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Research @ the University of Glasgow
Autumn 2009 - Providing a platform for discovery
In this issue we take a look into BBSRC research at the University of Glasgow, one of the oldest universities in the world, with a long history of cross-faculty collaborations that address contemporary problems in biological and biomedical science.
Today, Glasgow’s electrical engineers are developing platform technologies to address a number of biological problems, working with neuroscientists, cell biologists, physiologists and clinicians across the Faculty of Biomedical and Life Sciences (FBLS) and beyond.
Lab on a pill
Electrical engineers Jon Cooper and David Cumming have developed a biosensor which can be ingested to detect blood in the GI tract. Their technology combines remote electrochemical sensing with microfluidics and sample processing for a ‘lab on a pill’. Working with one of the University’s spin-out companies, Mode Diagnostics, the pair are currently looking to produce a hand-held device for measuring blood in the faeces, which can indicate colon cancer.
They are also in discussion with a number of companies, with the aim to combine their lab on a pill device with miniaturised cameras. Camera pills can provide a lot of information about the GI track, but the structure of the colon is extremely highly folded and so a camera on its own cannot be used to diagnose colon cancer as lesions and polyps can be obscured.
Cooper and his team have also developed a tool using holographic optics, working with physicist Professor Miles Padgett, to look at fields of flow around biological structures as well as protein-protein interactions in solution, and the changes in the biophysical properties which result as a consequence of this.
“The basic idea is that you have a bead and you can track where that bead moves using an optical trap – like tweezers. If you repeat this many times you can build up a picture of the flow within a system. But we can also look at the interaction of that bead with the fluid surrounding it,” explains Cooper. “So, for example, if you have a cell with moving parts – cilia or flagella – which are involved in creating flow across the cells, you can study this using the holographic optical array”.
The team are now applying their tool to study flow within complex protein systems including the growth of amyloid plaques – implicated in diseases like Alzheimer’s where the properties of the solution change with the growth of the plaque.
Creating order from disorder
Platform technology is allowing scientists to determine the fate and growth of cells by changing the topography of the surface they are fixed to.
Working with Glasgow cell biologist Dr Matt Dalby, on research that formed the basis of his BBSRC David Phillips Fellowship, Dr Nikolaj Gadegaard produced a series of patterned surfaces to study the differentiation of adult stem cells. Together they found that pits and pillars as small as 20nm can be the difference between the production of bone cells or lack of differentiation.
“Importantly, we found that we needed to introduce a degree of disorder to our patterns for cells to differentiate,” says Gadegaard.
The pair has patented nano-disordered surfaces and, with funding through BBSRC’s Follow-on Fund, are looking to develop biodegradable surgical implants (see BBSRC Business, April 2007).
Light at the end of the tunnel
Working on a BBSRC-funded project with neuroscientist Professor Sue Barnett and cell biologist Dr Mathis Riehle from the Centre for Cell Engineering, Gadegaard is applying his nanofabrication patterns to design 3D scaffolds for vascular and spinal cord repair, varying the scaffold to guide the development of different cell types and to prevent scarring.
“We’ve designed tiny polymer tubes with pores to provide nutrients and internal microscale patterns to help cells grow in alignment and fill a 3D space,” reports Gadegaard. “In this way we can form organised bundles of nerve fibres, ensheathed with myelin”.
The model has the potential to replace the use of large numbers of animals for the study of spinal cord injury, which Professor Barnett is leading on with parallel funding from the National Centre for the 3Rs.
“We can grow axons in vitro and induce CNS myelination, we now want to cut them and then see if we can work out how to promote repair using combined therapies of biochemicals and cell types,” says Barnett.
From molecules to medicine
The University of Glasgow is leading efforts to integrate biomedical and life science research in order to address a number of today’s key questions. Their research in systems biology and systems medicine involves numerous cross-Faculty collaborations and is supported by state-of-the-art facilities for genomics, proteomics and metabolomics.
Science with the ‘X Factor’
BBSRC-funded studies into adenovirus infectivity are providing insights for basic virology, translational research and clinical gene therapy protocols. Using a range of biochemical, cell-based and animal-model approaches, Professor Andrew Baker and colleagues at the British Heart Foundation Glasgow Cardiovascular Research Centre have identified a novel pathway used by adenoviruses to infect cells and organs. The team is also working with Glasgow’s protein crystallographers to identify nanoscale details of adenovirus’s interaction with Factor X.
