Ronald Bontrop Van Loghem Laureate 2013

“Marveling at the complexity of the immune system”

Ronald Bontrop02.jpgVan Loghem Laureate 2013 is Prof.Dr. Ronald Bontrop, Director of the Biomedical Primate Research Centre (BPRC) in Rijswijk. He works with non-human primates in order to develop medicines against seriously debilitating and deadly human diseases. His focus is on the co-evolution of the highly complex immune system and pathogens. “Viruses are key to understanding the immune system”, he says. Bontrop is not only a leading scientist in his field, but also the head of a unique research facility where the wellbeing of 1,500 primates is vigorously defended.

Biochemist by education, Bontrop turned to medicine for his PhD. “Growing algae in vitro can be interesting, but in a hospital you can see the actual results of your work in patients. I was lucky to get a PhD position at the Department of Immunohematology and Blood Transfusion of Jon van Rood at the Leiden University Medical Center. We worked at the characterization of MHC class II molecules; the better we could characterize these polymorphic molecules, the better matching protocols influenced transplantation outcome.”

Acclaimed BPRC research
Bontrop got so fascinated by the immune system that his inner biologist roared himself. “I became highly interested in the evolution of the immune system, constantly adapting to new threats.” So when he was offered a position at the TNO Primate Center in Rijswijk (now the BPRC), he jumped at the opportunity. “We can learn a lot by comparing the evolution of the immune system of men and his next of kin, the chimpanzee and rhesus monkey.”
He illustrates this by acclaimed BPRC research on HIV. “We compared chimpanzees, rhesus monkeys and humans that are resistant to the virus and found that MHC molecules sharing particular functional specifics are present in all three species. These MHC molecules target the Achilles' heel of the virus, the part where the virus proteome is highly conserved and is least able to mutate. Chimpanzees are packed with these molecules. This led to the hypothesis that in the distant past, probably two million years ago, a precursor of the HIV virus caused high mortality among chimpanzees. Only chimpanzees with an immune system that could control the virus survived. The current chimpanzee population is descended from these survivors. Our team worked hard to put all pieces of the puzzle together and managed to verify our hypothesis.” This was absolutely a highlight in the career of Bontrop, who has traveled the world explaining the findings. “Time is scarce, but I think it is important that scientists explain about their work and its societal relevance. We have an obligation to account for our work towards society that funds our research.”

Innate immune system
Part of the human population too is able to control the virus and not develop AIDS. Bontrop: “Both chimpanzees and certain humans are lucky to have a set of the correct molecules, but whereas - thanks to the HIV-pandemic - most chimpanzees are in the clear, the human evolutionary battle where selection will favor the persistence of particular MHC molecules has only just begun.”
Today, one's genes identify one's ability to fight HIV/AIDS. In time, evolution can provide mankind with protection, but until then the people who missed out on the good genes depend on a vaccine for protection.
Bontrop points out that HIV-research on non-human primates has also shown the importance of the innate immune system. “The adaptive immune system kicks in three or four weeks after infection, but by that time the virus has already started killing immune cells. When non-human primates were infected with the virus, we learned that in some individuals the immune system already started cleaning up the virus before the adaptive immune system responded to the threat.” Understanding these processes is highly important and may aid vaccine design.

Viruses key
Bontrop keeps marveling at the complexity of the immune system and the interaction between the innate and adaptive mechanisms. “In millions of years of evolution so many mechanisms have been developed, and there are also examples of redundancy. If we peel of one layer, another appears. There is still so much to discover.”

If we want to improve our understanding of the immune system, one has to study viruses, is Bontrop's conviction. “Viruses have developed alongside the immune system, always on the lookout for weak spots in the system. In fact, one can consider viruses the best molecular biologists in the world, since they have dedicated themselves for hundreds of millions of years to manipulating the immune system. Fundamental research at this level can teach us a lot.”

Immunology on the map
Research of the BPRC is of course not limited to HIV/AIDS. The centre also carries out research on Tuberculosis, Malaria, MS & Arthritis, Genetics, Flu and Parkinson, always with the immune system as leitmotif. “Immunology has become the common concept in so many fields of biomedical research and medicine”, says Bontrop. “35 years ago one single person could monitor the entire field of immunology, today that would be totally impossible. Immunology has grown up, expanded, advanced and is making significant contributions to human health. Only think of the vaccines that have been developed, of successful transplantation strategies, of the treatment of rheumatoid arthritis and cancer. Immunology research has amazed the world.” Dutch research is internationally renowned, says Bontrop. “Many colleagues ask me how such a tiny country can be the breeding ground of so many good immunologists. Van Rood, Van Bekkum, Ballieu and many others were trend setters and have put Holland on the map. Many good young researchers follow in their footsteps.”

Top level facilities
For Bontrop, the highlight of his scientific career so far was the discovery of the selective sweep which targeted the MHC of chimpanzees  two million years ago. “It was an a amazing discovery for which I highly credit my team. It put the BPRC in the international spotlights.”
The second highlight concerns the BPRC as an institute. “When I became director of the Primate Centre in 1998, the institute was in bad shape: facilities were old, the housing of our animals was poor. We worked hard to underpin our role in immunology research, testing vaccine candidates and therapies in a pre-clinical stage. We also lobbied hard to convince politicians that our animal facilities desperately needed an upgrade. We managed to convince all parties of our relevance and in 2001 the Ministry of Education, Culture and Science awarded the BPRC with funds to build highly advanced facilities, where the wellbeing of our animals is secured. We meet today's and future EU standards.” The new base grant also made it possible to transform the BPRC from a contract research organization into a respected independent scientific research centre that breeds its own second generation offspring and thoroughly characterized nonhuman primates. Bontrop: “We are very grateful to the people who made this possible.”

By being entirely transparent on the work done at the BPRC, the centre has also created a lot of goodwill with the general public. “In the late nineties animal activism was very strong. We opened up about our work and enjoy showing people around”, says Bontrop. “At the BPRC animal welfare is a main priority. When people actually see how the animals are housed and taken care of, and understand that primate research is vital for the identification and development of medicines for common deadly diseases, acceptance strongly grows.” He stresses that the BPRC only uses non-human primates where there are no suitable alternatives and that the BPRC has an active programme to develop alternatives to animal testing.
It is not easy to combine a scientific career, a professorate at Utrecht University and the general management of the BPRC. “One cannot do it in regular working days”, Bontrop says. “But I enjoy all aspects of my job and have never ever regretted the choices I have made.”
His achievements have earned him the Van Loghem Laureate 2013. “This is very special to me, following in the footsteps of our best and brightest”, he says. “It is an honor and I am really looking forward to giving the lecture in December.”

Streamer: “One can consider viruses the best molecular biologists in the world, since they have dedicated themselves for hundreds of millions of years to manipulating the immune system”

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