By: Ali Cranage, science writer at the Wellcome Sanger Institute
How Sanger scientists are using genetic surgery to understand the blueprint of life
CRISPR technology burst onto the scene nine years ago and it’s been hitting the headlines ever since. It’s the fastest, cheapest and most accurate way to edit the DNA in a genome. CRISPR has the potential to revolutionise diagnostics, drug discovery, and the treatment of genetic diseases. Sanger Institute scientists are using it to understand illnesses, from cancer to malaria. They are also at the forefront of refining this genome editing technology to realise its full potential, as well as define its limitations
Great power involves great responsibility
The technology is not without its ethical challenges though. While it holds the potential to treat cancer and genetic disorders it also comes with a darker side.
Most infamously, the technology was recently used to edit the DNA of human embryos, resulting in the birth of twin girls. Chinese scientist He Jinkau claims to have made the world’s first genome edited babies. He announced that he had used CRISPR to edit two embryos to become resistant to HIV, and the baby girls were born last year. The claims, still unverified, caused shock and outrage around the world.
While editing the genomes of embryos holds the exciting potential of curing genetic diseases, the way He undertook his work was unethical and illegal. There wasn’t a medical need for the procedure, there wasn’t any transparency and there wasn’t any oversight. There could be unintended side effects – at the moment these are poorly understood.
It is possible that in the future, faulty genes could be edited and fixed in sperm, eggs or embryos, meaning parents at risk of passing on genetic diseases could ensure their that children are not affected. But such changes would continue to be passed on through following generations too, as they would affect every cell in the body. This raises huge ethical questions. The safety and long-term health implications of editing like this is also still unknown. And so editing the genomes of embryos which are then implanted is currently banned in most countries in the world, including China.
While societies around the world debate the future of editing human embryos, the use of CRISPR in other areas of research continues – rapidly advancing our understanding of both health and disease.
Why edit genomes?
Humans have been manipulating the genomes of other species for millennia. Animals and plants have been selectively bred to give us varieties of food that are tasty, produce high yields and are resistant to disease. Companion animals have been bred to have showy pedigrees, be fast, or good at hunting, herding, pulling carts or sniffing out explosives – the list of desired characteristics goes on.
Genome engineering speeds up the process, by altering the DNA in a genome directly rather than waiting for generations of offspring and choosing amongst them. It began in the 1970s when scientists first changed the genomes of bacteria and viruses. Now, drugs, vaccines, laundry detergent and enzymes to make cheese and beer are all produced on an industrial scale by microorganisms with altered genomes. But the early techniques were based on a scattergun approach, and it was not always possible to predict how DNA was going to be changed.
CRISPR, a system first discovered in the 1990s, has changed that. Scientists can be more accurate than ever before, changing DNA sequences of their choosing. It does have limitations, and won’t work in every type of cell or every organism as yet, but it has huge potential for our health. It brings the possibility that we can fix faulty genes which cause disease.
The CRISPR gene editing tool is also a huge boost for research. Experiments are quicker and cheaper than before, meaning more is possible. Scientists are able to precisely change genes in order to understand how they function in both health and disease.
How CRISPR is cracking cancer
Cancer research is benefitting from CRISPR technology. Cancer is an incredibly diverse disease, caused by the genome in a cell becoming disordered and dysregulated. There are possibly hundreds of different types, each defined by their specific genomic changes, rather than the location of the tumour.
To understand more about the genomic changes that cause cancer, researchers at the Sanger Institute and Open Targets have harnessed the power of CRISPR. They used it to disrupt 18,009 individual genes in the genomes of 324 different cancer ‘cell lines’. The cell lines are tumour cells, originally taken from a patient but now grown in the laboratory. The 324 cell lines they tested represent 30 different types of cancer.
If a cell line stopped growing, they classified the gene that had been disrupted as essential to that cancer’s survival. They discovered thousands of such genes across all the different cancer types. They systematically integrated other information about the genes to prioritise them as potential drug targets. The result? A list of 600 genes that are potential targets for cancer treatments. 400 of the genes are new.
Identifying such precise targets for cancer treatments has been a limiting step in drug development. The findings represent a massive advance towards developing new treatments. If a treatment can take out an essential cancer gene, you just might be able to stop the cancer in its tracks – without harming non-cancer cells.
The experiment is one of the largest of its kind. The majority of genes in the human genome were disrupted in the 324 different types of cancer cells. And it was done with CRISPR technology.
How does CRISPR work?
CRISPR was originally discovered as a bacterial defence mechanism against invading viruses. It has been developed and refined by hundreds of scientists across the world to become a genome editing tool.
CRISPR acts like a sat-nav, and can be coupled with the Cas-9 enzyme, which acts like molecular scissors. The scissors cut DNA at a precise location, guided by the (programmable) Satnav. It is also possible to load the system with DNA to insert at the cut. This brings scientists the ability to edit genes, and other parts of a genome.
Genetic surgery – fixing faulty genes
Due to its precision, it is possible that CRISPR-Cas9 could be used to fix faulty genes. (Sanger Institute scientists demonstrated the use of ‘genetic surgery’ in 2011 using a different gene editing technology). It is set to become the tool of choice when it comes to editing human genomes.
Editing an adult’s cells could treat genetic diseases from cystic fibrosis to forms of blindness. Clinical trials are already underway to test if editing the genomes of a patients’ own immune cells can help them attack and destroy a tumour.
But the feasibility of using CRISPR-Cas9 in the clinic was called into question last year. Sanger Institute researchers sequenced whole genomes of human and mouse cells after CRISPR-Cas9 editing. They showed, for the first time, that CRISPR-Cas9 causes unexpected genome changes. The changes were frequent, large, and often far away from the target site. Previously, researchers had only tested regions near target sites. Such changes could unintentionally switch genes on or off, with the possibility of triggering cancer or other unwanted changes.
Their work also made headlines. The DNA changes caused by CRISPR-Cas9 had been seriously underestimated and they urge caution for those developing the technology to use as therapy.
Gazing into CRISPR’s crystal ball
The future of CRISPR technologies as a therapy or treatment remains unclear. A panel set up to advise the World Health Organisations have recently (19th March 2019) called for an open, global registry to list all experiments related to human genome editing – whether that uses CRISPR or any other technology. The panel describe the need for such a list as ‘urgent’. Other scientists have called for a moratorium on editing the genomes of human embryos, eggs and sperm as a clinical therapy.
The future of CRISPR for research is bright. It is a powerful tool. It is cheap and effective, meaning studies that were unfeasible just a few years ago are now possible. It’s not just cancer cells that can be edited, but malaria parasites, disease-causing bacteria and more. Altering DNA allows researchers to gain fundamental insights into how it builds the proteins that make our cells and bodies. With such power, there will also come important questions – difficult and vital questions related to both the science and the ethical use of this tool.
Partner organisation: Open Targets
Sanger Institute policy statement: Call for global moratorium on clinical use of germline editing
Blog: Editing the debate