Research highlights

A brief overview of some of the research papers published as a result of DHT-funded projects. For more information about the papers please click on the 'read more' links.


Image: © 2016 The Authors, Mol Cell Biol 36:1464–1479. doi:10.1128/MCB.00039-16


Inositol depletion in disease

Bipolar disorder is a neuropsychiatric condition characterised by cyclic mood changes. Presently, there is no cure for the disease. Commonly used therapies do not completely control mood swings and also have adverse side effects. Designing improved treatments is however hindered by poorly understood molecular mechanism of current therapies and an unknown aetiology of the disease. Molecular pharmacology methods offer efficient means of determining how bipolar disorder therapies affect cells during the disease.

This paper, by Anna Frej, a PhD student in Professor Robin Williams’ lab, funded by the DHT, outlines how inositol, a key molecule that is depleted in current therapies, is regulated and how the loss of the biosynthetic enzyme inositol-3-phosphate synthase (Ino1), a key enzyme in the production of inositol, affects inositol levels as well as other cellular functions.

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Image: © 2016 The Authors, Human Brain Mapping, DOI: 10.1002/hbm.23107


Abnormal signalling in schizophrenia

Schizophrenia is a long-term mental health condition that causes a range of different psychological symptoms. Many symptoms of schizophrenia manifest themselves as various psychoses where a person may not be able to distinguish their own thoughts and ideas from reality.

In this paper, the authors have used magnetoencephalography and other imaging techniques alongside mathematical modelling, to identify the specific responses and brain signalling and processing that occurs in relevant and irrelevant stimuli.

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Table © 2016 The Authors, Human Brain Mapping, DOI: 10.1002/hbm.23115


Mathematical formulae for neuroimaging

The development of all the different neuroimaging techniques has led to the concurrent rise and development of mathematical techniques and formulas to analyse and understand the vast amount of information produced by these techniques.

The authors of the paper evaluate many of the various other methods that have been proposed in the past decades to address the need to combine data sets from disparate sources and techniques. The review of such methods identifies the methods that provide the best control over error rate and power across a range of situations.

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Human brain slices for epilepsy research

This paper, written by former DHT grant holders and partly as a direct consequence of DHT funding, explores the ways in which human brain tissue can be used and manipulated in order to answer some of the fundamental questions that remain about epilepsy. All the methods, techniques and research papers reviewed within this paper have only been developed since 2006, which was when the last major review of this field of research took place.

The number of different techniques and methods that have been developed in the interim 10 years is truly astounding. The data and information that can be obtained from human brain slices via these new techniques and methods, in many cases, would not be obtainable in traditional in vivo experiments.

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image: © 2016 Roberts et al. doi: 10.1371/journal.


Humanised matrix-free 3D cell culture systems for breast cancer

3D cell cultures are emerging as more physiologically meaningful alternatives to monolayer cultures for many biological applications. They are attractive because they more closely mimic in vivo morphology, especially when co-cultured with stromal fibroblasts.

In this 2016 paper, the authors, all from the Leeds Institute of Cancer and Pathology at the University of Leeds, compared the efficacy of 3 different 3D cell culture systems, co-culturing several breast cancer cell lines (that represented the different molecular subtypes of breast cancer) with human mammary fibroblasts.

By comparing collagen I, low attachment culture vessels and a modification of Fibrolife®, a specialised humanised cell culture medium devoid of animal-derived components they were able to develop a matrix free spheroid culture system avoiding the use of animal derived biomaterials. Immunohistochemical examination of these co-cultured spheroids showed fibroblasts scattered throughout the epithelial spheroid, not dissimilar to the relationship of tumour stroma in human breast cancer.

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image: © 2015 Brookes et al. doi:10.1371/journal

Complexity Measures in MEG: Measuring "Disorder" in Schizophrenia

This paper, written by Brookes et al. together with the team at the University of Nottingham, explains a new methodology which is capable of measuring the spatio-temporal dynamics of ‘disorder’ in the human brain. This method enables scientists who work with MEG data to better use signal entropy (a measure of signal strength and significance) to gain further insights into their data.

For schizophrenia, the results support the ‘breakdown in salience network connectivity’ theory, and further, that disrupted connectivity is accompanied by a concomitant increase in local entropy at each network node. Such increases might reflect ‘inefficient processing’ where more than the required degree of variation in the signal is necessary for carrying out specialised regional brain functions.

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Dictyostelium discoideum

© Journal of Cell Science (2014)
adapted with permission



Battling Dementia with the Social Amoeba Dictyostelium

Alzheimer’s disease (AD) is a devastating condition which leads to dementia. The disease is becoming more prevalent, and we are yet to fully understand its cause. The DHT have been funding Professor Williams at Royal Holloway, whose current research has focused on understanding the mechanisms behind the inherited form of AD, shown to be associated with mutations in two proteins called presenilins. Williams et al. pose a novel way of studying these proteins and their involvement in the development of AD using the amoeba Dictyostelium discoideum, to replace the extensive use of rodents in this field. Professor Williams has demonstrated the suitability and functionality of Dictyostelium as an important non-animal model for future work understanding the role of presenilin proteins, and could provide an important versatile system for future research into this devastating disease and the testing of potential new drugs. This year, the team have had their recent findings published in the Journal of Cell Science!

