CRISPR, and the ethics of gene editing
In this edition of The Naked Scientists, we take a closer look at CRISPR gene editing. What is it? And what are the ethics involved in rewriting the human genome?
In this episode
What is CRISPR?
Neville Sanjana, NYU
Clustered regularly interspaced short palindromic repeats, or CRISPR, is a gene-editing technology that allows scientists to make manual changes to our DNA with incredible precision, allowing us to deal with genetic illnesses and crop modification in timescales previously thought impossible. In 2020, its pioneers, Jennifer Doudna and Emmanuelle Charpentier, were awarded the Nobel Prize in Chemistry for their groundbreaking work on it. But CRISPR also raises ethical questions and potential dangers. Could it lead to designer babies and unintended mutations? And would life changing treatments be doled out equally for everyone? First though, what exactly is CRISPR, and where did it come from? NYU’s Neville Sanjana...
Neville - One of the key breakthroughs, which I find really fascinating, came from food scientists working on yoghurt production. These food scientists were tasked with understanding why certain bioreactors failed to culture yoghurt. Very practical problem, you know, we have invested all this money, we put all these raw materials in, we need to make yoghurt at scale, but occasionally we're getting these failures. What's going on? And this is how they discovered that CRISPR in its natural role is an adaptive immune system in bacteria. It protects the bacteria from phages, which are a type of virus that can attack bacteria. CRISPR enables bacteria to store a memory of a phage that it's previously seen, it stores a tiny bit of the phage genome, and this CRISPR system can protect the bacteria when that same phage or a similar phage comes back to attack and try to infect the bacterial cells.
Will - So was the idea, then, that we looked at these bacteria and went, 'they're snipping viral genomes at certain points and storing them so that they can remember them when the virus comes back later. What if we could use those same scissors?'
Neville - It's exactly that. So we can take CRISPR and instead of just using it in the way that the bacteria use it to protect themselves from phage, we can take advantage of its programmability and redirect these CRISPR systems to target anywhere, even in a large genome like a human genome. Because it's such a programmable system, it can be moved into really any other organism and reprogrammed using a small piece of RNA called a guide RNA. And that's something that can easily be made in the lab or bought. So it's easy to direct those CRISPR scissors to any place in the genome. And it's really the programmability that led to that widespread adoption of CRISPR.
Will - So we have these biological scissors with which we can go into a faulty genome and snip a bit out or alter a bit or delete a bit as is necessary.
Neville - That's right. So the scissors themselves actually stimulate the endogenous repair pathways because it's very important for all living organisms to be able to repair anything that happens to their DNA. And so what you can think of is that it takes two to tango. So the CRISPR scissors go in there and they make the cut and that cut calls the repair proteins to this particular site. And using that we can either delete a gene or we can add a few bases in or we can make a very precise edit to change maybe a variant that leads to a particular disease to a non-pathogenic variant.
Will - What do we use CRISPR for?
Neville - One of the practical uses of it is definitely to develop therapeutics that could edit in somatic cells, that's adult cells, genetic variants. So if somebody carries a variant for a severe genetic disease we want to be able to correct that disease. That's the dream of this one and done therapy. Instead of a drug that you need to take continually you can give them a gene editing therapy that they take once and then from that point on that disease no longer impacts them. That's one of the main uses of CRISPR. There are other uses of CRISPR for editing genomes that are not human genomes like plant genomes. Plants have notably complex genomes with many many copies of different genes and the ways that particular traits have been bred over decades and centuries has led to very inbred crops which is great because we have those traits in particular crops but those crops, because they're inbred, are maybe not hardy or resistant to climate change and so could we transfer some of the desirable traits that have been accumulated over the years through human agricultural breeding and transfer them to other strains that might be more hardy and resistant to climate change.
Will - Where do you come into it? What does your work with CRISPR involve?
