CRISPR/Cas-9 has been hailed as a breakthrough technology for gene editing, which allows the introduction of DNA sequence changes that correct a genetic defect in whole animals (C&I, 2015, 10, 32). The technology was recently used to help make pig organs more suitable for human transplants by eliminating retroviruses. But there are safety and ethical worries.
Fears over genome editing technologies were stoked after a Chinese group ran experiments with non-viable human embryos in 2014. There is an often unspoken worry that countries beyond Europe and the US, particularly in Asia, may usher in genome editing for human embryos. Earlier in 2015, some called for a moratorium on such research.
In September 2015, the Hinxton Group, an international consortium on stem cells, ethics and law, released a statement on genome editing and germline modification that crystallised these concerns. ‘Especially given the recent experience with purposed stem cell-based treatments in unregulated clinics, there is serious concern that genome editing technologies might be used in reproductive contexts long before there are data sufficient to support such use, and before the international community has had the opportunity to weigh the benefits and harms of moving forward,’ the group wrote.
In December 2015, an International Summit on Human Gene Editing will be held in Washington DC. Organised by the National Academy of Sciences, National Academy of Medicine, Chinese Academy of Sciences and Royal Society of the UK, it will scrutinise recent scientific developments in human gene editing and examine ethical and governance issues.
‘How to control renegade users is one of the biggest concerns,’ says Sarah Chan, a bioethicist at the University of Edinburgh, UK. However, she adds that national regulation is not the only solution; soft laws and international agreements also matter, as well as funders and publishers.
While some researchers express concerns about a possible transition from editing the DNA of our bodies for therapeutic purposes towards editing embryos for enhancements, Chan cautions that we should not dismiss its promise out of hand.
‘Think about vaccination. That is not curing a disease, but it is a sort of enhancement. So the slope between therapy and enhancement is conceptually slippery,’ she says.
Research is under way investigating how to harness CRISPR to treat and cure HIV, sickle cell anaemia and several forms of cancer. ‘There are grave safety and ethical concerns about germline modification,’ says Sarah Haecker at the Alliance for Regenerative Medicine in the US, co-author of an article calling for a voluntary moratorium on this kind of research (Science, doi:10.1126/science.aab1028). Her group wants to ensure that the legislative and business environment remains supportive of somatic [body] cell research.
‘Research to modiy the germline would be premature,’ says Haecker. ‘We don’t want to trigger a regulatory backlash.’ Companies interested in Cas9 for gene therapy have raised $600m since 2013 from public markets and venture capitalists.
There are also potential safety hurdles with somatic gene editing. ‘Safety issues such as off-target effects and on-target effects with unintended consequences need to be investigated. It is also possible that Cas9 exhibits toxicity or immunogenicity,’ says Sabine Schneider at the Technische Universität München (TUM) in Germany, who co-authored a recent review on gene editing (Angewandte Chemie, doi: 10.1002/anie.201504741).
Stray breaks could result in harmful mutations or DNA rearrangements, leading cancer genes to be turned on or tumour-suppressors to be switched off.
These off-target impacts are a big concern, agrees Blake Wiedenheft at Montana State University, US, and need to be quantified. ‘We’ve been down this path before.
‘Adenoviruses were developed for targeted gene therapy and when it went to clinical trial, kids died of cancer after the virus integrated into the wrong place [in the genome]. That set the field back a long way, not to mention that kids died. And those kinds of things are certainly potential concerns for the CRISPR/Cas system,’ says Wiedenheft. ‘Off-target cleave effects are a hot area of active research.’