, it's cheaper and it's more accurate and it's easier to use as well. It's also more targeted and so just to explain it quickly, it's made up of two components. The first component is a guide RNA, which finds the target DNA sequence, which is that little bit that we want to edit, and then an enzyme, which is the Cas9 part that acts as molecular scissors and cuts the DNA so that it can be removed or altered and new DNA can be added, and that's known as a double stranded break.

These are highly toxic for the cells, and so it harnesses the cells inbuilt repair processes to repair that damage, and that can either disrupt or it can include functional sequences. 

Ofori: You've said that it's exciting because of its potential to cure genetic conditions. Could you tell us a little bit more about how it could be used to improve health?

Tanya: So in terms of applications, there are broadly three key ways that this technology could be used in the clinic. The first is for cell-based therapy, and this is cells that have been genetically modified in the lab to carry out a therapeutic function and then transfer it back into the patient. So essentially you take biological material, you modify it in the lab, and then you deliver it back into the patient.

An example of that would be CAR T-cell therapy, which is a cancer immunotherapy, but it works on the same principle to bone marrow transplants. The second are gene therapies. So this is the introduction of a gene therapy agent directly into the patient to modify the DNA in their own cells in situ. And the reason you do that is because genome editing can be used to fix a genetic mutation which causes a disease.

So for example, sickle cell disease. And these two gene and cell-based therapies would be classified as somatic genome editing and somatic cells are just cells in the body... well all cells apart from sperm and egg cells. And that brings us onto the third category, which is reproductive uses. And one of the challenges with gene therapy is delivering the editing system into the organ system where you want that gene to be expressed.

And one way to ensure that this happens is to make the changes to an early embryos that you can be sure that the change will be replicated in every cell. But this is very controversial and it's not permitted in the UK at the moment. 

Ofori: So you just mentioned reproduction, and in this podcast we'll be focusing on somatic genome editing.

But could you tell us more about the difference between somatic and editing for reproductive purposes? 

Tanya: Yes. So the term somatic and germline referred to the different cells that we can edit and in term that leads to different outcomes. And it's important that you raised it because we need to differentiate between these because they have different technical and ethical legal implications.

So somatic genome editing is where changes are made in cells in adults and children, and so the changes only affect that person being treated. Germline genome editing is currently used in a research context, and it's where edits are made to eggs or sperm or embryos that then go on to affect all the cells in the embryo as it grows.

And legally edits can be made in these early embryos for up to 14 days, at which point they have to be destroyed. So, the embryo can't be implanted into a woman or taken to term. Heritable genome editing though, is used to subscribe these germline changes that are then used for reproduction. So this is a much more controversial application because it leads to changes that impact not only the person who was born as a result, but might also be passed on to future generations.

Ofori: And is somatic genome editing used in clinical practice, or is it still in research stages? 

Tanya: Yes. So we're starting to see some uses in clinical practice, which is very exciting. So the MHRA, which is the UK's medicines regulator, was the first in the world to authorise a therapy called Casgevy, which is a CRISPR based medicine for sickle cell disease and for beta thalassemia.

Genome editing is also used for cancer immunotherapy, so gene T-cells, which are immune cells, have been used to treat children with leukemia in Great Ormond Street Hospital. Having said that, largely though applications are still being researched and trialed, particularly for diseases caused by a single gene mutation like sickle cell anemia or cystic fibrosis, and for diseases that have no known cures.

It's also very promising for other blood disorders, for neurodegenerative disorders, and for hereditary blindness. But where... it's important to note that where genome editing isn't currently feasible is for conditions that are caused by multiple genetic variants. So this would be for complex diseases like heart disease or diabetes.

Ofori: Do many of these conditions already have treatments? And then if they do, what makes gene editing more appealing? 

Tanya: So some of them, yes, do have treatments, but often those are drug therapies which only really manage symptoms. So to use the example of sickle cell disease, again, those patients might normally be treated with blood transfusions or medications to manage their symptoms.

But if they stop taking those, then they might get unwell. And undergoing treatment affects quality of life and it's very time consuming to have regular transfusions and probably, I imagine pretty unpleasant. Whereas genome editing is a one-time treatment to fix the genetic mutation cause in the disease, so it's curative rather than having to go through a lifetime of medical interventions to manage the symptoms.

So, it really would have a transformative impact on those patients, which is why it's so exciting because instead of treating the symptoms, we are correcting the cause. 

Ofori: So now that we know what it is and what it can be used for, could you talk us through some of the problems and concerns that these approaches raise?

