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Conversation with Lluis Montoliu. Part 3

Lluís Montoliu, Research Scientist at the National Center for Biotechnology, of the Spanish Research Council, in Madrid, Spain.
For doing that you have had many traditional systems, and now it seems that there is a system, or the CRISPR systems in general, that represent a main shift in the way of obtaining transgenic mice. Could you explain us? Yes, absolutely. This is a revolution what we are living in, and it’s a revolution in the sense that no matter how many methods we have developed to produce transgenic or knockout mice; the overarching, the fundamental question has always been whether we can do a modification (in a) targeted way, we can be in control in which gene we are modifying, or whether we have to be satisfied by doing a genetic modification randomly.
Of course, being in control of the gene that you want to modify it’s, or it was, more expensive; it took us a lot more time and a lot more efforts. Whereas doing modifications randomly, which means, delivering a gene and hoping that it will be inserted somewhere in the genome and it will be doing what we predicted in the lab, it was kind of cheap and it was easy, but we didn’t learn much by doing this second. So what the CRISPR are bringing to the mouse genetic engineering is this precision, so now we can decide. We no longer need to do random experiments anymore. Basically, now we can decide which are the genes that we want to inactivate.
And this is very simple because we are using a tool that we haven’t invented, we are using a tool that has been with us billions of years, thousands of millions of years and bacteria and archaea, in general prokaryotes, they have used these tools, to defend themselves from bacteriophages. And of course they had this interest on defending, and they are in a way this kind of defense system, which is an adaptive system, it’s different from our own immune system. If we don’t want to be exposed to measles we get vaccines against measles, but our daughter, our son, they need to be vaccinated. They don’t inherit this resistance to measles virus.
The bacteria, once they develop this resistance against a phage, they can transmit this resistance to their daughters and to the granddaughters; so it’s got a genetic basis, this defense mechanism. This defense mechanism, that by the way was discovered by a Spanish microbiologist from the University of Alicante, Francis Mojica, is now being converted into what is called a molecular scissor. A molecular scissor because basically it enables us to cut a gene somewhere very precisely. That’s all what it does. The CRISPR is about cutting the DNA.
But once the DNA it’s been cut, now our own cells they repair this cut, and while repairing this cut they commit mistakes, and the readout, the output of the experiment, remember we only cut the gene, the output of the experiment is that the gene gets inactivated. It was never ever that easy to inactivate a gene. The only thing we have to do is that we have to direct, we have to drive this molecular scissors to the gene that we are interested, and we get the correspondent mutant. Of course we can do things even more sophisticated, which are really important, because we can tell the repairing system what to use as a template.
We can use as a template something that carries information that wasn’t there in the genome before, either because we want to introduce a mutation, because we want to reproduce a mutation that we have diagnosed in a patient, and we want to reproduce this mutation in an animal model, or because the animal model or the cell, or the human cell, has this mutation and we want to correct to the wild-type sequence, to the correct sequence. Now we can bring this sequence that can be used as a template, and by bringing this additional element, we can tell the system to edit the genomes.
This is why we’re calling this CRISPR editing tools, because similar to what we do when we type in a computer, and then we commit a mistake, and we take the mouse and we go to the wrong word, and we delete the wrong letter, and then we insert the correct letter… that’s exactly what we’re doing nowadays in the cells.

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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