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Let’s focus on the system

Posted on September 9th, 2016 by in Pharma R&D


As a researcher, I spent a considerable amount of my time and energy thinking about (and then conducting) experiments to identify new targets in neurological conditions such as migraine and stroke. This is some years ago now, and if only our team had some of the resources then that are available today! The use of ever-more-precise assays investigating the generation and differentiation of cells into specific cell types, and much better understanding of the genetics of these diseases would have provided much more knowledge and understanding for our investigations.

Recently, I read with great interest the summary and perspectives on the genome wide scan recently conducted in migraine (Ayata, 2016). The original meta-analysis (Gormley et al., 2016) encompassed a large number of individuals both with migraine with and without aura. The study suggests considerable difference in the heritability of migraine with (lower) aura compared to migraine without aura. This again raised the debate about whether these expressions of migraine phenotype are really biologically distinct.

A range of gene products were confirmed to be linked to migraine and perhaps even new ones identified. Genes were linked to vascular smooth muscle, ion channels and genes expressed in the brain (Ayata, 2016). I remember plenty of discussions in the 1990s about whether migraine was a neuronal or vascular disease. This debate seems to be continuing today, even with the development of the successful triptan treatments going off patent. Well, then, perhaps a different perspective; maybe it is both? Both the vascular and neuronal components are involved in the system. This would certainly fit with the physiology of what is happening in the moment in vivo, and is a different focus compared to descriptions of professional expertise.

These works are great genetic studies that really help put all the key players in place. Taking time to think about the work, my initial reflection was: with all this knowledge, would our team have been more productive? Honestly, I think it is difficult to say. This led to my next reflection on this work, and others of this type of investigation to determine the genetic links to disease. This was: the high focus of the industry and researchers on the molecular mechanisms of disease, a focus on developing linear systems with causality.  Finding a new target, a specific target to engage the incredible resources we can bring together to develop new medicines on particular targets.

There is one thing I have learned and re-learned over the intervening 15 years from my time as a migraine research leader, and I do believe this would have been a useful “mindset” in finding those new targets. It is to remember that biology is really about systems. Homeostasis provides a huge impetus to determine the overall response of a system to a stimulus. Systems have a range of feedback mechanisms around key control structures. These control points have elaborate feedback mechanisms that focus the system to its set point.  Pathophysiological processes perhaps occur when these system control points are no longer able to deal with the real situation. This is perhaps a way to think about how we link these “weak” points in the system, when genetic mutations give rise to a condition or disease. When the control mechanisms are no longer fit for purpose.

Computational biology has, perhaps, a great deal to offer in this space. To me, this is more than associations – it is really like trying to model weather systems. How does all this information come together to make an impact on what the cell, the organ, the system and even what the individual is experiencing? Like weather system modelling, I am sure there will be a range of different opinions. However, modelling simple and complex biological processes will hopefully enable quick decision-making around where to spend time and money.

Ayata, 2016. Nature Reviews Neurology
Gormley et al, 2016. Nat. Genet. 48: 856-866

Enable better understanding of biological processes underlying disease progression and treatment response with Pathway Studio.


All opinions shared in this post are the author’s own.

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