Scientist Stories: Martina Cornel, Gene editing and NIPT

We'll talk about bioethics for dummies, and the kind of audience that we had in mind is the average ESHG member, which often is a scientist not with a very big knowledge of bioethics. So I'll give an overview where, first of all, I'll talk about some domains in which ethics applies. Then I'll talk about some principles, and then we'll see how those two relate to NIPT and gene editing. So first, three domains: research, ethics, clarifying the debate— I'll come back to that— and healthcare. But if you think about ethics, then many people will think, isn't that just about doing good, or maybe telling what is allowed or not? If as a researcher I have to go to my ethical committee, it is mainly to ask them whether I can do the test I want to do, or the investigation I want to do, or the research I want to do. And so this is the other side of, of course, the same coin. The main question then is, if you talk about doing good, why exactly is something good? What do you mean? What values are behind that? And these questions apply in healthcare, but as I mentioned already, also very much in research. And many of those debates in the healthcare setting and in the research setting are very much interlinked, so they are not separate, but they come back to the same kind of values. I already kind of mentioned that this is not only about answers. Yes, you get permission to do your research, but it's also about asking good questions, and that could be even more important. When you talk about what is good, there's often a lot of debate about why do you mean this is good, what is behind that, what kind of values are implied. And often it's very important to start with looking at that level beyond the surface. So in your research ethical committee or institutional review board, the main question would be, is it allowed to do this experiment? And then I'll focus on humans, even if many other experiments also would have to go to an institutional review board. And what would they focus on? For instance, on the information you give to the people that are invited to— what intervention exactly is it that you propose? Will you be drawing blood, just a little bit, as much as you would do in regular care, and then using a little bit of the leftover? Will you be taking extra samples, and is that somehow for them rather difficult or painful or whatever? Are you giving medication, and would that be the medication that is not the standard? And all these kind of things need to be documented then for your institutional review board. And a very important element here is that the consent must be organized very well. Now, you may think of a kind of a form where you say, tick this box, tick that box, sign here. But what I mean is actually, in what way are we explaining to our research participants what exactly might happen to them? It's more the discussion about this consent, and then at the end, of course, signing.. But this whole process would need to be explained to institutional review boards, and then in the end, when they think it's okay, they will say, "Okay, I will give approval for your study, and you can go on." Now, much of that research ethics nowadays is building on a rather old document, the Declaration of Helsinki, that was adopted in 1964. It's, say, after the first half of the previous century. It's after the Second World War. It's in a time where that idea that consent is very important and that people should be free to choose whether they want to participate in your research, when that idea became very much kind of good practice. So it's not the law. I said good practice because it's not a law, but still the effect in the medical community is very large, so all university medical research centers would build on this declaration. Often nowadays, even if you submit a paper to a journal, they will ask you to say that this is in line with the Declaration of Helsinki. Now, the second domain where ethics is relevant is clarifying the debate. If, say, a life scientist says, "I'm going to do this, and I think it's very important," Then a medical doctor might say, "Hmm, I'm not so sure." And in politics they might say, "But it's not allowed." And in law they might say, "Yeah, this is the law where this is written." And in philosophy they might say, "I don't quite understand what the two of you are saying, or the three or four." So bioethicists tend to help to understand the relationships between those different scientists and between the way they argue. So this question of why we argue the way we argue that's typically a philosophical or ethical kind of science. So when we talk about science, we often refer to laboratory science, but also ethics is a science, and especially this analyzing why we argue the way we argue, what values are beyond our stances, why is something controversial, and does, say, a scientist from the laboratory say this is extremely important, and does a medical doctor say, but I'm not so sure whether that's important for my patients, so finding out what values are behind that. And then for a decision to be made, often also it is comparing the arguments in favor and the arguments against. If there's a lot more to be won than to be lost, if there's more good than bad, it's very important to kind of oversee all those elements. And then I come to the third domain. Domain where ethics applies, and that's in healthcare. Now many doctors will say, of course, in a profession-led healthcare where medical doctors work not the way they want but the way their profession tells them to work, of course