Carolyn Riley Chapman is a Bioethicist and Faculty Affiliate with the Division of Medical Ethics at NYU Grossman School of Medicine. Having worked as both a bench scientist and within the business sector of science, Chapman has a range of perspectives that enable her to discuss medical ethics. Chapman’s research focusses on the bioethical issues raised by advanced genomic technologies as well as within the pharmaceutical setting.
Please note the transcript has been edited for brevity and clarity.
FLG: Hi everyone and hi Carolyn, thank you so much for joining me today as we shine a spotlight on some of the social and ethical issues surrounding genomics. Today, we’re going to be covering the ethical issues surrounding gene editing technologies – looking both at the current situation and also considering it from a more futuristic angle. But before we do that, Carolyn could you introduce yourself and tell us a little bit about your background.
Carolyn: Thank you so much for inviting me to talk with you today. I’m currently a Faculty Affiliate with the Division of Medical Ethics at NYU Grossman School of Medicine and I’m also Director of Research Ethics Education at the Translational Research Education and Careers unit in NYU CTSI, which is also part of NYU Grossman School of Medicine. So, I’ve had a kind of winding path to bioethics. I first started as a bench scientist, I got my PhD in genetics at Harvard Medical School studying yeast cell cycle genetics, and then from there I actually went into the business side of science. I worked as a business management consultant for pharmaceutical companies, and I worked in a biopharmaceutical start-up and I worked as a freelance science writer. Then after spending a few years with my kids, raising my kids, I decided to re-enter my career by going back for a Masters in Bioethics at Columbia. Then since I got my master’s, I worked at Columbia by teaching in their programme and then I went on to do a post doc with Arthur Caplan and Alison Bateman-House at NYU. It’s kind of winding but I’ve worn a lot of different hats and so I think that gives me certainly interesting perspectives to lean on as I think about medical ethics.
FLG: As a bioethicist you are obviously aware of how much genomics is becoming integrated into society and I think with the whole pandemic, even the public are hearing more about genomics (we are constantly hearing about variants emerging, etc). But with gene editing we often assume that it is futuristic, but we can actually edit the genome now, and quite well in fact. One example of its success can be seen with gene therapies. Would you be able to provide a history of this area and also the current landscape?
Carolyn: As a geneticist, gene therapy, or the concept that good DNA could be used to fix bad DNA or non-functional DNA, has sort of been the Holy Grail of clinical genetics. I remember when I was first entering graduate school in genetics class (the fall of 1993), and the Professor stressed at the time that it took a lot of time to identify a gene that was causing a particular disease. But that even despite that challenge, once the gene was identified scientists still didn’t have a way to treat that disease even knowing it’s cause – there wasn’t a clear path to treatment based on that knowledge. And so here we are basically 30 years later, and we have been able to identify many more gene-disease links. In other words, we have become very good at identifying how variants are associated with disease genotype-phenotype links and that’s because of the power of the Human Genome Project and a lot of other technological advances (like the cost of DNA sequencing). But we still have a hard time figuring out how to leverage that knowledge to treat and cure genetic diseases. But I think that we’re really at an inflexion point now.
By the way, I’m probably going to have a very US focus here because I’m based in the United States – so I apologise for that. So, in the US the FDA defines gene therapy as anything that is used to modify or manipulate the expression of a gene in order to treat or cure disease. It may involve introducing a new gene, or modifying a gene, or inactivating a gene or placing a disease-causing gene with a healthy copy. Although this in theory sounds straight forward and easy, in reality it’s been extremely challenging, and it’s mainly been due to issues around delivery.
In 1999, the field suffered a very big setback when a patient named Jesse Gelsinger died as a result of receiving a gene therapy. The reason he died was because he had a systemic and severe immune reaction to the vector that was used to deliver the gene. The coverage of that event was that the science had moved too quickly from bench to bedside and there wasn’t enough precaution taken. It really set the field back and, actually, probably also made them realise that we didn’t have a firm grasp of how to deliver gene therapies safely. So, it’s taken a really long time to get to the point where scientists have been able to figure out ways to deliver gene therapies into humans safely.
