Research Vision
MEDGEN already has a world-class reputation and expertise in genetics in different rare disease groups with shared challenges and opportunities. A first commonality is that the clinical spectrum of these disorders ranges from severe, typically very rare, pediatric-onset conditions with a strong genetic component to adult-onset conditions for with suspected interplay between genetic and environmental factors. The former group represents the more severe end of the spectrum from which important pathophysiological lessons can most readily be learned. This knowledge can then be translated into patient care. In addition to severe pediatric-onset disorders, the knowledge gained is also of added value for common adult-onset conditions. Secondly, locus heterogeneity is a common characteristic of many genetically determined adult-onset conditions (e.g., otosclerosis, arrhythmia, obesity, …). Thirdly, in some of the diseases we study, important intra-familial phenotypical variability has been identified. This observation and the already existing knowledge on the primary genetic cause of the disease pave the way for studies in search of modifiers as alternative therapeutic targets. We collectively tackle these disorders by sharing identical methods, scientific strategies, bio-informatical approaches and genetic technologies.
MEDGEN has very successfully applied cutting edge genetic technologies to gene discovery in the field of rare disorders. Although gene discovery will still be relevant in the future, the major challenge ahead lies in the functional characterisation genetic variation and translation of these new findings into better patient care. The major hurdles we foresee are explained in the challenges below:
Clarify biological significance of variants identified by NGS
The major bottleneck at present is the ability to distinguish causal mutations from benign variants. The ability to interpret and functionally annotate variants of unknown significance (VUS) will be necessary to effectively use whole genome sequencing in the clinic and to fulfil the dream of personalised medicine. Robust and efficient in vitro and in vivo systems representative for the different human disease conditions will have to be developed. Therefore, MEDGEN aims to strongly invest in iPSC development and the creation of zebrafish and mouse models. This approach will require full embracement of all available omics approaches. Furthermore, expansion of our bio-informatics toolbox will be key to fully grasp the wealth of data from all omics approaches.
The use of liquid biopsies to revolutionise diagnosis and treatment follow-up in different types of cancer
Cancer is the second leading cause of death worldwide, claiming around 9.9 million deaths and 19.2 million cases in 2020 alone. Given the importance of early detection in cancer treatment and prognosis, both genetic and epigenetic alterations in cancer present a unique opportunity for use as biomarkers for screening, early detection, prediction and prognosis of cancer. Biomarkers can be detected at a solid biopsy point (tissue) or in circulation (whole blood, or plasma) or in secretions/excretion (stool, urine, sputum). Solid biopsy markers are still relatively invasive, while liquid biopsies on the other hand are more easily accessible, minimally invasive and easier to monitor. While genetic mutations have already been established as drivers of carcinogenesis, more recently, the role of epigenetic modifications in cancer has been widely demonstrated. The value of DNA methylation as a marker for early cancer detection and diagnosis, and the scientific interest around it, have been steadily increasing over the last decades. The practical translation into the clinic is still lagging behind, however.
Translation of (epi)genetic discovery into innovative diagnostics and therapies
MEDGEN anticipates that very soon whole genome sequencing will be standard genetic analysis and the next step towards personalised medicine. This will significantly increase the societal impact of our research and this opportunity should be fully embraced. These unprecedented genetic possibilities will indeed improve our ability to provide better molecular diagnosis and genetic counselling. But along with the pathomechanistic insights derived from challenge 1, we also need to strongly invest in prevention and treatment of disease. As such, GENOMED will seek collaborations with clinicians, hospitals and industrial/pharmaceutical partners to develop genetic knowledge into biomarkers and to translate our genetic understanding into innovative therapies.