The continued impact of the CRISPR revolution

Genome editing using CRISPR/Cas9 is transforming genomics research and human medicine at an unprecedented rate. As the use of this method enters a new era, the anticipated impact on clinical, ethical and legal aspects of genomics is impending and vast.

Following the discovery of the CRISPR/Cas9 system as a genome editing method in 2012 by Professor Jennifer Doudna, of UC Berkely and Professor Emmanuel Charpentier, of the Max Planck Institute, Berlin, Germany, the potential of this system for genome editing in eukaryotic cells was very quickly realised. Just one year later, a group of researchers led by Professor Feng Zhang of the Broad Institute, Cambridge, Massachusetts, successfully adapted the CRISPR/Cas9 system for genome editing in human cells. By effectively acting as a pair of programmable molecular scissors, the CRISPR/Cas9 system enables scientists to precisely introduce desired genetic variants to target regions of DNA.

Since its discovery, CRISPR-based genome editing has revolutionised genomics research, with far-reaching applications ranging from agriculture to biotechnology. Arguably most influential, however, is the projected impact of this technology on the diagnosis and treatment of human disease.

Through the creation of desired edits in known disease-related genes, scientists have been able to use CRISPR-based methods to home in on disease-causing variants. In the era of high-throughput next-generation sequencing, exciting new methods have been developed that can assess the effect of hundreds to thousands of genetic variants at once.

These technologies, known collectively as multiplexed assays of variant effect (MAVEs), 'allow us to explore variation at a scale and with the accuracy that we would want and that we've dreamed of for a long time,' said Dr Dave Adams of the Wellcome Sanger Institute in Hinxton.

One such method, termed saturation genome editing (SGE), uses CRISPR/Cas9 genome editing in human cells to test the effect of all possible single nucleotide polymorphisms (SNPs) in a gene. In diagnostic practice, even where genome sequencing data is available, there is often insufficient evidence to establish with confidence whether a given variant is responsible for a patient's condition. By generating large-scale comprehensive datasets, SGE can address this challenge directly and improve clinicians' understanding of which variants are likely (or unlikely) to cause disease.

Despite being a relatively new technique, SGE is already proving to be clinically useful. To date, SGE data has been generated for a range of disease-related genes. This includes the breast cancer gene BRCA1, which – if mutated – can predispose women to breast and ovarian cancer. SGE in BRCA1 has been shown to identify disease-causing variants with very high accuracy, meaning that individuals at higher risk can be more easily identified, and clinicians can proceed with the necessary interventions.

Data from CRISPR-based MAVEs are also contributing to the Atlas of Variants Effects Alliance. This international collaboration between multiple institutes has set out the ambitious goal of assessing the effect of all possible variants in the human genome. As more MAVE data is generated, these methods have huge potential to prove invaluable for the diagnosis and treatment of patients with cancer or rare disease.

Beyond diagnosis, the anticipated therapeutic utility of CRISPR-based genome editing has, in part, already been borne out. Just last year, the UK became the first country in the world to approve a CRISPR-based gene therapy as a potential cure for sickle-cell disease and transfusion-dependent beta thalassaemia (see BioNews 1216).

This therapy went on to be approved by the US Food and Drug Administration (FDA) and the European Medicines Agency, the director of the FDA Biologics Evaluation and Research, Dr Peter Marks, said that 'these approvals represent an important medical advance with the use of innovative cell-based gene therapies to target potentially devastating diseases and improve public health.'

For the moment, the development of CRISPR-based gene therapies quite correctly remains gradual and deliberate. But as more of these gene therapies are developed and enter clinical trials in coming years, these techniques are likely to transform treatment opportunities for patients with genetic conditions.

Although CRISPR-based methods hold great promise for the future of medicine, the clinical translation of CRISPR/Cas9 genome editing has at times been the crux of serious ethical and legal debates. Back in 2018, the Chinese biophysicist Dr He Jiankui stunned the scientific community after creating the world's first genome-edited babies (see BioNews 977). Dr Jiankui, who created twin sisters with edited genomes, claimed that he did so to make the girls immune to HIV. Guised under a veil of altruistic intention, Dr Jiankui was ultimately condemned for his risky, unethical and medically unnecessary actions (see BioNews 1029).

The result was global controversy that posed important and lasting questions regarding the potential dangers of germline genome editing. Implications permeating medical, ethical and moral aspects of research led specialists to write a comment article, published in Nature, proposing a 'global moratorium' on the clinical use of human germline editing. In one fell swoop, this incident fuelled concerns of a dystopian future enabling so-called 'designer babies'.

As technologies continue to improve, scientists and policymakers alike will be forced to consider how genome editing – particularly in the world of reproductive medicine – may violate patient autonomy, exacerbate existing economic divides and fail to secure societal endorsement.

For some, the fear of a distant. dystopian civilisation that endorses eugenics is enough to dismiss the notion of genome editing entirely. But with a new wave of genomics research on the horizon and new gene therapies in the pipeline, there is no doubt in my mind that the next wave of the CRISPR revolution will bring many benefits.

What was once the stuff of science fiction is slowly becoming a reality, and that reality is brimming with discoveries and clinical applications that promise to transform clinical practice. Research using CRISPR-based methods will, however, inevitably run in parallel with new bioethical questions and legal challenges. Genome editing within the confines of a laboratory, or even in a patient's somatic cells, may not be very ethically contentious, but germline genome editing requires careful attention to ethical guidelines and legal frameworks.

Whether in terms of scientific advances or in terms of bioethical dilemmas, the impact of CRISPR-based genome editing during the next 25 years will undoubtedly be significant and lasting.