The secret life of bacteria

Trained at ULiège with Prof. Jean-Marie Frère, Christine Jacobs-Wagner is now Professor of Biology, Microbiology and Immunology at Stanford University, where she heads a laboratory devoted to the study of bacteria. She has been invited to ULiège as part of the “Alumni en lumière” (almuni in the limelight) program. Read the story of an exceptional career.

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hristine Jacobs-Wagner was a “student athlete” before her time, more than two decades before ULiège inaugurated this special academic status enabling certain students to combine university studies with high-level sport. A fan of badminton, a sport which led her to take part in several international competitions in the early 1990s, this native of Liège, originally from Grâce-Hollogne, had the ambition, for a time, of representing Belgium at the Olympic Games. But to play a sport at an international level, you need more than just talent,” she explains. You also need muscles and tendons that are not prone to injury. But that wasn't the case for me: I got hurt as soon as I trained too hard. I ended up injuring my shoulder for good, and realized that top-level competition was over. At the time of the accident, Christine Jacobs-Wagner was completing a five-year degree in biochemistry, which she had chosen after considering a degree in law - “ because I liked arguing and debating, which, incidentally, you also do a lot of in science ” - and engineering. “ I had no idea that I would one day make a career in scientific research. I simply chose an orientation based on the subjects I enjoyed most at school: biology and chemistry.”

From Meuse to Missouri

At the time, the final year of the biochemistry curriculum was entirely dedicated to research. At the age of 21, the Liége native realized that she had to think outside the box. “ I realized that, to succeed in science, you had to know English. But if there was one subject in which I was mediocre, it was English. So I convinced myself that there was only one way to make sufficient progress: by immersing myself completely in the language. So, since a few students had already done their final year research in England, I asked to do the same. Neither the research topic nor the laboratory was of any great importance: I wanted above all to learn the language.

The young researcher then benefited from the support of Prof. Jean-Marie Frère, a key figure in the biochemistry department of the Faculty of Science and the Protein Engineering Centre (CIP) at ULiège. This specialist in bacterial enzymes and antibiotic resistance, who was to become his mentor, could not but be sympathetic to this project, having obtained a master's degree and a doctorate in biochemistry at the Université de Montréal, and then completed a post-doctorate at the prestigious MIT. A scout for young talent, he agreed to cover the travel expenses. He also convinced Swedish researcher Staffan Normark, a scientist at University of Washington in St. Louis in the USA, to host the biochemist from Liège in his laboratory and finance her stay for six months. “ My first research experience was truly transformative. Not only because I learned English, but above all because I discovered an interest in the study of bacteria, those 'champions of cell proliferation' ”. An interest that would never leave her. They're fascinating creatures,” she continues. Invisible to the naked eye, they are nonetheless the most essential organism for life on our planet.

During her undergraduate studies, Christine Jacobs-Wagner made the following observation: “ Bacteria are capable of protecting themselves in a multitude of ways, against the responses of our immune system and against antibiotics. Among other methods, some bacteria are able to produce an enzyme - a protein - toclip the antibiotic they detect, rendering it inoperative. These enzymes, and antibiotic resistance in general, were at the heart of Prof. Jean-Marie Frère's research. The aim was to isolate these enzymes, and thus separate them from the bacteria, in order to study them in a test tube. In other words, Jean-Marie Frère was doing enzymology.

It is this clipping phenomenon that the researcher will be studying once she returns to Belgium to complete her degree. But in Professor Staffan Normark's laboratory at Washington University in Saint Louis, the young woman became captivated by the workings of the bacteria themselves. In particular, she aims to understand how certain bacteria produce enzymes that inactivate antibiotics only after detecting their presence. This phenomenon is observed in opportunistic pathogens such as Citrobacter freundii - which only cause infection under conditions normally absent in a healthy host, such as a weakened immune system - commonly found in the soil microbiome, food and intestinal flora of humans and other animals, but some strains of which tend to develop resistance to antibiotics.

Scientific prize

How do bacteria detect the presence of antibiotics? “ They must receive a signal that alerts them to the presence of antibiotics in their vicinity ”, she postulates. It was this nagging question that Christine Jacobs-Wagner set out to answer at the end of a doctoral research project that kept her busy for five years, between 1991 and 1996. At the University of Liège, but not only: “ I wanted to tackle this problem mainly by combining the expertise of Jean-Marie Frère and Staffan Normark, and visiting other scientific teams if that proved beneficial. So I worked in several laboratories, from Saint-Louis (Missouri) to Stockholm via Paris and Boston, as well as Liège of course, to learn the techniques needed for my project. ”

