Gene-editing therapy – using biotechnological techniques to replace a “faulty” gene with a properly functioning one – is now a reality. In 2020 a young woman in the US suffering from sickle-cell anaemia underwent an experimental treatment that made changes to her DNA. Sickle-cell disease is caused by a heritable variant of a gene that produces haemoglobin, the protein that carries oxygen in red blood cells. It can result in extreme pain and is life-threatening. In the 2020 trial, a gene-editing tool called CRISPR, using enzymes found in some bacteria, was used to snip out the errant gene from the patient’s blood-forming stem cells extracted from her bone marrow and replace it with a “healthy” version of the gene. The cells were then returned to her body. In late 2023 both the US Food and Drug Administration and the UK’s Medicines and Healthcare products Regulatory Agency approved a therapy called Casgevy based on the same principle.
Since many diseases are influenced by our genes, some herald such editing of the human genome as a new era in medicine. But diseases associated with just a single gene, like sickle-cell disease and thalassemia (which Casgevy can also tackle), are the exception. Most common diseases, such as heart disease, type 2 diabetes, and susceptibility to cancers, are influenced by several or even many different genes: they are polygenic. To address such problems using genome editing would demand editing many genes at once, perhaps in a bespoke way for each individual, depending on their genetic make-up.
Could that be done? A paper recently published in Nature suggests that polygenic genome editing of disease-linked gene variants in IVF embryos could indeed have significant benefits for human health, lowering the risk of common conditions such as coronary heart disease, schizophrenia and Alzheimer’s. They say that editing 10 genes could bring a 50-fold reduction in the prevalence of type 2 diabetes in the population. Such changes would be inheritable by later generations. The researchers haven’t actually tried this – such embryo gene editing isn’t legal in the UK, and polygenic genome editing is still in the early experimental stage. Rather, they have conducted mathematical modelling, based on what we know about disease-associated genes, to predict how much effect it would have in a population.
Unusually, Nature simultaneously published a commentary on this work by other researchers arguing that polygenic editing against disease “is unsafe and unproven” and that it would be foolhardy to try it given what we do and don’t know about the links between genes and diseases and the effects of editing. The critics are correct.
Some of the problems with polygenic genome editing are agreed by all. Gene-editing tools like CRISPR are not 100% accurate, and are likely to create some “off-target” effects, altering the genome elsewhere – with unpredictable consequences. The more genes that are being altered, the greater the chance that this will occur. But even with more accurate editing, there are fundamental uncertainties. Simplistic narratives about the genome as our “instruction book”, long promoted in genetics, encourage a misleading view of how variations in genes lead to differences in traits or disease risks. In fact, the risks associated with many disease-linked genes vary depending on our other genes and our lifestyles.
Besides, many, maybe most, human genes affect not just a single trait but several. If you tamper with a gene to influence one trait, you may be altering others in ways you don’t know about – perhaps raising the risk of some other condition. In essentially single-gene diseases like sickle-cell anaemia, we can be pretty confident about the effects of gene editing (so long as it happens in the right place). But we don’t understand the relationships between our genes or the influences on traits and disease anything like well enough to contemplate tampering with whole suites of genes. The new study’s authors acknowledge these uncertainties, but their critics say they underestimate the dangers they pose.
Nature claimed in an editorial that it was publishing the paper despite such concerns because it is important to start the conversation about polygenic genome editing now. This is a risky gambit. Private-sector medicine is not regulated everywhere as tightly as it is in the UK, particularly in the US, and companies will surely be considering polygenic genome editing to be a commercial opportunity – not even just for health-related reasons, but also to “enhance” positive characteristics such as intelligence. The existence of a paper in the prestigious pages of Nature apparently demonstrating the potential of such a procedure will surely be used to advertise its benefits, regardless of the caveats expressed by others.