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Dr garnett

Credit: Vllasaliu et al. (2014)
Used with permission
(CC BY-NC-SA 3.0)

Development of Epithelial Cell Models for Drug Transport and Toxicology Studies

The development of medicines suitable for absorption via the gastrointestinal (GI) tract following oral administration relies on evaluation of the transport dynamics of the compounds across the GI tract. Recent advances in ‘nanotechnology’ (a technology that investigates dimensions and tolerances of particles of less than 100 nanometres, and the manipulation of individual atoms and molecules) has led to a pressing need for the development of an improved epithelial model to study the absorption, delivery and screening of these particles across the epithelium. To date, much of the work carried out in this field has involved the experimental use of surgically operated dogs. The DHT have been funding Dr Martin Garnett at the University of Nottingham, whose recent work investigating the movement of macromolecules and nanoparticles across the basement membrane (BM) of the epithelium has recently been published in the Journal of Experimental Cell Research. Current non-animal models do not accurately represent the intestinal epithelium or its environment, partly as models lack a BM and poorly reflect the true physiochemical conditions of the human intestine. Dr Garnett’s novel work has revealed that the movement of macromolecules and nanoparticles was hindered across their novel cell-culture model incorporating BM cells, suggesting that the delivery of bio-therapeutics and nano-medicines via this route may be different to previously thought. In addition, the group has revealed that the BM plays a significant role in cell attachment and morphology, and the protein network does have an effect on the movement of macromolecules and nanoparticles, meaning the BM acts as a barrier. This is the first time this has been shown, and now these findings must now be taken into consideration in the development of future cell-culture models. Dr Garnett’s research has already provided an advanced understanding of the transportation dynamics of a variety of therapeutics across this epithelial barrier in humans.

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Image reproduced from J Clin Pathol, D. Holliday et al., 66, 253-255, 2013 with permission from BMJ Publishing Group Ltd.

The practicalities of using tissue slices as preclinical organotypic breast cancer models

Breast cancer is complex and extremely diverse disease, which makes the development of a truly accurate and human-relevant model for breast cancer research extremely difficult. To date, many models used in breast cancer research have primarily consisted of cell lines, which lack adequate complexity, and are often grown in matrices which are unrepresentative of the native breast, or animal models, which very rarely bear appropriate resemblance to the human mammary gland, given the notable differences between rodent and human physiologies. Animal models do not allow an understanding of tumour biology, nor do they take into account the multiple human cell types involved in the progression of Breast cancers. Despite these major limitations, a lack of alternative models mean these continue to be used.

This novel research model offers an attractive alternative to those currently available, as tissue is preserved in its native state for morphological and immunohistochemical analysis. The Group’s 2012 publication in the Journal of Clinical Pathology summarises their work on the evaluation of tissue slice culture as a model to be used for breast cancer research.

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Functional neuroanatomy using MEG

Magnetoencephalography (MEG) provides scientists with the means to directly visualise the functioning of the human brain in a non-invasive manner. By funding the MEG machine at the Aston Brain Centre (ABC), the DHT has been helping to drive forwards the development and use of MEG as a non-animal based method for the replacement of animal experiments.

The ABC MEG team have been working towards characterising the sensitivity of MEG in order to evaluate the functional neuroanatomy of the unique sensory and cognitive processes that occur in humans and how those processes are altered in disease.

The vast majority of current scientific and clinical neurophysiology research is carried out by using invasive techniques in animals. One major reason for this reliance on animal research is the paucity of alternative methods to measure neural activity in the human brain.

The ABC MEG research has focused on using non-invasive brain imaging techniques in humans to create what scientists refer to as ‘virtual electrodes’ – these are computationally derived brain signals achieved by measuring the magnetic fields of the brain while humans perform tasks.

Read more about all the papers that have been published by the ABC team

© van Dolleweerd (2014)
DOI: 10.1093/infdis/jiu085

The development of a plant-based production system for rabies antibodies for human prophylaxis

Rabies has the highest human case to fatality ratio of all infectious diseases known to man, and there remains no effective treatment after onset of symptoms. At least 60,000 deaths occur annually from rabies, half of which are children (WHO statistics). Although a rabies vaccine is available, immunisation of entire human populations is impractical and unaffordable. Although almost always fatal, rabies ispreventable, through the swift administration of postexposure prophylaxis (PEP) after an attack by a suspected infected animal, which is nearly always effective in preventing the onset of symptoms and fatal clinical disease. Rabies PEP is comprised of 3 actions: cleansing the bite wound, administration of a rabies vaccine, and infiltration of rabies immunoglobulins (RIGs), which will usually have been derived in horses. However, insufficient access to RIGs is a problem across the developing world where the vast majority of rabies fatalities occur. In addition, there is no early diagnostic test to determine whether or not an animal bite carries rabies virus, so PEP needs to be administered in all suspect cases as a precaution, generating a large demand for RIG which is expensive and in global short supply.

