Quinquennial prizes of the fnrs 2020

(Source FNRS)

Jean-François Collet, Professor of Biochemistry at the Faculty of Medicine of the UCLouvain and co-Director of the de Duve Institute, was awarded the Joseph Maisin Prize (Basic Biomedical Sciences) for his research on bacteria and their response mechanisms to external aggression. "It is by understanding how bacteria defend themselves that we will be able to disarm them."

Watch the interview of Jean-François Collet made by the FNRS and broadcast on CanalZ on 26/10/2021 (in French): Z-Extra Prix Quinquennaux

Bacteria, an early vocation?

"Not at all! I am a bioengineer by training (at UCLouvain), and I did my PhD thesis on a human enzyme whose deficiency is the cause of a metabolic disease. But, as I was starting to consider a post-doc, I attended, almost by chance, a course on protein folding, given by an old German professor who was absolutely fascinating, and who talked about this field of science that I knew very little about with an infectious passion. As I listened to him, I thought, "That's it! This is what I want to do!" So I went to find him after class and asked him who I could talk to about doing a postdoc in this field. He took a blank sheet of paper and wrote down ten names, and next to one of those names - James Bardwell at the University of Michigan - he scribbled three stars, telling me that was his first choice, a bacterial specialist. But I wasn't interested in bacteria! So I contacted all the other researchers on his list one by one, and several were willing to take me on, but without any real enthusiasm. I then decided to send an e-mail to number 10 on my list and, two hours later, James Bardwell phoned me from Michigan to tell me that he was expecting me!

And it was in his lab that you fell in love with Escherichia coli?

"Indeed yes, and I'm not afraid to say it, because my wife, who accompanied me to the United States - two of our four children were born there - has known all along! I fell in love with Escherichia coli, the bacterium I'm still working on. It's a little organism that I like all the more because I'm rather impatient by nature. And bacteria grow very fast. You put them in the incubator in the evening before going home and the next day you have the results. Escherichia coli was made for me: we never left each other's side, even after I returned to Belgium.

A bacterium is a unicellular organism, and much simpler than our cells, which have a nucleus, mitochondria, a reticulum... so different compartments. A bacterium is a kind of bag containing the complete kit for an independent life, namely DNA, RNA, proteins. And I - or rather we, because it's really a team effort - we're working on what's called the envelope of Gram-negative bacteria.

Is it a family of bacteria?

"It is one of the two major families of the bacterial world, indeed, of which Escherichia coli is one of the main representatives. It owes its name to a staining technique developed over a century ago by the Danish physician and bacteriologist Hans Christian Gram. The dye used is gentian violet. Bacteria that retain the purple stain are Gram positive bacteria, those that lose it are Gram negative bacteria. At the time, researchers had no other way to classify bacteria. It wasn't until the 1960s and the advent of electron microscopy that they were able to see what the envelope around them looked like. And to realize that their different behaviors in relation to the Gram stain were explained by differences in the layers of this envelope.

You mean the bag is surrounded by several layers?

"Exactly. In the case of Gram-negative bacteria, the bag is surrounded by three layers, which makes them particularly hard to attack. I often compare them to a fortress with three walls around it, so they are particularly well protected. And what fascinates me is that we send men - or women - into space, but we still don't know how bacteria build their outer shell. But bacteria are everywhere, in us, on us, and in every corner of the planet. When I talk to you, I am talking to bacteria, because, like me, like all of us, you are more bacterial than human: in a human body, there are up to ten times more bacteria than human cells! Some are harmless, some useful, and some dangerous, even deadly. But without them, life as we know it would be impossible! And yet, they remain shrouded in mystery...

A mystery exciting enough to keep you busy for years?

"For ten, twenty or even thirty years, yes, definitely. When Neil Armstrong walked on the moon in 1969, he must have felt something incredibly exciting, because he was the first. Well, at our small level, when one of my students is the first to unravel one of the many mysteries of bacteria, we feel the same excitement, we share in the same exhilaration of discovery. It is not necessary to go into space to take an important step. A step that prepares others, even more important. This is my first motivation.

« You can't learn research by reading syllabuses. You have to be tenacious, a bit stubborn, not give up too quickly, see the goal in the distance and say to yourself "I'll get there, even if it takes me years" " J.-F. Collet

Do you have several?

"Three, in fact. The first is the excitement of discovery. The second, in an academic laboratory like mine, is to train young researchers in the rigor of scientific research, which requires a real critical sense and rationality. And the third is to put ourselves, my team and I, at the service of society, because today's discoveries prepare others for tomorrow. We hope that our expertise will contribute to the development of a new antibiotic or to the optimization of bacterial cells for the production of antibodies against diseases such as cancer... When we know that bacteria already produce half of the proteins used for therapeutic purposes, this third motivation is not the least...

But, when you solve the mystery of the first wall, there will be two left behind.

"I don't even know if we'll ever get there, but we can't give up, because we have to face reality. Our species has been roaming the planet for about 200,000 years, and until 1940, the main causes of death for human beings were not cancer or heart disease, but bacterial or viral infections. So it's been 80 years since antibiotics changed things and literally revolutionized human life on Earth. But in 80 years, bacteria have managed to find weapons against existing antibiotics, while we have put the search for new antibiotics on airplane mode. As a result, in 20, 30 or 40 years, we may be entering a post-antibiotic era.

So why did they stop investigating?

"Because it is not profitable for the pharmaceutical companies. It takes between 1 and 2 billion to develop a new antibiotic, but sooner or later the bacteria become resistant to it, so the company can't break even. If we look at the few small companies that have managed to bring new antibiotic molecules to the market in the last 5 years, the majority are now bankrupt. As for stimulating this research with financial incentives, decision-makers are thinking about it, but the miracle recipe has not yet been found. This is the same attitude that presided over the destruction of masks before the current pandemic: as long as the problem is not there, we close our eyes! It's a bit discouraging, but as long as we stay on the battlefield, at least we feel like we're doing something! And we've already made some great discoveries.

For exemple ?

"I'll mention two. Until our work five or six years ago, no one knew that Escherichia coli decorated its outer wall with pretty little proteins. Proteins that become potential targets for new antibiotics. This is a discovery - made in a team, of course - of which I am extremely proud! And then we also realized that by modifying the length of the pillars that attach the outer enclosure wall of Gram-negative bacteria to their intermediate wall, we could modify the dimensions of the bacterial envelope itself, and thus make it more fragile...

Have you ever wanted to try your luck in another field?

"No. I stay in bacteriology, because I really like those microorganisms. And I always find students who are attracted to that aspect of the biomedical sciences. In the Middle Ages, someone who wanted to be a stonemason had to find a good master to teach him how to cut. It's the same thing with research: you can't learn it by reading syllabi. You have to be tenacious, a bit stubborn, not give up too quickly, see the goal in the distance and say to yourself "I'll get there, even if it takes me years". But above all, you have to find people to teach you, as I was taught by Emile Van Schaftingen in Belgium and by Jim Bardwell in the United States. Now it's my turn to initiate students. And, both humanly and scientifically, it is one of the most beautiful things one can do...

The motivations of the Jury of the Joseph Maisin Prize (Basic Biomedical Sciences)

Professor Collet's discoveries have consistently and comprehensively uncovered new fundamental cellular mechanisms, including a novel pathway that confers resistance of periplasmic proteins against reactive oxygen species, as well as the beta-barrel (BAM) machinery that assembles outer membrane proteins and exports the lipoprotein RcsF to the cell surface where it acts as a sensor of cell envelope damage. These findings pave the way for the design of a new class of antibacterial agents.