Our research spans key areas of molecular, cell and systems biology using model organisms ranging from bacteria, yeast, plants through to Drosophila and mouse in addition to translational work in humans and cell culture, including stem cells. Our research encompasses and integrates the following themes:
Our Institute works in a number of different translational areas including crop stress resistance, pharmacology, cell and tissue engineering and protein bioprocessing technologies. Research in these areas involves collaborations with both stockholders (e.g. NHS, Scottish National Blood Transfusion Service and industrial partners (e.g. Bayer, BASF).
Through such national and international collaborations, we aim to facilitate technology spin outs e.g. Caldan Therapeutics Ltd, led by Prof Graeme Milligan, which recently attracted £4.5M of venture capital to develop novel therapeutics for type 2 diabetes, as well as licence opportunities. For instance, Prof Anna Amtmann is currently partnering Bayer to go to in-field crop trials for improved stress tolerance to help feed the world.
To aid translation, we have also worked to develop a range of clinical links. These include orthopaedic surgery with Prof Matthew Dalby collaborating with Mr Dominic Meek to form GLORI. In addition, work involving Dr Mathis Riehle and Prof Andrew Hart aims to crack the supply of primary human neurons (e.g. for drug testing), whereas work from Prof Darren Monckton focusses on myotonic dystrophy and Huntington disease.
A number of impact case studies are presented below. We are continually looking to build new collaborations. Please contact us if you would like to collaborate on any aspect of translation.
Professors Matt Dalby and Manuel Salmeron-Sanchez have developed a novel polymer coating that can be applied to complex shaped orthopaedic implant materials. The coating causes biologically correct organisation of the cell adherence protein fibronectin. As fibronectin is adsorbed it unfolds into a fibrillar confirmation forming biological networks and exposing the RGD cell adhesion group and also the growth factor binding site in close proximity. This allows BMP2 to be bound to the growth factor site at very low yet highly efficient doses. Clinical use of BMP2 is currently widely used but of great concern as it is administered at supraphysiological doses to achieve effect. Our technology allows for biologically safe doses to provide greater and more targeted effect. Further, the team have developed plasma polymerisation techniques to allow us to apply the coating to many different implant designs. Patent has been filed and we are working with Taragenyx to develop the technology further.
Professor Matt Dalby and Dr Stuart Reid have developed the NanoKick bioreactor. It uses tiny vertical movements to mechanically stimulate mesenchymal stem cells to form bone in vitro. Unlike other bioreactors it uses standard cell culture consumables (e.g. 6 well plates) and so does not have issues of complex perfusion tubing, tricky sampling ports and expensive single use consumables. This makes scale up easy and prevention of culture infection simple. Further, it requires no complex media formulations / supplements to achieve osteogenesis – the NanoKicking alone is enough. It can be used to stimulate 3D and 3D samples with the vision of tissue engineering bone graft. Patent has been filed and Dr Peter Childs has been appointed as Royal Society of Edinburgh BBSRC/STFC entrepreneurial fellow (Peter.Childs@uws.ac.uk).
Using Drosophila for kidney disease therapeutics
Professor Julian Dow is at the forefront of research in ‘omics, ion transport and kidney function in the genetic model Drosophila melanogaster (1,2). This has shown commonality of kidney function between humans and Drosophila, allowing the modelling of kidney disease using Drosophila, with the aim of therapeutics development. The group has now developed a successful model for kidney stones in the fly ‘kidney’ (3, 4) with funding from National Institutes of Health, USA as well as BBSRC Sparking Impact funds that enabled development of in vivo screening of kidney stone formation using the fly kidney.
The key advantage of the Drosophila system is that it permits rapid, reproducible formation of stones in an intact, transparent tissue,so allowing informative analysis and compound screens to be performed for the first time. He and Professor Shireen Davies are also partners in an EU-funded H2020 Marie Curie Innovative Training Network on renal development and disease, using Drosophila to model other kidney diseases including Inborn Errors of Metabolism.