Neville - My work focuses on understanding the human genome, the genes in it and all the rest of the genome. The other 99% of the genome that's not genes non-coding elements that regulate gene expression. There are 20,000 genes in the human genome and let's say we want to find which of those 20,000 genes are important for cancer growth. If we test each gene one by one it's almost an impossible task. You know you need an army of robots or an army of graduate students and post-doctoral fellows and staff scientists and everybody here. But with CRISPR we can actually target all 20,000 genes in one single experiment and measure the effects on cancer growth. So if we have six different CRISPRs for a gene we can say okay I've knocked this gene out in six different ways and six different cells and look they all have the same effect. One of the earliest CRISPR screens we did examined a region of the human genome that's important for switching between different forms of haemoglobin, a protein that carries oxygen in red blood cells. Using a few thousand CRISPRs we found a part of the genome that switches blood cells back to using foetal haemoglobin, something we normally only make right up until the time we're born. But this is very useful because some people with diseases like sickle cell anaemia have problems with adult haemoglobin. They have a defect in the adult haemoglobin. A biotech company just a few years later was able to modify the blood cells of someone here in the United States. Her name is Victoria Gray and she became the first person to be cured of sickle cell anaemia using CRISPR and about a year ago this treatment became the first FDA approved gene editing therapy of any kind. That's just kind of a bonkers thing to think about. It's absolutely amazing that we can go from basic discovery to an approved cure with a totally new modality of therapy for a painful disease that impacts millions of people and do that all in less than a decade.
How does CRISPR gene editing work?
Adrian Thrasher, UCL
What does the application of gene therapy look like in practice? Adrian Thrasher is a professor at UCL, and a little over 20 years ago, he pioneered the use of viruses as a means of delivering gene therapy to sufferers of ADA deficiency, a genetic metabolic disorder that causes immunodeficiency. This treatment proved successful, showing that gene therapy can transform lives, but there are risks doing this with viruses. Therefore, if we can edit genes more safely and discreetly, as happens with CRISPR, then that is safer...
Adrian - We can identify the genes that are involved in causing a disease using conventional sequencing methods. Once we know that we can decide to treat the patients using synthetic genes which were conventionally delivered using vectors such as lentiviral vectors which will deliver the genes randomly throughout the genome. Or more recently technology has advanced so we can now use CRISPR to more precisely correct the defects within the cells.
Will - So what does that procedure involve?
Adrian - For the patient what it means is that we can remove the stem cells in the bone marrow and modify those in a laboratory in a sort of clinical grade laboratory and then give them back to the patient. Now that sounds very simple but there are a few nuances to that because the technology to introduce the genes into the cell or the CRISPR into the cell is fairly complex and also the treatment of the patient to enable them to receive the gene corrected cells is also complex. For example it may involve giving some chemotherapy to eliminate the diseased bone marrow before giving back the corrected bone marrow.
Will - So the idea is because bone marrow is where all new cells are made, if you can pop your new good gene cells in there, they'll administer themselves appropriately out into the body?
Adrian - That's exactly right. So the bone marrow has some very specialised cells called haemopoietic stem cells which live within the bone marrow. They divide and create more stem cells but more importantly they populate the whole body with all the blood lineages that we're familiar with. So red blood cells, white blood cells and platelets.
Will - How long does it take for these new engineered cells to sort of have an effect?
Adrian - Well it's variable it depends on the disease that's being treated but, very similar to a bone marrow transplant where another person's cells are used to correct a disease, It takes time for the stem cells to engraft and then repopulate all the lineages in the blood and so that usually takes a few months.
Will - CRISPR is as we keep repeating in this programme pretty cutting edge so it probably doesn't have the track record of other types of gene editing when it comes to treating genetic diseases but if we look at a few of its predecessors what kind of genetic diseases have been involved in treating with this method?
Adrian - Some of the haemoglobinopathies, so sickle cell disease, has been treated using CRISPR. There are big efforts to try and use it in other haemoglobinopathies and immune deficiencies such as ADA deficiency which we know is treatable by gene therapy using lentiviral technology, gene addition technology, and therefore it will make it amenable to CRISPR based technologies, which hopefully will make it a more accurate fix to the cells and therefore safer for the patients.
Will - Do you foresee many more genetic diseases being able to be treated with these means?
