by Nessa Carey
But for the first time in our history we are now facing a future where we can use technology to change the DNA in every cell in a human body. In this case, the treated individual will pass on this deliberately introduced mutation to their children. We’re there already, with the ill-timed and disastrously mis-handled work from He Jiankui which was described in the Prologue. We need to take a step back as a society and ask why would we even contemplate this?
In bitter need
Much of the debate around germline gene editing concerns the creation of super-beings with enhanced genomes that will make them taller, faster, more attractive. We actually understand very little about the genetic basis of these traits and what we do know suggests that it will be very difficult to enhance humans in this way. This is because most of these traits are influenced by a large number of interacting genetic variants, each of which contributes only a small amount to the final presentation, and it’s just not feasible to edit enough of these to make a difference.
The costs and complexity of gene editing also mean that we’re unlikely to see gene editing employed just so that parents can be sure their child has blue eyes and blond hair. Or black skin and ginger hair, or whatever combination you fancy.
But there are situations where single discrete variations in the human genome have a huge and fairly predictable effect on the individual, and these effects are highly pathological. This is where the debate around germline gene editing really lies.
Lesch-Nyhan syndrome is a genetic condition whose symptoms are so severe and appalling as to be almost incomprehensible. The boys (and it is almost exclusively boys who are affected) suffer from terrible joint pain and kidney malfunction, as a compound called uric acid is deposited at high levels in various parts of their bodies. The deposition in the joints is the same process that occurs in gout, which usually affects adults. Adults who suffer from gout will often tell you it is the most excruciating pain imaginable. Now, try to imagine being a small boy and going through that.
Tragically, this isn’t the worst thing that happens to children with Lesch-Nyhan syndrome. They also develop a range of damaging neurological behaviours, most distressing of which is self-mutilation including extensive biting injuries to their extremities and lips. To prevent this, about 75% of sufferers are in physical restraints much of the time, often at their own request.
The affected boys rarely survive past their teens. The most common cause of death is kidney malfunction due to the uric acid deposits. The kidney effects are one of the easier ones to control, and this has introduced a heartbreaking ethical dilemma for families and their clinicians. Is it ethical to treat the kidney problems, and prolong life, when for many of the affected individuals that life is one of physical agony?
Even with all the tools under development for gene editing, it will be incredibly difficult to correct the genetic defect in the brains of these boys. The brain can be a remarkably difficult tissue to introduce drugs or other agents into, as it has specific barriers to prevent ‘contamination’ from the rest of the body. It’s likely that the neurons are the type of brain cells where we would really need to carry out the gene editing. But neurons are cells that don’t divide, and gene editing efficiency tends to drop in cells like this. That’s a big problem when we consider that there are about 100 billion neurons in the brain. We also can’t be sure of when the neurological damage becomes irreversible, so we don’t know how large a time window we have for carrying out the gene editing.
If we knew that a couple was at risk of having a son with Lesch-Nyhan syndrome, wouldn’t it be much better to intervene as early as possible, so that the symptoms never develop? Ideally we would intervene at the very earliest stage of life, when there is just one cell. Why not correct the mutant DNA sequence in the zygote, that extraordinary single cell formed from the fusion of an egg and a sperm, that ultimately gives rises to all 70 trillion cells of the human body?
It’s not just Lesch-Nyhan disease where this could be applicable. In Huntington’s disease, the presence of a specific mutation leads to lethal neurodegeneration. Although this sometimes presents in childhood, more commonly the symptoms don’t appear until late adulthood. Frequently, by this stage the affected person has already had children. In addition to knowing that they themselves are facing a horrible and deeply distressing decline, they also know that each of their children has a 50% chance of inheriting this genetic grenade.
Once clinicians know that Huntington’s disease is present in a family, wouldn’t it be a great thing if they could use gene editing of zygotes to ensure that this mutation isn’t passed on? For each edited zygote that is implanted and develops into a new human being, the editing will have brought a stop to a devastating condition in that part of the family tree.
In a world where gene editing gives us the possibility of preventing appalling disease before it even develops, has the ethical paradigm shifted? Have we moved to a situation where ethically we no longer have to justify why we would do something? Are we now in a position where we would have to justify non-intervention?
Think first, act later
How close are we really to being able to carry out this type of germline gene editing safely and routinely, where we will change the DNA sequence of every cell in a human body, and in every cell of the descendants of the edited individual person? The answer at the moment is probably not quite as close as we might think, and certainly not close enough to have justified the use of this technology by Professor Jiankui.
Germline gene editing will require that we use the technology of in vitro fertilisation (IVF). Many laboratories and clinics around the world are able to use this technology to fuse a sperm and an egg, to create a zygote. This zygote is typically cultured in the laboratory for a number of cell divisions before it is implanted into a woman’s uterus. It is theoretically perfectly possible to use gene editing to change the DNA of a zygote. But you’d want to test that the editing had actually worked before you inserted the result of that procedure into the future mother’s uterus. And the only way to test that requires destruction of the zygote.