1 Proc. Natl Acad.Sci. USA 111, 14301-14306 (2014).
2 Nat Commun 6, 6800, doi:10.1038 ncomms7800 ncomms7800 .(2015).
3 Am. J. Physiol.-Renal Physiology 303, F1555-F1562 (2012).
4 J. Urol., doi:S0022-5347(13)03645-8 (2013).
Stress tolerance in crops
Researchers in the group of Professor Anna Amtmann have discovered a protein in the chromatin of plants that attenuates gene induction under salt or water stress, and enhances biomass. Before publishing their results in The Plant Cell  they discussed their discovery with Matthew Hannah, project leader at Bayer CropScience, Gent, Belgium.
Following independent testing of the transgenic lines in the Bayer laboratories, a licence agreement was achieved between Bayer and UoG, and a common patent application was filed. Bayer provided bridging funds for the post-doctoral researcher at Glasgow during the negotiations, and they committed to a £0.5 M Industrial Partnership Award from the BBSRC. The 3-year project on the molecular and physiological functions of the gene is now well underway.
Professor Amtmann describes the experience as very positive. “The scientific feedback we are getting from Dr Hannah is well-informed and constructive, and it is exciting for us to follow the progress of our gene in the crop improvement programs at Bayer. It was hard work and sometimes nerve-wrecking to get to this stage but it in the end it is a net gain for all partners involved. Clearly, fundamental science and commercialisation can go hand-in-hand.”
 Perrella et al. (2013) Plant Cell 25: 3491-3505. doi:10.1105/tpc.113.114835
Novel treatments for cancer
Dr Catherine Berry has expertise with using magnetic and gold nanoparticles (NPs) in living cells.
Dr Berry employs in-house NPs from collaborators, or source from companies. Integrated Magnetic Systems Limited (IMSL) are a company based in Dundee who specialise in synthesising magnetic protein particles. Their product was interesting to Dr Berry for a specific bioapplications; magnetic induced heating of cancer cells (cancer cells die at temperatures >42oC). Initial aims were to do a short project to assess whether their magnetic particles were suitable for use in cell culture. They were awarded a 3-month First Step Award, which allowed them to do a pilot study; IMSL supplied the materials and Dr Berry ran the cell tests. This was successful, with the samples proving biocompatible in cell culture and readily uptaken into the cells. The next step was to run an Impact Acceleration Account project. This allowed them to hire a 4-month dedicated PDRA to work on progressing the work towards an application.
The outcomes were mixed. Whilst the samples behaved well in extended culture studies, they did not generate sufficient heat for the bioapplication they were intended.
Optimising antibody production in CHO cells by engineering protein folding and secretion
One of the major challenges facing the biopharmaceutical industry is to produce sufficient therapeutic proteins in a cost effective way to meet market demand. Over the past twenty years great progress have been made in both upstream and downstream processing which has enabled some products to reach the market place. To improve the level of protein production from mammalian cells we need to consider not only the expression levels of the protein but also the capacity of the cell to fold assemble and secrete recombinant proteins. The folding, assembly and secretion of proteins from mammalian cells has been a major focus for the laboratory of Professor Neil Bulleid. Following discussions at a conference and at the company; UCB Pharma decided to fund two PhD students in the Bulleid lab. The main aim is to increase the yield of therapeutic antibodies for use as biopharmaceuticals following expression in modified CHO cells. It has provided an opportunity to relate fundamental research into antibody folding and assembly to the production of biologics.
The company benefits from access to the knowledge base in the Bulleid lab and by being engaged in projects that would be too risky for them to fund internally.
The Protein and Nucleic Acid Characterisation Facility (PNACF)
The Protein and Nucleic Acid Characterisation Facility (PNACF), managed by Dr Sharon Kelly, offers a wide variety of biophysical techniques, including fluorescence, circular dichroism, UV-VIS, FTIR, isothermal calorimetry, and surface plasmon resonance (SPR), to support Research & Development by analysing structural integrity, stability, and interactions with other macromolecules, ligands, and membranes. The PNACF can provide a biophysical characterisation service to test the integrity of bio-therapeutics during drug development. Extensive characterisation underpins all product development activities and therefore must be done thoroughly to fulfil FDA and ICH guidelines (ICH Q6B).
