Every cell controls its function by regulating intracellular calcium levels. Neuronal transmission, cardiac contractions, white blood cell movement, insulin secretion…all these events happen because calcium floods into the cytoplasm, binds proteins that trigger cell-specific effects. Studying calcium dynamics is important and provides insights that guide our understanding of human physiology and our ability to control disease.
We know that calcium dynamics regulate human kidney function but we’re not clear how or why. Studying human kidneys is, as you’d imagine, extremely challenging, so models are used instead. Here at BU we use the fruit fly Drosophila melanogaster to model aspects of human cardiac and kidney function – paying particular attention to how genes control cell biology.
Recent work being presented this week at the British Society for Cell Biology’s ‘Dynamic Cell’ conference demonstrates how the fly’s kidney like cells (called nephrocytes) have regular ‘calcium waves’ lasting about twenty seconds. Using a combination of transgenic flies and pharmacology, this is the first time we’ve appreciated that nephrocytes have a rapid and ever-changing calcium biology. They are a window into what’s going in our own kidneys. The image above shows a calcium wave rising and falling in a single nephrocyte – imaged within a living larval fly.
What’s particularly tantalizing is the likelihood that these calcium waves are controlled by mechanisms of direct relevance to human physiology – so the hunt is now on to identify these mechanisms!
Touker Suleyman of Dragon’s Den fame, said that, in business, ‘Cash is King’. Gender-dependent references aside, I’d say it’s data that tops the hierarchy in research. Whilst leading grants is a complicated, bureaucratic and often thankless task, it is balanced by the joy and reassurance of data rolling in. With data, the mind is stimulated, the reasoning begins and interpretations are developed. These datastreams feed the outputs, they feed the applications. Data is the cash of research. As the datastream dries-up, the returns on research investment dwindle. Research eventually goes bust and talented people are lost from the system.
The hiatus to research activity caused by lockdown has been double edged. Researchers have used what was otherwise wasted commuting time to develop new grant proposals, helping shift an equilibrium from the fiscal reliance on students towards fully economically costed grant income. By doing so, the future of research-led university teaching is more secure; that synergy between research, practice and teaching has been reinvigorated by new logistics and necessity. On the other hand, lockdown has been a nightmarish experience; a threat to the datastreams we rely on. Labs have been closed, projects are on hold, careers are in jeopardy.
Grant awarding agencies have mitigated the negative outcomes of lockdown, by providing extensions to staff contracts as well as no-cost extensions. It’s important that researchers at all career stages appreciate the existence and importance of extensions. The medical science grants I’m associated with have received very generous no-cost extensions (thank you Kidney Research UK!), allowing us to sustain our efforts but they’ve also indirectly helped by allowing me to completely re-write a major grant application affected by lockdown. Circumstances have dictated that I apply for extensions a few times, to support staff and protect projects. In my experience, most awarding agencies employ a flexible (yet diligently cautious) approach to extending grant deadlines. This provides security for early career researchers and research assistants, which therefore protects that all important datastream.
Thankfully, the response to the current situation has seen extensions being applied across all areas of research activity. It’s in everyone’s interest to request and be given these extensions. They protect people and by doing so, the datastream.
Not all early career researchers are aware of extensions but you should be, they are an important means for successfully managing your future team! All grant awarding agencies have extension policies and I’d recommend re-reading the information posted by BU’s RDS team with links to the UK funding agencies Covid-19 info. https://blogs.bournemouth.ac.uk/research/contact/rds-advice-to-academics-during-covid-19/uk-funder-news/
Colleagues at Cornell University and I have used the fruit fly, Drosophila to tease apart the relationship between immunity and the gut microbiome. The work (which took six years to complete) is to be published in Immunity (impact factor 20 for the ‘metricists’ out there) and has major significance because it starts to explain how the human immune response ‘tolerates’ the billions of ‘good’ bacteria in our body.
Many animals carry billions of bacteria in their intestines which are critical for the digestion of ingested foods. This poses a problem for immune cells because signs of the bacteria regularly end up outside the gut and in circulation. Normally, bacterial signals would elicit a powerful immune system but it would be bad news if the gut microbiome was targeted for destruction by immune cells. How this cordial relationship is maintained is therefore of major interest to immunologists and medical science because it has implications for how we understand inflammatory diseases.
We show for the first time that cells called nephrocytes remove bacterial signals (proteoglycans that make bacterial cell walls) from circulation and that this dampens immune responses. Disruption of this removal system causes immune cells to be over-active – a state not unlike chronic inflammation.
I’m duty bound as a basic scientist to make the point that this work also impacts our understanding of insect ecology. Having an over-active immune system shortened the lifespan of Drosophila – an effect likely to be seen in ecologically and medically important species such as honeybees and mosquitoes. How immune responses are affected by the environment in these species is also a very hot topic of research – one that can also be modeled in Drosophila.