In the United States, there are now a handful of products that fall under the definition of gene therapy that are now on the market and there are also hundreds more in various stages of clinical development. So, it’s a really exciting time. Just to name a few of them, there’s what’s known as CAR-T cell therapies, which are chimeric antigen receptor T cell therapies in which T cells are removed from the patient’s body and then genetically modified to be able to express chimeric antigen receptors that can specifically target the patient’s cancer (such as lymphoma) and are then infused back into the body. There’s also a gene therapy for an eye disease that causes vision loss due to mutations in the RPE65 gene. And basically, that therapy involves just delivery of a good copy of RPE65, and it’s given through an injection into the eye. Novartis have also developed a treatment for spinal muscular atrophy (SMA) in which they basically provide a good copy of the gene that is mutated in patients – called SMN1 gene. They basically just deliver a good copy of the gene and that’s done by infusion into the vein. So that’s really exciting because it’s a one-time treatment for a mutation that causes very serious disease and so I think it’s opened up the possibility for a lot of other patients with other types of genetic diseases.
FLG: Gene therapies go through a lot of preclinical and also clinical research, which ultimately make them very expensive. Who currently has access to these therapies and how can we ensure that there is equity of access to these therapies? Because a lot of people are often concerned that the wealthy will end up getting the best treatment.
Carolyn: These are really important concerns that ethicists would certainly be concerned about, along with you. So, I mean in terms of who controls access, obviously the companies that have gone through the development process and own the product and have obtained marketing authorisation, they set the prices, so that’s one consideration. But as you said it’s very expensive to develop these products and test them. And also, often, at least the current therapies, the patient populations can be relatively small and so to recoup their costs, they are extremely expensive. So, the company pricing is one factor. But it can sort of be understandable in that we want these companies to succeed so that more companies will enter the space and we will have more options for therapies for genetic-related diseases. And of course, insurance companies also play a role, whether that is a government insurance or a private insurance (like in the US). Some insurance companies may include gene therapies in their coverage plans, and some may not.
There’s been push back from patient advocates and patient groups – for example, there’s a group called Maisie’s Army that fought for a toddler’s coverage on insurance for the SMA treatment. Then, patients might also appeal to companies directly if they don’t have insurance or if their insurance isn’t covering it. Some patients have resorted to things like Go Fund Me to raise money for direct payment of medical expenses for a variety of things. Another question will be of course, global access. I heard yesterday that the American Society for Gene and Cell Therapy is planning a conference in June on addressing the challenges of global access, for example, for patients in developing or lower income countries, which of course will be extremely challenging. Because often, for some of these gene therapies, particularly the CAR-T cell therapies, you have to take cells out and modify them and put them back in, which is a complex supply chain. So, there’s also a geographic access issue as well. That’s going to be a challenging thing to address and needs attention. I think most people would hope that it’s early days of this new therapeutic class and that hopefully pricing will go down and that will increase access overtime as competition comes in and the industry gets more comfortable and familiar with the technology too.
FLG: It is very heart breaking when you see families having to set up Go Fund Me pages just to get the money to get access to this type of therapy. I recently saw that you co-authored a paper about expanded access – would you be able to discuss that a bit further?
Carolyn: I should mention that another way that patients can access gene therapies is by participating in clinical trials – that would be before the gene therapy is approved, so it would be experimental. But in that case, not all patients will qualify for the trial because they might not meet the inclusion criteria which is developed in the protocol for variety of reasons. In terms of the paper, I should probably step back and explain what expanded access is first. For patients who don’t qualify for a clinical trial in the United States, and in many other countries, there’s a pathway called expanded access. In the US, this is regulated by the FDA, so if you don’t qualify for a clinical trial and you have a severe life-threatening disease (for which gene therapies are typically targeting given their level of risk at this stage in this new therapeutic class) patients can appeal to the company to get access to that investigational product outside of a clinical trial. It’s entirely up to the company to decide whether or not to grant such access and there’s certainly no legal or ethical obligation to do so because these are experimental products.
But in that paper that you’re referencing, a few of my colleagues and I put forth the opinion that we believe that it’s ethically appropriate for companies to proactively think about the potential to receive expanded access requests, given that gene therapies are being developed for serious and life-threatening diseases. And further than that, they are being developed for diseases that may have a short window of therapeutic opportunity and so patients are really desperate. We don’t argue that companies have to provide expanded access, but we argue that they have an ethical obligation to think proactively about whether they could, or should, provide expanded access and under what circumstances. And that it also should be part of their clinical development planning, that they should also be willing to communicate their policies openly and transparently with the patients that they are trying to target in the population for the product that they’re developing.
FLG: What are some of the concerns regarding expanded access?