One company we worked with were required by ICH guidelines to demonstrate the integrity and stability of their protein therapeutic drug using the recommended biophysical characterization procedures described above. Different batches of a protein therapeutic drug were tested and compared with reference drug using Far and Near UV Circular Dichroism and Fluorescence studies to ensure structural integrity and stability.
It was found that batches older than 6 months gave spectra which were dissimilar from freshly prepared reference therapeutic drugs (prepared under identical procedures). Older batches were prone to aggregation and were less thermally stable than freshly prepared therapeutic.
The results of the stability trial allowed the Company’s Research and Development team to alter the formulation of the therapeutic to improve stability.
Targetting receptors for short chain fatty acids to treat and metabolic and inflammatory diseases
In recent years Professor Graeme Milligan has been exploring ways in which mimicking the health beneficial effects of short chain fatty acids that are produced in high levels by the microflora could be applied to the production of ‘functional foods’, via either pre-biotic or pro-biotic strategies. In parallel with this effort Professor Milligan has been studying the underlying biology of the receptors that are activated by these receptors and whether they might be novel and tractable targets for the treatment of metabolic dysfunctions such as type II diabetes.
Publications stemming from this research have attracted great interest from both large and medium sized pharmaceutical companies. Professor Milligan was invited to travel to a number of companies to give presentations and discuss potential collaborations.
The most satisfactory potential partner in terms of providing each of potential funding, beneficial non-overlapping expertise and a history of previous links between Professor Milligan’s group and scientists employed by the company, was Astra-Zeneca.
Following discussions, Astra-Zeneca supported an Industrial Partnership Award (IPA) application led by Professor Milligan to BBSRC. This provides a total of £1.5 Million in funding over a 4 year period and Astra-Zeneca provides £150K in cash. The company has also provided a range of non-commercially available ligands and in return will gain pre-publication insights into which of the receptors for short chain fatty acids is most suitable to target as well as a number of animal models that will be generated within the project.
Provision of sensory neuronal cells to the pharma industry
The Centre for Cell Engineering is being funded by research councils to work with industry partners, to meet the challenges facing the pharma industry. Working with Pfizer, Neusentis and Grunenthal, the NC3Rs raised the DRGNEt challenge as part of their CRACK IT open innovation programme. The aim of the challenge is to identify sustainable sources of sensory neurons isolated from human dorsal root ganglia (hDRG). Pharma is facing the issue that recently several drugs for pain that had been successful in animal testing subsequently failed phase 1 human trials. Access to an affordable and reliable source of hDRG sensory neurons may enable the pharmaceutical industry to identify and discard early in development compounds destined to fail.
We formed a very capable team with expertise in cell isolation, maintenance and characterisation that was led by, from Glasgow, Prof Andrew Hart, Dr Mathis Riehle, David I Hughes and Mair Crouch, and Gareth Miles from St Andrews, alongside collaboration with the Glasgow based SME and human tissue research experts, Biopta. After ethics application and verification of the ability to isolate the hDRG cells we are now starting to fully engage with the industrial partners to establish a sustainable system to source human dorsal root ganglion cells.
Site-specific recombination for rapid, efficient DNA rearrangements in Synthetic Biology
Professor Marshall Stark and Dr Sean Colloms are leaders in the field of site-specific recombination which was recognized in the award of a £4.3M 5-year ‘sLoLa’ grant by BBSRC to the University of Glasgow (P.I. Professor Stark), for development of a platform for rapid and precise DNA module rearrangements in Synthetic Biology, using sitespecific recombination. Our principal industrial partner for this project is Ingenza Ltd. The aim of our research with Ingenza is to develop novel recombinase-based tools and systems for assembly of metabolic pathway genes and regulatory components, and subsequently manipulate the assemblies to optimize metabolite production. The grant runs from 2013-2018, so the experimental programme is still at an early stage. However, we are already investigating promising approaches, both in vitro and in industrially useful producer organisms. The research will enhance Ingenza’s portfolio of methodologies for systematic genome modification and thereby support the interests of their customers. Demonstration of utility of our methods in an industrial context will also fulfil an explicit aim of the BBSRC funded research programme, will increase the publishability of the research, and may lead to valuable intellectual property.