During his PhD at Ghent University, Bart Lambrecht became fascinated by asthma and allergies. He went to Rotterdam to specialize in lung diseases and became the head of a research group studying asthma and viral infections at the Erasmus University Medical Center. After ten years, Lambrecht returned to start a new asthma research group at Ghent University in 2007. Four years later, he joined VIB as a group leader and became director of the VIB-UGent Center for Inflammation Research, while remaining active as a pneumonologist. Since then, research into inflammatory diseases such as asthma has accelerated rapidly at VIB.

"Asthma and other allergies have been on the rise – particularly in the Western world – over the past one-hundred years," Lambrecht explains. "Antibiotics, vaccines and better hygiene have trained our immune system to beat life-threatening diseases, such as tuberculosis and malaria, but made us vulnerable to allergies.

"Because of the low risk of infection we're dealing with today, our dendritic cells – which constantly 'scan' the body to identify antigens from foreign substances and pathogens – might label some sources, such as dust mites and pollen, as harmful. The consequence is that some people's immune systems start producing antibodies, causing inflammatory responses by the skin and the mucous layers of the respiratory tract – places where most antigens enter the body."

That's why Lambrecht and his fellow scientists have been focusing on the immune systems of patients with allergies, rather than the specific allergy-inducing antigens, also known as allergens. A remarkable study led by Lambrecht and his VIB colleague prof. Hamida Hammad has highlighted a central role for one specific protein.

Lambrecht: "We investigated the hypothesis that people who grow up on farms have fewer allergy and asthma problems. First, we found that exposure to dust from a dairy farm made mice immune to dust-mite allergy. By studying the mechanism protecting the mice, we discovered that the animals produced a protein called A20 when being exposed to farm dust. When removing A20 in their lungs, the mice were no longer protected against dust mite and developed allergic reactions.

"In the next phase of our research project, we tested 2,000 children who lived on farms and found that those suffering from allergies – despite being raised on a farm – had a mutation in the gene encoding for A20, causing the protein to malfunction. At that time, the most important conclusion was that the structural cells composing the inside of the lungs, and not the immune cells, are first to recognize allergens."

Two years later, in 2019, Savvides and Lambrecht solved an age-old mystery. A specific type of crystal, called Charcot-Leyden, was observed in the air tracts of asthmatics as early as the 1850s. Later, these crystals were also linked with chronic inflammatory diseases, such as bronchitis. But for more than a century and a half, scientists had no clue why they were there. In the 1990s, researchers discovered that the crystals were made from the protein Galectin-10. But the actual link between the crystals and respiratory diseases remained a secret.

Lambrecht: "Normally, proteins don't form crystals in a well-functioning human body, which means there had to be more to it. That's why we used patient-derived crystals to determine the 3D structure of Galectin-10 down to the atomic scale, using a synchrotron – a particle accelerator producing a beam of X-rays. This allowed us to verify that, when produced experimentally, Charcot-Leyden crystals are identical to patient-derived crystals.

"When administered to mice, lab-grown crystals induced a full-blown immune response with the main features of asthma, including the production of altered mucus. We proceeded by investigating whether interfering with crystal formation would be a therapeutic option for asthma. This is where argenx, a Ghent-based biotechnology company specializing in engineering antibodies, stepped in.

"Together with argenx, we developed antibodies to specifically react against Charcot-Leyden crystals and tested them in our labs – with unexpectedly great success. The antibodies not only neutralized Galectin-10, they also dissolved crystals in a petri dish in the lab within minutes. The crystals that seemed insoluble, dissolved in front of our eyes. If you'd ask me to indicate that one eureka moment in my career, this would definitely be it.

"Later, we performed more tests in vitro and saw that the antibodies removed the crystals in the mucus of patients within a few hours. Other experiments with these antibodies in mice showed a strong reduction in lung inflammation, and diminished alteration of lung function and mucus production."