PoLiMeR’s Systems Medicine approach was based on the idea that generalized computational and cell models can be adapted to study patient-specific responses. In essence, liver metabolism is largely the same in different people. However, history, lifestyle and genetic make-up may cause differences in the amounts and quality of metabolic enzymes and the way in which they interact. These enzymes are the core machinery for all metabolic processes in the liver. In their research projects the PoLiMeR students have collaborated in interdisciplinary teams that tackled fundamental challenges in the metabolism of carbohydrates and fats.
PoLiMeR’s theoreticians constructed computer models that simulate liver metabolism at different levels of detail. At the most detailed level we visualised how a glycogen molecule grows and forms branches by addition of glucose molecules, and shrinks when the body needs glucose as a fuel. We also studied how this process is perturbed in patients with an enzymatic deficiency, the so-called glycogen storage diseases. At the intermediary level, we can simulate how large triglyceride molecules (fat) are degraded in over 50 sequential enzymatic reactions, to harvest the energy that supports the production of new glucose and other processes in the liver. For almost all of these enzymes inherited defects have been described. The model shows in detail how such deficiencies increase the concentrations of toxic metabolites in the cell, and also how they may lead to a deficiency in essential vitamin-B5 derived molecules. When zooming out further, we have also worked with a computational model that contains all the biochemical reactions known to occur in a human liver. This allows to study the impact of hundreds of known inherited enzyme deficiencies and how how the metabolism of these patients is affected by the available nutrients.
Yet, computer models are not the whole story. PoLiMeR’s experimentalists have collected data from patients and mice with a glycogen storage disease or a fatty-acid oxidation disorders. Mice are valuable if we want to study how the different organs are affected by the disease and how the organs respond in a concerted way. Using stable isotopes, it was possible to reveal the rates at which glycogen is synthesised and broken down at the same time, and that this cycling is much faster in mice with a glycogen storage disease. Zooming in, when we are interested in the role of one specific organ, the liver, we can generate a so-called ‘Liver-on-Chip’, a mini-organ that performs many of the functions of a real liver, but without any need for use of animals or taking invasive biopsy from a children. In a series of experiments, we have validated our computational predictions and collected data to make computer models specific for individual patients. Such individualised models revealed differences between patients that may explain why some show more severe symptoms than others, even if they have the same genetic defect. Finally, since data management is increasingly important in the era of big data, and it is a particularly challenge to find the data that you need, one of the PhD students focused entirely on this topic as a research project.
The PoLiMeR training programme was composed of different components. All PhD students had a research project in their specific field of expertise, in which they collaborated between different disciplines and institutes. As part of their training they visited each other’s institutes for short and long internships. During the COVID-19 pandemic we continued our collaborations online and exchanged samples and models. Fortunately, most of the planned internships could take place when the pandemic declined. Furthermore, the PhD students followed advanced scientific courses, in which our principle investigators shared their knowledge on the different aspects of Systems Medicine and inherited metabolic diseases. Moreover, students met a patient, and were trained in the lab and at the computer. Last but not least, the PoLiMeR PhD students received complementary skills training, focusing on data management, communication, grant writing and entrepreneurship. A highlight was the career training in which each PhD student got an individual assessment and coaching, wrote a proposal for an activity to spearhead his/her next career step, which then was funded by the consortium. With their grant, they went to foreign labs to explore options for research jobs, followed language training, had coaching for personal effectiveness, or invested in a start-up company.
