BIG QUESTION OF THE MONTH: Should we use CRISPR, the new technique that enables precise DNA editing, to change the genes of human embryos to eradicate disease – or even to enhance desirable traits? LeapsMag invited three leading experts to weigh in.
Over the last few decades, the international community has issued several bioethical guidelines and legally binding documents, ranging from UN Declarations to regional charters to national legislation, about editing the human germline--the DNA that is passed down to future generations. There was a broad consensus that modifications should be prohibited. But now that CRISPR-cas9 and related methods of gene editing are taking the world by storm, that stance is softening--and so far, no thorough public discussion has emerged.
There is broad agreement in the scientific and ethics community that germline gene editing must not be clinically applied unless safety concerns are resolved. Predicting that safety issues will indeed be minimized, the National Academy of Sciences issued a report this past February that sets up several procedural norms. These may serve as guidelines for future implementation of human embryo editing, among them that there are no "reasonable alternatives," a condition that is left deliberately vague.
I regard the conditional embrace of germline gene editing as a grave mistake: It is a dramatic break with the previous idea of a ban, departing also from the moratorium that the UNESCO International Bioethics Committee had recommended in 2015. But in a startling move, the Academy already set the next post, recommending "that genome editing for purposes other than treatment or prevention of disease and disability should not proceed at this time" (my emphasis). It recommended public discussions, but without spelling out its own role in facilitating them.
"The international community should explicitly ban embryo gene editing as a method of human reproduction."
To proceed ethically, I argue that the international community, through the United Nations and in line with the ban on human reproductive cloning, should explicitly ban embryo gene editing as a method of human reproduction. Together with guidelines adjusted for non-reproductive and non-human applications, a prohibition would ensure two important results: First, that non-reproductive human embryo research could be pursued in a responsible way in those countries that allow for it, and second, that individual scientists, public research institutes, and private companies would know the moral limit of possible research.
Basic human embryo research is required, scientists argue, to better understand genetic diseases and early human development. I do not question this, and I am convinced that existing guidelines can be adjusted to meet the moral requirements in this area. Millions of people may benefit from different non-reproductive pathways of gene editing. Germline gene editing, in contrast, does not offer any resolutions to global or local health problems – and that alone raises many concerns about the current state of scientific research.
I support a ban because germline gene editing for reproductive purposes concerns more than safety. The genetic modification of a human being is irreversible and unpredictable in its epigenetic, personal, and social effects. It concerns the rights of children; it exposes persons with disabilities to social stigmatization; it contradicts the global justice agenda with respect to healthcare; and it infringes upon the rights to freedom and well-being of future persons.
"Reproductive germline gene editing directly violates the rights of individual future person."
Apart from questions of justice, reproductive germline gene editing may well increase the stigmatization of persons with disabilities. I want to emphasize here, however, that it directly violates the rights of individual future persons, namely a future child's right to genetic integrity, to freedom, and potentially to well-being, all guaranteed in different UN Declarations of Human Rights. For all these reasons, it is an unacceptable path forward.
The way the discussion has been framed so far is very different from my perspective that situates germline gene editing in the broader framework of human rights and responsibilities. In short, many others never questioned the goal but instead focused on the unintentional side-effects of an otherwise beneficial technique for human reproduction. Some scientists see germline gene editing as an alternative to embryo selection via Preimplantation Genetic Diagnosis (PGD), a procedure in which multiple embryos are tested to find out which ones carry disease-causing mutations. Others see it as the first step to human enhancement.
Some physicians argue that in the field of assisted reproduction, not every couple is comfortable with embryo selection via PGD, because potentially, unchosen embryos are discarded. Germline gene editing offers them an alternative. It is rarely mentioned, however, that germline gene editing would most likely still require PGD as a control of the procedure (though without the purpose of selection), and that prenatal genetic diagnosis would also be highly recommended. In other words, germline gene editing would not replace existing protocols but rather change their purpose, and it would also not necessarily reduce the number of embryos needed for assisted reproduction.
In some (rare) cases, PGD is not an option, because in the couples' condition, all embryos will be affected. One current option to avoid transmitting genetic traits is to use a donor sperm or egg, though the resulting child would not be genetically related to one parent. If these parents had an obligation, as some proponents argue, to secure the health of their offspring (an argument that I do not follow), then procreation with sperm or egg donation would even be morally required, as this is the safest procedure to erase a given genetic trait.
There are no therapeutic scenarios that exclusively require reproductive gene editing even if one accepts the right to reproductive autonomy. The fact is that couples who rightly wish to secure and protect the health of their future children can be offered medical alternatives in all cases. However, this requires considering sperm or egg donation as the safest and most reasonable option – the condition the NAS Report has set.