Adrian - Yes absolutely because you know in theory you could target any genetic disease using CRISPR or CRISPR-like technologies. The issue which has been the issue for all gene therapies is how do you deliver the therapeutic agent to the cells that you want to correct? Now for bone marrow it's relatively easy because we can take the bone marrow out of the patient and modify it in the lab. For other diseases we may want to deliver the CRISPR to organs in the body and that may be more difficult but in theory yes many many genetic diseases will be amenable to this sort of treatment.
What ethical dilemmas does CRISPR pose?
Nessa Carey
CRISPR offers the capability to rewrite the code of life. From curing genetic diseases to maybe even enhancing human traits, the possibilities of CRISPR are both exciting and unsettling. Should we use this technology to eliminate inherited disorders, or does that open the door to designer babies and a new era of genetic inequality? Could editing DNA in one generation have unintended consequences for future ones? And what about the risk of creating genetically modified organisms that could disrupt ecosystems?
The ethical questions surrounding CRISPR are as complex as the science itself. Nessa Carey is a molecular biologist, and author of ‘Hacking the Code of Life: How Gene Editing Will Rewrite Our Futures'...
Nessa - With CRISPR, you're doing something extraordinary in that at its most extreme, when you're using CRISPR in humans, you could be trying to change just one base pair of DNA in 3 billion. And that's a really big technical ask. And the two biggest safety concerns, the first is around off-target effects. And what this means is that what if the CRISPR, instead of just hitting the gene you're interested in, hits other genes and changes those as well? What will be the safety impact of that? Because you could be changing lots of things in the system. So off-target is a big issue to think about. The other thing to think about is we've had a very old-fashioned view of DNA for a long time, which is that one stretch of DNA only does one thing. So very often we think in terms of a stretch of DNA that codes for a protein, what we in the past were always referred to as a gene. The problem is that in DNA, information is multilayered. So yes, a particular stretch of DNA can be coding for a protein, but within that, it can also be coding for other things, like little stretches of nucleic acids, which control expression of other genes. And so there's always this fear that you could target the change you want in a protein, but you might be disrupting some of these other regulatory signals. So those are the two biggest safety concerns. And of course, the thing with CRISPR is any change you make is permanent and it's passed on to daughter cells. So if something does go wrong, it's not easy to reverse it. You can't just do what you would do with a traditional drug and say, well, just stop taking the drug. You've created a permanent change. And so that's where the safety concerns lie, really.
Will - On the subject of CRISPR treatment in humans, a lot of the concerns seem to centre on embryo experimentation and people being not too keen on that for various reasons. But I was wondering if there was a particular inciting incident for all of this, where we sort of sat up and realised that this was a real thing that was happening, it could have interesting consequences.
Nessa - Oh, yeah. I mean, there had been effectively a moratorium among scientists working on CRISPR that they would not edit embryos. And by embryos, they meant very, very early stage embryos. And the reason for not editing those embryos, well, one of the main reasons was that any change you introduce into those embryos will be maintained in the cells that create the egg or the sperm in later generations. So you wouldn't just be changing the DNA in that individual, you'd be changing it in all of their future offspring and their offspring's offspring. And it was sort of assumed that everybody was adhering by this ethical moratorium. And then a scientist in China announced that he had gene-edited embryos and those embryos had gone to term in the mother. And there were two girls who had been born who had been genetically edited. And that caused enormous controversy.
And it caused enormous concern because the technology really isn't mature enough to be confident that we're doing that safely at the moment. This technology moves so fast that it is very difficult to control how it's used except by consensus. And once that consensus broke down, that caused a great deal of concern.
Will - With that, again, comes the question of if you're performing a medical procedure on an embryo, they can't say whether or not they want it.
