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Research @ Imperial College London

Spring 2010 - Ageing research - the appliance of science

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From developing new tools for molecular imaging to uncovering the genetic control of cartilage production, scientists at Imperial College London are applying a whole range of expertise to understand some of the underlying causes of health problems that affect us as we grow old.

Introduced by Professor Maggie Dallman, Principal of the Faculty of Natural Sciences: "When scientists consider diseases of ageing, we tend to think of them in isolation. Take the example of Altzeimer's disease, which in itself has a number of contributory factors: genetic and most likely environmental, lifestyle etc. What is now emerging is that there may be similar underlying causes in a whole range of age-related diseases.

"This represents a real breakthrough in the way of thinking about how ageing research is carried out. As a College we are committed to developing this area in a multidisciplinary manner. We're not just looking at the basic biology or medical research in isolation, but adjusting our thinking away from individual diseases and towards understanding the
ageing process to deliver novel solutions. Most importantly we are bringing all our expertise from engineering to physical sciences to bear on this biomedical problem."

Glycomics comes of age

Glycans - the sugars that coat cells of the immune system - have a profound influence on both health and disease. Changes in the structure of glycans can affect responses to infection, food intolerance, and vaccination strategies, all of which can change with age.

With long-term support from BBSRC, Professor Anne Dell CBE, FRS and her colleague Dr Stuart Haslam from the Division of Molecular Biosciences have developed high-throughput tools to study the structure of glycans, to relate these structures to glycan recognition, and to understand how this affects cell function.

Interestingly, research to understand glycosylation during biological processes at the very beginning of life is starting to help explain ageing-related auto-immune diseases. Pregnancy relies on immune suppression/tolerance in the reproductive tract, when this doesn't happen, conditions like pregnancy-related diabetes and pre-eclampsia can occur.

"The structure of glycans plays an important role in the body's normal recognition of self and non-self," says Haslam. "We're now looking to understand how this recognition process triggers something to happen or, indeed, not to happen in health and disease situations."

Catalysed by Dell's BBSRC Professorial Fellowship, the pair established the Glycobiology Training, Research and Infrastructure Centre (GlycoTRIC) in 2004 to provide hands-on training to raise awareness in the wider research community of what glycobiology could do for them. Together with their structure-defining mass spectrometry tools, it has helped kick start new collaborations, including work to investigate the causes of age-related changes in the gut.

Working with scientists at the Institute of Food Research, an institute of BBSRC, Dell and Haslam are mapping glycan expression in the guts of mice, "We know that 'germ free' mice live significantly longer than mice with a normal gut microflora," says Dell. "We want to understand the influence that microbes play on the mucin lining of the gut and how this changes with age."

"The field of glycobiology is really starting to open up - it could be the new genomics," says Dell.

And, like genome projects, mapping the human and mouse 'glycome' has already generated a vast amount of data, which both Dell and Haslam are keen to share as widely as possible. Within Europe, Haslam is leading efforts to develop databases that summarize the structure, characteristics, biological origin and potential function of glycans that have been experimentally verified and reported in the literature. The long term objective is to be able to position such databases inside the European Life Sciences Infrastructure for Biological Information (ELIXIR) therefore thoroughly connecting glycobiology with the other branches of life sciences and assuring long term infrastructure support.

New chemical approaches to proteomics

And staying with the 'omics' theme: huge strides have been made in the identification and quantification of proteins within 'the proteome', but the ability to detect and distinguish active forms of individual proteins has proven more challenging.

Post-translational modification is one of the later steps in protein biosynthesis, whereby chemical molecules, such as lipids, carbohydrates, phosphate and acetate, add functionality to the amino acid chain. But, traditional detection methods, such as radiolabelling, often fail to distinguish between modified and non-modified forms of a protein within a cell.

Funded by a BBSRC David Phillips Fellowship, Dr Ed Tate from the Department of Chemistry and the Chemical Biology Centre has developed a chemical tagging method that not only provides a tool to identify proteins of interest, but, importantly, allows the tagged protein to be purified for further analysis. Already, this tool is being applied to real-world problems, including the affect of post-translational modification in the development of certain age-related cancers, and the discovery of potential new drug targets for Clostridium difficile - a leading cause of hospital-acquired infections, which can be serious in vulnerable groups such as the elderly.

"Our BBSRC funding has enabled us to deliver multiple enhancements to this chemical method, and apply them to the basic biology of multiple species from humans to bacteria, and in parasites that cause diseases such as malaria," explains Tate. "This work continues to demonstrate the power of chemical proteomics to enable the study of otherwise intractable systems, and has contributed to securing over £3M worth of technology transfer funding from industry, charity and the research councils."

Multidimensional imaging for living systems

Bioscience has come of an age where we no longer want to study molecules in isolation, but rather to understand how molecules interact and to look at these processes in a living system in a 'biologically friendly' manner.

