Interdisciplinary research into dementia: a personal view

Neurology Central presents professor Frank Gunn- Moore and research in to dementia:

As a researcher for the last 25 years, I have seen the coming and goings of a range of approaches to research into dementia and science in general. Currently, the in-vogue approach, as seen in the review of many grants and publications, is described in the terms of either ‘interdisciplinary’ or ’multidisciplinary’, which have become the favourite adjectives of recent times. Of course these terms imply that the author has broadened their approach in tackling a particular problem, or there is an attempt to bring in new individuals and therefore new skills to tackle a problem. This is on the whole is to be applauded and has more chances of success than the ultrafocused approaches that were in-vogue in the 1990’s.

There is a tendency as there is in all walks of life, with the rise of social media and bulletpoint reporting, to try and think of snappy terms to capture an apparent new trend, for example other common phrases in grants and publications are: “from bench to bedside” or “disease in a dish”, so this leads to the question: how ‘interdisciplinary’ is this apparently ‘new’ approach?

At one stage, it was fashionable to draw triangles with different disciplines feeding into the apex of the triangle, which somehow was always reported as being the clinical position or problem. However, from my own experience, and sincere apologies to the clinical folk reading these thoughts, please remember chemists make drugs, clinicians use them. However, I have also heard it stated that chemistry dictates the biology, but of course physics dictates the chemistry, but of course mathematics dictates the physics, and then of course we can get into the realms of metaphysics and abstract thoughts. However, this linear approach is of course also wrong.

As a product of the tertiary education of the 1980s, where I studied Biology, Chemistry, Physics and Mathematics in my first year at University, my own approach/philosophy has not been one of triangles or linear pathways but more of Venn diagrams, where the different disciplines feed into tackling a specific problem i.e. the problem takes the central point, and the approach, in some ways, is irrelevant as long as it answers the original overall question/problem — I dislike being discipline-led.

There are of course many attempts to claim that work is a new interdisciplinary approach such as big data from next-generation sequencing or mass spectrometry, which are supplying enormous amounts of data. The solution apparently is to have mathematicians or computer science to help process this mass of information.

In reality is this a new approach? Biology has always used mathematics especially in the realms of ecology. This is just a scaling issue. However, from this new approach, we now seem to have two types of research: ‘hypothesis driven research’ and now what is called ’hypothesis generating research’; though in reality in former years, as was written on a review of a grant of mine: fishing (I still got the grant).

From my own personal experience, I would suggest that a mark of true interdisciplinary research is when investigators start (or intend) to publish in areas of science where they did not start from — see if they publish in biology, chemistry and physics journals and not the same discipline that they have always published in.

In my own research, we have shown that mitochondrial and synaptic dysfunction, two agreed hallmarks of the early stages of Alzheimer’s disease, are indeed linked irrespective of the importance of either amyloid or hyperphosphorylated tau [1, 2]. This was achieved by starting from a biologist (biochemist’s) approach, of uncovering the proteins that change expression in dysfunctional mitochondria and establishing which proteins change their expression outside of the mitochondria environment [3–6]. This led to the identification of synaptic proteins that change their expression in dementia and in so doing cause synapses to be remodelled and/or work incorrectly [4, 7, 8].

As part of this original biologist’s approach, we identified a potential drug target and have begun the synthesis of compounds to help reverse these processes. Though drugs are somewhat in the future, we have been exploring, as a colleague described it, ‘chemical biology’ [9–13].

With regard to physics, a chance email from a colleague, led us to explore if we could manipulate cells, utilizing the power of laser light, to take up our novel compounds (what we termed “Photoporation” [14]), or even directly manipulate neuronal growth [15, 16]. More recently, based on our ability to shape laser light, this has allowed us to explore the development of novel microscopes to see the effect of our new chemical compounds and help us further describe the biological changes that we had previously described [17–19]. As such we have indeed now published in biology, chemistry and physics journals. However, be warned this means that you are now asked to review grants in all three disciplines.

Of course the UK research regulatory systems i.e. Research Excellence Framework (REF) does not account for such an approach (or its attempts to do so are not broadly accepted as being adequate by the research community) as researchers are forced to choose under which unit of assessment they are to be returned. Maybe the new REF202X will be different? We will have to wait and see, though it is now hinted that REF panels will have interdisciplinary champions, which has to be a good thing, in order to explain the vagaries and differences in the other disciplines.

However, despite this apparent successful approach I won’t claim that it is the only way. One thing I have learnt is that it is important to realize that for chemists, physicists and mathematicians to be involved in solving the big biological problems it is important to understand that these scientists are driven, as are all scientists, by the uncovering of new chemistry, physics or mathematics and are not there to be seen as technical support for an idea, however noble it may be (i.e. the triangle approach mentioned above). I would argue that no discipline is more important than another. To succeed in true interdisciplinary research then it is imperative to initially collaborate and learn to understand each other’s work and approach.