Tanya: Yeah, so this is a, it is quite an ethically contentious area and is often the case with new innovative technologies, before we get carried away with using them, it's important to think about balancing any potential benefits against any kind of risks or harms that might arise. And so when need to think about the broad implications of introducing this sort of approach to the treatment of disease, thinking about the ethical challenges, I think first and foremost, safety is of course one of the most important considerations.

CRISPR systems are a more targeted way of introducing genetic changes, but it still carries risks like off-target effects, which is where changes are made in the wrong place and could potentially cause harm. Even more of a challenge is the risk of on-target effects, which are unintended effects at the target site, and there's also something called mosaicism. Which is where only some copies of the gene are altered, and that can lead to problems as well. So we have to remember that CRISPR systems have only been around since 2012, and it's a relatively new technology, and so it's not perfect. But I also think that the concept of acceptable risk needs to be taken into account through the lens of the specific disease or patient situation. So when you have a severe or life-threatening disease, the level of risk that patients are willing to take on is higher than in diseases where there's an alternative therapeutic option. And we're seeing options and pathways that are being developed that acknowledge this.

So for example, there's a, a 1-year-old girl called Layla, who was the first person to receive a gene edited immune cell therapy to treat her leukemia. And she received it under something called compassionate care, which means that she could access the therapy outside of clinical trials, even though it hadn't been approved by a regulator yet, and this is because she'd had quite an aggressive leukemia and had unsuccessful chemotherapy and palliative care was her only option left.

It was... it was risky and had previously only been tested in the lab, but she, or her parents, were able to take on more risk because otherwise she would've died. And so actually there's a good ending in that, in that now she's cancer free and doing really, really well. 

Ofori: So safety is of course the paramount consideration. Assuming then that those concerns are addressed in future, are there any concerns about making them available for patients? I understand that these are very expensive therapies. 

Tanya: Yes. So you are right. There are considerable challenges around equitable access, both in terms of access to participate in research as well as equitable access when it's finally used in clinical care.

So on the one hand, genome editing could be a tool to reduce inequalities in the sense that some people are dealt a really unlucky hand in living with a rare disease. And genome editing could be used to correct that, but it can only reduce inequalities if it's accessible to the people who need it. And regardless of socioeconomic status or geographical location, rather than being available to particular groups and restricted on the ability to pay and, and yes, you are right, they're very expensive therapies and we've recently seen this challenge play out.

So Casgevy, the CRISPR based gene therapy that I mentioned earlier, has been approved by the MHRA, who is our medicines regulator in the UK for use in patients with sickle cell disease and beta thalassemia, both of which are blood disorders. And so that means that they have decided, there is evidence that it's safe and effective, but it doesn't automatically make it accessible to patients.

So what happens next is that the National Institute of Health and Care Excellence, so NICE. Are responsible for assessing whether it should be funded in the NHS in England. And in the case of Casgevy, initially recommended that it be offered to patients with beta thalassemia but not sickle cell disease on the grounds that they thought there wasn't sufficient evidence that it was cost effective for sickle cell disease.

Now, this is partly a challenge with evidence generation for these types of therapies, so it's really hard to gather data on the long term effects of those treatments. However, in January this year, they updated their decision and it's now available for eligible sickle cell patients through something called a managed access agreement, which means that patients have faster access to these treatments whilst evidence is still being collected.

It's worth noting though, that NICE estimate that about 50 sickle cell patients a year will benefit, which means there's gonna be many who still require treatment and care, but I think the reality is that we can't fund everything. And so we need to think about which groups might be disadvantaged. We need to think about how we define the real value of these therapies in terms of improvement of quality of life. And I know that at the moment there's a real emphasis on identifying reimbursement models that might make these therapies more affordable for the NHS. 

Ofori: So we've talked about safety and equity and touched on challenges around evidence generation. Are there any other considerations that you think are important?

Tanya: Yeah. So something that I think is important here is determining what informed consent looks like in this context. So just to unpick that a little bit more, in research and clinical care, patients need to provide informed consent. And this is an important process for several reasons. The first one being that it provides legal protection for the patient against any unwanted procedure.

Secondly, it supports autonomous decision making, and it helps make sure that the patient's making a decision that's consistent with their values, which is really important. So for patients to give valid consent, they have to fulfill certain criteria. So it has to be informed, which means they have to be given information about the treatment that involves its benefits and risks, and whether there are reasonable alternative treatments and what will happen if the treatment doesn't go ahead. It also has to be voluntary, of course, so the decision has to be made without any undue influence. 

