The complexity of glycogen storage diseases like diabetes means a reductionist approach just won’t cut it. Here we learn how systems medicine could lead to symptom reduction and quicker detection
Metabolic diseases are an increasing burden on health services in Europe, with some 60 million people suffering from diabetes.
It is recognised that progression of the disease differs between individuals and the reason is thought to be due to alterations in the underlying metabolic network and its regulation.
Glucose provides the energy for life and excess sugar is stored as glycogen in the liver and muscles.
If the mechanisms for controlling storage are impaired, then either too much or too little sugar is released into the blood, which can have a massive impact on the body.
Novel systems medicine approach to capture complexity
The complexity of the metabolic network means a simple reductionist approach will not help researchers and medics gain an understanding of all the pathways and their interactions, so a major EU project, PoLiMeR (Polymers in the Liver: Metabolism and Regulation), is taking a Systems Medicine approach to the challenge. This requires truly interdisciplinary researchers, trained in the three ‘pillars of Systems Medicine’ – experimental, computational and clinical research. The programme is a training network with PhD students working on different aspects of the challenge.
PoLiMeR is a focussing initially on Glycogen Storage Diseases (GSDs), a collection of rare conditions that are very hard to treat and can be fatal. The challenge with such metabolic disorders lies in the fact that perturbation of one part of the network – for instance through the impact of a genetic defect – can give rise to impact at quite a remote part of the network. Trying to pin down cause-and-effect is not trivial, which substantially hampers both diagnosis and therapeutic intervention, hence the need to take an holistic approach and study all aspects of the network at once. This Systems approach offers opportunity to gain insight into the underlying mechanisms of disease that would not be accessible by conventional research approaches.
So, instead the project is creating a computational model of the glycogen breakdown process - a type of digital twin - that, once fed with patient data, has the potential to provide the basis for a personalised diagnosis and treatment strategy for each individual.
Some work has already been done in this area to model human metabolism and create organ-on-chip technology, however, this has so far focussed on small metabolites, which are relatively straightforward to analyse - unlike the glycogen polymers and lipids that have a central role in metabolic diseases.
Professor Rob Field is co-founder of Iceni Diagnostics, leaders in glycoscience and partners in the PoLiMeR project. He says the outcomes of the study could be significant.
Rob says: “Our concern is for the children that have GSD, a rare genetic condition that impacts their ability to store glycogen and it builds up in other organs. At the moment, not enough is known about the relationship between the gene sequence and the disease state to identify the genetic markers one might use for diagnosis of disease. So, we are approaching the problem from a different perspective. We are looking to understand the structure of glycogen and the proteins that act on it, in order to assess the impact of the genetic mutations on both of these classes of biomolecule.
“This condition has strong parallels with diabetes, which also results from issues with glucose metabolism, so our work could also benefit other types of disease.”
Fluorescent probes react to change in structure
Gaia Fancellu, of Iceni Diagnostics, is one of 15 PhD students involved in the project; she is using fluorescent probe technology to better understand the structure and metabolism of glycogen.
Gaia explains: “GSDs, are caused by deficiencies in the specific enzyme involved in the breakdown or synthesis of glycogen. I’m working on characterisation of glycogen, a branched polymer, to understand how its structure differs between healthy people and that of patients affected by these diseases.
“I am following a top-down approach. The first step will be based on breaking down glycogen using specific enzymes to determine polymer length, positions and number of branching points at different cleavage points. The results will be analysed by high performance chromatography and mass spectrometry.
“In the second step, I’ll work with fluorescent probes to detect the structure of glycogen based on changes in fluorescence, using spectrophotometer as the reference tool to study the results.”
Gaia investigated Alzheimer’s disease for her Masters in Pharmaceutical Chemistry from The University of Pisa, Italy. She is deploying similar fluorescent probe methodology used in her earlier research to detect the activity of some synthesised compounds on amyloid fibrils, to further her understanding of GSDs.
Fluorescent probes are chemical compounds that act like a molecular rotor, changing colour when its movement is constrained. When the glycogen is broken down there is a change in viscosity in the cell and so a fluorescent probe can provide an indicator for micro environmental changes within a live cell.
Gaia continues: “I’ll be using this same fluorescent probe, in a different environment, to detect any changes in the internal viscosity and hence the structure of the glycogen molecules.”
Prescription diet could alleviate the symptoms
It is hoped that in addition to the development of biomarkers for diagnosis it may also be possible to alleviate some of the symptoms of the disease.
Professor Field continues: “These children have problems metabolising sugars, so could potentially benefit from different types of starch that are digested more slowly lower in the gut. It is well established that diet can be used to control diabetes, so this work offers the opportunity to identify interventions in other metabolic disorders associated with glycogen metabolism.”
Iceni Diagnostics is a spinout from the John Innes Centre in Norwich, UK, where there is a substantial programme looking at how plants store glucose as starch. This includes work on resistant starches found naturally in crops such as peas, which could be used within a prescriptive diet to control sugar levels.
Field says: “We are using the knowledge gained from plants and agriculture and trying to learn how to use some of those tools to tackle the medical challenges associated with GSDs.
“It is highly unlikely that there will be cure GSD any time soon, but it is possible to identify new diagnostic markers that would allow this condition to be identified sooner and to find potential dietary solutions that can ease the symptoms and improve the quality of life for affected individuals”.