Hunting for the Crohn's Holy Grail

"She was a young athlete, studying to be a doctor and looking forward to having children. Until Crohn's disease entered her life. She suffered from substantial weight loss, fatigue and pain, including an abscess near her anus that she didn't dare to tell her boyfriend about. Ultimately, her relationship broke down, she had to quit her studies and could no longer run. She was desperate. Thanks to medication, an appropriate diet and operations, we were able to give her life back step by step: she resumed her studies and had a child, with whom she sat in the consulting room with me. And she went back to athletics. In the end, we ran the Lille half marathon together." 

It is a story that Jean-Frédéric Colombel will not forget. "Crohn's disease and ulcerative colitis (UC) often strike at a young age, when people are in their twenties or thirties. Exactly when they are building their lives: their work, their family, their circle of friends. Then they suddenly suffer from severe diarrhoea, pain and other symptoms. It destroys their lives, which often makes them depressed as well. For a doctor and researcher, it is the greatest reward if you can make these young people smile again." At the end of his life, no one remembers his presentations or publications, says Colombel. "That all disappears into the trash can of history. What remains are the lives of the patients you met and the young researchers you helped." 

Road movie 

The fact that Colombel has focused his academic attention on inflammatory bowel diseases (IBD) for almost fifty years is, as often happens in science, a coincidence. At the beginning of his career, large groups of these patients appeared quite suddenly in the hospitals of northern France. "It was a real wave, especially Crohn's disease. I knew the clinical picture of my Belgian colleagues, who had had to deal with it before. I wanted to learn more about this new disease, I wanted to treat the patients, preferably cure them." It is here that Colombel's fanatical search began for what every medical scientist wants to find: the major cause of disease and therefore also a cure. "There were very few medicines for these patients, they were often still given artificial nutrition and most had to be operated. There was still so much to do." 

But there was hope, hope that much more knowledge about the nature of Crohn's disease was out there and, thus, that effective treatment was within reach. Colombel: "With some colleagues, I discovered that Crohn's disease was very common in certain families in northern France: for example, in all four children and both parents. Wow, I thought. What a fascinating clustering, maybe there's an infectious cause that we can discover in these families." 

It led to a special search in the French countryside, which resembled a scientific road movie. "The three of us set off in a big car: me, a nurse and the American professor of Pathology Herbert Van Kruiningen, who was fascinated by these families thanks to one of my publications in The Lancet. Then we sat together at a large table with coffee and cake, asking all those children and parents questions about their symptoms and habits. They were all neatly dressed because 'the professor from America' was visiting. We took blood and stool samples on the spot. We loaded it all into the car and then drove to the next village." Unfortunately, the egg of Columbus was not in the French countryside. "But I have always continued to believe that it will." 

The first seeds 

A new opportunity arose when Colombel gained access to a gigantic database of more than 80 million blood samples at the US Department of Defense more than fifteen years ago. These samples were taken from soldiers from the age of eighteen and then every two years. "That was great, of course, because it allowed you to detect the first germs of a disease retroactively, years before someone actually developed symptoms. This made it possible to pinpoint the earliest form of a disease in a person's blood, including Crohn's disease or UC." 

This early detection via biomarkers is of utmost importance, emphasizes Colombel. "Early is the key word in the treatment of Crohn's disease. What if we can catch the disease 'yesterday', even before the first symptoms appear?" This does not only apply to IBD patients: "Also to people with diabetes, asthma, rheumatism, MS and other immune mediated diseases (IMD). These are conditions that overlap: people with Crohn's disease, for example, are more likely to develop asthma and MS. There seems to be a common breeding ground for it. That is why we are working more and more intensively with these disciplines. In this way, we can join forces and achieve more." 

DNA route 

Colombel also works closely with various Amsterdam UMC colleagues. Together with MDL expert Geert D'Haens, his host at the Anatomy Lesson, he is active in an extensive European study into the early prediction and prevention of Crohn's disease: INTERCEPT. "Geert, also a friend, is a master in setting up trials. I have years of experience in predicting and preventing diseases. That's how you complement each other as a scientist." Colombel has a unique memory of MDL doctor and internist Sander van Deventer, who successfully tried the drug infliximab for the first time in Crohn's patients from the former AMC. "In my eyes, this was a real breakthrough, thanks to a brilliant mind who thought outside the box." 

The DNA pathway remains an important avenue to find the holy grail of cure for Crohn's. Colombel and colleagues discovered the first gene linked to Crohn's disease: NOD2. This also did not lead to the cure of the disease. "Unfortunately," he smiles. "My last point of reference is the group of patients who remain free of complaints after stopping medication or after operations. While the vast majority of patients then experience a relapse. What characteristics does this 'successful' group have? We tend to study the sick, but you also have to look at the good guys."