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Use and misuse of CRISPR/Cas9 genome editing

Since its discovery in 2012, the use of the CRISPR/Cas9 system to edit genomes has raised the expectations for the cure of untreatable disorders. Very often, as biomedical geneticists we found ourselves talking about the potentials and drawbacks of CRIPSR/Cas9 both at scientific and layman level.

One of the most frequent conversations I have been involved in is about correcting life-threatening disorders in human embryos. Even though it is amongst the possibilities of the technique and certainly one of the most notorious applications, we need to wonder whether there is a real need to put too many eggs in this basket, and meanwhile disregard other potential uses that are far more urgent for public health and advancement of our societies in general. In this article, I would like to discuss the potential uses and their urgency in the race to improve gene editing.

The expectations of genome editing have arisen in a wide variety of fields encompassed in biomedicine and biotechnology, from drug discovery to food engineering and generation of biofuels. All these possibilities can be pursued mainly to the presence of the Cas9 targeting signal (PAM) in the DNA of most of cell types and organisms. Besides, the generation of multiple Cas9 modifications to improve both its sensitivity and performance avoiding undesirable off-target effects is one of the main assets of the incorporation of CRISPR/Cas9 as key player in genome editing.

Therapeutic approaches of CRISPR/Cas9

The application of CRISPR with therapeutic purposes have been explored since the very initial moments of the tool description. An inflexion point in the race to establish efficient gene therapy approaches with real therapeutic potential for genetic disorders was published in October in Science. A proof-of-principle that mutations in the dystrophin gene, leading cause of the lethal Duchenne Muscular Dystrophy syndrome, were corrected in the muscle in mice, human cells in vitro and more relevant, in dogs. To this purpose, adeno-associated viruses (AAV) delivered the corrected genomic region in a targeted manner, correcting this way the mutations in the dystrophin gene with surprisingly high efficiency.

Long-term studies need to be done to study the stability of these mutations for DMD and other genetic disorders, but the success in large mammal models is a great promise. The Cas9 /gRNAs delivery systems infectivity, chromatin state and self-renewal rate of the targeted cells are key for the success of the technique. Another point to be addressed is whether chronic and metachronic gene editing treatments can be performed with minimal risks to maintain “correcting” levels throughout a patient’s life.

For non-genetic disorders such as cancer, CRISPR/Cas9-based therapeutic approaches are very promising since it can be used as a selective-labelling of tumoral cells in combination with targeted therapies. One even could think that binding small chemical compounds or peptides to the Cas9 that be used as an direct or indirect apoptotic signal. This type of cell directed approach is a promising horizon to reduce the exposition to long treatments with high toxic not-specific chemotherapy drugs. Again, the delivery system is a key stem to overcome before it can be used in oncologic patients.

Pharma and biotech uses for CRISPR

I dare to suspect that direct therapeutic approaches of CRISPR/Cas9 are probably the mainstream of investment in gene therapy, especially in academia. However, the uses of CRISPR/Cas9 for pharma and biotech companies are almost limitless, and should deserve further attention from funding agencies and investors as well as media.

Personalised medicine is pushing towards the generation of biological compounds and antibody-based therapies. For this particular purpose, the development of tools for high-throughput genome editing is a growing need for the pharma companies. CRISPR/Cas9-based high-throughput production systems will drive to more cost-effective biological therapies and most-likely to the generalisation of better patient-based therapies.

Lastly, CRISPR/Cas9 applications for biotech will enhance the use of yet under-used production systems as well as introducing a new era in GMOs. In an increasingly populated world with less than ever resources to support the basic needs for the population, genome editing can offer increased production of food. Nevertheless, adaptation of the CRISPR/Cas9 technology to plant biology requires further investigation since the efficiency of targeted editing remains at low frequency while off-target effect have been reported to remain very high.

Controversial and misuses of CRISPR/Cas9 genome editing

In this post, I have analysed from a general and superficial perspective the uses and potential of CRISPR/Cas9 without entering the particularities of each of the uses. However, I would not like to finish this post without a bit of autocritics in what I think will become one of the most revolutionary innovations of the 21st century. My feeling is that there is a clear unmatched in what basic science is exploring and the urgencies of the society. Myself, adapting the current CRISPR/Cas9 technology to my research project, I came up with a high efficient method for modifying mouse stem cells.

The first question I heard from my colleagues was if it could be used to “cure” genetic disorders in human embryos. Recently, I assisted an ethical round-table about CRISPR/Cas9 uses in human therapies and the expert in in vitro fertilisation highlighted two interesting points of why CRISPR will ever be relevant in such disorders: 1) embryo screening and selection is a common practice before in vitro fertilisation, 2) dominant pathogenic mutations of fertile parents tend to be heterozygous, thus healthy embryos can be easily selected, 3) cases where healthy embryos cannot be selected are rare and yet, there is a healthy embryo bank that is often used.

To conclude, I want to encourage a multidisciplinary debate in which real needs are transmitted into academia to move into successful approaches for the current needs of biomedicine and biotech and enhance the change and expansion of safe gene editing methods. Solutions would probably spin on the increase in partnerships between industry and academia that work towards the solution of problems and not to achieve high-ranked publications to warrant lab funding.


Sandra Acosta Verdugo is the Senior Postdoctoral Fellow at the Centre for Vascular & Developmental Biology, Northwestern University. She will present “2-HHR: an efficient method for bi-allelic homologous recombination in mouse embryonic stem cells” at the 4BIO Summit: Europe.


The 4BIO Summit: Europe will take place in Rotterdam in under two weeks and places are limited. Book now to avoid disappointment.

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