Nessa - Yeah, that is absolutely true. In terms of an embryo. And let's be very clear, most of the time, CRISPR will not be used in embryos, it will be used in people who have been born, it will be used in children or it will be used in adults, it will be very rare at the times that it's used in early embryos. But there is a real concern around that, in that the embryo cannot give consent. There is no point waiting till the embryo turns into an individual who gets to the year of 18 years of age and then saying, by the way, we did this, would you have consented? That's not informed consent. And the parents can't give consent in any meaningful way, because they're not the individuals who are going to be gene edited. It is worth bearing in mind, though, that that is true of any intervention in embryos. And we intervene surgically, etc, in later stage embryos for certain conditions. So the question always with embryos is around who consents and have you created a permanent change to the genome. And for some people, creating a permanent change to the genome that will be passed on, that's the critical bit that will be passed on, is taking things too far. However, it is interesting to contrast that with the attitudes of some families in whom there are devastating genetic diseases, where they say, all we are asking you to do is change our embryos DNA so that in that one position, it is the same as almost all the other 6 billion people on this planet. Why is that such a big deal? And I think that's an area that really needs exploration. And I don't think this is a simple question. The issue around CRISPR is the technology will become so good that it has flipped the ethical question. Jennifer Doudna, who is one of the inventors of the technology, pointed out that what CRISPR potentially means is that instead of thinking, do we have the right to do this? We will have to start thinking, do we have the right to withhold this? And that's a very unusual situation for us to be in ethically.
Will - Indeed. And it also extends out far beyond the human experimentation question and onto the non-human experimentation question, because we are at a point where we need to consider altering foods, perhaps as best we can to survive sudden changes in climate. But again, with the concerns outlined with safety on the CRISPR procedures on humans, is there a potential chance that we create a food that is harmful for us?
Nessa - Yeah, I think there's very little chance that we'll create foods that are harmful unless we explicitly set out to create foods that are harmful. A lot of this debate has been influenced by the concerns around genetically modified crops. And we have to remember that Europe is very out of step with most of the rest of the world. But if you look at things like the American rulings on this, from things like Food and Drug Administration, their attitude has very much been, if you're just using CRISPR to create a change that occurs in nature anyway, but where you'd have to use decades of breeding to introduce that into a food, all you're really doing is speeding up a process. And I think that's actually a very sensible way of doing things. I think we desperately need agriculture to become less damaging environmentally. And if we can thereby create crops that need, say, less land, or less fertiliser, or less water, or are more resistant to drought, that actually, in my view, is a good thing for the planet. It decreases the load that agriculture creates. Where I think I have considerably more concern is around using CRISPR and a technology called gene drive to do things like wipe out mosquito populations. The idea of wiping out entire insect populations from large areas, that worries me far more because our understanding of how food chains and how biodiversity operates, and how entire ecological nets operate, we would be being very bold if we knew exactly what the consequences would be of removing a species from an ecological net like that. So that worries me much more than the changes to food.
20:54 - Can CRISPR be used responsibly?
Can CRISPR be used responsibly?
Hank Greely, Stanford University
What comes next for CRISPR? It is advancing at an unprecedented pace. In the near future, we could see CRISPR-based treatments for currently incurable diseases, more resilient crops, and even the ability to edit genes before birth to prevent inherited disorders. But, with such power comes a need for caution. So, what regulations are in place to assuage these concerns, and what kind of event could shift the goalposts? Hank Greely chairs the Steering Committee of the Center for Biomedical Ethics at Stanford University.
Hank - The aspect that people are worried about is using CRISPR on human beings. Using CRISPR on human beings is regulated in, I think, every country that has a substantial bioscience infrastructure. There are really two different kinds of uses that are subject to different levels of regulation. One is CRISPR to try to treat diseases of people who've already been born. That's regulated everywhere as a therapeutic and has to be proven safe and effective, whether it's under the FDA in the US or the EMA in the EU. That kind of CRISPR is regulated the way any new drug would be regulated. What people mainly worry about is CRISPR embryos. That seems to be either strongly or weakly illegal in almost every country where it's plausible that it could happen.
Will - It does seem a pretty tough nut to crack in that regard because it is an embryo that cannot consent. Is there any legislation that can be put in place or is that just something you anticipate will just be left alone indefinitely?
Hank - Legislatures have a tendency to be reactive rather than proactive. They tend to react to scandals. Most of the regulatory activity with respect to embryo editing is a result of He Jiankui's CRISPR babies from 2018. Unless or until there's another scandal, I think we're not likely to see another wave of regulation. We live in societies, many of which are built on hype. Science hype is a real thing. Will somebody try to do something with modified babies? Maybe. If so, will there be a reaction? Almost certainly there will be, particularly if the babies turn out to be damaged and disabled in some important respect. The CRISPR babies from China, they're now six-year-olds. We know nothing about them. China has released no information about their health or well-being. That's disconcerting.