Professor Julian Ma, DHT Grant Holder, of the infection and immunity research centre at St George's Hospital Medical School in London specialise in genetically modifying plants to produce useful drugs, a process called pharming. Professor Ma and his team at St Georges aim to establish the production of RIG in tobacco plants to replace the use of horses in this pharmaceutical production process. This process in plants, in addition to replacing the use of horses, offer many other advantages in terms of affordability and scalability, and the technology is very amenable to transfer to developing countries.

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TAM family receptor tyrosine kinases in Neurofibromatosis type 2

Neurofibromatosis type 2 (NF2) is a hereditary disorder characterised by development of multiple tumours in the nervous system such as schwannomas, meningiomas and ependymomas. All NF2 tumours are caused by mutations in a gene coding for the tumour suppressor gene merlin. Approaches to developing an effective and systemic treatment are needed as chemotherapy is not effective to schwannomas and many other merlin-deficient tumours. The benign character of merlin-deficient tumours makes them relatively unresponsive to conventional chemotherapy, leaving invasive surgery or radiosurgery as the main treatment options.

However, these treatments carry significant risks, particularly when the tumours are close to important neurological structures or if there are multiple tumours, as in NF2. Therefore new therapeutic strategies are needed.

As schwannoma is the most common tumour and hallmark for NF2, Ammoun et al. in their 2013 paper “Axl/Gas6/NFκB signalling in schwannoma pathological proliferation, adhesion and survival” have investigated the tumour pathobiology and merlin signalling pathways, using a human primary schwannoma in vitro model comprising human primary Schwann and schwannoma cells.

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© Peake MA, et al. (2014) Wound Repair and Regeneration. doi: 10.1111/wrr.12170

Identification of a genetic signature for wound healing

A chronic wound is a wound that does not heal normally, in an orderly set of stages and in a predictable amount of time as most wounds do, often persisting for longer than 3 months. Chronic wounds seem to remain in one or more of the phases of wound healing. Such wounds are characterised by prolonged inflammation, impaired re-epithelialisation and faulty extracellular matrix remodelling, and are affecting 3% of the population over 60.  Fibroblasts (cells found in connective tissue such as skin, which produce collagen and other fibres) play an important role in the closure of skin wounds as they replace and remodel the lost tissue and influence both re-epithelialisation and angiogenesis; the formation of new blood vessels.

Numerous in vivo animal models for investigating chronic wound have been proposed to permit trials of potential therapeutic agents. However, these models fail to accurately model human chronic wounds. The development of an in vitro model based on human cells would permit the testing of novel drugs for efficacy more accurately, and reduce unnecessary and invalid animal experimentation.

This is exactly what previous grant holder Professor Phil Stephens and his PhD student Matthew Caley focused on developing during their DHT funded project. Their aim was to develop an in vitro chronic wound bioassay based upon a human chronic venous leg ulcer with patient-matched fibroblasts, to allow the identification of a number of genes expressed in these chronic wound conditions. One area of the team’s findings has been reported in their 2014 publication in the journal Wound Repair and Regeneration.

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© 2013 Huneke NTM et al. PLoS ONE 8(10): e78278.
doi: 10.1371/journal

Experimental placebo analgesia changes resting-state alpha oscillations

Chronic pain, often defined as any pain lasting more than 12 weeks, is a growing health problem, with very few effective medications available to treat long term sufferers. Whereas acute pain is a normal sensation that alerts us to possible injury, chronic pain is very different and persists often for months or even longer. Chronic pain may initially arise from an injury, or an ongoing illness, however, often there may be no clear cause.

The lack of treatment options is likely as a result of a poor understanding of the pathophysiology of chronic pain, having traditionally been investigated and treated as a localised condition rather than a systemic one. There is no strong correlation between localised tissue damage and the pain experienced in patients, which suggests that other mechanisms, as well as tissue damage, might be involved in chronic pain, such as abnormalities of the central nervous system.

In this 2013 publication in PLoS one, previous DHT Grant Holder Professor Anthony Jones and his team at the University Of Manchester Institute Of Neuroscience aimed to ascertain whether the administration of an experimental placebo to healthy volunteers causes changes in the activity in the cortex region of the brain during periods without any noxious stimulation (damage to tissue which is liable to cause pain).

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Click here for a list of all research papers published by current and former Grant holders due to DHT-funding

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