And then lastly, the person consenting has to have the capacity to make that decision. By which I mean, the patient has to not only be able to understand the information, but use it to weigh treatment options in light of their values, and then make and communicate decision.

And so I guess the problem that we have now is how does this work in the context of therapies that we don't have a complete picture of possible risks. There's a really high degree of uncertainty and so what does informed mean in this context? And these patients also tend to have very serious disease and perhaps a lack of treatment options.

And so in some instances, their eagerness to receive a potentially curative intervention might cloud their ability to weigh options and could affect the validity of their consent. So I think that's also a problem that we need to navigate. 

Ofori: So I imagine there's a plethora of challenges and considerations for something like genome therapy, and many of these are relevant more broadly to other innovative therapies.

Are there unique challenges in this field that aren't found elsewhere? 

Tanya: Yes. So you are right. And I think if we're thinking about genome editing specifically, a unique challenge perhaps is around the potential to use it beyond just therapy. So far, we've been talking about genome editing as a therapy, so to treat disease, but it can also be used for non-therapeutic purposes, and those are sometimes known as enhancement purposes.

And so obviously this is a more controversial application of the technology. But enhancement involves engineering traits like athletic ability or physical features or intelligence in a healthy person to make them faster or taller, for example, because these have, genetic underpinnings. And this is kind of a new problem that we're facing because it's the first time that we've had the technology to make that possible.

Although just to caveat, it's not really possible yet because we have an incomplete knowledge about genetic contributions to complex traits. And it's vastly more difficult to do the editing because generally you'd need to edit multiple genetic variants. But it's not impossible that some point in the future, this could be on the cards.

So it raises the question, you know, how do we use this technology? Should it be limited to therapeutic uses? And an additional complication, I suppose, is the lack of a clear binary divide between what therapy is and what enhancement is. So there's this gray area. So I suppose at one extreme it's very clear that using genetic editing to edit a genetic mutation that causes Huntington's disease is clearly a therapy.

And then using it to enhance something like intelligence or muscle building capacity in someone without a genetic condition clearly isn't. But there's a gray area between those two places where it's not obvious what constitutes disease. So would deafness be counted as a disease? Is achondroplasia? Which is a genetic condition that causes short stature and crucially does therapy encompass prevention as well?

Ofori: So you just mentioned deafness and achondroplasia, how do these communities feel about the prospect of genome editing? 

Tanya: Yeah, so I think there's probably a range of opinions. There's definitely some pushback because many of the people in those communities don't perceive themselves as having a disability and don't see it as something to be fixed.

So I think there are strong arguments and these are very fair ones, that impairments don't necessarily need to be disabling and that a disability in some instances isn't caused by genetic variation, but it's caused by the lack of inclusivity in our environment and the impact that has on people. So that could be environmental barriers and societal attitudes, which might exclude or oppress some people with impairments.

Having said that, it's important to distinguish, for example, the harm of a severe inherited metabolic disease from the harm of a sensory impairment like deafness or moderate learning disability. So of course there are gonna be cases where removing environmental barriers wouldn't have a large impact on the suffering and disadvantage, which affects someone with a severe genetic condition.

But I think it's important to be aware that not all disability is the same, and there's a component which extends beyond the medical aspect of the disease. 

Ofori: So do you think then as a result of genome editing, it might lead to more stigmatisation for those who have genetic diseases, but choose not to take up genome editing therapies or those who are unable to?

Tanya: Yeah, I think that's definitely a concern. I think another consequence of there being fewer people with certain disabilities could be that there's less. Familiarity and social acceptance of those conditions. And perhaps also less investment in research, treatment and support services.

And so the impact on society and on marginalised or minority groups, as you pointed out, really needs to be taken into account when thinking about the uses of genome editing. 

Ofori: So we've spoken predominantly about somatic editing. Can we touch upon heritable genome editing for a little bit? And the additional considerations that that raises.

Tanya: Yes, absolutely. So heritable genome editing is a bit different because the purpose and outcomes are a bit different in this situation. It's not only about treating the person in front of you like somatic genome editing is. It's also about preventing generations of disease and making changes that can ensure that you have disease free children.

Something to note about heritable genome editing is that it isn't approved for clinical use anywhere in the world yet, although having said that, it's not prohibited everywhere either. And that's because there are lots of technical and ethical considerations to work through. First, there was a controversy a few years ago now where a rogue scientist in China genetically edited twins to disable a gene called CCR5 in order to protect them from the HIV virus.