Perhaps you could let the zygote undergo a few rounds of cell division and then remove a tiny number of cells, most likely from the bit of the still very early embryo that will generate the placenta. We already know that embryos can survive this procedure. Then we could test the cells from the embryo to see if the gene editing has taken place successfully. But we have to make the assumption here that we edited the zygote at exactly the right time, so that every copy of DNA that it creates is identical. Otherwise, we run the risk of implanting embryos which are a mixture of edited and non-edited cells, and we may not get the clinical outcome we want.
Right now we can’t really be 100% confident that we can make the assumption that a subset of the embryo’s cells will be representative of the entire embryo. Indeed, this seems to be one of the things that has gone wrong in the edited twins, which is one reason why there won’t be immediate wide-scale adoption of this technology. Research on other mammalian species has been promising, but we don’t know how well this represents human embryological development. In the UK there’s also a moratorium on working with human embryos that are more than fourteen days old, so British scientists are limited in how long they can monitor an embryo in the lab, which makes it hard to assess the consequences of the gene editing. There are quite a few countries where even this much experimentation would be incredibly difficult within the relevant regulatory frameworks.
It’s highly likely that as gene editing technologies mature and become more effective and more predictable, we will be able to develop confidence around the issues of extrapolating from a few cells to the entire embryo. But given the constraints on research using human embryos, it could be many years before we see general agreement that this approach should be used therapeutically. But the potential is so clear, it’s almost inevitable that therapeutic intervention using germline modifications via editing of eggs, sperm, a zygote or an early embry
o will happen again. It’s not just scientists who are preparing for this, though. In preparation for this likely future we are seeing increasing collaboration between scientists, lawyers, philosophers and ethics experts to identify, articulate and make recommendations about the moral and ethical issues around this unprecedented intervention in the genetic script of our species.
Be prepared
It may seem odd that various organisations have been putting significant effort into something that at the time was only hypothetical. But there were very good reasons to hold this conversation, both among experts in the relevant fields and with the wider community, including the general public.3
One of the reasons is that we couldn’t predict accurately how long it would take before this technology was deemed sufficiently mature for a group to attempt human germline modification. Professor Jiankui’s jumping of the international gun notwithstanding, ethical and legal frameworks rarely develop best when created under time pressure, so it’s important that the issues are considered well in advance of widespread implementation.
Another reason is that the ethical and legal considerations will actually influence the research that can be conducted, and the directions in which it will travel. Ideally, ethics should not be dragged along in the wake of scientific advances; the two should progress together, informing one another.
It’s also tempting to think that germline gene editing will be so rare that we don’t really need to worry about developing an ethical framework, as each case can be dealt with individually. But we need to be careful about that assumption. The history of medical interventions is that if they are effective they often are taken up remarkably broadly. IVF seemed an extraordinarily niche procedure when the first ‘test-tube’ baby was born in 1978, but she’s been joined by around 5 million more in the 40 years since that day.
It’s also hoped that open discussions of the ethical and legal implications of gene editing of the human germline will increase the chances of developing frameworks that are consistent across international boundaries. Inconsistencies in the legal systems in different countries can lead to bizarre situations, and nothing exemplifies this better than the case of the first baby born with an altered genome.
This wasn’t a case of gene editing but of the creation of a three-parent embryo. About 99% of the DNA in a human cell is in the nucleus. Half of this is inherited from your mother and half from your father. But about 1% of the human genome is in 1,000 to 2,000 tiny subcellular structures called mitochondria. These are essentially the power generation units of our cells, and we inherit mitochondrial DNA only from our mothers.
Just as mutations in the nuclear DNA can cause disease, mutations in the mitochondrial genome can also cause problems. There is a rare condition called Leigh syndrome in which babies typically start to develop symptoms in the first year of life. These symptoms include a failure to thrive, and progress to extensive neurodegeneration with loss of mental and motor functions. The children usually die within three years of onset. About one fifth of the reported cases of Leigh syndrome are caused by mutations in mitochondrial DNA.4
This was the case for a Jordanian couple who were desperate for a family. The woman had suffered four miscarriages; gave birth to an affected daughter who died at the age of five; had an affected son who died before his first birthday. Genetic testing demonstrated that the mother’s mitochondrial DNA was mutated. Although she herself was relatively unaffected, the mutation levels in the 1,000–2,000 mitochondria she passed on in her eggs had reached a tipping point. Any pregnancies were likely to result in miscarriage or a child with a lethal condition.
