One of the greatest experts in genetics explains the revolutionary leap that CRISPR has brought: Insert Coin with Lluis Montoliu

From saying so much, that of "playing Gods" became a phrase. A decaf idea that looked good to raise suspicions, pique curiosities, and write scripts for science fiction movies to air on television on Saturday afternoons. But then CRISPR came along, a truly revolutionary genetic editing tool, and it changed everything.

For this reason, we speak with Lluis Montoliu, who is not only one of the people who knows the most about CRISPR in Spain but someone who has been working in the first line of genetic engineering for more than thirty years.

Did we discover the totally disruptive genetic editing tool and is it going to be in Spain?

"Not only is it in Spain, but it is in Alicante. Neither in Madrid, nor in Barcelona, ​​in Alicante," says Montoliu. And indeed, 25 years ago, while studying the ecosystem of the Salinas de Santa Pola, Francis Mojica began to try to understand how the microorganisms that give the salinas their characteristic pink color survive.

That pink color is not due to water or anything like that, "it is given by archaea (as these microorganisms are technically called) who, unlike other bacteria, love salt." Mojica and her thesis supervisor decided to sequence the genome of these critters and found repeated structures. "They weren't the first to see them. They had been seen by Japanese and other Dutch microbiologists a few years earlier in very different microorganisms, far apart."

"That was the first major contribution Mojica makes, realizing that something that was present in such diverse microorganisms had to be relevant. If not, it was not understood how billions of years later these structures were still present." However, the essential contribution occurred in the summer of 2003.

"In the summer of 2003, he did a different thing than his peers did. While they were absolutely amazed and delighted to verify these repeated sequences that the bacteria had, but no one knew what they were." Mojica noticed that between the repeats there were virus fragments. "White and bottled, he said: This is an immune system." He had just discovered how bacteria defended themselves against viruses. "It was an impressive find."

When we talked to Mójica, he himself recognized it: "When we discovered CRISPR, I said to myself:" this is going to be crazy in biology "and then absolutely nothing happened." "Indeed", Montoliu tells us "What's more, he tried to publish it and it took him three years to convince the scientific community. Imagine a job that came from Alicante, a job that had no international collaborators and that told us that bacteria have a system immune".

The hidden history of CRISPR and genetic engineering

Montoliu has just published a book "Editing genes: cut, paste and color. The wonderful CRISPR tools" in which he talks a lot about the real history of CRISPR. But, why, of all the fascinating stories genetics has given us] (, CRISPR?

"There are only two types of laboratories: those that already use CRISPR and those that will use it soon"

"I believe that this is a subject that is here to stay. There are few subjects that can produce a revolution in all of science and this is one of them.

Perhaps the most similar is the one that occurred in the 80s with Kary B Mullis who was awarded the Nobel Prize for a DNA amplification reaction. All forensic medicine, all CSI, all DNA sample and evidence detections are based on that discovery. Imagine the revolution it caused. CRISPR is something similar ”.

How big is the CRISPR revolution? “I usually say that there are only two types of laboratories: those that already use CRISPR and those that are going to use it soon. There is not going to be any kind of laboratory. ” But, in addition, "it is such a powerful technology that society has to be a part of it"

Learn genetics with a hundred words

Genetics is often spoken of as a language. It is a recurring metaphor, However, if we had to assess the level of that language we have, it is clear what qualification we would have. "We have 3 billion letters in our genome. We know 2% of them quite well. We know quite a bit, 60 or 70% of what there is to know about those letters. But what about the remaining 98% of the genome? "

Montoliu is right, there are many sequences (as in the case of CRISPR) that, evolutionarily speaking, have reached our days. This means that it is reasonable to think that they must fulfill some function. In that 98% are the switches, the sequences that determine that a gene is activated in a specific cell and that another one is not activated or that it is activated at this specific moment in embryonic development and no later.

We have spent decades tiptoeing over 98% of the genome, now we can see what happens in there

That is to say, there, in that 98% are the rules, the instructions that govern the function of genes and, as Lluis explains, "this is something that we had tiptoed through for many years because there was no way to get our hands on it."

