It is risky to predict who and what will win a Nobel prize. But some discoveries are so big that their receipt of science’s glitziest gong seems only a matter of time.
One such is CRISPR-Cas9, a powerful gene-editing technique that is making the fraught and fiddly business of altering the genetic material of living organisms much easier.
Biologists have taken to CRISPR-Cas9 with gusto, first with animal experiments and now with tests on humans.
In March researchers in China made history when they reported its first successful application to a disease-causing genetic mutation in human embryos.
But their results were mixed. Although they achieved 100% success in correcting the faulty gene behind a type of anaemia called favism, they tested the technique in only two affected embryos.
Of four others, carrying a mutation that causes thalassaemia, another anaemia, only one was successfully edited.
Now, in a study just published in Nature, a group of researchers from America, China and South Korea have pulled off a similar trick, with striking consistency, among many more embryos, while avoiding or minimising several of the pitfalls of previous experiments.
Their work suggests that, with a bit of tweaking and plenty of elbow grease, CRISPR-Cas9 stands a good chance of graduating, sooner or later, from the laboratory to the clinic.
The researchers involved, Hong Ma of Oregon Health & Science University and her colleagues, obtained sperm donated by a man who carries a mutated version of a gene called MYBPC3 that causes hypertrophic cardiomyopathy (HCM), a condition in which the walls of the heart grow too thick.
As with the genes that cause thalassaemia and favism, inheriting even a single copy of the malformed version of this gene is enough to cause HCM.
These sperm, half of which would have been carrying the mutated version of MYBPC3, were then used to fertilise eggs containing a normal copy of the gene.
The resulting embryos thus had a 50:50 chance of containing a defective copy. In the absence of editing, and had they been allowed to develop, those with a faulty version would have grown into adults likely to suffer from the disease.
CRISPR-Cas9 editing has been developed from a bacterial defence system that shreds the DNA of invading viruses. CRISPR stands for “clustered regularly interspaced short palindromic repeats”.
These are short strings of RNA, a molecule similar to DNA, each designed to fix onto a particular segment of a virus’s DNA. Cas9 is an enzyme which, guided by CRISPRs, cuts the DNA at the specified point.
The hope was that, by being given such templates, embryos could be purged of nascent genetic disease.
That hope appeared fulfilled, at least in part. By the end of the experiment, 72% of the embryos were free of mutant versions of MYBPC3, an improvement on the 50% that would have escaped HCM had no editing taken place.
In achieving this, Dr Ma and her colleagues overcame two problems often encountered by practitioners of CRISPR-Cas9 editing.
One is that the guidance system may go awry, with the CRISPR molecules leading the enzyme to parts of the genome that are similar, but not quite identical, to the intended target.
Happily, they found no evidence of such off-target editing. A second problem is that, even if the edits happen in the right places, they might not reach every cell.
Many previous experiments, including some on embryos, have led to mosaicism, a condition in which the result of the editing process is an individual composed of a mixture of modified and unmodified cells.
If the aim of an edit is to fix a genetic disease, such mosaicism risks nullifying the effect.
Dr Ma and her colleagues conjectured that inserting the CRISPR-Cas9 molecules into the egg simultaneously with the sperm might help.
That way the process is given as much time as possible to complete its work before the fertilised egg undergoes its first round of cell division.
Sure enough, after three days, all but one of the 42 embryos in which the technique had worked showed the same modifications in every one of its cells.
So far, so good. But a third problem that has bedevilled experiments with CRISPR-Cas9 concerns the quality of the repair. There are at least two ways for cells to repair DNA damage.
One of them simply stitches the severed strands of DNA back together, deleting or adding genetic letters at random as it does so. Because it introduces mutations of its own, this process is not suitable for correcting DNA defects for medical purposes.
Fortunately, the other mechanism patches the break with guidance from a template, and thus without introducing any additional mistakes.
But cells seem to prefer the slapdash approach. In previous CRISPR-Cas9 research, the more precise method was involved only 2% to 25% of the time.
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