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We carry the story of animals within us

Interview with Denis Duboule

A specialist in molecular genetics and developmental biology, Denis Duboule is particularly interested in the genetic regulatory mechanisms that govern gene expression and embryonic development.
Visiting Professor at the international Evolution of Genomes and Development Chair since 2017, he will become holder of the Evolution of Development and Genomes Chair in 2022.

How did you become interested in the field of molecular biology ?

Denis Duboule :Having grown up in the countryside, I've always loved nature and animals. When I studied biology, I first turned to plants and fungi, because I have a taste for classification - old-fashioned biology. Then, little by little, I got into embryology, which didn't really appeal to me at university, because it all seemed so complicated. However, when you take a closer look at it, almost as an examination requirement, you realize that it's a discipline of inexhaustible conceptual and historical richness. After my doctorate, I went to Strasbourg to study with Professor Pierre Chambon, who went on to teach at the Collège de France. After a few months, he received an unpublished manuscript written by a Basel researcher, Walter Gehring, who had made an incredible discovery concerning developmental genes in the drosophila fly. Pierre Chambon was convinced that these genes and their functions also existed in vertebrates, so he asked me to set up a group on the subject. I didn't have a very good idea of what it was all about, but I was intrigued, so we started working with these genes in an extraordinary scientific environment. It's important to understand that, for the last fifteen years of the last century, developmental biology and genetics were in a constant state of flux. Every year, there were incredible new results, right up to the sequencing of genomes at the turn of the millennium. I'm not suggesting that the current period isn't as rich, and I'm not being nostalgic. But there has been a turning point, a meeting of two worlds : developmental biology - a science that is above all experimental, almost like cooking with its manual recipes - and genetics, which has a more intellectual, abstract approach. Two seemingly opposed states of mind, which came together thanks to molecular biology. That's when we began to understand that genes control the development of embryos.

How can we explain the years of circumspection that followed the discovery of this mechanism in Drosophila ?

When the first vertebrate Hox gene - from a frog - resembling those of the fly appeared, it became clear that the animals shared similar genes. Yet it took a few more years to understand that the general organization of this essential body-building genetic network was conserved between vertebrates and invertebrates - that the same fundamental rules were at work. This only foreshadowed the analysis of genomes at the end of the last century, which showed that, while there were clear differences between the genomes of distinct species, the number of genes and the way they were regulated were very similar between species. We carry within us the history of animals. The 1965 Nobel Prize winner for medicine, French biologist François Jacob, was already saying this in the 1970s. At the time, elephants were thought to have trunks, because they possessed a trunk gene. This view was supported by a skewed vision of evolution and genetics, which associated a gene with a specific characteristic. But it doesn't work like that. So, if we have the same genes as the elephant, why don't we have a trunk ? It's a reversal of the question that led us to ask : how is it that animals are so different from each other, when they share so much of their DNA ? An incredible field of research opened up at that time, and it's still a work in progress.

In this context, how does a researcher involved in this paradigm shift manage to project himself into the future ?

All researchers tend to think that their results are extraordinary ; in reality, this is not necessarily the case. On the scale of the history of life, it's a hiccup. It needs to be taken up by people outside this science - historians and epistemologists who will be able to highlight the degree of interest in the research at any given time. Personally, I think these fifteen years have had a major impact on evolutionary theory. It has relativized Darwin's position that variation in biological systems is clearly not entirely random. As humans, we thought at the time that we had the best arms, the best eyes, the best sense of taste... when in reality, we're pretty rubbish at all these things. But the sum of these elements is extremely powerful. In the years 2000, at the end of the human genome sequencing, specialists - knowing that the fly had 15 000 genes - predicted that between 120 000 and 130 000 genes would be found in humans. That's how arrogant we were as a species. And then - soufflet ! - just over 20 000 genes in our genome. A Swiss journalist called me to ask if I wasn't too disappointed by this number... which just goes to show the surprise it caused. Today, we know that it's simpler, from an evolutionary point of view, to have one gene capable of doing several different things than to have as many genes as functions.

With your laboratory, you have developed the TAMERE and STRING molecular biology tools. What have they enabled you to achieve ?

The discovery of homologous recombination in the 1990s, which won the Nobel Prize in Physiology, revolutionized the field. It made it possible to destroy genes and see what effect this had. At the same time, we were the first to use these methods, not to study gene function, but gene regulation - a subject which is part of the French tradition, going back to the Institut Pasteur with Monod and Jacob. We developed these genetic tools for chromosome engineering because we wanted to know the importance of a gene's position on its chromosome. How are these genes controlled ? Why does their expression start at one point and stop at another ? In research, when you do something new, the first publication is pretty straightforward, because it's new. Afterwards, when you want to develop the same subject further, it becomes much more complicated, as the announcement effect is attenuated. Thanks to these technologies, we were fortunate to be able to maintain visibility (and therefore funding) for thirty years, as few people were working on this subject, which required very heavy genetic logistics.