“This is a paradigm shift. Previous research has focussed on direct interactions between the virus and the host cell surface. We have identified that adenovirus uses a host protein, Factor X, for infectivity. The in vivo aspects of this work have been critical in defining the ‘infectivity’ pathways used by the virus,” says Baker. “We are working with animal scientists across the University, sharing new technologies and best practice”.
His approach epitomises the ethos of a virtual integrative mammalian biology (IMB) centre between the Universities of Glasgow and Strathclyde, which was set up in 2007 with a capacity building award from BBSRC (see BBSRC Business April 2009).
Integrated approach to remodelling
“The IMB initiative is part of our plans to set up a systems institute,” explains project leader Professor Mandy MacLean. “It is also helping to foster collaboration with industry-based scientists”.
Professors MacLean and Baker are also developing an integrated approach to study the role of serotonin in vascular remodelling – a dynamic set of processes by which blood vessels sense and respond to changes within their local environment.
“We are looking to manipulate the enzyme that synthesises serotonin, both in vitro and in vivo, to see if that is a therapeutic route to interfering with pulmonary vascular remodelling,” explains MacLean. “This could have implications for the treatment of pulmonary hypertension”. MacLean believes that understanding the role of serotonin in remodelling may also help to explain why nearly three times the number of women develop pulmonary hypertension compared to men.
Leading industry down the signalling path
G protein-coupled receptors (GPCRs) act as ‘gatekeepers’ in signalling pathways, detecting hormones, growth factors and other molecular ‘triggers’. Collectively, GPCRs are the targets of around half of all modern medicines. Professor Graeme Milligan is looking at the molecular structure and organisation of GPCRs and how this will lead to the development of new drugs.
“Our fundamental research into how you study these receptors has already led to a number of patented technology applications being used by the pharmaceutical industry to help them develop medicines more rapidly,” says Milligan.
His research into the cross-regulation of GPCRs could also help improve the performance of existing medicines such as morphine, which loses its effectiveness over time with chronic use. “We are trying to come up with strategies that will reverse or prevent tolerance to morphine by co-activating other receptors that are present in the same nerve cells,” Milligan explains.
Combining function with structure
Chemist Professor Neil Isaacs together with Professor Gerald Graham and Dr Robert Nibbs from Glasgow’s Biomedical Research Centre are using modern X-ray diffraction techniques to investigate the structure of an unusual GPCR with no known signalling function. Instead D6 acts as a decoy which scavenges and destroys molecular ‘triggers’, known as chemokines, to prevent them from activating other receptors. Importantly, this scavenging role makes D6 a natural anti-inflammatory and tumour suppressant.
“We need to know the structure of the receptor to understand why D6 has this special property,” says Isaacs. “Furthermore, as D6 is a member of the chemokine family of GPCRs and binds many of the same ligands, its structure will provide an excellent model for other GPCRs of the same family”.
In related research, Dr Nibbs is looking at the importance of D6 for the biology of B cells. “D6 appears to play an indispensable role in controlling B cell abundance, trafficking, and their differentiation into antibody-secreting cells,” explains Nibbs. “We want to know why B cells have D6 receptors and what they are actually doing at the molecular, cellular and whole animal level”.
Fruit fly genomics were laid bare online recently: FlyAtlas is a comprehensive tool for Drosophila researchers around the world to measure gene activity in different tissues.
“FlyAtlas provides a one-stop lookup-shop for Drosophila expression, and a rich bioinformatic resource for novel meta-analysis,” says Professor Julian Dow. “Since its launch in the autumn of 2006, it has attracted thousands of users, confirming the hunger for such data”.
Drosophila melanogaster is used widely as a model organism to explore potential causes and treatments for human diseases. Prof. Dow’s own research, in collaboration with Professor Shireen Davies, has focussed on the Malpighian tubule, which absorbs salts, water and wastes much like the human kidney.
“We have found that the functions of these structures in humans and Drosophila are more conserved than you might think,” says Dow. “Comparing Drosophila gene activity to a database of human genetic diseases, we have discovered whole sets of genes for human kidney diseases, such as the formation of calcium oxalate stones, that are conserved”.
