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Unlocking the future: where is gene editing going next?

As advancements in genetic technologies accelerate at an astonishing pace, the potential for gene editing to transform our world becomes closer to being realised. With the advent of revolutionary tools like CRISPR, scientists now possess an unprecedented ability to target and modify DNA with exceptional precision. This has opened the door to a myriad of possibilities, revolutionising fields as diverse as healthcare, agriculture, and conservation. The gene editing industry is predicted to be worth around $36 billion by 2027, and will continue to grow.

In this feature, we explore the areas already being transformed by gene editing and delve into emerging applications and technologies, while also addressing the obstacles that must be overcome to fully unlock the potential of gene editing.

The past and the present

From early transduction experiments in the 1960s, the first recombinant DNA molecules in the 70s, and the introduction of the world’s first GMO consumer drug – insulin – the history of gene editing is long and complex. To get an overview of this topic, you can check out our recent feature ‘Gene Editing: A Controversial Legacy.’

But the only thing perhaps more controversial than the history of gene editing is its future. With continuing development of increasingly intricate technology, it can be hard to tell where the path is heading. And with so much potential in the field, almost anything seems possible.

Whilst the world we live in does not yet resemble a science fiction movie, gene editing is in fact already widely used – famous examples include the alteration of T-cells in cancer treatment (CAR-T therapy), and the use of gene editing tools in drug discovery.

But where are we headed next?

A need for precision

Early gene editors like restriction enzymes and zinc finger nucleases are still commonly used in a laboratory setting, but the future of gene editing hinges on more innovative and novel technologies.

You would be hard pressed to find someone who hasn’t heard of CRISPR-Cas9 and its immense potential. This technique gained prominence in 2012 thanks to Jennifer Doudna, Emmanuel Charpentier and Feng Zhang, and was the subject of the 2020 Nobel Prize in Chemistry. Nevertheless, despite the continuous influx of CRISPR-based research and news stories, it is no longer the most cutting-edge gene editing tool available.

Base editing is one of the more recent gene editing technologies. Pioneered by David Liu in 2016, base editing operates by chemically altering bases rather than introducing double strand breaks (DSBs) in the same way that CRISPR does. This has the potential to mitigate off-target effects and improves the accuracy of the process. Additionally, the advent of prime editing has further revolutionised the field, with the ability to generate or correct any kind of point mutation. This surpasses the capabilities of base editors, which are limited in the changes they can make.

Figure 1: Diagram showing different gene editing techniques. Taken from Matsoukas, 2020.

And while CRISPR’s potential has certainly not diminished, many scientists have come up with ways to complement the technology. For example, one team of researchers have developed synthetic RNA guided nucleases that allow for better specificity than the commonly used Cas9 protein. Therefore, whilst the Nobel-prize winning efforts certainly deserve their status, it is likely that the future of gene editing will rely on new and improved technology, most of which we haven’t even heard of yet.

Transforming our health

There is no crystal ball that can tell us how gene editing technologies will change our world. But why don’t we take a look at some up-and-coming examples?

In April of this year, researchers achieved a significant breakthrough by successfully correcting the mutation responsible for sickle cell disease. This debilitating, yet alarmingly prevalent, condition is characterised by the presence of misshapen blood cells that cannot adequately transport oxygen throughout the body. The disease stems from a point mutation in the haemoglobin-Beta (HBB) gene, and previous attempts to combat it used base editors to eliminate the detrimental mutation. However, due to the limitations of base editing – specifically its inability to convert thymine to adenine – restoration of the wild type allele was not possible. Prime editing emerged as a solution to this challenge. By effectively correcting the mutation and reinstating a healthy version of the gene, prime editing demonstrated remarkable efficacy in mice.

Similarly, researchers have also recently used CRISPR-Cas9 technology to perform gene editing in the lungs of mice. This has previously been a challenge due to the difficulties faced when trying to deliver gene editing tools to cells within the lung – a notoriously difficult cell-type to reach. By enhancing lipid nanoparticles to transport the CRISPR-Cas9 system to the tissue, the team were able to effectively alter the genetic material for the first time – giving hope to those with conditions such as cystic fibrosis.

Furthermore, a recent breakthrough has showcased the ability to eliminate antimicrobial resistance (AMR) genes from bacteria using CRISPR technology. This achievement holds immense significance, considering the grave threat posed by AMR, which is projected to cause the deaths of 10 million people annually by 2050. This application of gene editing has the potential to revolutionise healthcare by addressing this critical issue.

Figure 2: Graphical abstract describing the use of CRISPR-Cas9 to combat antimicrobial resistance. Taken from Walker-Sunderhauf et al., 2023.