there's ethics. And many people would call that an element of professionalism. Some years ago, people asked patients in Canada what exactly does a doctor need to know and what skills should he develop once you want to say that he is a good doctor, and in the CANMEDS, it's described what medical expertise a person would need to have, but also the communication skills and also the professionalism. And that element is encompassing ethical practice. So when you read, for instance, the statutes of ESHG, you will find the word professionalism, but so far you will not find the word ethics, which doesn't mean ethics is not in there, but it's probably hidden in the professionalism. So if a medical doctor works, he cannot just do what he likes, but he is kind of hold to a kind of professional standard, including the ethics. And that's going back to documents that are even older than the one I referred to earlier, to the Hippocratic Oath, which is thousands of years old. And some of the texts you can still find in relevant documents, like, I will use treatment to help the sick according to my ability, but never with a view to do injury. And in very beautiful words, they call that beneficence, or doing good, and non-maleficence, or not doing harm. Sometimes you also find not harm, or that kind of words. And it is simply going back to the patient that's in front of you, and to whom you want to do more good than bad. Often, if you are not so sure whether you would not harm, you might even preferably do nothing instead of potentially harm. A second element that's in that Hippocratic Oath already is the respect for privacy. Holding such things to be holy secrets is a more or less literal translation of that 2,000-year-old text. So the individual that's in front of you is often telling things where you think, hmm, probably that person doesn't want me to share that with just anyone, and you're supposed as a medical doctor to hold those things secret. And the third element that we still see coming back in many of the healthcare professionalism texts is that you have to recognize the skills of yourself and colleagues. So if there is something where you have to say, "I know not about something another person knows," then you may need to refer to that other medical doctor. If you are a specialist in something and you know very much about most of your field, but not about some other fields, then you just ask another doctor to look into that specific question. And that's already also found in the Hippocratic Oath, where the doctors are not supposed to do surgery. The physicians and the people that were doing surgery were at that time different professions. And today we find that in words like you have to be qualified and competent to do something. It's not only sufficient to have a diploma, but also you need to be skilled enough and confident that you can do that yourself. So these— those two elements, qualified meaning that you are in legal terms allowed to do it, but competent also meaning that you still have the skills today to exercise part of medical work. Now we're going to apply these elements on gene editing and NIPT, not yet immediately, but we have to realize that both are questions at the beginning of life. So the non-invasive prenatal testing during pregnancy to see whether a child's got an aneuploidy, a chromosome too many or too less. And of course, I cannot discuss everything on the ethics of these fields, so I will focus on the contributions of the Public and Professional Policy Committee of ESHG. As Francesca already introduced, these are topics both of which have been on the agenda of the PPPC. For NIPT, it's already out there in the journal, and for gene editing, it was approved by the board 2 days ago. So this committee tends to develop recommendations for responsible healthcare. Also, this is a word referring to ethics, but kind of implicit. The committee also wants to clarify debate, and there we are mainly in the second and third domains of ethics, although when we speak about gene editing, then we might automatically also imply things that are relevant for research. But mainly, we'll talk about those second and third domains. Okay, then I come to the principles. Again, to clarify why we argue the way we argue, often we need to look beyond the surface. What exactly are the principles? What are the values? Why are people saying that something is good? And of course it's good, and why could somebody have another view? Now, if I would advise you to just read one paper on human research ethics, I would advise you to read this paper from Barton Oppers and Ruth Chetwyck from 2005, which is kind of comparing the principles that have been there for decades and some principles that have come in, say, the last decade. It's basically for human genetics research, but anyway, it's giving a very nice background of all those principles that are relevant for our field. And basically, they introduce a kind of set of principles that are relatively new in the last decade., and they mentioned some principles that have been there for a long time, to start with autonomy. Now, remember, these were principles for research, but also when you think about genetic healthcare, autonomy was the first to be mentioned. Now, this is an old definition of what is genetic counseling from '75, so that's already quite long ago. It's a communication process about the medical facts including the diagnosis, to appreciate how heredity contributes to the disorder, to understand alternatives. Well, this is, for instance, about having children or not having children, using prenatal