Scientists in favor of germline gene editing argue against this: the desire for genetic kinship, they say, is a legitimate expression of a couple's reproductive freedom, and germline gene editing offers them an alternative to have a healthy child. In the future, proponents say, these (very few) couples who wish for genetically related offspring will be faced with the dilemma of either accepting the transmission of a genetic health risk to their children or weighing the benefits and risks of gene editing.
But here is a blind spot in the whole discussion.
Many scientists and some bioethicists think that reproductive freedom includes the right to a genetically related child. But even if we were to presuppose such a right, it is not absolute in the context of assisted reproduction. Although sperm or egg donation may be undesirable for some couples, the moral question of responsibility does not disappear with their reproductive rights. At a minimum, the future child's rights must be considered, and these rights go further than their health rights.
It is puzzling that in claiming their own reproductive freedom, couples would need to ignore their children's and possibly grandchildren's future freedom – including the constraints resulting from being monitored over the course of their lives and the indirect constraints of the children's own right to reproductive freedom. From a medical standpoint, it would be highly recommended for them, too, to have children through assisted reproduction. This distinguishes germline gene editing from any other procedure of assisted reproduction: we need the data from the second and third generations to see whether the method is safe and efficacious. Whose reproductive freedom should count, the parents' or the future children's?
But for now, the question of parental rights may well divert the discussion from the question of responsible gene editing research; its conditions and structures require urgent evaluation and adjustment to guide international research groups. I am concerned that we are in the process of developing a new technology that has tremendous potential and ramifications – but without having considered the ethical framework for a responsible path forward.
In November 2020, messenger RNA catapulted into the public consciousness when the first COVID-19 vaccines were authorized for emergency use. Around the same time, an equally groundbreaking yet relatively unheralded application of mRNA technology was taking place at a London hospital.
Over the past two decades, there's been increasing interest in harnessing mRNA — molecules present in all of our cells that act like digital tape recorders, copying instructions from DNA in the cell nucleus and carrying them to the protein-making structures — to create a whole new class of therapeutics.
Scientists realized that artificial mRNA, designed in the lab, could be used to instruct our cells to produce certain antibodies, turning our bodies into vaccine-making factories, or to recognize and attack tumors. More recently, researchers recognized that mRNA could also be used to make another groundbreaking technology far more accessible to more patients: gene editing. The gene-editing tool CRISPR has generated plenty of hype for its potential to cure inherited diseases. But delivering CRISPR to the body is complicated and costly.
"Most gene editing involves taking cells out of the patient, treating them and then giving them back, which is an extremely expensive process," explains Drew Weissman, professor of medicine at the University of Pennsylvania, who was involved in developing the mRNA technology behind the COVID-19 vaccines.
But last November, a Massachusetts-based biotech company called Intellia Therapeutics showed it was possible to use mRNA to make the CRISPR system inside the body, eliminating the need to extract cells out of the body and edit them in a lab. Just as mRNA can instruct our cells to produce antibodies against a viral infection, it can also teach them to produce the two molecular components that make up CRISPR — a guide molecule and a cutting protein — to snip out a problem gene.
"The pandemic has really shown that not only are mRNA approaches viable, they could in certain circumstances be vastly superior to more traditional technologies."
In Intellia's London-based clinical trial, the company applied this for the first time in a patient with a rare inherited liver disease known as hereditary transthyretin amyloidosis with polyneuropathy. The disease causes a toxic protein to build up in a person's organs and is typically fatal. In a company press release, Intellia's president and CEO John Leonard swiftly declared that its mRNA-based CRISPR therapy could usher in a "new era of potential genome editing cures."
Weissman predicts that turning CRISPR into an affordable therapy will become the next major frontier for mRNA over the coming decade. His lab is currently working on an mRNA-based CRISPR treatment for sickle cell disease. More than 300,000 babies are born with sickle cell every year, mainly in lower income nations.
"There is a FDA-approved cure, but it involves taking the bone marrow out of the person, and then giving it back which is prohibitively expensive," he says. It also requires a patient to have a matched bone marrow done. "We give an intravenous injection of mRNA lipid nanoparticles that target CRISPR to the bone marrow stem cells in the patient, which is easy, and much less expensive."
Meanwhile, the overwhelming success of the COVID-19 vaccines has focused attention on other ways of using mRNA to bolster the immune system against threats ranging from other infectious diseases to cancer.