In 1997, at the age of 27, she was awarded the Prix des Jeunes chercheurs de biologie moléculaire for the processes she highlighted. This prize, awarded by Pharmacia Biotech (a Swedish pharmaceutical company) in collaboration with the scientific magazine Science, is a world-renowned award. “ Bacteria have a protective cellwall, a semi-rigid layer that surrounds and reinforces the cell membrane. This 'wall' can only be enlarged by adding material to the existing framework, a process which involves first destroying part of this wall - in the same way that, to enlarge a building, it is sometimes necessary to break down existing walls ”, the researcher schematizes. She notes that, as the bacterium expands its cell wall, some of the wall material is reabsorbed before being recycled, like old bricks being salvaged to build a new wall. “ I discovered that this process of cell wall synthesis is deregulated in the presence of an antibiotic: once in the vicinity of the bacteria, the antibiotic damages the cell wall, affecting the amount of “old bricks” absorbed by the bacteria, thus revealing its presence. This triggers the familiar response: the production of enzymes that cleave and thus neutralize the antibiotic ”.

At the time, this phenomenon was only partially understood: although it had long been known that certain bacteria were capable of triggering the expression of such “routines”, we didn't yet understand how they worked. “ Beyond the importance of this discovery, the interest of this research for me, and perhaps for the jury who awarded me this prize, also lay in the fact that it connected two fields of research which had not really spoken to each other until then: studies of cell wall recycling and those relating to antibiotic resistance. ” But above all, while she had initially envisaged a career in some private company where she would have acted as an intermediary between the scientific and business worlds, Christine Jacobs-Wagner had in the meantime acquired a taste for research. She had experienced a “ sublime instant ”, a rare but unforgettable moment of excitement and discovery. And she understood that she would spend the rest of her life chasing these almost archimedean moments.

Lyme disease

Christine Jacobs-Wagner then moved to Stanford University School of Medicine, California, where she joined the laboratory of Prof. Lucy Shapiro, a world leader in developmental biology. During her post-doctoral work, she continued her interest in bacteria, but changed her focus to study cell multiplication, which fascinated her. This is particularly rapid in bacteria. “ This cell cycle is at the origin of life, which begins with a single cell, which multiplies to create a second cell, and from these two cells emerge two others, and so on. Isn't that incredible? Yet this process is not simple: many elements must be present, at the right time, in the right order, for this multiplication to take place. And yet, if you observe a bacterium, or any cell for that matter, this process almost never fails. It's truly remarkable. ”

In 2001, she joined Yale University, where she climbed the academic ladder and, in 2014, became Director of the Microbial Sciences Institute, while continuing to study the molecular mechanisms underlying bacterial multiplication with a multidisciplinary team. Christine Jacobs-Wagner has received numerous awards for the quality of her research, including the Ely Lilly Award from the American Society of Microbiology (2011) and the American Society of Microbiology Award for Basic Research (2024). In 2015, she was elected a member of the National Academy of Sciences - founded by Abraham Lincoln in 1863 - and, more recently, a member of the illustrious American Academy of Arts and Sciences - one of the oldest learned societies in the USA. In 2019, she returns to Stanford, where she is now Professor of Biology and, secondarily, Professor of Microbiology and Immunology. But Christine Jacobs-Wagner, who has just been elected a member of the Académie Royale de Belgique, is above all, since 2008, aninvestigator at the highly prestigious Howard Hughes Medical Institute, one of the world's best-endowed philanthropic foundations, whose funds contribute primarily to medical research.

Part of her laboratory is currently focusing on Borrelia burgdorferi, a bacterium transmitted to humans through the bites of infected ticks. This bacterium is at the root of Lyme disease, the most widespread vector-borne disease in the United States and Europe. Although easily treatable with antibiotics if diagnosed early enough, it is sometimes overlooked because of its flu-like symptoms. Having spread throughout the body, it can cause neurological or joint problems that can persist even after intensive antibiotic treatment.

In addition to the issue of the gradual loss of effectiveness of antibiotics, which as we know is a major public health problem worldwide, the case of Borrelia illustrates a separate problem that should be of equal concern to us: the resurgence of vector-borne diseases," warns the Professor. Indeed, under the influence of climate change, the tick's habitat is expanding considerably, and with it the spread of Borrelia burgdorferi and therefore the occurrence of Lyme disease. In some parts of the USA, the majority of ticks are infected with Borrelia or other pathogens. In Europe, this spread is also a considerable problem. But we know very little about these bacteria. “ So we're pretty ill-prepared to combat them. I don't want to speculate about the next pandemic, but it would be wise to invest more, not only in research into viruses such as coronaviruses, whose dangers we have seen, but also in research to improve our knowledge of bacteria and other parasites. ”