diagnosis or not using prenatal diagnosis, and then if an anomaly is found in prenatal diagnosis, deciding to terminate a pregnancy or not. And as you feel already, these might be rather difficult decisions, so a very important element here is to help people choose the course of action which seems to them appropriate in view of their risks, their family goals, etc. So it's not what the medical doctor considers appropriate, but it's what the person that has to choose for his or her life and his children finds appropriate. And then also to make the adjustments to the disorder and the family circumstances. So this is autonomy in different wording. In simpler words, you might say it is the fact that the patient or participant chooses, not the healthcare system or the doctor, and also for research that the patient or participant can say no. If we talk about choosing, it may often imply that we explain very long what can be done, but for the simplest decisions, it could be simply the question, do you agree? Or not. People at least should have the possibility to say no. I mentioned already that our topics for today that the Scientific Program Committee asked me to speak about are questions at the beginning of life, where the choices may be pretty difficult, and where also we recognize that people, individuals, cultures, populations, religious groups may make very different decisions and may have different values. If you choose to have children or not, in the Netherlands or in Denmark, you might simply say, oh yeah, both are an option. Why would I need to have children? But in some other countries, people may feel that's not really an option. I simply have to have children. Like in Africa, in many countries, you may choose not to have your next child this year, but perhaps postpone it somewhat. But you could not choose not to have children. It's simply not accepted. A very difficult one that I was never allowed to mention by Leo ten Kater, who was my educator, you might say. Is choose a different partner. Well, in some cultures, for instance, if Tay-Sachs is pretty frequent, people are tested first, and then they kind of match, see whether their genes hook up. They call that themselves nowadays a Tinder. So you kind of see whether you can meet with a certain person, and if you're both carriers of the same recessive disorder, then you'd better skip to the next page and find another partner. Well, it's interesting that this Tinder model is coming in there as well. Anyway, in some cultures you would say, but for a medical problem you're not going to leave your partner. Love is the most important thing in life, of course, but as you see, there are other cultures where they think this is something that could be acceptable. Prenatal testing and abortion I already mentioned, which clearly is also a very sensitive topic. Avoiding the risk by using donor sperm might sound like an interesting possibility for many people in Denmark. Or the Netherlands, but in some other cultures also the biological parenthood is pretty important, and not becoming a biological parent might also be a very big issue. Now, still at a much wider level, why is this autonomy so very important in much of our ethical thinking? It's also relating back to this first half of the previous century where in many countries We had ideas about greater social and genetic worth and less social and genetic worth. And people that were on this side of the triangle were supposed to have many children or encouraged to have many children. And some other people were not encouraged or even compulsorily sterilized. And here the element of autonomy definitely was absent. Some of this was built on Francis Galton's science. He says in this citation, "What nature does blindly, slowly, and ruthlessly, man may do providently, quickly, and kindly. As it lies in his power, so it becomes his duty to work in this direction." Now you may consider this a soft way to say we should have more of this kind of people and less of that kind of people, but in many countries actually it led to forced sterilizations and forced forced choices where people afterwards felt that that's not where we want to go ever. So it should always— if we apply genetics, there should always be this element of autonomy and freedom. Okay. Next level. When we talk about saying yes or no, it's often I agree to participate or not. Also in research, it's often the individual participant that we think about. But of course, in genetics, we never talk about individuals. It's always about the patient in the family. If you talk about me and you do a test for me, then you know half of the risk for my brothers, sisters, children, and parents, well, especially children and brothers and sisters then. And if a couple decides, then it's not only the woman, for instance, who is pregnant, but also her husband that is somehow, well, taking this decisions. So it's not one person. So does individual autonomy exist in our field? And also in research, many values nowadays relate to this collective level. So in law, often we speak about individual autonomy. In practice, there's often much more behind that. Now if we read again that paper of Knoppers and Chetwyck— I forgot to mention that Ruth Chetwyck will be here on Tuesday morning, So if you want to know the update on this thinking, you should go to the Tuesday morning early session on ethics. But anyway, these collective ethical principles come in, in this right-hand side, where people speak about, for instance, solidarity, citizenry, universality. And when you think about why should you genotype a certain