In 2016, the woman gave birth to a healthy baby boy, following a particularly complex IVF process. The team who carried out the procedure removed the nucleus from a donated egg, where the donor had healthy mitochondria. They then inserted the nucleus from the woman whose mitochondria were mutated. This created a hybrid egg, where the nuclear DNA was from one woman and the mitochondrial DNA from another. The team fertilised this hybrid egg using the husband’s sperm. This procedure was conducted using a number of eggs, and the fertilised ones were cultured in the laboratory. Only one developed and this male embryo was implanted into the woman who was desperate for a healthy baby.
The complexity in this case wasn’t just technological or medical. The manipulations of the egg and the IVF with sperm were carried out in the New Hope Fertility Centre in New York City. This was perfectly legal, but implanting the egg into the woman would have broken the law in the US. So the implantation was conducted in Mexico. Although Mexican fertility clinics don’t have the expertise to carry out the complicated nuclear transfers, they also don’t have any rules or legal barriers to prevent them implanting an embryo that is created from these procedures. But neither the US nor the Mexican clinic possessed the technology and expertise to analyse the embryo fully before implantation, so this part was conducted (with full ethical approval by the relevant bodies) in the UK.5
That’s quite a mess, and far from ideal. The UK has now become the first country to change its regulations so that a variant of this kind of three-parent procedure can be performed from beginning to end, and with proper scrutiny.6
So the mitochondrial replacement technique has produced a precedent for germline modification of human DNA, as every cell derived from this three-parent zygote will contain the same hybrid complement of DNA from the two nuclear genomes and the mitochondrial one. If all babies born using this technique are boys, this complex genetic cocktail won’t be passed on to the next generation, as mitochondrial DNA is inherited only through the maternal line. But if the babies are girls, then the barrier on transmission of a deliberately altered genome in humans will have been irreversibly breached. This will inevitably lead to increased pressure to extend this precedent to targeted germline gene editing.
What’s the driving force?
Why is there even a need for germline DNA editing? One way of looking at this is in terms of numbers. Let’s assume that such gene editing would be reserved for the types of conditions that we call single gene disorders. These are situations where a mutation in just one gene is sufficient to cause a serious illness. Each individual disorder is rare. But we know that there are at least 10,000 human diseases caused by a defect in a single gene. As DNA sequencing and data handling become cheaper and more accessible, scientists will undoubtedly identify even more. Collectively, more than 1% of people globally are affected by a single gene disorder, so together they represent a significant health issue.
Once a genetic disease has been identified in a family, there are currently various ways for ensuring that a woman can give birth to a child who isn’t carrying the disease mutation. The most obvious is pre-natal testing. In this situation, pregnancy takes place in the old-fashioned two-people-having-sex way. At a certain stage in the pregnancy, it’s possible to test the foetus to determine if it has inherited the disease-causing mutation. If it has, the pregnant woman can opt for a termination.
For some women of certain faiths, such as Roman Catholic or Muslim, this may not be an option because of religious objections. But it’s also a distressing approach for most women and their partners.*
Another option is a variant of IVF, where tests are conducted on the embryos to select an unaffected one before implantation (pre-implantation genetic diagnosis).
But there will be rare situations where neither of these approaches will solve the problem anyway. We have two copies of most of our genes, one inherited from our mother and one from our father. In some diseases (known as dominant genetic disorders), if just one of these two copies is mutated the individual will develop the condition. Huntington’s disease is an example of this. In rare cases, an affected person with a dominant disorder may have inherited a mutated gene from each parent. This means they will have two copies of the mutant gene, and therefore all their offspring will inherit one copy and develop the disease.
Even under ‘normal’ circumstances, if you have a geneti
cally dominant disorder all your children are at a 1 in 2 risk of inheriting your mutated gene and therefore developing the same disease. Those are very high odds and are the same whether conception is natural or through IVF. When using IVF, the number of eggs that are available for fertilisation for any given woman is relatively low, and it could easily be the case that all the embryos contain the mutation (because the woman carries the abnormal gene or because they are all fertilised by sperm carrying the mutation). Perhaps a small number won’t, but the success rates of the laboratory culture, implantation and survival to term are all on the low side. This is one of the reasons why gene editing to remove the mutation is so appealing, because it increases the likely number of ‘normal’ embryos and hence the chances of a successful pregnancy.
In diseases known as recessive genetic disorders, symptoms only develop if both copies of the gene are mutated. The child of two people affected by a recessive disorder must inherit mutated genes from each parent (because their parents don’t contain any normal copies) and so will inevitably develop the same condition. Although it might seem unlikely that two affected people would get together and decide to have a child, there are good reasons why this might happen. The two people would after all share some similar life experiences as a result of having the same condition. These types of diseases often reach their highest levels in populations which have a decreased tendency to ‘marry out’, often for religious reasons, so there will be a strong degree of cultural understanding of each other which may also increase compatibility.