Using a microarray approach to analyse gene expression the team are uncovering new insights into Malpghian tubule function, which performs not just like a kidney, but also like a liver and an autonomous immune system, opening up many new avenues of research.
Coping with a changing environment
Glasgow plant scientists are looking at plant responses to their environment. Their research into plant metabolism and signalling pathways is increasing our understanding of basic plant biology as well as providing insights into how plants will cope with a changing environment.
Why don’t plants get sun burn?
Plants have evolved in sunlight. So it stands to reason that they have developed inbuilt UV protection mechanisms – let’s face it they can’t apply sun screen from a bottle or move to a shadier spot!
Professor Gareth Jenkins has identified a plant gene regulator called UVR8 that co-ordinates protective responses to UVB light. His team has found that UVR8 is even present in mosses, which suggests that the gene was an early plant evolutionary response to UV.
“If you remove UVR8 plant survival in sunlight is compromised,” says Jenkins. “Conversely, if you over express it you get a hyper response and more protective pigments. This work could help breeders to tailor plants to cope better with changing climates”.
Interestingly, he has found that UVB also switches on a number of genes for other protective responses, such as cold- and drought-induced genes.
“This also has implications for studying responses to environmental stresses in a laboratory setting because fluorescent tubes don’t have UVB in them,” explains Jenkins. “If, for example, you study plant cold responses but you do it in an environment without UVB then you could miss interactions between different stress response pathways”.
The hunting of the SNARE
Like Lewis Carroll’s poem of a similar name, Professor Mike Blatt’s 25-year quest, to understand the mechanisms that plants employ to control water use, has led to the discovery of an improbable protein that performs a surprising role.
“We originally set out to find signalling proteins associated with the water-stress hormone abscisic acid (ABA),” explains Blatt. “What we found was a vesicle trafficking protein, a so-called SNARE homologue that we named SYR1 (now called SYP121), which was critical for the short-term regulation of ion channels in guard cells by ABA. This finding was outside the boundaries of functions commonly attributed to SNARE proteins”.
Blatt’s team showed that SYP121 does indeed function in the classic role of a SNARE in vesicle traffic to the plasma membrane, and is important in anchoring potassium ion channels within the plasma membrane. They also found that ABA triggers the selective endocytosis of the same potassium channels in guard cells, and that these channels subsequently recycle over many hours back to the plasma membrane.
Water use and inorganic nutrient use by plants are closely interwoven. So the team’s next step was to look for a direct interaction of SYP121 with the ion channels or proteins that associate with them. Recently they showed that SYP121 binds directly with KC1, a channel subunit that has long been known to regulate several potassium channels. They also demonstrated that the SYP121-KC1 complex is essential for potassium nutrition in Arabidopsis under conditions common in the field.
“Harnessing this interaction to improve potassium and water use efficiency in crops would have a direct financial impact for farmers in the UK and around the world, and would help meet the challenges of environmental change,” Blatt says.
Wild plants often grow in conditions where crops cannot. Dr Peter Dominy is taking lessons from nature to identify the molecular basis of salt tolerance in plants. BBSRC funding has allowed his team to perform glasshouse studies on their transgenic plant collection and several genetic lines of the model plant Arabidopsis have been identified where subtle changes in the abundance or structure of specific target proteins appear to affect drought and salt tolerance.
Dominy and former Glasgow colleagues Dr Ari Sadanandom (Warwick) and Dr Lucio Conti (Milan) have found several unsuspected underlying stress tolerance mechanisms in Arabidopsis, including a protease (OTS1) that removes a regulatory peptide (SUMO) from proteins involved in salt tolerance responses.
In collaboration with the Universities of Zhejiang (China), Kenyatta (Kenya), and Peshawar (Pakistan) they are now attempting to confirm whether similar mechanisms operate in cereals. In addition, the global research team has assessed the hardiness of over 300 poorly characterised landraces of Asian barley. One line from western Pakistan appears to be particularly hardy of high salinity and temperature and Dominy’s team wants to begin mapping its genes with a view to understanding the mechanisms that confer tolerance. It is hoped these two approaches will lead to the development of cereals that produce good yields in arid regions.
Professor Paul Hagan, Faculty of Biomedical and Life Sciences
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