population, it's also because all the people from the population might profit when you find a variant and you want to know whether it's of unknown significance or of known significance, then you might better also genotype the people from Iceland to know what the variant means in Iceland. If you have only done the Western Europeans, it might be difficult in Amsterdam to interpret the variants that we find in the 100 or more nationalities of the people that visit our clinic. So this is about sharing what you know about me with the people that might also profit from it. So this level of individuals versus group, you can also find in research. There's organizations called PatientsLikeMe that kind of say, I will now participate to a trial because I know that there's a small chance that I profit, but for people like me, patients like me, it might be very relevant. Again, if a population is studied, then my genome will provide information about people with the same ancestry. So there again, that collective value is surfacing. In debates about children, this was also often pretty important. Many people have been reluctant to include children in research because it's, of course, easy to do harm if you just take a sample of blood that's already doing some harm to a child. But on the other hand, for some childhood disorders, one would never be able to further develop therapy if you don't accept to include children in research. So also in many countries, this idea has been progressing somewhat to allow more research in children because of this specific reason. It's the patients like them that might also profit. And if you want to do something for patients with childhood disorders, you cannot study 80-plus, 18-plus persons. So now we come finally to the topic that the Scientific Program Committee invited us to speak about. NIPT stands for non-invasive prenatal testing. And just to remind you all what this is about in technical terms, but of course very brief, in the blood of the mother, if you separate the cells and the plasma, in the plasma there is some DNA from the fetus, around 10%. So that's even quite a lot. Now, the first application of this was for rhesus. If the mother is rhesus negative, you may find in her blood only one peak. And if, for instance, the father is Rhesus positive, in his blood you would find also many peaks. Now, if one of these peaks would be seen in the blood of the mother, then definitely that has to come from the fetus. It can't be the mother's. So if you want to know whether a Rhesus negative mother is pregnant of a Rhesus positive child, you can use non-invasive prenatal testing. This has been integrated very fast into medical healthcare because there are very few ethical issues. But when it was also possible to look into the trisomies, more ethical problems surfaced, or questions. So around 2010-11, first trisomy 21, and then also trisomy 13 and 18 appeared to be possible to identify them with NIPT. And in technical terms, that sounded like a very good possibility. So already in many countries, we did screen for Down syndrome and other chromosomal anomalies. And if an anomaly was detected, options are to terminate the pregnancy or not. So we are back with our difficult ethical choices. But if we did this first test, the combined testing, 5 to 7% of the people had to be referred for follow-up testing for chorionic villi sampling or amniocentesis. Well, that's quite a lot. So all these women then are in a period of uncertainty for quite some time, several weeks., and needed a confirmatory diagnostic test. These tests are not without a risk. There can be a procedure-related miscarriage, so due to the test itself. Now NIPT has improved the accuracy, so it's— if you use NIPT instead of combined testing, far less invasive testing is needed. The test has a higher sensitivity and specificity, so you pick up even more of the chromosomal anomaly cases, not just 70 to 90%, but 99.9% or something like that. The specificity depends, of course, a bit on the population, but also that is very high. So if you are not pregnant of a child with an aneuploidy, the chance that you will have a true negative result is very high. But still confirmation is needed because basically we're looking at DNA from the placenta. So it's not the DNA from the fetus itself, but it's the placental DNA. So this sounds like we should move on very fast because we have a much better test for a field which is already pretty complicated. But thinking from an ethical stance, of course, we should not lower our standards then for the pre-test information and for the counseling, because still that potential next step, terminating a pregnancy or not, that is pretty complicated, and people should think about that early. So having a very good test still implies that we need to organize our healthcare very good, and we need proper pretest information and good counseling so that people only take this step to NIPT if they are really overseeing the potential next steps. Now, in this field, we developed recommendations that appeared last year in the European Journal. So we definitely recognize that it has the potential to help practice better achieve its aim of facilitating autonomous reproductive choices. So here again, we have this word autonomy. If people choose to do this test because they would want to be informed about a chromosomal anomaly in the fetus, then if it's got a better sensitivity and specificity, it indeed helps them better understand whether they carry such a child or not. But then immediately linked to that, to evaluate this aim, it's not sufficient to report