Carolyn: Obviously safety is of the utmost concern. If a company is developing products in order to get it approved, they have to show that the product is safe and effective. So, if a patient, for example, is in a late stage of the disease, the risks of giving an investigational gene therapy product may be very high. In other words, they may have more of a chance of developing adverse events or potentially dying from the investigational product. So, for a company developing the product with the aim of getting it approved so that it can help other future patients, that’s a true real valid consideration. But then for that one patient who is willing to take that risk of undergoing a significant event because they’re facing death or a very poor quality of life, without the chance, it’s a different calculus. So that’s why it’s a hard thing. And again, as you pointed out, these therapies even at the investigational stage are not cheap, they’re not easy to deliver. But we are talking about patients’ lives, we are not talking about commercial products like sneakers or clothing. We are talking about patients’ lives here. So, I think there are ethical considerations that companies in this space need to think about and take seriously.
FLG: I think when people think about gene editing at the moment, the first thing people think about is CRISPR – everyone is saying how it is going to revolutionise genetic medicine. In your opinion, when do you think it is acceptable to clinically use CRISPR?
Carolyn: CRISPR is a really exciting technology as you say, where scientists in the last decade have learned to leverage an adaptive immune system that bacteria use to protect themselves against invaders. And scientists have harnessed that system to be able to edit DNA at a place that they want, by using a guide to a particular sequence that can cut, and then either replace the DNA with a sequence that you want to change it to or another process where the ends just kind of fuse together. CRISPR has been used in the laboratory for a few years now on all types of cells, and of course CRISPR would be an example of gene therapy where you would use it to modify gene expression. There are some clinical trials using CRISPR technologies in the United States and I’m sure also in other countries as well. I think that there’s a general consensus that it would be okay to use CRISPR to try to treat diseases in adults or children in somatic cells, and that’s happening. I think that there are clinical trials in a variety of conditions like sickle cell disease, beta-thalassemia, cancers, eye disease, chronic infections – and from what I can tell, some of them look promising. So, it’s very exciting. I think the more ethically controversial use of CRISPR, in terms of a clinical usage, is human heritable genome editing. In other words, modifying an embryo or editing the genes of an embryo before it’s put into a woman’s body to establish a pregnancy or potentially (and I haven’t seen as many examples of this) future uses of gene editing for enhancement purposes. And I want to stress that this is not happening at this time as far as I know of.
FLG: Do you think it’s ethically okay for someone to use it on themselves? For example, a recent biohacker (Josiah Zayner) injected his arm with DNA encoding for CRISPR to theoretically enhance his muscles.
Carolyn: In the US, there is a potential loophole that a small group of people have been publicly known to take advantage of, which is an example of what you’re citing right there. So, the regulatory agencies have just looked the other way or had regulatory discretion about people who want to quote ‘self-experiment’ with materials that are really intended for research or laboratory use, and of course this is really ill advised. The reason for the regulation of investigational products is that many of them are proven unsafe and don’t work, and so as individuals we don’t have the capability and the resources to evaluate the safety and efficacy – so there is a system in place in all countries to make sure that the products that are for sale are safe and effective. I can understand the sentiment that biohackers seem to express, which is that they want to have access and that the system of regulation impedes access and not everybody can have access because the products are expensive. But I think that it’s worth politicians and clinicians and ethicists to stress that these regulatory bodies are really intended to protect individuals and public health, and they’re valuable to our society and we need them. In a sense it’s maybe frustrating on some levels, but I think that the expense of making sure that these products are safe and effective, the ones that companies want to make those claims about, are true.
FLG: The biohacker considers himself an educator and for many biohackers their presence is widely accessible through social media (e.g., YouTube) and you get concerned that this may be detrimental to the field.
Carolyn: I definitely support the democratisation of science and that science should be available to everybody. But I do also think that there’s reasons that regulations are in place. Even laboratory research can be dangerous. I’m of the opinion that it’s better to work within the system and I think that if you’re interested in science, then there are ways to get into the system. I definitely respect the importance of education and bringing in all different kinds of people.
FLG: I think one of the most prominent events that has happened in the space over the past few years was the researchers in China who genetically engineered embryos to hopefully make them resistant to HIV. What impact do you think this has had, not only on the field itself, but also on public perceptions of this technology?