You collaborated with Steve Gaunt, with whom you proposed in 1988 that Hox gene clusters in vertebrates are subject to spatial collinearity. What impact did this discovery have on the discipline ?

Spatial colinearity, whereby the time and place of gene activation depend on the position of the genes in their chromosomal group, is a phenomenon almost unique to these famous Hox genes. Despite this singularity, the results of this work have led us to much broader phenomena. Previously, the gene was all-powerful and truly represented the basic genetic unit. Today, we see that the gene is often of a fairly generic nature, and that it is all the regulatory elements close to it that count, which can be distributed over long distances, in " regulatory landscapes ". The paradigm has thus been inverted. Taken out of context, if there's nothing around it, the gene isn't worth much. Also, studying flies is very interesting, because their development is rapid and we can observe the succession of generations in a short space of time. This type of development is not applicable to almost any other animal, and yet the fly has provided us with most of the basis for our knowledge of human development. By studying a highly adapted trait, we can identify some very fundamental principles. This is the principle of the model organism.

As a major contributor to this discipline for several decades, what is your perception of the current status and direction of developmental genomics ?

There's a very interesting debate about the future of this discipline. Some people think that there's nothing new to discover and that the younger generation is just producing data without thinking too much about it. It used to be a case of hypothesis-driven research - you'd ask a big question and then wonder how you were going to tackle it. Nowadays, methodologies are very powerful and many laboratories produce data, which they make available to the community and then examine. Some of my generation think this is a lot of hard work, but I don't agree. The only way to do good research is to be honest and precise. And I'm convinced that this approach will be just as productive as the old method, which is ultimately rather arrogant, since it implies that humans have the ability to ask and answer the right questions. But who can claim that ? The idea of being able to create de novo genomes, with perhaps unprecedented capabilities that could help us master some of the problems we're going to face, seems extraordinary to me. We can already do it on the scale of a bacterium, and we may soon be able to do it with more complex animals. In biology, there are few theoretical impossibilities, only technological limitations which, one after the other, are being overcome. In 1985, when we had done our homework, we were reading 30 base pairs a day to sequence a piece of DNA. Today, we can sequence several entire genomes, i.e. 3.5 x ¹⁰⁹ base pairs, per day.

The expansion of our knowledge of developmental genomics is sometimes accompanied by public distrust of the possibilities of gene editing. To what extent does this problem occupy the minds of those involved in this science ?

I've invested a lot in scientific communication in general, not just about our work. In fact, this is what the Collège de France is all about, in a specific, topical scientific context. These societal and ethical issues have been in the air for a very long time : the difference is that people start to become aware of these issues when technologies make it possible to put them into practice. Researchers should not base their work on ethical criteria, but solely on the desire to uncover truths in order to understand the world around us. However, when the application of this knowledge enters the public domain, problems arise. In Switzerland, where there is a system of direct democracy, such questions are often put to a popular vote. However, this raises the enormous problem of the quality and dissemination of information. People need to be sufficiently informed to make an informed decision. But how can this be done ? Therein lies the challenge posed by these technological developments.

From 2017 to 2022, you were a visiting professor in an international chair at the Collège de France. What did you learn from this experience, so far ?

The Collège de France is an extraordinary institution, which doesn't exist anywhere else. When I talk to colleagues in the U.S. and the U.K. about it, they tell me they've had the same experience with students. So I explain to them that we don't lecture exclusively to students, but to the general public. They retort : " What kind of public is ?How are they selected ? How much do they pay ?Are they graduates ? " They're taken aback when I point out that anyone can come, that it's free, and that it's not popularization, but actual science explained by those who do it. It's a unique concept that I think is great, with great accessibility. Every year, we have to produce a new lecture, and everything is made available on the Collège's website, so I sometimes receive messages from faraway countries, from strangers asking me for a particular clarification on this or that lecture. In concrete terms, the Collège de France has had a major impact on my professional life. For my lectures, I sometimes chose subjects on which I was moderately informed. So, above all, it's been an incredible source of personal culture. For example, after six months of research and reading, I created and taught a lecture on organoids, which then enabled me to write coherent and informed grant applications for research on the same subject. But above all, my joy at the Collège de France is the openness to colleagues from all walks of life, brilliant and warm, who take you out of your laboratory and give you a view of the outside world. You've given your lecture, you're tired, so you put your ear to the ground, catch a phrase, an idea, then you go and eat in the Place de la Sorbonne. That's when ideas come to you, projects, hopes, because it's an inspiring process. Afterwards, when I go back to my laboratory at EPFL in Lausanne, full of energy, I sometimes find it hard to believe.

Interview by William Rowe-Pirra