on the number of participants, the uptake, or the prevalence of aneuploidies, which we often find in many publications. But if autonomy is the goal, we need to measure in some way informed decision-making. If we have an uptake of, say, 30 or 35% now in the Netherlands, I believe, some people say that's more than it was before. But that doesn't prove anything. We have to know whether the women that are now making the choice indeed make informed decisions, not whether more problems are identified or whatever, but indeed whether women are happy with this situation, whether they made a choice that suits them. And then a crucial element there is that NIPT is not just a test, but we need counseling, education of professionals, the midwives that are doing the counseling, accountability to all stakeholders, including the children born from screened pregnancies and persons living with the condition. So that's the people that have Down syndrome or have a chromosomal anomaly and that need to be taken care of. And the promotion of equity of access. So who can afford to have the NIPT? That shouldn't be only for the rich. Now I come to a point that often ethical principles are connected. I mainly focused on autonomy, but already we now talk about equity. Who can have NIPT? Somebody who is rich enough to pay for the test, or would that be all pregnant women, and would it be kind of for free so that everybody can do it? But then you might again say, but then people might easily take the test without thinking about it. Anyway, there is an element in the fact that if women are to make an autonomous choice, then that can only be achieved if all women have access. So if it's so expensive that it costs thousands of euros or dollars, then probably few can pay for it, which means that the access is limited and equity is not achieved. So this other ethical principle then is not achieved. And the other element here is that whatever their choice, they and their children should be taken care of. If people decline or accept the test, have a child with Down syndrome, or terminate a pregnancy, that should not matter if indeed we want to achieve both autonomy and equity, then all elements of, say, healthcare should be there to guarantee that people can make autonomous choices and equity is achieved. I recognize that this was a very brief summary of our NIP recommendations, but we still move on to gene editing now. When we think about gene editing, the potential first application would be somatic gene editing. From a person, you could take the patient's cells, introduce some different gene, you introduce it to the editing system, analyze the on- and off-target effects. Like if it's a patient with sickle cell disease, you should see whether indeed the hemoglobin disease has— the hemoglobin has been changed and not any other elements of the DNA, and then you could give back. Some of the stem cells. Now in this case, you might also understand that doing good sounds like very well possible, and doing harm, of course, we have to avoid that. So we should study the off-target effects. But as soon as we know that it's safe— this question, how safe is it, is still not answered today, but it sounds like there's very promising clinical trials ongoing— if it would be safe and effective, then changing a gene in stem cells and giving them back to the patient for instance, lacking an enzyme, if you then would give back some cells that at least have this enzyme, that might be a very easy way to treat a patient. And in terms of ethics, this sounds like a very simple case. But it's of course getting far more complicated when we think about germline gene editing, and that's the recommendations that have been approved by the board 2 days ago. Much of the argumentation that you find now in this field is building on two documents, at least when I talk about Europe. One is the Council of Europe committees for the Oviedo Convention. So this is a very broad, internationally legal binding treaty that prohibits any gene modification of embryos that would be passed on to future generations. So this is clear, no gene editing. And even last year, the clinical trials regulation came into effect., which literally said no gene therapy clinical trials may be carried out which result in modifications to the subject's germline gene identity. Maybe this is a word to think about a little bit. We should not sort of change the identity. If we change a gene causing a severe genetic disorder, are we changing the identity? I'll come back to that later. Anyway, we have to realize that this legislation came into force only last year, and development of this kind of legislation takes 10 years or longer. Also, the Oviedo Convention is a very old piece of legislation that we're not going to change next year, but if we think germline gene editing could be safe at one point, then this regulation makes it impossible today, and also next year, and also in 2 years' time. So basically what we are saying in the documents is we should rethink this legislation. I have to mention that this document we developed, it was together with ESHRAE, the European Society of Human Reproduction and Embryology. And together we developed those recommendations for reproductive germline gene editing. And we focused on what were the arguments behind this legislation, do they still apply, and are they still considered convincing. But basically, if a technique can help to avoid serious genetic diseases in a safe and effective way, we wondered whether that would be a reason to reconsider earlier standpoints. Now this is maybe a bit complicated