It's been a little over four years since a five-minute video brought the scientific community to a standstill. In the clip, Chinese scientist Dr He Jiankui claimed he'd created the world's first genome-edited babies – twin girls called Luna and Nala. He is said to have recruited couples whose husbands were living with HIV. He offered to edit the genomes of their embryos to not only prevent inheritable transmission but prevent them and all future generations ever catching the disease.
After initial praise, his methods and motivations were called into question. In the time since, He has been sent to prison for his part in the research, and subsequently released. The researchers behind the technology used by He received the Nobel Prize for Chemistry, and the first gene-edited tomato has gone on sale in Japan. Three examples of just how varied and complex the narrative around gene editing is.
In fact, ever since scientists first announced they had found a way to edit genomes in 2012, using a tool known as CRISPR-Cas9, the technology has been both lauded and marred by controversy in almost equal measures. On one hand, gene editing holds incredible promise in eradicating disease in plants, animals and humans. There are more than 16,000 deletion variants – small numbers of DNA bases missing from a person's genome – that have been causally linked to disease. In cystic fibrosis patients, as one example, some 70 per cent of cases are caused by the deletion of just three DNA bases. Editing these could improve the quality of life and lifespan of millions.
Yet fears about how such technology could be used (and abused) continue to fuel the debate around whether its benefits outweigh its dangers – fears that were somewhat confirmed when He posted his landmark video, and which have snowballed since.
Before we detail where the debate around genetic manipulation stands today, it's worth providing context. Gene editing allows scientists to add, replace, remove or disable sections of existing DNA to achieve a desired effect. It's fundamentally different from gene modification. Gene modification involves introducing DNA from one species into the genome of another to achieve an outcome. The first genetically modified organisms, or GMOs, date back to the mid-1970s, 40 years before anyone had heard of CRISPR-Cas9.
The changes made using genetic modification are typically faster and more extreme, whereas gene editing is closer to conventional breeding processes. Which raises a pertinent point.
Humans have been 'editing' the genomes of plants and animals for centuries through selective breeding. You only need to look at the hundreds of species of dogs, cattle or sheep that have been bred to meet certain needs. Or the fact we've bred new strains of vegetables and fruits. The humble mustard plant was the source of today's cabbages, cauliflower, broccoli and brussels sprouts, to take just one example.
The reason why modern genetic manipulation techniques are seen as so controversial, in comparison, is largely because they're more direct and explicit. It's also in the language that's used.
"Plant breeding has evolved over a thousand years and gene editing is simply the next step, yet people don't necessarily view it in this way, and I think that's because of the use of the word 'gene'," says Professor Lesley Torrance, plant virologist and executive director of science at the James Hutton Institute in Scotland. "If it was called precision breeding, which is what it is, it may not have seen the same resistance." It's notable that the UK government used that term for the Genetic Technology (Precision Breeding) Act, which received Royal Assent on 23 March 2023.
Then there's the general tendency for any new technology to be viewed with cynicism and an innate fear of the unknown.
"Many people look back on the early conventional breeding technologies nostalgically and see the idea of grafting apples, for instance, as quaint," comments Ruth Garde, creative producer of the Francis Crick Institute's Cut + Paste genome editing exhibition in London. "It feels more 'natural' than people in lab coats making injections in cells with syringes. New technologies bring uncertainty and there's a widespread aversion to synthetic things, especially when they see it as people 'playing god'. As a result, gene editing feels more divorced from nature, and this makes it more unpalatable."
Image credit: Great Ormond Street
Yet the technologies are also deeply rooted in confusion. A large problem surrounding the ethical debate on genetic manipulation is that editing and modification are often used interchangeably, and are even regulated in the same way in certain states. As a result, the concerns surrounding gene modification are often cited alongside, or confused with, those surrounding gene editing, despite gene editing being closer in technique and outcome to conventional breeding. This makes it a complex terrain to navigate.
This confusion is pertinent to understanding where at least some of the criticism and debate stems from – as are the key areas where the technology is being used today.
