The rapid progress in genetic technologies is bringing the transformative potential of gene editing closer to reality. Revolutionary tools like CRISPR have given scientists unprecedented abilities to precisely target and modify DNA. This breakthrough is opening up countless possibilities and revolutionizing diverse fields from healthcare to agriculture and conservation. The gene editing industry is projected to reach a valuation of approximately $36 billion by 2027 and is expected to continue its significant growth.
This article will explore the areas already being transformed by gene editing, examine emerging applications and technologies, and discuss the challenges that must be overcome to fully realize the potential of gene editing.
Gene Editing: A Journey from Past to Present
The journey of gene editing is a long and intricate one, marked by milestones from early transduction experiments in the 1960s, the creation of the first recombinant DNA molecules in the 70s, to the introduction of insulin, the first GMO consumer drug. For a comprehensive overview, refer to our previous article, ‘Gene Editing: A Controversial Legacy.’
However, perhaps even more debated than its history is the future of gene editing. With ongoing advancements in increasingly complex technologies, charting its future direction can be challenging. The vast potential within this field makes almost anything seem achievable.
While the world isn’t quite like a science fiction movie yet, gene editing is already in practical use. Prominent examples include modifying T-cells in cancer treatment (CAR-T therapy) and employing gene editing tools in drug discovery.
But what are the next steps in the evolution of gene editing? Where is the future of this technology leading us?
The Critical Need for Enhanced Precision in Gene Editing
While early gene editors like restriction enzymes and zinc finger nucleases remain useful in laboratory settings, the future of gene editing depends on more innovative and advanced technologies that offer greater precision and control.
CRISPR-Cas9 and its immense potential are widely recognized. This technique gained prominence in 2012, thanks to the pioneering work of Jennifer Doudna, Emmanuelle Charpentier, and Feng Zhang, and was recognized with the 2020 Nobel Prize in Chemistry. Despite the continuous stream of CRISPR-related research and news, it is no longer the most cutting-edge tool in the gene editing toolkit.
Base editing is a more recent advancement in gene editing technologies. Developed by David Liu in 2016, base editing works by chemically modifying DNA bases instead of creating double-strand breaks (DSBs) like CRISPR. This approach has the potential to reduce off-target effects and enhance the accuracy of gene editing. Furthermore, the development of prime editing has further revolutionized the field, enabling the generation or correction of any type of point mutation. This capability exceeds the limitations of base editors, which have restrictions on the types of changes they can make.
Figure 1: Different gene editing techniques are illustrated in a diagram, showcasing the evolution from older methods to newer, more precise approaches like CRISPR, base editing, and prime editing. (Diagram adapted from Matsoukas, 2020).
While CRISPR’s potential remains significant, researchers are continually finding ways to improve and complement this technology. For instance, a research team has developed synthetic RNA-guided nucleases that offer better specificity than the commonly used Cas9 protein. Therefore, while the Nobel Prize-winning CRISPR technology is foundational, the future of gene editing is likely to be shaped by new and improved technologies, many of which are still in the early stages of development.
Gene Editing’s Transformative Impact on Health: Future Applications
Predicting the exact future impact of gene editing technologies is impossible, but we can examine some promising examples that offer a glimpse into what lies ahead.
In a significant achievement earlier this year, scientists successfully corrected the genetic mutation responsible for sickle cell disease. This widespread and debilitating condition results in misshapen red blood cells that impair oxygen transport throughout the body. Sickle cell disease is caused by a point mutation in the haemoglobin-Beta (HBB) gene. Previous efforts to treat it used base editors to eliminate the harmful mutation. However, base editing’s limitation in converting thymine to adenine prevented the restoration of the wild-type allele. Prime editing provided a solution to this challenge. By accurately correcting the mutation and restoring a healthy version of the gene, prime editing demonstrated remarkable effectiveness in mice.
Similarly, researchers have recently utilized CRISPR-Cas9 technology to perform gene editing within the lungs of mice. Delivering gene editing tools to lung cells has historically been difficult due to the lung’s complex structure. By optimizing lipid nanoparticles to transport the CRISPR-Cas9 system to lung tissue, the team successfully altered the genetic material for the first time. This offers new hope for treating conditions like cystic fibrosis.
