Scientists use gene editing to correct mutations in humans
Each year, millions of people around the world are affected by diseases caused by mutations that occur in the very early stages of development.
But many of those diseases could soon cease to exist, thanks to a gene editing technique that uses the controversial CRISPR-Cas9 system.
In a world first, scientists have used the technique to correct a mutation for a heart condition in embryos, so that the defect would not be passed on to future generations.
The findings could pave the way for improved IVF outcomes, as well as eventual cures for some of the thousands of diseases caused by mutations in single genes.Â
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In a world first, scientists have used the technique to correct a mutation for a heart condition, so that the defect would not be passed on to future generations. Pictured top is a previous technique, which saw some cells still with the mutation. Pictured bottom is the new technique, in which all cells are repaired
The work is a collaboration between the Salk Institute, Oregon Health and Science University (OHSU) and Korea's Institute for Basic Science.
Professor Juan Carlos Izpisua Belmonte, an author of the study, said: 'Thanks to advances in stem cell technologies and gene editing, we are finally starting to address disease-causing mutations that impact potentially millions of people.
'Gene editing is still in its infancy so even though this preliminary effort was found to be safe and effective, it is crucial that we continue to proceed with the utmost caution, paying the highest attention to ethical considerations.'
In the study, the researchers were able to correct a mutation that causes an inherited heart disease, called hypertrophic cardiomyopathy (HCM).
HCM is an inherited disease of your heart muscle, where the muscle wall of your heart becomes thickened.Â
This sequence of images shows the development of embryos after the sperm and CRISPR-Cas9 was injected into a healthy egg. Pictured left are the eggs shortly after the injection, pictured centre are the embryos two days later, and pictured right are the embryos five days later
It is caused by a mutation in the MYBPC3 gene, and those affected have a 50 per cent chance of passing the disease on to their own children.
Using a skin biopsy from a man with HCM, the researchers generated stem cells to use in their study.
The researchers used a technique based on CRISPR-Cas9 â€" a genetic tool that can 'cut and paste' small sections of DNA, deleting or repairing flawed genes â€" to correc t the HCM mutation in the cells.
CRISPR-Cas9 works as a pair of genetic scissors designed to cut the DNA near the position of the mutation.
The cut is then spontaneously repaired by the cell with different mechanisms: one repairs the DNA without leaving any trace, while the other introduces some unwanted insertions or deletions of a few base pairs near the cutting site.
While previous studies have injected CRISPR-Cas9 after IVF, they faced problems due to 'mosaicism' â€" in which embryos have some repaired cells, and others that carry the mutation.
During testing, none of the embryos were allowed to develop beyond five days after conception. But had they produced offspring, those with the repair would no longer be at risk of developing HCM, or passing the defective gene onto their own children (stock image)Â
To overcome this issue, the researchers injected the CRISPR-Cas9 and the sperm into the egg at the same time.
Using this technique, they found that the mosaicism did not occur.
During testing, CRISPR-Cas9 cut the DNA at the correct position in all tested embryos.
Forty-two out of the 58 embryos tested did not carry the HCM mutation.
In other words, this technique increased the probability of inheriting the healthy gene from 50 per cent to 72.4 per cent.
In the study, the researchers were able to correct a mutation implicated with an inherited heart disease, called hypertrophic cardiomyopathy (HCM), which can lead to heart failure and sudden death of apparently healthy people
The researchers also found that human embryos have an alternative DNA repair system, where the Cas9-induced cuts in the DNA coming from the sperm are repaired using the healthy egg's DNA as a template.
This explained why the remaining 27.6 per cent embryos still had the HCM mutations.
Additionally, the researchers found that there were no off-target changes made during the testing.
CRISPR-Cas9 works as a pair of genetic scissors designed to cut the DNA near the position of the mutation (stock image)Â
Dr Jun Wu, one of the paper's first authors, said: 'Our technology successfully repairs the disease-causing gene mutation by taking advantage of a DNA repair response unique to early embryos.'
During testing, none of the embryos were allowed to develop beyond five days after conception.
But had they produced offspring, those with the repair would no longer be at risk of developing HCM, or passing the defective gene onto their own children.
Dr Shoukhrat Mit alipov, who also worked on the study, said: 'Every generation on would carry this repair because we've removed the disease-causing gene variant from that family's lineage.
'By using this technique, it's possible to reduce the burden of this heritable disease on the family and eventually the human population.'
While the results are extremely promising, the researchers warn that they are very preliminary, and that further studies will be needed to make sure there are no unwanted side effects.
Professor Belmonte said: 'Our results demonstrate the great potential of embryonic gene editing, but we must continue to realistically assess the risks as well as the benefits.'
Dr Daniel Dorsa, senior vice president for research at OHSU added: 'The ethical considerations of moving this technology to clinical trials are complex and deserve significant public engageme nt before we can answer the broader question of whether it's in humanity's interest to alter human genes for future generations.'
But not everyone is happy about the study, and claim that it is the first step in the development of designer babies.Â
Dr David King, director of Human Genetics Alert, said: 'If irresponsible scientists are not stopped, the world may soon be presented with a fait accompli of the first GM baby.Â
'We call on governments and international organisations to wake up and pass an immediate global ban on creating cloned or GM babies, before it is too late.
'There is absolutely no medical need to use this technology to avoid the birth of children with genetic diseases, since genetic selection techniques can prevent their birth, where that is appropriate.Â
'So scientists racing to develop this techno logy must be driven by something else: irresponsible technological enthusiasm, the desire for fame, or the financial gain of being the first to market designer babies.
'James Clapper, US director of national intelligence was right to call the creation of GM babies a 'weapon of mass social destruction.''
WHY CHARLIE GARD WOULD NOT HAVE BEEN SAVED BY CRISPRÂ
Charlie Gard would not have been saved by gene editing his embryo in the way described by Dr Shoukhrat Mitalipov and his fellow scientists.
The technique worked for the heart failure condition hypertrophic cadiomyopathy because the disorder is due to a fault in a si ngle gene inherited from one parent.Â
Charlie's illness, infantile onset encephalomyopathy mitochondrial DNA depletion syndrome (MDDS) is an 'autosomal recessive' disorder, which only manifests itself if the gene fault is inherited from both parents.
The disease leads to a loss of mitochondrial DNA, housed in cellular 'power plants' that supply energy to vital organs.Â
Charlie Gard would not have been saved by gene editing his embryo using the Crispr technique. It worked for the heart failure condition hypertrophic cadiomyopathy because the disorder is due to a fault in a single gene inherited from one parent
Because of the gene defect Charlie was unable to transfer energy to his muscles, kidneys and brain.
Although it affects mitochondrial DNA, the rare condition is triggered by a fault in the cell nucleus passed down by both a child's mother and father.
The American researchers admitted that fixing such a 'recessive' genetic error caused by two mutated copies of a gene would be far more challenging.
This is because the repair they carried out depended on having one 'good' copy of the gene.
The scientists used a 'molecular scissors' technique cal led Crispr-Cas9 to snip away precisely targeted elements of defective DNA carried by fertilising sperm.
Once the dysfunctional DNA was removed, Mother Nature took over as the embryos' own repair systems fixed the damage using the 'good' gene copy - inherited from the egg donor mothers - as a template.
Without the mothers' functioning genes, it is unlikely the fix would have succeeded.Â
Although the scientists introduced their own healthy gene template, at the end of the day this played no part in the repair.
Charlie died on July 28, aged 11 months, after being at the centre of a painful legal battle between his parents and London's Great Ormond Street Hospital.
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