Now things have changed, we have learned to take advantage of what bacteria use to defend themselves against viruses. "What we do is use a Cas9 protein to make a cut to somewhere in the genome using a little guide that tells you where to cut. Then the cell's own system will repair the cut to produce the mutation that we want. This is something we simply could not do. Not that we did it more slowly. No, we couldn't do it ”.

“In 96 we published a study in which we proposed that one of these switches of one of the genes that we studied could be important. We did it indirectly, but the reviewers told us that what we had to do to demonstrate it was to go to the genome and eliminate this element. It took us 20 years this experiment to do that experiment, 20 years without finding anything until, suddenly, this new technology appears. ” "There are quantitative jumps, there are qualitative jumps, there are quantum jumps and then there is CRISPR," Montoliu passionately explains.

The creation of Avatar mice

But perhaps the most interesting thing about CRISPR is that it is not science fiction. In Montoliu's laboratory they use what they call 'mouse avatar'. "I use the metaphor for the James Cameron movie because in it, blue beings are somehow connected to people."

In that sense, Montoliu's team is able to create mice that have exactly the same mutations in the same place as the person they want to study. In this way, before administering to the human patient a drug that we do not know clearly if it will work, we can explore it in the avatar model. It is a new dimension in the field of validation of safety and efficacy of treatments.

But it is ethically controversial. The debate on animal experimentation raises more and more passions and, it seems, the positions do not stop festering. How do you deal with this dimension of your work? "I understand that nobody wants to cause harm to animals and I am the first who is convinced that we have to have a humane treatment with all our fellow humans and with all the species that we inhabit on the planet."

“But we also have a responsibility, and researchers in particular, with health. We have to learn to better detect diseases and develop better therapies. And what we cannot do, in this I think we would all agree, is to investigate using human beings ”.

Montoliu reminds us that, in Europe, there is very strict legislation and they can only work with animal models in the absence of alternative methods. “It is not that we can use alternative methods, it is that we must do it.So the first thing we must prove is that there is no other way to do it. "

From hero to villain

Speaking of investigating directly with humans, on November 26, 2018 the world woke up to the news that ** a Chinese researcher had edited human embryos **. "Well, that would not be news. There were already other researchers in China and Europe who had been doing it since 2015. What nobody had thought of was implanting those embryos so that they would become babies. ”

"What the Chinese researcher did is what we do every week in the laboratory with mice, so when I saw him, I put my hands to my head. Everyone who works with CRISPR knows that it is very precise to modify the gene that we decided to modify, but what we do not control yet is the end result ”.

"The case of the Chinese researcher is paradigmatic because we would be wrong if we thought he was a lone wolf"

As we explained before, CRIPSR-Cas9 is capable of cutting DNA with unprecedented precision, but it is the genome repair mechanisms that "solve" that cut. The problem is that those repair tools don't have the same precision. In this case, the most serious thing is that they have no memory, they do not coordinate.

That is, each time they find a cut they repair it in a different way (even if it is the same). For this reason, Montoliu tells us, “my mice, when they are born, are mosaics. Mosaics in the sense of a patchwork quilt: each area of ​​the mouse has a different genetic variant ”

In mice, the problem is managed by discarding specimens that do not have the desired mutation (which are, today, 19 out of 20). "Now tell me how I do this with human beings." "The case of the Chinese researcher is paradigmatic because we would be wrong if we thought that he was a lone wolf or a person locked in his garage who had come up with a crazy idea and carried it out. None of this happened. "

“There are several American investigators who knew for more than a year of the intentions of this gentleman. Some recommended with more or less vehemence that he did not have to go there, that he was wrong. But either they thought he was cheating on them or they didn't see him capable and they didn't raise their hands to say "be careful that we have a guy here who says he's going to do something that we know shouldn't be done."

How do you explain all this? We asked. I sincerely believe that “this man was self-convinced that he was doing something good for humanity and, in fact, believed that the rest of humanity would see him as a hero. In the end, what has happened is that he has been a villain. ”

The complete program at Insert Coin

You can listen to the entire conversation with Lluis Montoliu below in our new Insert Coin program. In addition, if you wish, you can subscribe (iVoox, iTunes, Spotify) to directly receive future installments of our talks with super specialists and technical guests on some of the topics that fascinate us.

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