Moreover, a recent breakthrough demonstrated the ability to eliminate antimicrobial resistance (AMR) genes from bacteria using CRISPR technology. This is particularly important given the serious threat of AMR, which is projected to cause 10 million deaths annually by 2050. This application of gene editing could revolutionize healthcare by directly addressing this critical global health issue.
Figure 2: A graphical abstract illustrates the application of CRISPR-Cas9 technology in combating antimicrobial resistance, representing a significant advancement in addressing global health threats. (Image from Walker-Sunderhauf et al., 2023).
Expanding Gene Editing’s Reach: Agriculture and Conservation
The potential of gene editing extends beyond healthcare into agriculture, offering opportunities to improve food security, reduce waste, and address challenges related to climate change. Applying gene editing to modify crop genomes is a subject of intense research and debate. It offers the prospect of enhancing food production and potentially eliminating the need for harmful pesticides, benefiting both consumers and the environment. However, despite its significant potential, the widespread use of gene editing in crops is not yet common, mainly due to concerns about the safety of genetically modified products.
Beyond GMO production, gene editing’s ability to combat AMR has implications for agriculture. A significant portion of AMR cases originate within the food chain, highlighting the need for solutions beyond healthcare. Integrating gene editing in agriculture provides a multifaceted approach to address various challenges and promote sustainable practices.
Gene editing also offers promising tools for conservation efforts and protecting endangered species. For example, researchers at the University of California, Davis, discovered that CRISPR can be used to create screens for the identification of endangered fish among similar-looking species. This innovative use of CRISPR could transform conservation and ecology fields. Many see these technologies as crucial for combating climate change and preserving biodiversity, although these applications are still in development.
The Regulatory Landscape: Navigating the Path Forward for Gene Editing
Given the vast potential of gene editing, why are these tools not being utilized to their full capacity?
Several obstacles impede the widespread application of gene editing, despite its revolutionary possibilities. Optimizing these technologies is still a work in progress, and many applications have only been tested in model organisms.
Currently, gene editing is subject to strict regulations. While significant progress has been made, the field is still relatively new, and the long-term side effects of gene editing are not fully understood. A crucial distinction exists between somatic gene editing, which affects specific cells or tissues in an individual, and germline gene editing, which alters heritable genetic material passed to future generations. Germline gene editing raises additional ethical and safety concerns.
A 2020 study examining genome editing policies in 106 countries revealed that 75 prohibit heritable human genome editing in early-stage embryos for IVF, and no country explicitly permits it. Using edited embryos in reproduction raises serious concerns about potential long-term consequences for future generations that have not been adequately evaluated. The uncertainty surrounding the long-term effects of germline gene editing contributes to stringent regulations. These concerns underscore the need for ongoing research and careful ethical deliberation to ensure responsible decision-making.
The case of Chinese scientist He Jiankui highlights the risks of unregulated gene editing. In 2018, He Jiankui announced he had modified the genomes of twin girls to protect them from HIV. While seemingly beneficial, his actions were widely condemned due to safety concerns and ethical violations. Furthermore, the edited gene, CCR5, while providing HIV resistance, also plays a role in immunity to other diseases, raising concerns about unintended and long-term health consequences.
He Jiankui faced imprisonment for his experiment, but has reportedly continued his gene editing work. His actions led the Chinese government to tighten regulations on genome editing. Despite the condemnation, some, like George Church, a prominent figure in genomics, have argued for a more nuanced perspective on He’s work, suggesting he was a ‘sacrificial lamb’ in the field.
Figure 3: He Jiankui is pictured speaking at the Second International Summit on Human Genome Editing, where he announced the controversial alteration of twin girls’ embryos, causing widespread shock and ethical debate within the genomics community.
Gene editing in agriculture also faces strict regulations. This year, the EU announced plans to heavily regulate CRISPR-modified crops. Concerns include the possibility of unintended mutations in the genome and the uncertain long-term impacts of these changes. Policymakers aim to balance the potential benefits of gene editing in agriculture with the critical need to address safety and environmental concerns through robust regulations.
Quality Control: Ensuring Safety and Efficacy in Gene Editing
Will regulations eventually permit the widespread application of gene editing?
A major challenge is quality control. CRISPR, a widely used gene editing tool, is known to have off-target effects.). A 2022 study found that CRISPR increased off-target DNA rearrangements in about 5% of human cell line samples, which could potentially lead to cancer.