one. We talked about two kinds of objections: categorical objections where you say no by principle, it's not allowed to modify the germline because it's not natural, because it goes against human dignity, never do it. And the second kind of objection would be about the consequences, the consequentialist objections. No, because of the consequences, it's too dangerous, don't do it, never start it, it's, well, If you take the first step, then many would follow. The slippery slope argument— if you start modifying something very serious, in the end you'll even modify hair color or whatever. Now, what our document says, the categorical objections in terms of being at odds with naturalness, human dignity, the preservation of the human gene pool as a common heritage, they are often used in the public debate, so many people find these arguments pretty important, so if we speak to our patients, still we may encounter this kind of arguments. But we considered that they seemed unconvincing when it comes to the potential applications with a clear therapeutic or preventive aim. So in going through the ethical literature, these objections were not considered convincing. Now, that's a bit too strong. We considered that they seemed to be unconvincing. So no convincing arguments for never edit the genome, the germline, for serious conditions, but we should still better understand why people are using these categorical arguments, because we need to inform the debate. If we as geneticists would say, well, there might be possibilities at one point to do it, then still we'll have to speak to many people outside of our ESHG and ASHRAE societies.. So we'll have to speak to lawyers, to people with a legal background, to medical doctors from other fields. So still understanding where this comes from and why people are arguing this way remains important. But another element is that safety indeed still is not sure and is a very important question, not only for this child, if we speak about a specific pregnancy, but also for future generations. And many people have said, but aren't there many other ways to avoid serious conditions? Can't we use preimplantation genetic diagnosis, prenatal diagnosis, and termination of pregnancy, which in a number of cases be too small, so why are we developing this technology at all? And the examples that are currently mentioned are, for instance, when both patients have cystic fibrosis— both parents, I should say— or when in PGD there are very few embryos and you want to investigate two traits, like hemoglobin and HLA. If it's about thalassemia and you want to have the next child potentially be a donor for the oldest affected child, then you're looking at two traits, and then the number of embryos might be pretty small. So do you want another IVF cycle, or do you want to use an embryo after modification? So this could potentially be a much larger number of cases to treat with germline gene editing. Anyway, this point that we have to consider where we put our efforts is, of course, an important argument. Still then thinking about when this potentially could be applied, of course, we need, first of all, robust knowledge from basic research before any future clinical applications could be considered. And both for scientific and moral reasons, then, I think that should even be a precondition. If ever you would consider to have clinical applications, you'd better first investigate it in basic and preclinical research. I may remind you that, for instance, IVF was not that much investigated in basic and preclinical research, but we kind of moved on pretty fast to just have children born after IVF. So the first kind of experiment was more or less in persons. Born after IVF. So we are arguing that the use of research embryos could be morally justified, subject, of course, to ethical, legal, and societal oversight. So this is not something that should just be done for no reason, but good oversight is needed. But better first do good basic and preclinical research before stepping into potential clinical applications. And then scrutiny and debate is needed on the potential consequences. So these consequentialist arguments are the most important ones that we recognized. Okay, so I come to a conclusion. Ethics is not only about questions— can I do my research— but it's also very much about answers. It's both sides of a coin often. And looking at the arguments behind our— the way we argue, that's a very important element of the science of ethics. We discussed a few of the principles that are relevant: autonomy, equity, and recognized that individual autonomy may not be very suitable for genetics, since we often talk about collective levels of science, of patient care for families. For NIPT, we saw that autonomy is a very important principle, which leads to good information and evaluation being very important, but evaluation not only on the level of numbers that participate, or uptake, or whatever, but the especially on the informed decision-making. If we take autonomy as the goal, then evaluation should be on have we reached autonomy sufficiently. And for germline gene editing, in just one sentence, categorical objections do not seem convincing, but we do need a lot of debate. And if that kind of legislation that's now in place is making it impossible today to use germline gene editing, then maybe we should investigate whether it's possible to do that evaluation again and stimulate the Council of Europe and other organizations to get in touch with us, or we get in touch with them, to do again this debate. Thank you very much for your attention.