Systems biology is a relatively new concept of applied systems thinking, most widely used in biological studies since the turn of the century. At its core, this interdisciplinary field covers the computational and mathematical analysis and modelling of complex biological systems that, before systems biology, would have been near impossible to describe.
A primary aim of systems biology is to identify and model properties of cells, tissues and organisms functioning as a system – typically for metabolic networks or cell signalling networks. The Human Genome Project, run between 1990 and 2003, was an early high-profile example of systems biology in action.
The complexity of the systems being studied and the technological requirements for conducting such research necessitates a collaborative, interdisciplinary way of working that has heralded exciting new opportunities for researchers.
At the University of Birmingham, experts from a range of fields are drawing on these new approaches to deepen our understanding of the heart and identify new pathways for patients with cardiovascular diseases.
Taking on the challenge
Katja Gehmlich is an Associate Professor in the Institute of Cardiovascular Sciences, plays a catalysing role at the University in deploying systems biology approaches to cardiovascular science.
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Prof Katja Gehmlich
“One of the stimulating things about systems biology as a field of study is that it is undergoing such marked change. There’s the computational side that underpins a lot of the new opportunities we have for research, but then there is also scope for more exploratory ‘fishing exercises’ that are only possible thanks to the continued advancement of next generation sequencing techniques. As these methodologies become more powerful and sensitive, we can learn much more than ever before.”
She goes on to highlight one of the primary advantages to Systems Biology approaches – the unexpected insights. “Not only do you get an answer to your initial question, but you tend to stumble upon new questions entirely. It may be that data points to certain pathways or mechanisms within a cell that we had not previously considered in relation to the disease we’re investigating. That’s really exciting from a researcher’s perspective.”
However, such advances come with new challenges, and they require the support of the University’s breadth of expertise and nurturing interdisciplinary environment.
“We have these incredible tools now,” says Dr. Gehmlich, “but you really need experts who know how to get the most out of them and, crucially, how to properly design the computational side of the research. Scans of the genome can give you two terrabytes of data and it is easy to get lost in the denseness of it all. That’s where you want to have a really collaborative approach so you can tease out the meaningful insights.”
For Fabian Spill, Professor of Applied Mathematics, finding that common language between biology and mathematicians is helping drive some of the most interesting developments in his field.
The scale of development for systems biology is really something, it has almost become a discipline in itself. It is to the credit of those involved that they recognised that these tasks could not be tackled in silos, and for mathematicians like myself it is a chance to apply our expertise to incredibly complex questions.
Prof Fabian Spill
The interconnected nature of cells – with links between biological systems that are not simply causal but much more complex – presents the sort of challenge that can only be answered by models at the cutting edge of applied mathematics. Now that new computational models and tools have been developed, the real focus is on developing mathematics further to the point at which it can better guide our understanding.
Professor Spill continues, “I had initially explored mathematical models in the context of cancer science – which has a slightly less mechanics focus than cardiovascular biology. Then, through collaboration with Katja and others it became clear that there are such interesting questions about how maths can help us get to grips with the heart. So, we sought out some initial funding to bring a group of experts together and discover what might be possible.”
The first port of call was to the Institute of Advanced Studies (IAS) at the University, who provided seed funding for a workshop to ‘spark’ conversation around ‘System Biology of the Ageing Heart’.
Among the attendees was Dr. Vijay Rajagopal (University of Melbourne, Australia), an expert in modelling the heart who could add significant value to the workshop and future work.
“That initial support in getting a forum for new ideas, and bringing subject matter experts like Dr. Rajagopal to the University, was paramount,” says Professor Spill. “Of course, we had an agenda for the workshop but we also wanted it to be a space where our conversations could spawn other collaborations and ideas. You don’t always find that in academia – whether it’s due to a slightly restrictive culture or structural obstacles – so having the IAS support as a catalyst really helped set the tone.”
Investigating Alström syndrome
A number of prospective projects have stemmed from the workshop on systems biology approaches to the ageing heart, held in September 2022. Following the event, the IAS has funded pilot studies to aid the team in gathering preliminary data to support applications for larger grants down the line.
There are proposed workstreams to investigate multiscale organisation of the heart in health and disease, and to explore metabolic crosstalk in the ageing and diseased heart.
One of the core ideas to come from it, though, was to study of accelerated cardiac and biological ageing in Alström patients.
Alström syndrome is a particularly rare genetic problem found in fewer than one in every 500,000 people – there are only around 80 people in the UK. Though symptoms of the condition vary between individuals, the disorder can affect many different parts of the body with the potential to cause obesity, diabetes, blindness, deafness, bladder weakness and high cholesterol levels. It can also lead to kidney failure, liver disease and glandular problems.
A commonly seen symptom in Alström patients is the premature ageing of the heart, and abnormal stiffness and reduced function of the heart muscle (cardiomyopathy).
University Hospitals Birmingham NHS Foundation Trust is home to a specialist centre looking after the vast majority of these UK patients – and so the basis of an idea was born. Alongside the academic thrust of the University, it made Birmingham the perfect place to explore the hypothesis that accelerated ageing is an underlying mechanism of this disease.
Dr. Gehmlich adds, “Our first goal is to support this cohort of Alström patients, for whom there is no current treatment. But beyond that we also believe that looking at this selected group might inform how our grasp of how the heart ages in the general population, particularly as a result of ‘western lifestyle’ traits such as having too much junk food or not getting enough exercise. We can delve into the downstream consequences of stiffness of the heart and further our understanding of the basic science at play. All of that work will depend on combining systems biology with mathematical modelling around ageing and it starts with this kind of project.”
“Having the seed funding available within the University to get preliminary data can open up so many doors. If we can find experimental evidence that an ageing heart is the problem within this cohort of patients then we can look at some of the pathways available to manipulate ageing, whether that is using drugs or nutritional supplements to slow the process or otherwise.”
Again, the interdisciplinary systems biology approach may yield a number of different routes for exploration. It may be that data suggests new evidence for the mechanisms at play in the ageing heart, it may be that entirely new questions are presented to the team.
Another core component of this work, of course, is the Alström patients themselves. As often seen in small cohorts, there is real appetite to be involved in the research to improve outcomes. As such, researchers are working alongside the patient organisation and clinicians at the Trust.
“You absolutely have to marry that patient insight with modelling in order to be effective,” says Dr. Gehmlich. “They can often feel quite disparate and so it’s another element of a ‘translator’ role you can play when overseeing interdisciplinary projects. It is a challenge for sure, but it is what makes it interesting. Fortunately, I’ve been working with clinicians for almost 25 years and though it took some time to find common ground I’ve learned so much from observing how they work. I find clinicians are very good at breaking things down because they’re used to communicating with patients – and that skill can really bridge the gap between disciplines.”
Professor Spill agrees, “It can take years to come to terms with new approaches to research and subtle differences in the language, but that is what’s required in systems biology at the intersection of maths and healthcare. I find that talking to experts, reading books, and taking biology and medicine lectures has helped me to understand the problems my colleagues are facing. I will never be a fully-fledged expert in their world by any stretch, but understanding some of the core principles of their field can be greatly beneficial.”
“After all, straddling those interdisciplinary lines is where true intellectual collaboration takes place. You are not solving two sides of one problem individually; you are solving the problem together. As a researcher, that’s what I find truly invigorating.”
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