The 'mothers' Of Crispr/cas9: "in Spain The Cuts In Research

The ‘mothers’ of CRISPR/Cas9: “In Spain the cuts in research have lasted too long”

Jennifer Doudna and Emmanuelle Charpentier, creators of the revolutionary genetic editing tool, calculate that with these ‘scissors’ diseases will be cured in just a few years.

Emmanuelle Charpentier and Jennifer Doudna, in Madrid

The genetic revolution most important of recent times began as the great stories of science: simply curiosity. In the nineties, the microbiologist Francisco Martínez Mojica (Elche, 1963), who worked at the University of Alicante, insisted on finding out why some bacteria from the Santa Pola salt flats They were behaving strangely.

In his genome appeared genetic sequences repeated at regular intervals. After ten years studying it and with hardly any funding, the researcher from Alicante reached his eureka moment. The bacteria had developed a Defense mechanism in their immune system to face their enemies, something unheard of in these beings.

What Mojica did not imagine then was that his discovery – which he named CRISPR– would lead to gene editing tool fastest, most accurate and cheapest in history, with which scientists hope to be able to cure a long list of diseasesincluding various types of cancer and AIDS.

After reading Mojica’s research, the scientists Emmanuelle Charpentier (Juvisy-sur-Orge, France, 1968) and Jennifer Doudna (Washington, USA, 1964), decided mimic bacterial behavior in the laboratory and created the technology CRISPR / Cas9, with the Cas9 enzyme functioning as pair of scissors to cut regions of DNA.

The publication of the tool in Science in 2012 it kicked off for thousands of scientists around the world to rush to use it in their laboratories. In recognition of the revolution that the technique has brought about, the three scientists have received the BBVA Foundation Frontiers of Knowledge Award in Biomedicine.

EL ESPAÑOL spoke with Charpentier, director of the Max Planck Institute for Infection Biology (Germany), and with Doudna, professor at the University of California Berkeley (USA), on her way to Madrid to receive the award.

In 2011, the Japanese Shinya Yamanaka also received the Frontiers of Knowledge Award in Biomedicine and a year later, he won the Nobel Prize. Will history repeat itself with CRISPR/Cas9 next year?

Emmanuelle Charpentier: I think that, in general, the committees take their time.

Jennifer Doudna: There is no way to predict it and, besides, the decision is not up to us.

EC: Someday, it is not known when, in ten or twenty years, there will be recognition for the CRISPR technique. Beyond that, not much more can be said.

As scientists, what would it mean to win the Nobel Prize?

EC: It is considered the great recognition, the most important. It is also the most well-known award, but there are many others with committees of highly prestigious scientists that have their value.

Last year there was no woman among the winners. How is it possible?

EC: In general, there are not many women in the Nobel Prizes. I think it depends on the subject that is being recognized because many times there are fields of work in which not too many women investigate. It must be taken into account that in our area, at the level of leaders, the percentage of researchers who become leaders is low.

How did the idea of ​​working together come about?

EC: We met at a conference on bacteria that Jennifer was attending as a sort of weirdo, because she had focused on RNA research but not specifically on bacteria. He then started working with these microorganisms to understand the structure of proteins and interact with CRISPR RNAs. I was working on a CRISPR/Cas9 system and we decided to do it together to find the mechanism of action. Jennifer was already well known in the research area. She was the most active publishing articles that, in addition, were very good. As we began to get along very well, we began to collaborate.

J.D.: For my part, with my team we were working on CRISPR biology but not like what Emmanuelle was studying in her lab. I thought it was a good idea that we collaborate to study the functions of proteins in this system, especially that of the CRISPR/Cas9 protein. Perhaps one of the most important moments of my life was a meal we had in Puerto Rico. We were walking through Old San Juan, in those cobbled streets, while we talked about the project. I remember you told me (looks at Charpentier): “This protein is very interesting and it would be even more interesting to understand how it works.” And it turned out very true. (Both laugh).

When they published their article in Science in 2012, did you think it was going to cause a revolution?

EC: You have to be modest and think that it is achieved step by step. Following the article, numerous studies on the applications of CRISPR were quickly published. We must also assess the number of scientists who have approached us because they are going to work on it. It is clear that it is something important and that what you have published can be a very interesting alternative, with a wide battery of useful applications that are being launched.

A few weeks ago, an article published in Nature Methods stated that the CRISPR/Cas9 technique was associated with mutations. Have you read it?