The wider world

Gene editing holds tremendous potential not only in healthcare but also in the field of agriculture. The application of gene editing techniques to alter crop genomes has become a subject of extensive discussion and research in recent years. This offers the opportunity to enhance food security, minimise waste, and address challenges stemming from climate change. Furthermore, there is potential to eventually eliminate the need for harmful pesticides, benefiting both consumers and the environment at large. However, despite its immense potential, gene editing in crops is not yet widely carried out, primarily due to uncertainties surrounding the safety of the end-products.

However, the advantages of gene editing in agriculture extend beyond the production of GMOs. As mentioned earlier, gene editing methods have the potential to combat AMR. This has significant implications within the agricultural community, as a substantial proportion of AMR cases emerge from within the food chain rather than through healthcare alone. Therefore, the integration of gene editing approaches in agriculture offers a multifaceted opportunity to address various challenges and promote sustainable practices.

Gene editing also has potential to help with conservation efforts and protect endangered species. For example, researchers from University of California, Davis, discovered that CRISPR could be used to create screens that allow for the identification of endangered fish amongst groups of similar looking sea creatures. This non-traditional approach to using CRISPR could revolutionise the conservation and ecology fields. Many see these technologies as an effective means to combat climate change and protect biodiversity, but we are not quite there yet.

A highly regulated practice

Why then are we not currently using these tools to their full potential?

As much as the technology could revolutionise these fields, there are several barriers that hinder the widespread application of gene editing. There is still much to be done to optimise the use of these approaches, and it is vital to remember that many applications have only been tested in model organisms.

Currently, gene editing is heavily regulated. Despite the huge advances made over the years, the field is still relatively young, and the side effects of gene editing are not fully known. Moreover, a crucial distinction exists between somatic gene editing, which affects specific cells or tissues in an individual, and germline gene editing, which modifies the heritable genetic material that can be passed down to future generations. Therefore, the implications of germline gene editing raise additional concerns and ethical considerations.

In a 2020 study of genome editing policy in 106 countries, it was revealed that 75 of these nations prohibit the use of heritable human genome editing in early-stage embryos for IVF, and not a single country explicitly permits this practice. The use of edited embryos in reproduction raises significant concerns about the potential long-term consequences for subsequent generations, which have not been thoroughly tested or evaluated. The lack of clarity regarding the long-term effects of germline gene editing has contributed to these stringent regulations surrounding its use. These concerns highlight the importance of ongoing research and dialogue to ensure responsible and well-informed decision-making.

An infamous case illustrating the consequences of illegal and untested gene editing is that of Chinese scientist He Jiankui. He made headlines when he announced in 2018 that he had modified the genomes of twin girls to protect them from HIV. Perhaps a novel pursuit on the surface, his actions were widely condemned due to safety concerns surrounding the procedure. Furthermore, the gene that was edited, known as CCR5, not only provides resistance to HIV but also plays a role in protecting against other diseases. This raised concerns about the unintended consequences and potential long-term effects of the procedure.

He Jiankui faced time in prison for his involvement in the experiment, but, surprisingly, has not given up on his gene editing endeavours. His actions also prompted the Chinese Government to tighten regulations around genome editing. Despite this, some believe that He Jiankui was a ‘sacrificial lamb’ in the gene editing community, and George Church, the ‘founding father of genomics’, stated that he felt ‘an obligation to be balanced’ when considering He’s work.

Figure 3: He Jiankui speaking at the Second International Summit on Human Genome Editing. He announced the alteration of the twins’ embryos at the summit, triggering shock in the genomics community.

The use of gene editing in agriculture is also highly regulated. In fact, just this year the EU have published plans to heavily regulate the use of CRISPR-modified crops. Concerns that have led to this decision include the idea that mutations could be made in areas of the genome that wouldn’t naturally occur, and the impacts of this remain uncertain. By implementing robust regulations, policymakers aim to strike a balance between the potential benefits of gene editing in agriculture and the need to address safety and environmental concerns.

A question of quality

So, will we ever get to a point where policy allows the widespread use of gene editing?

A significant hurdle is quality control. CRISPR, which is perhaps the most widely used gene editing tool currently available, is known for having considerable off-target effects. For example, a 2022 study revealed that the use of CRISPR in human cell lines led to off-target DNA rearrangements in around 5% of samples; rearrangements that could potentially trigger cancers.

However, there is a huge amount of work being done to combat this, such as the development of in silico prediction tools and the advent of DSB-free CRISPR systems that reduce the risk of harmful off-target cuts. There are also new systems for assessing the quality of gene editing strategies such as Droplet DigitalTM PCR, which improves upon the precision of current quantification methods. In addition, the use of base and prime editing strategies can somewhat address these risks, given that their precise mechanisms lead to far fewer harmful off-target effects than traditional CRISPR systems.