One of the most well-studied, and most debated, use cases for genetic editing is in agriculture.
In an increasingly warming world with a swelling population, the need for crops capable of growing in all environments to meet the needs of billions of people is one of the world's most pressing concerns. Thousands of researchers worldwide are turning to gene editing to solve this problem.
In the past three years alone, researchers have edited the rice genome to increase disease resistance, boosted the yield of maize crops by as much as 10 per cent by turning off a specific gene, and reduced the amount of a potential carcinogen found in wheat – field trials of which were the first in Europe. In 2021, the first gene-edited tomatoes with high amounts of gamma-aminobutyric acid went on sale in Japan. This chemical is linked with lowering blood pressure.
And it's not just the final product that can potentially benefit humanity. Gene editing is a key research tool for understanding gene function in plants more generally. The James Hutton Institute (JHI) has been able to determine why some potatoes cook quickly and others don't, for instance. This brings the possibility of producing potatoes that cook in half the time and use half the fuel, but it also helps researchers gain wider understanding about the potato genome. This in itself can inspire and unlock further breakthroughs around crop resilience, land management, nutritional content and more. This research has additionally helped JHI unlock the genome sequence of the yellow potato cyst nematode to see how it infects the plant and how it can be stopped.
The benefits these studies (and others like them) promise in improving the resilience and availability of crops are widely accepted. Yet that doesn't mean the gene-editing techniques being used to tackle these concerns are without criticism.
A review paper from 2020 is just one example calling for extensive field trials to test the performance of edited crops. A particular concern is to ensure that the editing of one gene doesn't create an unintended consequence by compromising another.
In fact, the potential for unintended consequences – or off-target effects – of gene editing remains one of the strongest arguments against the widespread adoption of the technology – especially when it applies to humans.
In October 2020, the same month the developers of CRISPR-Cas9 were awarded the Nobel Prize, a study revealed just how damaging off-target effects could be. While using CRISPR-Cas9 in human embryo cells to edit a gene that causes hereditary blindness, researchers found that around half of the specimens lost large or entire segments of chromosomes as a consequence of the edits.
Then there are concerns about the unintended consequences of gene editing on future generations. Changes made to an individual's genome could be passed down to their offspring, potentially affecting future generations in ways we cannot yet anticipate. This raises the question of whether we have the right to make such decisions on behalf of future generations, and was at the centre of many concerns raised around Dr He's research.
Beyond the direct impact, there are longer-term impacts to consider, such as the perpetuation of existing social inequalities. In a world where some people have access to gene therapy or 'designer babies' and others don't, those who can afford it could become 'genetic haves' while those who can't become 'genetic have-nots'. This not only raises questions about what constitutes fair competition, but also about genetic diversity.
Genetic diversity is essential for the survival of a species, as it allows for adaptations to new environments and resistance to diseases. Altering genes in a way that eliminates certain traits or creates uniformity could have long-term consequences for the species as a whole.
To advance the technology and address the potential for off-target consequences, CRISPR-inspired techniques have evolved in recent years to become more precise.
Base editing, for instance, allows scientists to change a single 'letter' or nucleotide using an enzyme called a base editor, without cutting DNA or affecting the rest of the gene.
Prime editing takes things a step further. It uses a prime editor enzyme that is guided to the location in the DNA where a change is needed. Once at the target site, the editor cuts the DNA strand and uses a molecule as a template to insert new genetic material.
"CRISPR-Cas9 started off as a tool to disrupt gene function," Dr Leopold Parts, a geneticist at Wellcome Sanger Institute, told E&T. "It works well but can be messy. Base and prime editors develop on this formula to enable more precise DNA modifications."
The early signs are promising. In December 2022, base-edited T-cells were successfully used to treat a patient's leukaemia, where chemotherapy and bone marrow transplant had failed.
Yet these techniques aren't without their own difficulties. "Prime editing is such a powerful technology but that comes at the cost of higher complexity," Parts continues. "There are many parts to the prime editing system which all interact with each other. Each region in the genome can produce different results when targeted, and each type of mutation that can be created behaves differently."
