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Skip to 0 minutes and 12 seconds And this is being done in somatic cells, cells in culture, or this also may be done in germinal, in germ cells in the sense that the whole animal inherits the changes that we’re choosing? For instance, in our lab we use mouse embryos, which means that we are doing this modifications modifications at the level of the germ cells, and basically we are obtaining mice that eventually either, they carry the mutation that we wanted to generate, or they carry the correction that we wanted to generate, and in all the cells. This is because we’re using these animal models for investigating, in this case, human rare disease, which is what we do in our lab.

Skip to 0 minutes and 53 seconds You can do this in cells in culture, and you can do this at the somatic cell level. So let’s say, you have an individual, you have a mouse that has a mutation in one of the genes that has a relevant function in muscles cells, and now we have methods to deliver this CRISPR reagents, this molecular scissors, that they can be targeted towards the muscle cells. So in a way, you could kind of “treat” this adult animal that carries a mutation. This is kind of the very beginning of what we hope it will be soon a new approach for doing a new format of gene therapy for treating patients or for treating human beings that are associated with congenital diseases.

Skip to 1 minute and 47 seconds So this method, CRISPR, is also applied to humans. It will be sooner or later applied. It’s not yet being applied. We need to be very clear about this, because as much as we know that this CRISPR system is very precise, the repairing mechanism that take over after the cut they are not as precise, or better to say, we don’t know enough about this repairing mechanism. Which means that you can obtain your desired corrected sequence, but in addition to this, you will obtain a variety of additional mutations that you are not interested.

Skip to 2 minutes and 33 seconds Of course, I can deal with this in cells and I can deal with this with mice, because I basically select the mouse that I’m interested and I discard the rest. But I don’t know how to deal with this in human beings. And this is why I keep saying that it’s not prudent at this right moment to transfer these preclinical developments into the clinic, until we reduce to an acceptable minimum, this possibility of generating additional mutations. And I’m not referring to mutations in other genes that are similar to the one that we would like to study, this is something doable. We can reduce these so-called off-targets. This is not the problem.

Skip to 3 minutes and 19 seconds The problem that is fundamental, that is preventing the application of this CRISPR technology in the human clinics is the on-targets. The tool is cutting in the gene, but the repairing is never done correctly or is not done always correctly. So we would like that all the repairing, if we are providing a template with a correct sequence, we would like to have most of the repairing experiments to be carried out from this template. We don’t want to create additional mutations on the top of the ones that we wanted to correct, and until we don’t fix this I think it’s not prudent enough to be using this technique in the human clinics.

Skip to 4 minutes and 8 seconds Okay, so we have seen how this new technologies, the CRISPR systems, systems that exist in nature, are being used by researchers, help us to understand our genome.

Conversation with Lluis Montoliu. Part 4

Lluís Montoliu, research scientist at the National Centre for Biotechnology of the Spanish National Research Council in Madrid, Spain.

He is interested in understanding how the mammalian genome works and is trying to identify the elements that regulate the expression of genes in time, space and level in order to improve the design of gene-transfer strategies used in animal transgenesis and gene therapy.

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Why Biology Matters: The Genome and You

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