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We are all genetic mosaics

Lies Van Horebeek, a researcher at the Laboratory of Neuroimmunology at KU Leuven, is the second Charcot PhD Fellow.  This Charcot PhD fellowship is possible thanks to all donors of the Belgian Charcot Foundation. Lies has now successfully completed her fellowship, supervised by the renowned team of Professor An Goris and Professor Bénédicte Dubois. In this article, Lies and her promoters tell us about their work.

The importance of the Charcot PhD Fellowship

Lies : I studied biomedical sciences at KU Leuven as from high school I already knew that I found biology very interesting, especially the human body. During my training, I noticed that I was particularly interested in neurology and genetics. Then following an internship with Professor An Goris and Professor Bénédicte Dubois, I was completely sold on MS research. I was therefore very happy to be selected as the second Charcot PhD Fellow.

Prof. An Goris : I am extremely grateful to the Belgian Charcot Foundation for their continued support of our research group’s research. The Charcot Fellowships are particularly important because they allow us to spend four years working with young researchers to investigate MS. In this way, we bring fresh new ideas to a renowned team. At the same time, we offer these young researchers the necessary framework to train in science, and in particular in good practices that ensure reliable and high-quality results.

Genetic risk factors for MS

Lies : If you imagine our genetic material as a book consisting of more than six billion letters, the genetic material of each of us is more than 99.9% identical. Only one in every thousand letters differs between you and me. It is these small differences or genetic variations that contribute to the many characteristics in which we differ from each other, such as height, colour of hair and eyes, aptitude for sports or music. This also determines a lower or higher susceptibility of developing a disease like MS.

Prof. An Goris : Our research group is a member, and I am currently coordinator, of the International MS Genetics Consortium (IMSGC), a collaboration of more than 25 research groups around the world from Australia to the US. With this international group, we have identified more than 200 genetic risk variants that confer a higher susceptibility to MS. These risk variants are passed on from parents to their children. This also explains why about 15 in 100 people with MS also have a relative with MS.

Novel insights: we are all genetic mosaics

Lies : The title of my doctoral research is “Somatic mosaics in MS: detection and insights into the disease”. Our body consists of thousands of billions of cells. Current school textbooks state that the exact same genetic material is present in each of those cells of our body. However, my research with the most recent, novel technologies sheds a different light on this. We note that there are not only variations between people, but that there are also variations between the cells of the same person. The number of genetic variations between cells of our body increases as we age. We did not get these variations from our parents. They can be caused by external factors, such as sunlight and smoking, and also by internal factors, such as during cell division when the genetic material is copied. This means that we are actually all mosaics of cells with slightly different genetic material. We were able to bring this to the attention of our international fellow scientists in a review article entitled “Somatic variants: new kids on the block in immunogenetics” in the scientific journal “Trends in Genetics”. This allows other researchers to validate and build on our findings. However, we are by no means the only ones who have demonstrated the extent of genetic mosaics. For example, Icelandic researchers at “deCODE genetics” found that even identical twins are not genetically identical as has been assumed up until now. The two halves of monozygotic twins show minor variations that begin just after fertilization, during embryonic development, and increase in number over the twins’ lifetimes. Twins are easier to study, but the fact that we are genetic mosaics applies to everyone. Therefore, the school books have to be rewritten!

Genetic mosaics and MS

Prof. Bénédicte Dubois : What do those mosaics now mean for MS? We are only able to investigate this thanks to the many people with MS and their partners who are willing to participate in scientific research.

Lies : When someone agrees to participate in scientific research, a blood sample is taken and in the laboratory we use this blood sample to sort the different types of blood cells. In our study, we examined immune-system cells that play an important role in MS, more specifically the T cells and B cells. We extracted the genetic material, DNA, from these cells and were able to read it with new technologies. We then compared a large group of people with MS with a large group of healthy controls.

Developing this method has been a major challenge in my research as we need to be able to reliably distinguish the real, biological variations from technical errors that occur because the DNA reading technologies are not yet perfect. This involved a big bioinformatics challenge!

Prof. An Goris : We are very grateful to the Belgian Charcot Foundation for making a such an innovative project possible. When we started this study, we hoped to find maybe one or at most a couple of these newly emerged genetic variations in some of the study participants. To our surprise, we found that the vast majority of individuals with MS carry such variations, and even healthy controls do. These results of Lies’ research have meanwhile been confirmed by Finnish fellow researchers.

Lies: The newly emerging genetic variations can change proteins and change cells, e.g., by making them divide faster or making them more pro-inflammatory. By combining my results with the results of international colleagues, we see that there are “hotspots” where new variation occurs more often. We can now compare those “hotspots” in larger groups of people with MS and healthy controls. We expect that if these hotspots increase MS susceptibility, they will be more common in individuals with MS than in control subjects.

Prof. An Goris : The finding that we are all genetic mosaics, and the scale of this phenomenon, are very important. In addition to the genetic variations that are passed on from the parents to their children, we now also need to study further the newly emerged genetic variations between cells for their role in MS. We believe it is very important to include this in future genetic research, including in collaborations with the International MS Genetics Consortium. With even newer and better DNA reading technologies, we can continue this research on a larger scale in the future.

Importance of genetic research for MS

Prof. Bénédicte Dubois : Scientific research, in which different studies build on each other over a longer period of time, is important not only for a better knowledge of the disease, but also to achieve tangible results for the person with MS.

The normal process towards developing a new treatment takes years. Reliable scientific insights, including those from genetic research, provide an opportunity to speed up this process.

Prof. An Goris : Many substances or molecules are suggested as possible new treatments. Only a small proportion of these successfully complete all the clinical studies required to develop an effective drug. Many molecules drop out along the way because they do not appear to be as effective or safe as hoped for. Genetic research can provide additional arguments for selecting the most promising molecules. If genetic variation in a molecule is associated with a disease, that molecule is a prime candidate for developing a potential treatment for that disease. It has now been repeatedly shown that support from genetic research for a molecule doubles that molecule’s chance of passing all clinical studies and leading to an effective drug. Pharmaceuttical companies have understood that importance very well: they are now extensively building on genetic research in the search for new treatments. The commitment of young, talented, and well-trained researchers such as the Charcot Fellows is therefore extremely important, at both universities and pharmaceutical companies!