And this caused a lot of shock and concern because it's widely agreed that genome editing isn't ready for clinical use yet in a heritable context. And we don't know what the unforeseen impacts on those twins might be. And so what it's done is really highlighted that people can and are using this technology and so it's important that we have these conversations about heritable genome editing sooner rather than later so that we can have the appropriate regulations and governance in place. 

Ofori: So you've just mentioned regulation. How is genome editing regulated in the UK? 

Tanya: Germline and somatic genome editing are regulated differently in the UK.

So somatic genome editing is regulated as something called an advanced therapy medicinal product, which is a bit of a mouthful, but it's a category of advanced biological medicines based on tissues, cells, and genes. At PHG Foundation, we've actually just released a briefing on the regulation of ATMPs. So if anyone is interested in finding out more, that's the place to go.

Germline genome editing is regulated by the human fertilisation and embryology authority, and as I think I've just said before, you can do research on early embryos if you have a license, but they have to be destroyed at 14 days and you can't go beyond that 14 day point. Heritable genome editing, which is where the embryo is then implanted inside the woman and carried to term that isn't legal in the UK or anywhere else.

That said, there are also jurisdictions where it's not explicitly illegal either, but that broad regulatory position against heritable genome editing reflects this international consensus that it's not really for implementation yet, and that more discussion, debate around the ethical and scientific trade-offs needs to be had first.

Ofori: How important is global consensus in order for regulation to continue to go in the right direction? 

Tanya: So I think in an ideal world, we would have global consensus. I think on the one hand, a single coordinated global approach would certainly make everyone's lives easier, and it would prevent medical tourism, which is where people travel to countries where genome editing is legal to have treatment there.

But on the other hand, I think we also want to respect all the differences between countries. We know that the cultural and social and religious norms in each country will shape perspectives on whether and how and in what circumstances to use genome editing and will likely lead to different regulatory approaches.

I think one step forward in trying to address this kind of global consensus issue is that the World Health Organization released a framework for governance of human genome editing back in 2021. And the purpose of that was to try and help create international governance solutions. And what they did there was call on countries to incorporate a certain kind of fundamental set of values and principles into their policies rather than pushing for everyone to adopt a single particular regulatory position. 

Ofori: In terms of public attitudes and understanding, do we know what the public thinks of this at the moment? 

Tanya: Yes. So, public engagement works incredibly important here, and we need to ensure that we facilitate broad and inclusive societal debate before we proceed with the application of genome editing.

I think, in answer to your question, the work done so far shows that there is a cautiously optimistic outlook on the contributions that genome editing might make to human health, but also that there are red lines. I think it shows that most people in the UK seem to support the use of genome editing to treat diseases in adults and children, but are far less supportive of enhancement uses.

There was a citizens jury undertaken in the UK in 2023 and that jury found that 17 outta the 21 jurors thought the government should consider changing the law to allow genome editing of human embryos with serious genetic conditions. A relevant consideration of that though is that all jurors had personal experience of genetic disease, and so their views might not be representative of the population, but it's an important finding from a group whose views really need to be captured. And the other point I want to raise here is that when thinking about public opinion, it's important to emphasise that public opinions do shift as norms change. 40 years ago, the prospect of IVF was really quite scary and there was a lot of resistance to it. But after Louise Brown was born, the first IVF baby, attitudes changed quite radically. So I think it's likely that public opinion will continue to change and shift, and I think we're gonna have to adapt to nuance and evolving feedback from society. 

Ofori: Tanya, thank you. You've given us quite a comprehensive look at genome editing today, but if at all possible, what would be your one sentence take home for us?

Tanya: Can I give two sentences? 

Ofori: Yes, of course. 

Tanya: So the first is that the technology itself I don't think is inherently good or bad, but the way that we use it is what confers the benefit or harm and so I think we need to think as a society about our values and our red lines and if we think we should harness this technology and in what circumstances.

I think the second thing is that somatic gene editing, although less of a hot topic than heritable, is here and it is being used in clinical practice. And I think although it presents fewer ethical challenges, there are some particularly pertinent ones around equity and accessibility that need to be thought through if we're gonna really harness the benefits of it.

And I think finding solutions to those challenges needs to be prioritized in the short term. 

Ofori: Great. Tanya, once again, thank you very much for joining us. 

Tanya: No, thank you for having me.

Ofori: And that brings us to the end of the episode. If you liked it, please leave us a rating and review and make sure to subscribe. If you would like to find out more about what was discussed in this episode, there are useful links included in the podcast description. You can also find additional information on our website, phgfoundation.org.

And if you have any further questions about the topic, then you can email us at intelligence@phgfoundation.org. Thank you for listening, and we look forward to bringing you a new topic in the next episode.