To address this, Parts has developed an algorithm to predict the chances of a mutation being successful. "Prime editing systems are being trialled to eventually enter the clinic and address genetic diseases that are currently not possible to address with any other technology. Studies like ours are required to help transform this technology into a productive tool, and into safe and effective medicine." With safe being the operative word here.
As a direct consequence of Dr He's YouTube announcement, the Chinese government tightened the rules around gene editing in humans. The World Health Organization separately convened an expert advisory committee to "examine the scientific, ethical, social and legal challenges associated with human genome editing" and it called on all countries to "not allow any further work in this area" until its implications had been properly considered.
The rules regarding gene editing in plants and non-human embryos are more open in comparison. In a growing number of countries, non-human genome editing is largely equated with conventional breeding and thus the regulations are less strict. A significant exception to this is the European Union. Under a 2018 directive, the EU considers any plant that has been genetically manipulated to be a GMO and thus its development, import and export is bound by the same laws that restrict GMOs.
When the UK left the EU, the government pushed through the Genetic Technology (Precision Breeding) Act in a bid to allow for genetic editing in plants "where genetic changes could have occurred naturally or could have been a result of traditional breeding".
In his video, He likens the criticism of gene editing to "the media-hyped panic about Louise Brown's birth as the first IVF baby". He goes on to say: "For 40 years regulations and morals have developed together with IVF... to help more than eight million children come into the world." In this way, he believes gene surgery is simply another IVF advancement and, in the future, will be as commonplace and accepted as IVF.
Yet regulation can only do so much. Francis Crick Institute's Garde believes that if we're to strive for equity in the technology, we need to be striving for equity in the conversations that are taking place around it.
"We need dialogue, and people who are systemically marginalised need to be in these conversations. You only need to look at the speakers at genome editing summits to see that few people with lived experience of genetic conditions are included. The topic is discussed through a medical lens, and it needs to be viewed more widely and with much greater context."
She adds: "We also need to ask the question whether a technical solution is always the most appropriate. On face value, genome-editing cows to produce less methane seems like an obvious choice in tackling climate change. Yet the climate crisis is more nuanced. We should be looking at what has created the climate crisis and how else should we be managing it. Should we be eating less beef? Should we be using land in more ecologically sound ways? For every technical solution, we should also be looking at the social, political and economical solutions."
Also looking at food production, JHI's Torrance adds: "We should be looking at regulations that consider the safety of the finished product, instead of regulating the way a product is produced." In other words, if a food item is safe to eat, it's safe to eat regardless of how it was produced. Doing this would still guarantee the safety of food but would do so in a way helps us meet the ever-growing need for more sustainable crops as the climate change clock keeps ticking.
And that final point is key. "Climate change means we have to develop crops that grow in changing environments, and we need them in the next 10 years," Torrance continues. "Conventional breeding will take too long. Genome editing is the only way we're going to see the sustainable advancement and development of crops that address the very pressing need the planet and its people are facing."
In short, there is a time-critical need – not just a want – for the debate on gene editing to move on. For better or for worse.
From 'scissors' to the molecular word processor
Developed in 2012, CRISPR-Cas9 is seen as the gene-editing technology that made the process easier and more accessible. Dubbed 'molecular scissors', the technology allows researchers to cut DNA at any position in the genome in order to remove, add or alter sections of the DNA sequence.
Base editors expand on CRISPR-Cas9 and are known as 'molecular pencils' due to their ability to substitute single bases of DNA. They don't cut the DNA strand; instead, they use an enzyme called a base editor to change a single 'letter' or nucleotide without affecting the rest of the gene.
The latest gene-editing tools, created in 2019, are called prime editors. They build on both CRISPR-Cas9 and base editors by using a prime editor enzyme to search and replace operations directly on the genome with a high degree of precision. This has led to them being dubbed 'molecular word processors'. (See diagram)