As a borne optimist, with regard to dementia research, I believe the future is bright and interdisciplinary research is the key to solve this collection of diseases that are the scourge of the aging population. Due to our approach, I am asked to give talks on how to collaborate and how to keep these collaborations going (I have had one that has lasted 20 years): the number one priority is you have to trust your collaborators, especially if they are in a different discipline, they will know more about their subject than you.

Find out more about Professor Frank Gunn-Moore’s research

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References

1. Muirhead K, Borger E, Aitken L, Conway S & Gunn-Moore FJ. The consequences of intracellular beta-amyloid in Alzheimer’s disease. Biochemical Journal. 426(3), 255–270 (2010a).
2. Borger E, Aitken L, Du H, Gunn-Moore FJ & Yan SD. Is Amyloid binding alcohol dehydrogenase a drug target for treating Alzheimer’s disease? Current Alzheimer’s Research. 10(1), 21–29 (2013).
3. Yao Y et al. Interaction of Amyloid binding Alcohol Dehydrogenase/Aβ mediates up-regulation of peroxiredoxin II in the brains of Alzheimer’s disease patients and a transgenic Alzheimer’s disease mouse model. Molecular and Cellular Neuroscience. 35, 377–382 (2007).
4. Ren Y et al. Endophilin I expression is increased in the brains of Alzheimer’s disease patients. Journal of Biological Chemistry. 283, 5685–5691 (2008).
5. Yao J et al. Inhibition of ABAD-Ab interaction reduces Ab accumulation and improves mitochondrial function in a mouse model of Alzheimer’s disease. Journal of Neuroscience. 31(6), 2313–2320 (2011).
6. Doherty G, Beccano-Kelly D, Yan SD, Gunn-Moore FJ & Harvey J. Leptin prevents hippocampal synaptic disruption and neuronal cell death induced by amyloid. Aging. 34(1), 226–237 (2013).
7. Purohit P et al. The Ca2+ sensor protein Swiprosin-1/EFhd2 is present in neurites and involved in kinesin-mediated transport in neurons. PLoS One. 9(8), e103976 (2014).
8. Borger E, Herrmann A, Mann DA, Spires-Jones T & Gunn-Moore F. The Calcium-Binding Protein EFhd2 Modulates Synapse Formation In Vitro and Is Linked to Human Dementia. J Neuropathol Exp Neurol. 73(12), 1166–1182 (2014).
9. Muirhead KEA et al. (–)-CHANA, a Fluorogenic Probe for Detecting Amyloid Binding Alcohol Dehydrogenase HSD10 Activity in Living Cells. ACS Chem Biol. 5(12), 1105–1114 (2010b).
10. Hroch L et al. Benzothiazoles — Scaffold of interest for CNS targeted drugs. Curr Med Chem. 22(6), 730–747 (2015).
11. Benek O, Aitken L, Hroch L, Kuca K, Gunn-Moore FJ & Musilek K. A direct interaction between mitochondrial proteins and amyloid-β peptide and its significance for the development and treatment of Alzheimer’s disease. Curr Med Chem. 22(9), 1056–1085 (2015).
12. Hroch L et al. Design, synthesis and in vitro evaluation of benzothiazole-based ureas as potential ABAD/17b-HSD10 modulators for Alzheimer’s disease treatment. Bioorg Med Chem Lett. In Press (2016).
13. Aitken L, Quinn SD, Perez Gonzalez DC, Samuel IDW, Penedo-Esteiro JC & Gunn-Moore FJ. Morphology-specific inhibition of β-amyloid aggregates by 17β-hydroxysteroid dehydrogenase type 10. ChemBioChem. 17(11), 1029–1037 (2016).
14. Antkowiak M, Torres-Mapa ML, Stevenson DJ, Dholakia K & Gunn-Moore FJ. Femtosecond optical transfection of individual mammalian cells. Nat Protoc. 8(6), 1216–1233 (2013).
15. Carnegie DJ, Stevenson DJ, Mazilu M, Gunn-Moore FJ & Dholakia K. Guided neuronal growth using optical line traps. Opt Express. 16(14), 10507–10517 (2008).
16. Carnegie DJ, Čižmár T, Baumgart J, Gunn-Moore FJ & Dholakia K. Automated laser guidance of neuronal growth cones using a spatial light modulator. J Biophotonics. 2(11), 682–692 (2009).
17. Vettenburg T et al. Light-sheet microscopy using an Airy beam. Nat Methods. 11(5), 541–544 (2014).
18. Yang Z et al. A compact Airy beam light sheet microscope with a tilted cylindrical lens. Biomed Opt Express.5(10), 3434–3442 (2014).
19. Pullman J, Nylk J, Campbell EC, Gunn-Moore FJ, Prystowsky MB & Dholakia K. Visualization of Podocyte Substructure with Structured Illumination Microscopy (SIM): A New Approach to Nephrotic Disease. Biomed Opt Express. 7(2), 302–311 (2016).