There are also concerns about the true efficacy of gene editing, particularly in an agricultural setting. It can take years to fully understand the effectiveness of a particular procedure, and we are yet to reach this chapter in the gene editing story. Widespread implementation of gene editing in an agricultural setting is also hindered by a lack of large-scale testing outside of the laboratory, meaning we have no way to truly know how effective the technology is or to perform proper quality control.

Delivering benefits

Another major hurdle in the gene editing world is delivery. Despite the unwavering potential of these tools, there have been significant issues noted regarding transport to cells, particularly in humans. Some researchers describe this as the ‘biggest challenge’ for gene editing. Currently, a common method of CRISPR delivery is the use of viral vectors. However, these tools can cause intense immune reactions and in severe cases can even lead to carcinogenesis. The widespread use of lipid nanoparticles holds promise in rectifying these issues, but is not yet fully efficient.

In fact, just this month a study suggested that the death of a patient in a Duchenne muscular dystrophy gene editing study was caused by the use of a viral vector, rather than by the CRISPR treatment itself. As such, there is still much research to be done before we can truly embrace the potential of gene editing.

The ethics of gene editing

In addition to safety considerations, the ethical and moral aspects of gene editing pose complicated questions. A plethora of different opinions exist regarding the applications of gene editing, which can vary depending on the specific context, whether you are discussing GMOs or pharmaceuticals.

For example, a major concern is informed consent. Some believe that if a patient undergoes germline editing, then they are forcing the consequences onto future generations who did not consent to the alteration of their genomes.

There are also qualms about access to gene editing – will it only be available to the wealthy? Currently, many personalised therapies extremely costly, and cannot be produced at scale. The idea that gene editing techniques could be prohibitively expensive has birthed concerns about a new type of health inequality. A review published earlier this year in Nature indicates that the gene editing revolution may fail if we do not address pricing issues.

To address the question of health equality and ethics, the World Health Organisation released new guidelines in 2021 relating to the future of gene editing. ‘Human genome editing has the potential to advance our ability to treat and cure disease, but the full impact will only be realized if we deploy it for the benefit of all people, instead of fuelling more health inequity between and within countries,’ stated Tedros Adhanom Ghebreyesus, WHO Director-General. The guidelines address a variety of issues, including safety, education and global equity in the field.

But perhaps the most important ethical question is ‘where do we stop?’ This moral dilemma is one that plagues the gene editing industry. Even if we solve all of the safety, efficacy and equality problems, should the practice be permitted in any circumstance? Should individuals have the opportunity to enhance their appearance, intelligence or personality with gene editing tools, and what impact would this have on society at large? These are questions that we simply cannot answer for now – but will likely be at the forefront of people’s minds in the future.

The future is now

Even though that crystal ball doesn’t exist, we’re already getting a glimpse into the future.

Earlier this year, the United Kingdom passed the Genetic Technology (Precision Breeding) Act, which allows for the breeding of genetically modified crops as a means to address food security. ‘Precision breeding’ has been used in research labs for over a decade and is believed to be relatively safe, only mimicking mutations that could have naturally arisen. The new law is similar to those enacted by countries such as the US and Australia, and is one of the UK’s first major deviations from the European Union, who do not yet allow this form of gene editing technology. The government are now working to ensure high quality and standards to introduce these GMOs into the food system.

The United Kingdom’s fertility agency HFEA has also decided that the use of gene editing to create so-called ‘three-parent babies’ is ‘morally permissible if it is in the future child’s interests and does not add to the kinds of inequalities that already divide society.’ However, the government does not view this type of editing in the same way as other germline editing techniques, and it is regulated in a distinct manner. These relaxations of the law have recently resulted in the first three-parent baby to be born in the United Kingdom, with mitochondrial DNA taken from a donor egg.

And even more recently, gene editing pioneer Feng Zhang and his team have developed what has been dubbed by some as the ‘next CRISPR.’ By using artificial intelligence and protein engineering, the researchers created a delivery system based off a natural bacterial characteristic that can deliver material to human cells. The work has so far shown promise in killing cancer cells, and Zhang believes the strategy addresses a bottleneck in creating effective therapies.

Figure 4: Image showing the basic concept of Zhang’s new protein delivery system. The extracellular contractile injection system (eCIS) is a 100-nanometre tube-like structure that can be used to inject and deliver proteins to host cells. Adapted from Kreitz et al., 2023.

It is clear that despite the regulations that currently prevent us from harnessing the full potential of gene editing, we are already well on our way to a revolution. Now, the work must be done to ensure equality, efficacy and education to make sure that new technologies are accessible and, above all, safe.