In the complex genetic map that surrounds the well-known Down syndrome, the problem is not that there is a lack of information in our cells, but that there is an excess. The presence of a third copy of chromosome 21 unbalances the entire cellular system that ends up generating an entire clinic that to this day had no type of cure. But thanks to clinical advances and revolutionary gene therapies, we have found a way to turn off this gene that is extra in the cells of people with Down.
A natural switch. To understand this advance, we must look at how nature itself resolves its own genetic imbalances. And, for those who do not know, in human beings sex is determined by two types of chromosomes: X and Y. If you are a woman, you will have XX chromosomes, and if you are a man, you will be XY.
The problem, reducing it to the most basic, is that one of the ‘X’ genes always has to be silenced so that the genetic load is compensated in humans. And this is something that is done thanks to the XIST gene, which encodes an RNA molecule that covers the chromosome and alters its chromatin, de facto silencing its genes. Something that has been developed by nature itself in order to maintain the species, and then the question is obligatory: why not use this natural switch to silence the chromosomes that generate diseases as important as Down syndrome?
It’s not something new. The idea of using this “switch” to be able to alter the gene expression of the chromosomes that we have in excess is not new, since in 2013 the researcher Jeanne Lawrence demonstrated for the first time that this RNA could induce the silencing of the extra chromosome 21 in human cells that she had in a laboratory in culture. Later, in 2020, it was applied to neural stem cells, but the historical problem has always been the same: the very low efficiency when integrating this gene into the affected cells..
A new milestone. This has changed radically, as a team at Beth Israel Deaconess Medical Center in Boston has published a new paper in PNAS with a solution to eradicate this bottleneck thanks to the CRISPR/Cas9 tool.
This system can be visualized as simple scissors that specifically cut into our DNA to eliminate something that was left over or altered. The problem is that it was not very efficient at integrating new genetic material, and to overcome this, scientists have developed a modified version of CRISPR/Cas9 that triggers the success rate of the integration of the XIST gene that will silence the third chromosome 21.
Good results. Here we recognize how XIST has been integrated into 20-40% of cell lines that have trisomy 21. Furthermore, the method reliably affects only the extra copy of chromosome 21 without silencing other genes that can cause other diseases.
There are problems. Despite the enthusiasm, the technique is far from being applied in humans, since one of the biggest challenges of CRISPR is mutations off-target, That is, it acts on other genetic points that are its marked objectives. And this occurs when these ‘scissors’ cut a sequence of DNA that closely resembles its target, but which in reality is not.
In this way, an error off-target It could trigger severe cellular problems or even cancer. Recent studies show that experimentation on embryos with these techniques often results in mosaicism with edited and unedited cells, as well as incomplete edits. This means that right now we have to work on having greater specificity in the genetic objectives of the therapy so that the consequences of using it are not much greater than the fact of curing a disease.
Ethical shock. The controversy is served with genetic therapies in general, since right now one of the lines that are open is to eliminate this extra chromosome directly in a human embryo before implementing it in a woman so that she is not born with this disease. This is where bioethicists point out that experimenting with human embryos damages their physical integrity and poses irreversible risks for future generations.
Furthermore, they underline the urgency of distinguishing between the use of CRISPR for purely therapeutic purposes, such as treating symptoms, and its use for “genetic improvement” or the selection of embryos that are much more advanced or genetically perfect. This is also added to the fact that genetic editing in embryos for reproductive purposes is currently prohibited in most countries.
Imagenes | Sangharsh Lohakare
In | The surprising thing is not that we have sequenced the DNA of a Neanderthal from 11,000 years ago: it is what it has revealed