Paul Hartley (Dept of Life and Environmental Sciences)
The Physiological Society is Europe’s largest network of physiologists, so it was a great privilege to be invited to give a plenary talk at the Renal physiology: Recent advances and emerging concepts satellite symposia in Aberdeen last week. This followed on from work conducted at BU using fruit flies to study human kidney function and which most recently contributed to research published in Nature Communications. We’ve been studying insect cells called nephrocytes for several years because of their tractability and genetic similarity to human kidney cells called podocytes – cells crucial to the kidney’s role in filtration and excretion. The insects cells offer us opportunities to modulate genes and infer what may happen in human diseases. The Nature Comms paper and Phys Soc talk detailed the work we collaborated on that identified a metabolic pathway in podocytes governed by a gene called GSK3, this pathway now represents a potential target for the control of kidney disease in diabetics.
A small gallery of microscopy images is being compiled to showcase some of the imaging done at BU. Whilst the images have been developed with the aim of being aesthetically pleasing they are derived from research questions and projects being conducted at BU. Producing such images helps with engagement, acting as a bridge between the onlooker and the science. The aim is to expand this gallery and for it to include images taken by students. Some of you may already have seen one of the images – it’s on a (well-known?) BU fridge magnet. Enjoy!
Aligning with BU’s 2025 Medical Science strategy and the proposed department of Medical Sciences, research findings to be published in Nature Communications describe a potential new target for the control of kidney failure in diabetics. BU (co-lead authorship), in collaboration with clinicians and scientists at the universities of Bristol, Edinburgh, Cambridge, Hong Kong, Toronto, Northwestern (Chicago), Otago in New Zealand, MRC Harwell and the pathology department in Glasgow (phew!), we have identified a metabolic signature in the kidney’s filtration cells (known as podocytes) that links insulin resistance to kidney failure. This is important because it details a mechanism which might be ‘tweaked’ in patients suffering from diabetic nephropathy – one of the most common causes of kidney failure in the world.
Paul S. Hartley.
Diabetes is the leading cause of kidney failure in the UK. In collaboration with the University of Bristol, BU is in receipt of (another) three year grant that ultimately, we hope, will lead to the discovery of new treatments to prevent kidney failure developing in patients with diabetes.
The work, using patient data and BU’s Drosophila (fruit fly) kidney model, will look at how preventing the disruption of energy within kidney filtration cells called podocytes might slow or prevent kidney failure. The image shows the surface of a podocyte-like cell within a fruit fly, with linear arrays of filtration slits covering its surface. These minute structures are common to both human and fly cells and become damaged when energy is depleted in the cells – leading to loss of cell function. Flies allows us to understand the molecular basis of how this leads to kidney failure in humans – and guides us as to which molecules to target in the patients.
Dr. Paul S. Hartley.
It may surprise you but your heart is nothing new. Insects that evolved nearly half a billion years ago had already developed beating hearts. Much of the genetic machinery that controls our own heart beat and heart’s contraction has been conserved during evolutionary time – nature has not deemed it necessary to change it much. OK, the scale and shape of our hearts has changed a little since flies evolved but the molecular mechanics underpinning each heart beat haven’t. This means we can use flies and their genetics to understand human hearts. This is especially useful for ageing research when other models are simply too challenging to manipulate. Research work funded both in the UK by the British Heart Foundation and the USA by the National Institutes of Health is now being summarised in this review. The image shows the Drosophila (fruit fly) heart tube (HT) with associated kidney-like cells either side of it (purple) and alary muscles which act like guy ropes, pinning the heart to the fly’s abdomen. Remember this the next time you wash your car’s window-screen – you’re scraping away a lot of very cool biology!
Dr. Paul S. Hartley – your local ‘heart Drosophilist’
We all get old. Whilst this can be graceful, it’s often associated with an increased incidence of physiological complications. Loss of kidney function in ageing may be mitigated against if we could identify changes at the earliest opportunity. However, studying this process in humans at a molecular and cellular level is extremely difficult, so model organisms are required.
British Heart Foundation funded research conducted at BU and led by Dr Paul Hartley has recently contributed to this field by looking at how fruit fly nephrocytes grow old. These cells, despite millions of years of evolution, share the same ‘filtration genes’ as human kidney cells called podocytes.
The research indicates that fruit fly nephrocytes grow old in a manner similar to podocytes and other kidney cells. This now sets the stage for future work aiming to identify biomarkers of failing kidneys.
The image shows different filtration proteins (denoted by different colours) on young (1 week) and old (6 week) nephrocytes. As the cells age, these filtration proteins are no longer maintained (arrow and asterisk) and the cells lose function. Scale bar = 25 microns.