The practicality of mRNA vaccines – relatively small quantities are required to induce an antibody response – coupled with their adaptable design, mean companies like Moderna are now targeting pathogens like Zika, chikungunya and cytomegalovirus, or CMV, which previously considered commercially unviable for vaccine developers. This is because outbreaks have been relatively sporadic, and these viruses mainly affect people in low-income nations who can't afford to pay premium prices for a vaccine. But mRNA technology means that jabs could be produced on a flexible basis, when required, at relatively low cost.
Other scientists suggest that mRNA could even provide a means of developing a universal influenza vaccine, a goal that's long been the Holy Grail for vaccinologists around the world.
"The mRNA technology allows you to pick out bits of the virus that you want to induce immunity to," says Michael Mulqueen, vice president of business development at eTheRNA, a Belgium-based biotech that's developing mRNA-based vaccines for malaria and HIV, as well as various forms of cancer. "This means you can get the immune system primed to the bits of the virus that don't vary so much between strains. So you could actually have a single vaccine that protects against a whole raft of different variants of the same virus, offering more universal coverage."
Before mRNA became synonymous with vaccines, its biggest potential was for cancer treatments. BioNTech, the German biotech company that collaborated with Pfizer to develop the first authorized COVID-19 vaccine, was initially founded to utilize mRNA for personalized cancer treatments, and the company remains interested in cancers ranging from melanoma to breast cancer.
One of the major hurdles in treating cancer has been the fact that tumors can look very different from one person to the next. It's why conventional approaches, such as chemotherapy or radiation, don't work for every patient. But weaponizing mRNA against cancer primes the immune cells with the tumor's specific genetic sequence, training the patient's body to attack their own unique type of cancer.
"It means you're able to think about personalizing cancer treatments down to specific subgroups of patients," says Mulqueen. "For example, eTheRNA are developing a renal cell carcinoma treatment which will be targeted at around 20% of these patients, who have specific tumor types. We're hoping to take that to human trials next year, but the challenge is trying to identify the right patients for the treatment at an early stage."
Repairing Damaged mRNA
While hopes are high that mRNA could usher in new cancer treatments and make CRISPR more accessible, a growing number of companies are also exploring an alternative to gene editing, known as RNA editing.
In genetic disorders, the mRNA in certain cells is impaired due to a rogue gene defect, and so the body ceases to produce a particular vital protein. Instead of permanently deleting the problem gene with CRISPR, the idea behind RNA editing is to inject small pieces of synthetic mRNA to repair the existing mRNA. Scientists think this approach will allow normal protein production to resume.
Over the past few years, this approach has gathered momentum, as some researchers have recognized that it holds certain key advantages over CRISPR. Companies from Belgium to Japan are now looking at RNA editing to treat all kinds of disorders, from Huntingdon's disease, to amyotrophic lateral sclerosis, or ALS, and certain types of cancer.
"With RNA editing, you don't need to make any changes to the DNA," explains Daniel de Boer, CEO of Dutch biotech ProQR, which is looking to treat rare genetic disorders that cause blindness. "Changes to the DNA are permanent, so if something goes wrong, that may not be desirable. With RNA editing, it's a temporary change, so we dose patients with our drugs once or twice a year."
Last month, ProQR reported a landmark case study, in which a patient with a rare form of blindness called Leber congenital amaurosis, which affects the retina at the back of the eye, recovered vision after three months of treatment.
"We have seen that this RNA therapy restores vision in people that were completely blind for a year or so," says de Boer. "They were able to see again, to read again. We think there are a large number of other genetic diseases we could go after with this technology. There are thousands of different mutations that can lead to blindness, and we think this technology can target approximately 25% of them."
Ultimately, there's likely to be a role for both RNA editing and CRISPR, depending on the disease. "I think CRISPR is ideally suited for illnesses where you would like to permanently correct a genetic defect," says Joshua Rosenthal of the Marine Biology Laboratory in Chicago. "Whereas RNA editing could be used to treat things like pain, where you might want to reset a neural circuit temporarily over a shorter period of time."
Much of this research has been accelerated by the COVID-19 pandemic, which has played a major role in bringing mRNA to the forefront of people's minds as a therapeutic.
"The pandemic has really shown that not only are mRNA approaches viable, they could in certain circumstances be vastly superior to more traditional technologies," says Mulqueen. "In the future, I would not be surprised if many of the top pharma products are mRNA derived."
"Making Sense of Science" is a monthly podcast that features interviews with leading medical and scientific experts about the latest developments and the big ethical and societal questions they raise. This episode is hosted by science and biotech journalist Emily Mullin, summer editor of the award-winning science outlet Leaps.org.