J.D.: Yes, it is a terrible study. The article talks about two mice that are created and make very unusual use of CRISPR scissors. Most scientists don’t use technology like that. Just by creating these mice, the authors were already generating mutations. Furthermore, they did not do adequate controls or perform statistical analyses. They published an article that was not reviewed by other scientists, which is also not something that is usually done. Normally, before publishing, you make it go through the criteria of other researchers, so it is not an article that can be taken into consideration. It bothers me a lot because it’s so irresponsible. It is an important issue and they have done it very badly.

EC: Maybe what they wanted was to gain attention, but it’s not good for anyone.

J.D.: Many scientists are outraged by this article.

It seems strange that it came to be published in a magazine like Nature Methods.

J.D.: Yes, it is a very well-known publication.

But the article has not had a peer review [realizada por otros científicos como se suele hacer en la revistas de este tipo]?

J.D.: No because they published it as correspondence to the editor and normally these articles are published according to their judgment.

[El 14 de junio la revista publicaba una nota editorial en la que advertía a los lectores que “las conclusiones de este documento están sujetas a críticas que están siendo consideradas por los editores”].

Do we know all the details of CRISPR/Cas9 or is more research needed?

EC: We need structural work to be able to explain the true diversity of the nature of the CRISPR system and thus be able to engineer the enzyme to potentially make it more specific and, at the same time, more flexible.

But is the technology safe?

EC: Yes. The least secure part has to do with the way it is delivered to the cell, not the technique itself.

J.D.: That has been another of the problems in the article that I mentioned Nature Methods. They just injected chemicals into the mice. They induced DNA damage that they never controlled for in the experiment.

Right now, are you still researching the technique in your laboratories?

EC: Not just about CRISPR.

J.D.: We continue to be interested in the fundamental mechanisms of genetic regulation. Some people in my lab are working on the CRISPR system, but I’ve always had two or three researchers working with other tools.

At a press conference they have stated that within two years we could see the first therapeutic applications of the tool. Personally, what would you like to see achieved?

J.D.: It would be fantastic to see a child cured of a genetic disease. Would be wonderful. For example, genetic blindness.

Could it be a reality in five years?

J.D.: It’s hard to say. From the work that Emmanuelle and I have done with the companies, it can be deduced that in two or three years some types of clinical trials can be started.

The technology makes it possible to edit the DNA of embryos, which raises ethical dilemmas. What are the red lines?

EC: When talking about human embryos, my theory is that it is very difficult to use technology to correct more than one mutation in them. There must be the possibility of selecting embryos in vitro and certain mutations should also be avoided. If research on embryos becomes possible, this technology can be used to study them, but always for research purposes.

And use it to improve the human condition? Would it be a red line?

EC: Create superhumans?

J.D.: For the near future is not a threat. It’s more of a fantasy.

EC: Natural evolution has done it so well that it is not necessary.

In Spain, public funding for research has been suffering cuts for many years. In fact, Mojica conducted his study on bacteria with little funding. Why do you think it is important to invest in science?

J.D.: Without funding, without basic science, we could not carry out our work.

EC: Many of the current developments and technologies, not only in biomedicine, come from basic research. Even mathematical models. Everything comes from basic science, from these scientists who do science for science’s sake.

The germ of this genetic revolution was Mojica’s curiosity about bacteria. Is curiosity the basic ingredient of science?

EC: I think so. It is very important to maintain that curiosity. And it’s important that some of us get paid to ask those questions, to be curious and to generate additional knowledge. That we wonder why we are on this planet and why we have a brain. In relation to what I said before, I think that Spain has been greatly affected by the cuts in public funding for research and I think that it has lasted too long. Spanish scientists have especially suffered from these conditions and it does not look like it will improve.

What advice would you give to teenagers who are thinking of studying a science career?

EC: It’s a matter of liking what you do, of vocation. You have to feel that strong attraction and, even if you have doubts, if they have the vocation, I would tell them “do it”, “take risks because whoever does not risk does not win”. It is true that it is difficult because young people are not as confident as before, but maybe it is a matter of taking risks, of changing the mentality a bit. At an educational level, it is important to prepare students psychologically so that they do not see this lack of clear perspectives as a negative aspect but as a positive one, because I believe that society is evolving. You have to keep the motivation of young people, so they know that, regardless of what they do, they will always have opportunities.

J.D.: For girls thinking of pursuing a career in science, there’s never been a better time. It is becoming easier for women to access the sciences. In addition, there are figures that are doing an important job and that can motivate the girls. Watching these women can feel like they can do it too if they love research. It is fortunate that we both have had very good mentors who can inspire future generations.