"There are a number of imaging techniques available to the researcher, many of which have been developed for rather specific purposes, in a relatively fragmented fashion" says Professor Paul French.

Working with colleagues in the Institute of Cancer Research, French and colleagues in the Department of Physics have developed novel high-speed 3-D fluorescence lifetime imaging (FLIM) systems that combine information such as localisation, dynamics and molecular environment in order to investigate protein interactions in living cells. As well as providing a robust tool for molecular cell biology, the technique has wide application for drug discovery and clinical imaging.

"Using a technique called Förster resonance energy transfer (FRET), our fluorescence lifetime imaging tools allow us to identify fluorescence from multiple proteins colocalized to within 10nm," explains French. "Importantly, this means we can tell whether the proteins we are looking at are interacting or are simply just in the same place at the same time."

Their approach has been extended to 'multiplexed' FRET imaging experiments - looking at two protein-protein interactions in parallel - in order to study how different events in cells are associated in a signalling pathway. This is being applied to study the EGF signalling pathway, which is an important target for cancer therapies.

FLIM can also be used to provide label-free contrast when imaging biological tissue. As well as exploring this as a means to diagnose cancer, French's group are also working with the Kennedy Institute of Rheumatology to investigate the potential of FLIM to provide an early warning of the onset of osteoarthritis: "Ultimately the goal is to relate what we can learn from studying molecular interactions to the signatures of disease that we can use for diagnosis."

Modelling bone development

Working at the crossroads between stem cell science and tissue engineering, Professor Molly Stevens from the Department of Materials and the Institute of Biomedical Engineering is seeking to understand processes that influence the development of bone and cartilage.

Using some of the latest imaging techniques, Stevens' team recently made a fundamental discovery that different stem cells form bone with different properties. The work, which was published in Nature Materials, showed that bone derived from embryonic stem cells had less mechanical strength and was chemically different than that produced by tissue-specific stem cells.

But, while these were striking results, Stevens is keen not to rule out the use of embryonic stem cells for tissue engineering just yet. "Using this live cell Ramen spectroscopy technique, we now have a platform by which we can study different culture conditions to generate more authentic bone tissue."

Now, as part of a £4M BBSRC project with stem cell scientists at the Universities of Southampton, Keele and Nottingham, Stevens is looking at the interactions between stem cells and 'bioactive' materials in order to produce something that mimics the structural and compositional complexity of native bone.

Stevens is also designing a number of novel bioactive materials through a CASE studentship, in conjunction with the spinout company RepRegen Ltd, which Stevens co-founded in order to take her inventions forward to clinic. One of which is an injectible hydrogel system for the non-invasive delivery of biomaterials.

"We are developing bioactive materials to repair complex defects in the body, from cartilage regeneration to the repair of heart tissue," says Stevens. "By introducing the materials in liquid form, plus or minus therapeutic cells, we are able to fill the required space perfectly, prior to transforming into robust hydrogels.""

Prevention is better than cure

Painful, aching joints are often viewed as Nature's way of telling you that you are growing old. Now BBSRC funded research into the genetic control of cartilage replacement is starting to uncover whether this needs to be the case. Dr Chris Murphy from the Kennedy Institute has shown that, with every decade of life, the cartilage in joints thins. But this usually only becomes obvious in old age when cartilage is lost, due to wear and tear, faster than it can be replaced.

Dr Murphy and colleagues have been looking at the mechanisms controlling age-related cartilage thinning. In particular, they are focusing on why cartilage-maintaining cells from older individuals tend to be less synthetically active than those from younger ones, and the role of 'microRNAs' in regulating cartilage specific gene expression.

"We have recently identified a specific microRNA which can enhance cartilage matrix production in adult human chondrocytes, and are currently investigating the molecular details of this exciting new pathway," Murphy explains. "Our challenge is to look for a way to make old chondrocytes young again."

Unlike bone, cartilage has no blood vessels, which affects the rate of growth and repair. And so a fundamental issue is how chondrocytes sense, and subsequently respond to low oxygen levels.

Murphy's team has shown previously that chondrocyte function is positively regulated by low oxygen levels. Now they have established that hypoxia switches on SOX9, a key 'transcription factor' in both mouse and man, which in turn switches on this microRNA.

Their next step is to test their latest findings in an animal model to determine if the microRNA can enhance cartilage repair, and ultimately to map the entire regulatory pathway for cartilage production. Their findings could help to identify the mechanisms by which cartilage thins and, most importantly, to treat it before it becomes pathological. Identification of these anabolic pathways will thus aid drug discovery, helping prevent the chronic degenerative changes in our cartilage that occur throughout adult life.

Professor Anne Dell

"The field of glycobiology is really starting to open up - it could be the new genomics"

Professor Maggie Dallman

"This represents a real breakthrough in the way of thinking about how ageing research is carried out"

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