Gene editing is no longer the stuff of science fiction, so we need to ensure that it is used in a safe and ethical way, writes Dr Hilary Sheppard
Genetic engineering or genetic modification has long been a headline grabber, often framed in a negative light. However we need to move on from outdated concepts of 'GMOs' and start talking about the potential of a new type of gene engineering called gene editing, and consider how it might transform human health.
The DNA double-helix was first identified more than 70 years ago, and we now know that more than 5000 diseases, affecting over 250 million people globally, are caused by changes in just one gene – including conditions like cystic fibrosis, Huntington’s disease and sickle cell anaemia.
Gene editing gives lab-based researchers the tools to more fully understand how changes in genes cause disease. It also has huge potential for biomedical applications because we can use gene editing to fix these diseases allowing genetic material to be added, removed, or altered at particular locations in the genome.
Several approaches to genome editing have been developed, but a particularly well-known technology is the CRISPR/Cas9 gene-editing tool, developed by Emmanuelle Charpentier and Jennifer Doudna, who shared the Nobel Prize in Chemistry in 2020 for their work.
Think of the CRISPR (which stands for 'clustered regularly interspaced short palindromic repeats')/Cas9 tool as a molecule-sized pair of scissors that can be guided to a specific site within our DNA. The tool was adapted from a naturally-occurring genome editing system that bacteria use as an immune defence against invading viruses.
CRISPR/Cas9 can recognise a sequence of just 20 ‘letters’ long among the six billion DNA ‘letters’ present in each cell. Mind-boggling! The ‘scissors’ then cut the DNA. Our cells don’t like DNA breaks and will work quickly to repair them, but the repair is often imperfect and can introduce errors in the DNA code.
However, we can use this natural repair process in a more specific way, by adding in a DNA template for repair at the same time as a specific break is made. This gives us the ability to introduce specific 'letters' of the DNA code to make targeted edits designed to repair broken genes and to restore them to normal function. The CRISPR tool is constantly being adjusted and improved, making the technology increasingly more precise and less likely to cause unintended consequences.
Clinical trials using CRISPR/Cas9 technology are in progress around the world, targeting various diseases caused by damaged genes. Trials have also been conducted in Auckland, including using CRISPR-based gene editing to treat three patients for hereditary transthyretin amyloidosis, a progressive and often fatal disease characterised by a build-up of misfolded protein.
One of my own research focuses is to use gene editing to treat a rare but debilitating fragile skin disorder – called epidermolysis bullosa (EB) - which affects around 200 individuals in New Zealand and half a million globally. People with EB can suffer from severe blistering and skin loss spontaneously or with minor abrasion, making everyday living a real challenge. In severe cases it can be fatal.
There is no cure - just palliative care which can involve hours each day dressing a patient’s wounds, costing up to $100,000 per year for those most severely affected. This condition is an ideal candidate for gene editing as it is caused by a single broken gene, and because skin is an easy tissue to access.
We are growing skin cells taken from people affected by EB and using CRISPR/Cas9 editing to repair the broken gene back to a normal version of the gene. Repaired cells can then be used to grow 3D sheets of skin in the lab that we hope one day can be used to patch up problematic areas of skin on these patients. This work is currently at the research stage, but we are developing methods for clinical translation. We hope that this type of gene editing application may pave the way for other health applications in New Zealand.
It is clear that if used appropriately this type of gene editing could help to treat, prevent or even eliminate, some of the most debilitating diseases that can affect humans. Unfortunately, this technology was used prematurely and inappropriately in 2018 by a Chinese researcher, Dr He Jiankui. He provoked global outrage when he announced that he had created two gene-edited babies with the aim to make them resistant to HIV, a disease that carries huge stigma in China. In the furore that followed, He lost his job and was jailed for violating medical regulations. An international commission into the case concluded that gene editing was far from ready for use on embryos.
There is much still to understand about gene editing before it is deemed safe or even desirable to be used in this way on embryos. However, the technology is here and the ‘genie is out of the bottle’, so we need to ensure that it is used in a safe and ethical way. This would include, in my opinion, using the technology to fix genes in the cells of adults. Here any genetic changes that are made are limited to the treated individual i.e. they are not passed down to future generations. There is also the issue of consent - and adults can, and should be, fully informed and consenting.
As gene editing improves we may reach safety levels that make it appropriate for use on embryos. However, in contrast to gene editing in adult cells, there are ethical issues that relate to consent and inheritance. Consent is impossible to achieve when editing embryos and, importantly, any genetic changes made to an embryo will be passed down to future generations.
Should parents have the right to decide if their offspring will have their genome edited - just as parents are able to vaccinate babies without their consent? Some may argue that editing of embryos should be allowed if it addresses an unmet health need, but who decides what is an unmet health need? Some may want to 'fix' a genetic condition where others feel it contributes to the rich tapestry of human life. Some, for religious or cultural reasons for example, may think it is wrong to edit DNA in any situation. And, of course, if gene editing is 'justified', who will pay? Who will be able to afford to take advantage of the new technology, and what might that mean for those who cannot? Finally, by opening the Pandora's box of gene editing of embryos these technologies could be used for unethical purposes - such as to create ‘designer babies’.
On the other hand, would it be immoral not to use gene editing for certain conditions? We already use technologies that change our future gene pool. For example, pre-implantation genetic testing (PGT) is a diagnostic test used in IVF that is carried out on a few cells from an embryo. The UK permits PGT screening of embryos for 400 conditions including intellectual disability and primordial dwarfism. So it could be argued that the end result of gene editing is fundamentally similar to PGT. In reality, editing of embryos may be an academic argument as I can think of very few situations where PGT, a safe and proven technology, could not be used in preference to gene editing of embryos.
Nevertheless, we need a global set of rules to govern how gene editing is used - regulation is currently piecemeal and often unclear. To this end the World Health Organisation has a committee to advise on human gene-editing with an aim to develop global governance standards for CRISPR-based therapies.
New Zealand needs to be part of this discussion, although currently it is difficult to get any gene edited therapies into the clinic due to our Hazardous Substances and New Organisms (NZNO) Act. Leading scientists, including Professor Dame Juliet Gerrard, a respected biochemist serving as the Prime Minister's Chief Science Advisor, have called for an overhaul of this outdated legislation. As the legislation is updated to align with the new gene editing technologies, we should all be involved in shaping the direction of their use. We need to consider the intended and unintended impacts of human gene editing in various scenarios. Gene editing in humans is no longer science fiction. It is here, and it is here to stay.
