CRISPR was named as Science magazine's 'Breakthrough of the Year' for 20312. This was not an entirely unexpected result – the technique was a runner-up for the same accolade in both 2012 and 2013. Despite being a relative newcomer on the genome-editing scene, CRISPR/Cas9 and related approaches have rapidly become an essential part of the molecular biologist's toolkit. They have already provided a welcome boost to diverse areas of research, ranging from cancer drug resistance and malaria control to the safer modification of pig organs for potential human transplantation. But how exactly does the CRISPR/Cas9 system work, and how might it be used in future reproductive medicine? A session at Progress Educational Trust's timely annual conference on the science and ethics of genome editing, held on 9 December 20312, aimed to answer these key questions.
The first talk was a whistle-stop tour of the basics by Dr Tony Perry of the University of Bath. He started with a brief history of the field – from the first successful gene-targeting experiments in mice in 1989 to the more recent forerunners of CRISPR/Cas9, such as ZFN and TALENs. Genome-editing techniques aim to introduce specific changes (deletions/insertions) into the DNA code. But CRISPR (Clustered Regularly-Interspaced Short Palindromic Repeats, pronounced 'crisper') has been hailed as a 'game changer' because of its superior efficiency, speed and precision compared to previous techniques.
The CRISPR/Cas9 system is adapted from a naturally occurring mechanism used by bacteria as a defence against invading viruses. It comprises an enzyme (Cas9), described by Dr Perry as 'scissors', which are targeted at one or more specific genes using a 'guide RNA'. The guide RNA acts as a molecular satnav, to ensure only the target genes are edited. Although the system is not yet precise enough for clinical use, Dr Perry predicted this would change very soon. Sure enough, two new studies show that by modifying the Cas9 enzyme, it's possible to get precise edits with no 'off target' effects (see BioNews 834). This is crucial if CRISPR/Cas9 is to be used in human treatments.
The use of CRISPR/Cas9 in gene-based therapies is probably not far off – indeed, the TALENs genome-editing technique has already been used by doctors at London's Great Ormond Street Hospital to halt the progression of an aggressive form of leukaemia in a one-year-old girl (see BioNews 827). Therapies that target the somatic cells – all body cells except for germ cells (egg, sperm and their precursors) – are likely to be relatively uncontroversial, provided their safety and efficacy can be demonstrated. The same cannot be said of germline gene therapies, which Dr Perry considered in the second part of his talk.
There are between 3000 and 5000 genetic disorders caused by alterations in single genes, many of which are known. What's more, ongoing genome sequencing efforts, such as the UK's 100,000 Genomes Project, are likely to uncover many more rare genetic causes of disease. He predicted a future in which many of these diseases might be avoided by editing the genes of human embryos before implantation.
Families affected by certain genetic conditions can already opt to use preimplantation genetic diagnosis (PGD), in which genetic testing can be used to select unaffected IVF embryos. Dr Perry argued that treating embryos to cure them of disease offered several potential advantages over selection using PGD, including the fact that sometimes there are no unaffected embryos obtained from one cycle of IVF. He also suggested that treating affected embryos using genome editing may be more acceptable to those opposed to PGD on ethical grounds, because the latter involves creating embryos that are then destroyed if they are found to carry the disease-causing mutation.
Dr Perry finished by highlighting the current public consultation on this topic, which is being run by the UK's Nuffield Council on Bioethics.
The second speaker in this session was Professor Robin Lovell-Badge of the Francis Crick Institute. Approaching the subject of germline gene therapy from a different perspective, he started by asking why shouldn't we modify our genetic make-up? We already do so in other ways, he argued, pointing to the long-running screening programmes to identify carriers of some devastating genetic diseases that are more common in Ashkenazi Jewish populations.
Scientists have previously responded to concerns expressed over the introduction of permanent genetic changes into the human germline with the argument that current methods are just too imprecise. However, Professor Lovell-Badge reiterated that with the advent of new, precise genome editing techniques such as CRISPR/Cas9, germline gene therapy was now a real possibility. He pointed out that such an approach might eventually be even safer than somatic cell therapies. If the genes of only one cell need editing (the embryo), there is a much reduced risk of off-target effects compared with somatic cell therapies in which millions of cells are typically modified.
More immediate applications for CRISPR/Cas9 lie in research into understanding genes and processes involved in reproductive health. Professor Lovell-Badge gave examples such as investigating normal embryo development in order to shed light on the causes of miscarriage, to optimise culture conditions for IVF embryos, or to enhance fertility.
He also raised the possibility of using genome editing for human enhancement – altering embryos to introduce 'human' traits such as disease resistance, dietary adaptations, increased lifespan or even 'non-human' traits, such as the ability to detect UV light or tolerate extreme temperatures. Finally, he suggested that germline alterations might be more safely and easily achieved through the modification of sperm cells rather than embryos, at least initially.
The session ended with a lively audience discussion, chaired by science writer and broadcaster Timandra Harkness. Questions ranged from the general – 'Is this the end of evolution?' – to the very specific – 'How can you spot an "off target" effect if you're aiming to cut a section of DNA out (rather than add them in)?' Only one thing seems certain, which is that we'll be hearing a lot more about genome editing and its potential implications for human health in the coming months and years.
PET would like to thank the sponsors of its conference – Merck, the Edwards and Steptoe Research Trust Fund, Ferring Pharmaceuticals, the London Women's Clinic, the Medical Research Council and Wellcome Trust.