However, extensive research is underway to address this issue, including the development of in silico prediction tools and DSB-free CRISPR systems that reduce the risk of harmful off-target cuts. New systems for assessing gene editing quality, such as Droplet DigitalTM PCR, are improving the precision of quantification methods. Base and prime editing strategies also help mitigate these risks due to their more precise mechanisms, leading to fewer harmful off-target effects than traditional CRISPR systems.
Concerns also exist about the actual efficacy of gene editing, particularly in agriculture. Fully understanding the long-term effectiveness of a gene editing procedure can take years. Widespread implementation in agriculture is also hindered by the lack of large-scale testing outside labs, limiting our ability to assess true effectiveness and implement proper quality control.
Delivery Challenges: Getting Gene Editing Tools to the Right Place
Another significant hurdle in gene editing is delivery. Despite the immense potential of gene editing tools, transporting them effectively to target cells, especially in humans, remains a major challenge. Some researchers consider delivery the ‘biggest challenge’ in gene editing. Viral vectors are commonly used for CRISPR delivery, but they can cause severe immune reactions and, in some cases, carcinogenesis. Lipid nanoparticles show promise for improving delivery, but are not yet fully efficient.
Recently, a study suggested that a patient’s death in a Duchenne muscular dystrophy gene editing study was linked to the viral vector used for delivery, rather than the CRISPR treatment itself. This highlights the need for further research to overcome delivery challenges before gene editing can be widely and safely applied.
Ethical Considerations: Navigating the Moral Landscape of Gene Editing
Beyond safety, the ethical and moral aspects of gene editing raise complex questions. Opinions on gene editing applications vary widely depending on the context, from GMOs to pharmaceuticals.
Informed consent is a major ethical concern. Germline editing raises the issue of imposing consequences on future generations who cannot consent to genome alterations.
Access to gene editing also raises ethical questions. The potential for high costs and limited scalability of personalized gene therapies raises concerns about exacerbating health inequalities. A Nature review suggests that the gene editing revolution may fail if pricing issues are not addressed, leading to unequal access.
To address health equity and ethical concerns, the World Health Organization released new guidelines in 2021 on the future of gene editing. WHO Director-General Tedros Adhanom Ghebreyesus stated, ‘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.’ The guidelines address safety, education, and global equity in gene editing.
Perhaps the most profound ethical question is ‘where do we draw the line?’ This moral dilemma is central to the gene editing industry. Even if safety, efficacy, and equality issues are resolved, should gene editing be permitted in all circumstances? Should individuals be allowed to use gene editing to enhance appearance, intelligence, or personality, and what would be the societal impact? These questions remain unanswered but will likely be critical in future discussions about gene editing.
The Future of Gene Editing: Emerging Now
While predicting the future with certainty is impossible, we are already seeing the future of gene editing unfold.
Earlier this year, the United Kingdom passed the Genetic Technology (Precision Breeding) Act, allowing the breeding of genetically modified crops to enhance food security. ‘Precision breeding,’ used in research labs for over a decade, is considered relatively safe, mimicking natural mutations. This new law aligns with regulations in countries like the US and Australia and marks a divergence from the European Union, which currently restricts this form of gene editing. The UK government is now focused on ensuring high standards for introducing these GMOs into the food supply.
The UK’s fertility agency, HFEA, has also deemed the use of gene editing for ‘three-parent babies’ ‘morally permissible if it is in the future child’s interests and does not add to the kinds of inequalities that already divide society.’ This has led to the first three-parent baby born in the UK, using mitochondrial DNA from a donor egg.
Recently, gene editing pioneer Feng Zhang and his team developed what is being called the ‘next CRISPR.’ Using AI and protein engineering, they created a delivery system based on a natural bacterial mechanism to deliver material into human cells. This system has shown promise in killing cancer cells, and Zhang believes it addresses a bottleneck in developing effective gene therapies.
Figure 4: This image illustrates the concept of Zhang’s new protein delivery system, the extracellular contractile injection system (eCIS), a nanoscale tube-like structure for injecting proteins into host cells, representing a significant advancement in delivery technology. (Adapted from Kreitz et al., 2023).
Despite current regulations limiting the full utilization of gene editing, we are clearly on the verge of a revolution. The focus now must be on ensuring equity, efficacy, and education to make these technologies accessible and, most importantly, safe.
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