Carolyn: So, you are referring to the announcement by Dr He Jiankui that in November 2018. He had used CRISPR to modify embryos and established pregnancy, which resulted in the birth of two twin girls, who by my estimates should be about 2 and a half years old now. The world was really stunned when that happened. In fact, I remember being at a CRISPR conference not too long before that announcement and somebody raised their hand in the audience and said, ‘When is the technology going to be ready to do this in embryos?’ and the panellists looked at each other and said, ‘Well somebody actually could probably do that with embryos, but this would not be advisable’. Then all of a sudden someone did go forward with it, and he was characterised as a ‘rogue scientist’ for doing this. Certainly, he was condemned by ethicists and scientists because there were concerns about informed consent of the parents – whether they really knew what they were getting into. There were concerns that he did not need to take this risk of editing the embryo in order to prevent transmission of HIV (that the risks do not justify the benefits). So, there was this huge out cry.
In terms of public perception, if there is any silver lining, it has certainly called the world’s attention to the fact that the technology has really made huge jumps in the past number of years, so that the public is now aware that this technology is possible. In response, there have been some international commissions that have been formed in order to start to really think and grapple with the questions of – if not now, when, and if ever should we be editing human embryos and establishing pregnancies? There’s been one commission. The National Academy of Sciences and the UK Royal Society were tasked with developing a framework for scientists and regulators to consider when assessing potential clinical applications for human germline genome editing, if society thinks that this would be acceptable from an ethical standpoint. And that was somewhat of a concern because they put that ‘if’ to the side and then said, ‘Okay then what would you need to do?’ (which as an ethicist was concerning). They just pushed the big ethical question to the side. Then, there was another commission formed by the WHO, and they are tasked with governance and oversight of human genome editing, both somatic and germline genome editing. They have yet to release their report.
FLG: The report emphasised that germline editing currently is far too risky and more research needs to be done. In your opinion, do you think we might be becoming too cautious?
Carolyn: The huge message from that report that they wanted to communicate was that the technology needs to be further studied before anyone, anywhere establishes pregnancies with edited embryos – so that was the big message that they wanted to convey. But as I said, they also said, ‘Well if we were to determine how you would do it, how would you figure out when it would be okay?’. And they sort of made those suggestions – for example, you would want to start with the riskiest cases where there’s no other alternative. There’s a 300-page report for anyone who is interested you can look up! But I don’t think we’re being too cautious because I think there’s a lot of agreement that the science isn’t there yet. There are still concerns about CRISPR, regarding on-target effects. In other words, does the CRISPR intervention do what you intended to do at the site that you’re intending to edit? Or does it cause unintended effects at sites in the genome that you’ve not intended to edit? And also, how does this cell or how does the embryo as a whole react to that intervention? These are questions that we don’t fully know or understand. I think that more experimenting needs to be done and that’s the clear consensus.
Then perhaps equally as important from my perspective as an ethicist is that I and many scientists don’t feel that we’ve had a complete and inclusive conversation. Even if from a technical standpoint, it would be reasonable to do (you know once we did all the preclinical research, we feel comfortable, we’ve tested it in animals and now we’re ready to try it in humans in very risky scenarios where there’s no other alternative for the parents to have a child that’s not impacted by a serious genetic disease), we still need to also make sure that we have the ethical conversation. Because ethicists are concerned about potential impacts on society and justice issues (which we started to talk about with gene therapies earlier) and how these technologies might change our lives or change our societies and our world.
FLG: If genomics is going to become more integrated into society, we are going to have to open up those conversations. How do you think we could ensure that a diverse representation of opinions and voices are heard?
Carolyn: I think it’s certainly a challenge. Sometimes I’ve actually expressed my worries that when we talk about reaching consensus (which I even did myself about human heritable genome editing), how do we include everybody in that conversation? And what if there are people who disagree and if they are the minority, do they just not matter? Or if they don’t ever come to agree with the consensus, then what? In theory we should all be involved in these conversations and these decisions that societies are going to grapple with, and by all, I mean citizens of the world as opposed to any particular country. But in practise, I think it will be important to pay attention to who has the power to make the policy, regulatory and legal decisions to establish laws and policy in each specific country.
FLG: I think that patient and public voices will be really important in shaping those policy and regulatory decisions, particularly rare disease patients and advocates who understand first-hand what it is like living with those conditions.
Carolyn: I hope that’s true, and I certainly think the patient voice brings the urgency and the inspiration to the scientists.
FLG: It’s been really interesting talking to you, and we’ve had some really insightful discussions. I think it is going to be important as we move forward, and as genetics comes even more integrated into society, that we open up these discussions a bit more and start getting the public involved. Thank you so much for talking to me today.
Carolyn: Thank you so much for inviting me to have this conversation, I really appreciate it.