Van Loghem Laureate Frits Koning

Cracking the mysteries of celiac disease

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Building on the impressive achievements of his predecessors, Prof. Dr. Frits Koning (1954) has given his own direction to the research executed at the Laboratory for Immunohematology and Blood Transfusion of the Leiden University Medical Center. Celiac disease has his special attention. “In The Netherlands alone, 160.000 people suffer from this high impact disease. We do our utmost to improve their lives.” This struggle has already lead to significant breakthroughs, for which Koning received several awards. Koning is the Van Loghem Laureate of 2012.

Unlike his father, it was never Koning's ambition to become an MD. The biology graduate took to research, investigating new scientific horizons. In 1986 he received his doctoral degree at the department of Immunohematology and Blood Transfusion at the Leiden University Medical Center. Subject was the identification and functional relevance of epitopes on the human lymphocytes. He managed to develop a panel of monoclonal antibodies, aimed at polymorphous determinants on HLA class II molecules. It was an inspiring period, he says. “This lab was built on HLA. It was here that professor Jon van Rood unraveled the polymorphism of HLA and thus made a large contribution to improving organ transplantation. In this house he developed a system to match donor and receptor of organs in the context of Eurotransplant, an achievement that cannot be overestimated.” HLA has the important physiological task of binding proteins and distinguishing  'self' from 'non-self'. Developing monoclonal antibodies against HLA helped Koning to understand the complexity of the immune system. “We gained insight into it at a molecular level and saw how molecules interact. Today molecular technology is everything. Back then it was revolutionary.”

Milestone
However inspiring the lab, Koning did not hesitate in 1986 to accept a postdoc position at the National Institutes of Health in Bethesda, USA, with Dr. John E. Coligan. “One should always jump at an opportunity like that. It inspires researchers to change their environment, they receive fresh ideas and expand their network.” In Bethesda, Koning studied the biosynthesis and assembly of the T-cell receptor-CD3 complex. “Bethesda possessed the biochemical technology that allowed me to do so. Also, they had impressive experience in the characterization of proteins.” Koning characterized the newly found gamma/delta T-cell receptor. He published no less than thirteen articles on the subject.
In 1988, Koning went back to Leiden where Van Rood secured him a job. Here, he proceeded his research and expanded it to the interaction between HLA-molecules and peptides. For this research, he was rewarded with a NWO Pioneer-subsidy in 1993. His research resulted in a significantly improved insight into the functional interaction of the HLA-class II molecule DQ2 and peptides. “In patients with celiac disease this HLA-DQ2 is significantly more present than in the average person. But what in gluten exactly induces celiac disease in these patients? How can specific proteins be so easily detected by their immune system? With NWO- and EU-funding we went looking for the answer to these questions. We found specific peptides in gluten involved in the expression of celiac disease. These peptides however do not bind to HLA-DQ2, so what was the missing link? We discovered an enzyme that gives these gluten peptides a negative loading, enabling them to bind with HLA-DQ2. This makes it much easier for T-cells to recognize them and induce an immune response. Discovering this was a real milestone.”

Celiac Disease Consortium
This work contributed greatly to the foundation of the Celiac Disease Consortium (CDC) in 2003. It is a public private partnership of five universities, the Netherlands Celiac Disease Society and a number of industrial partners. Koning was named director of the CDC, which is part of the Netherlands Genomics Initiative. The CDC is dedicated to improving diagnostics, prevention and treatment of patients with celiac disease and to creating safer foods for them. “The CDC partners for instance developed a kit for the detection of toxic gluten fragments in food. They came up with an improved prognostic kit and identified new genetic markers linked to disease development. You see, 'only' ten percent of the newborns in a family with celiac disease actually suffer from it. If we can predict whether a child is susceptible for celiac disease, we can prevent it from eating gluten and from developing the disease.” Another interesting line of research is the induction of gluten tolerance, by giving potential patients a minimal amount of gluten early in life. Next year we expect to be able to present results on this research.”

Enzymatic route
Koning himself was involved in an enzymatic route. “About fifteen years ago, DSM discovered an enzyme that is able to cut up proteins with many prolines. Together we figured that this might be used to improve the breakdown of gluten in the gastrointestinal tract, since gluten is rich in proline and this makes gluten very resistant to degradation. This is likely to be one of the reasons that so many people experience problems with gluten in food. With the DSM-discovered enzyme, we could speed up the process of breaking down the gluten considerably.” Koning aimed research at this enzyme. “In the TNO Intestinal Model (TIM) we discovered that with this enzyme, an entire fast food meal can be completely broken down in the stomach. We are now testing it in vivo. Our combined research may result in a pill that can be used to support gluten degradation and make it easier to cope with gluten in the food. The enzyme can be produced at large scale and is effective. If things go well - and I don't see why it wouldn't - it will be launched as a food supplement in 2013.”
This would be another milestone for Dr. Koning. “It is the first time that I will have been involved in the entire trajectory from the original idea up to the final, stable, effective and marketable product.”
In the meantime, Koning continues his quest to prevent the disease or induce tolerance. Today, he devotes part of his time to research on targeted therapy to eliminate certain T-cells that seem common to all patients with celiac disease. “If we could target and eliminate these T-cells, we hope to 'reset' our patients' immune system in a way that they no longer recognize gluten.” This research is based on a collaboration with Monash University in Melbourne, Australia, where Koning has spent a month early in 2012 to set up the collaboration. The first exciting results have just been published.

Not slow down
Koning has received several awards for his work. In 2010, he and his Norwegian confrère Professor Ludvig Sollid received the Rank Prize for Nutrition for their work in the field of celiac disease.
In 2011 Koning received the American William K. Warren Jr. Prize for his studies on gluten peptides, leading to methods to detoxify gluten proteins. And now he is the Van Loghem Laureate 2012.
The successes do not slow him down. “I still have so many plans. Not that I'm such a planner, my career has also been defined by coincidences. But I do consider myself a go-getter, I don't give up easily. I am motivated by the patients. I never had the ambition to become an MD, but I am driven by their fate: celiac disease has an enormous impact on their lives and I hope to contribute to their quality of life. There is still so much unknown. Why does one person have celiac disease and the other doesn't? Why does one person get it at early age and another later on in life? And what is the link with diabetes? These are still challenging questions, but we are closer to answers than ever before.”

Text: Alinda Wolthuis, bureau Lorient

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