Our genes are responsible for many of the medical conditions that affect millions of people around the world. Until recently, the idea that we could alter the genes that we are born with was little more than science fiction. However, new discoveries in the field of genetics have led to rapid advancements which could radically change the way we treat disease – something as controversial as it is revolutionary. Luke Barnes tells us more.

Carlene Knight has, until recently, been blind since childhood. Born with a genetic eye condition called Leber congenital amaurosis (LCA), a faulty gene has prevented the cells in her retina from properly detecting light. However, this changed when Knight was among seven patients who allowed scientists to modify their DNA with the gene-editing tool CRISPR. In September 2021, Knight reported the huge progress made in treating her condition: she can now “make out doorways, navigate hallways, spot objects and even see colours”. This was the first time CRISPR had been used to edit a person’s genes inside their body, but the technology has huge potential for the treatment of conditions such as cancer, blood disorders, and cystic fibrosis. In theory, CRISPR could be used to treat all genetic diseases, but in practice, therapeutic genome editing is still in its infancy, and there are several challenges to overcome before it achieves mainstream adoption.

How Does Gene Editing with CRISPR-Cas9 Work?

The CRISPR-Cas9 system we use to edit DNA was adapted from a naturally occurring defence system in bacteria. The bacteria capture snippets of DNA from invading viruses and store them in libraries (CRISPR arrays). If the same virus ever attacks again, the bacteria produce RNA segments which target the “remembered” viral DNA. Cas9 or a similar enzyme is then used to cut the DNA apart, which disables the virus.

Using this natural process as a basis, scientists over the last decade have co-opted the CRISPR-Cas9 system to add, delete or replace elements within a given target DNA sequence (Figure 1). By programming Cas9 with a single “guide RNA”, this method of gene-editing is much faster, cheaper and more accurate than previous technologies which required a custom DNA-cutting enzyme to be designed for each target sequence.

Genome editing is of great interest in the prevention and treatment of human diseases (Figure 2), and in addition to Knight’s treatment, a number of clinical trials are currently using CRISPR-Cas9 to determine whether it is safe and effective for use in people. However, despite the clear therapeutic potential of this technology, many researchers and bioethicists are worried about potential ethical implications. Have a think about the following questions:

Would it be right to use genome editing for non-therapeutic reasons – changing/enhancing traits such as height, beauty, intelligence, or personality?
Given the existing health disparities between the rich and poor, what would happen if this technology was only accessible to the wealthy? Could we end up with classes of individuals defined by the “quality” of their engineered genome?
Many of the proposed applications involve editing the genomes of somatic (non-reproductive) cells, but would it ever be appropriate to edit germline (reproductive) cells? These changes to sperm and egg cells would be passed on to future generations.

Some of these examples are clearly extreme, but by having these conversations now, the risks remain only hypothetical, and we may be able to mitigate some concerns through strict policy and regulation.

There are also still significant technical barriers that prevent genome editing therapies from entering the clinic. First, the risks and effects of off-target or unintended edits are still unknown, even for a technology like CRISPR that is many times more precise than previous techniques. Furthermore, there is still much to learn about how particular genes are involved in disease processes, and it could be argued that current clinical trials are overestimating our progress by going after “simpler” diseases where a single gene is at fault. Progress is undoubtedly being made, but diseases like LCA are very rare, and tackling more common conditions such as diabetes and asthma will involve untangling the complex interactions of multiple genes and environmental factors.

Conclusion

Upon the sequencing of the first human genome in 2003, our DNA sequence was thought to hold everything that it meant to be human. But, like a magic trick, the wonder and sanctity surrounding our DNA code has lessened as we have determined the function of the genes within it. Scientists now appreciate that our genome is far from perfect, being conceived by a blind process of mutation and selection occurring over countless years and generations. Its legacy is consequently an unfair one, where some people are born with high risks of chronic disease and disability due to random quirks in their DNA. Powerful technologies like CRISPR-Cas9 are now coming to the fore with potential to correct these genetic inequalities, but whilst there is certainly great benefit to be had in treating disease, we must tread carefully, and discuss the philosophical implications for individuals, for society as a whole and for future generations.

Luke Barnes is a Medicine student at St John’s College, Oxford