Will - What about the question of consent?
Hank - There is this interesting question about what can we do affecting embryos since embryos don't give consent? Is it ethical to do anything with respect to them? The answer is yes, because lots of things we do have effects on embryos. Any kind of food or drug or environmental perturbation could affect a pregnant woman and as a result affect the embryo. We let research go on people who can't consent, whether they're infants or children or people who are intellectually disabled, but we have safeguards for it. Usually we require that a guardian or a next of kin or a court or somebody give consent on their behalf. Yes, it's true that embryos can't consent, but that doesn't mean that they can't be appropriate ethical subjects of research as long as somebody with their interests at heart consents in an informed way for them. I have to tell you, I don't remember the consent form I signed as an embryo that said, I want to be born and I want to be born to these people.
Will - To stay on that and talk about the ethical side of medical treatment, because a lot of CRISPR is cutting edge and as you say, it's not something that a lot of the world is concerned about because it is still quite a complex and expensive procedure to be involved with. That naturally creates a disparity between who has access to these treatments. It sounds callous to say, but do we just think of CRISPR as any other medical treatment where the rich people can afford it and the poor people cannot afford so much of it and it's less of an ethical quandary as an accessibility quandary.
Hank - What accessibility quandary is an ethical quandary. You in the UK with the National Health Service, at least within your country, almost everybody, everybody or almost everybody has access to decent healthcare. My country, I can't say that because we don't have an organised and ethical healthcare system. Even if we did that, that's a long way from guaranteeing access to people living in villages in India or in South America. There are going to be international disparities just as there are international disparities in access to food and education and other good things. Those are big ethical questions. There are also big geopolitical questions for which we don't have good answers. Other than try to make things as even and as fair as we can. We see this sometimes good things happen. So I do think that the rich world ultimately did and has been doing a decent job with respect to HIV drugs. It's not a perfect job by any means, but we have come together to make HIV drugs accessible to people in many poor countries.
Will - And to look at the other side of this, we've been speaking primarily about human CRISPR, but obviously a lot of our food is increasingly coming from genetically modified sources, genetically edited sources. The primary concern, of course, being that we accidentally create a faulty gene down the line when treating genes today. Are there safeguards in place for our food sources as well?
Hank - I actually think that the non-human uses of CRISPR are going to turn out to be much more important and much more interesting than the human uses of CRISPR, in part because we're willing to take a lot bigger risks with non-humans than we are with humans. We're much more worried about harming babies than we are about harming calves or harming baby carrots, and that's appropriate. And so we will use CRISPR much more on non-humans. Our regulation of non-human uses of CRISPR varies enormously from place to place, and I haven't seen any regulatory scheme that I think gets it right. Some are too strong. Europe has, in effect, a ban on genetically modified organisms for agricultural purposes, and I think that's foolish. For plants in the United States, basically it's anything goes. For animals in the United States, the regulatory scheme is very tight. I think it's too loose for plants, too tight for animals. People are approaching it, but I don't think we've yet figured out a good, balanced, nuanced way to approach it. But we shouldn't say, no, no, no, that's not natural. We shouldn't do it. Nothing in our lives is natural. You and I are having this conversation. We are hundreds of miles apart. This is not a natural conversation. This is not my natural fur that I'm wearing as a blue shirt. And I think this naturalist fallacy is strong, particularly with respect to genetic modification, and it is not helpful.
Will - So to look ahead then, as a final question, do you anticipate us being able to shed this idea of everything needing to be natural in order for us to combat the fast approaching issues of increased disease and climate change?
Hank - The most important word in the question you just asked is we. There are 8 billion of us on this planet and we agree on almost nothing. And I think that's going to be true with respect to use of CRISPR. I do think that particularly under the impetus of the most important issue of this century, climate change, a lot of genetic modification is going to end up being allowed and even welcomed. And I hope carefully regulated because the alternative will be hungry, starving people.
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