Research funded by the British Heart Foundation looking at tissue fibrosis (scarring), will soon be published in Experimental Gerontology, one the world’s leading journal on ageing. Fibrosis occurs naturally as part of our injury response process but also develops in ageing and chronic disease. Treatments are scant despite fibrosis leading to organ failure and increased risk of death.
The image shows valves (v) in the hearts of young and ‘late middle aged’ fruit flies that have been genetically engineered to express fluorescent collagen, an key ‘scar protein’. Although the fly heart is just two cells wide it represents a lot of the genetic machinery for a human heart. Amazingly, the function of human and fly hearts declines as they age – and they both accumulate collagen.
Our previous work linked heart function with SPARC – a protein associated with fibrosis in humans. We’ve now demonstrated that the heart’s ‘health-span’ during ageing can be significantly lengthened if the expression SPARC is reduced. We also show that if SPARC levels increase – fibrosis is increased too. Hence, we’ve nailed a cause-and-effect relationship between SPARC and heart function which supports the idea of targeting SPARC clinically to control cardiac health and fibrosis.
Paul S. Hartley (Department of Life and Environmental Science).
BU research, (led by me, Dr Paul Hartley), was recognised at UK Kidney Week in Liverpool last week. We were invited to speak about our fruit fly model of human renal disease, work that has been variously supported by grants from the British Heart Foundation and Kidney Research UK. The conference was an excellent opportunity to showcase the model and highlight our current collaborations with consultant-scientists based at Great Ormond Street Children’s Hospital as well as a number of different groups at the University of Bristol, the University of Osnabruck in Germany, Harvard Children’s Hospital and the University of Edinburgh. The research work is based in Dorset House labs and is supported by a wide network of talented people within BU as well as our undergrad and post-grad students.
BU research will be prominent at UK Kidney Week this summer in Liverpool. The conference is led by the Renal Association with the International Society of Nephrology (ISN) and the British Transplant Society (BTS). We’re delighted to have been invited to speak at the conference, which is a great opportunity to showcase our research as well as BU’s commitment to developing biomedical research themes. We’re also contributing several abstracts, detailing collaborations with the Universities of Bristol, Oxford and Osnabruck, Germany. The work focuses on the molecular cell biology of human podocytes, cells critical for our kidney’s role in blood filtration. When podocytes ‘fail’, kidney failure ensues.
We use Drosophila (fruit fly) genetics and molecular cell biology to address intractable problems associated with podocyte aging, podocyte dysfunction in diabetic nephropathy and several rare genetic mutations affecting podocytes that cause kidney failure in the young.
The work, was primarily funded by a Kidney Research UK Innovation Award and a British Heart Foundation Fellowship.
Dr. Paul Hartley.
Representatives from Kidney Research UK conducted a site visit to Bournemouth on Monday hosted by the Department of Life and Environmental Science (Dr. Paul Hartley and Shruthi Sivakumar) as well as Prof. John Fletcher. The event was attended by clinician-researchers from Bristol and Brighton Universities and was intended as a ‘meet and greet’ between the charity and its funded researchers. The day was highly productive and KRUK’s representatives were very impressed by BU’s research labs, projects and learning environment (especially the spanking new Leica SP8 confocal microscope).
BU currently holds an Innovation Award from KRUK for the use of fruit flies to study the genetics of kidney failure in diabetes. This work is important because kidney disease is a common condition and major contributing factor to cardiovascular disease worldwide. Astonishingly, there are still very few treatments beyond dialysis and a very poor life expectancy (3 years) when diagnosed with kidney disease in your 40’s.
The charity stressed that they are highly receptive to new applications that tackle this problem. Funding is not restricted to basic science or clinical research…so if you have any good ideas…let them know and get an application started!!
An informative powerpoint by KRUK is available as pdf format – let me know if you’re interested in having a copy (email@example.com)
The heart of a fly. Two cells wide and capable of beating five times per second, the fly heart is helping us unlock the secrets governing our own heart’s function.
Research funded by the British Heart Foundation and conducted both here and at the Sanford-Burnham-Prebys Medical Discover Institute near San Diego in California, is to be published in the American Heart Association’s journal Circulation: Cardiovascular Genetics.
The work identified a genetic pathway linking cardiac function with expression of a protein called SPARC (Secreted Protein Acidic and Rich in Cysteine). In humans, increases in SPARC accompany cardiac ageing, inflammatory disease, obesity and cancer. As a consequence SPARC is a potentially very important therapeutic target in a wide range of important clinical settings. Our work, which utilised the fly Drosophila, demonstrated that heart dysfunction (cardiomyopathy) could be cured by reducing SPARC gene expression. Establishing this link allows us to ascertain the mechanism by which SPARC contributes to cardiac function in humans. Whilst the human heart is significantly more complex than that of a fly, their early development and function are controlled by similar genetic pathways; evolution may have added to the human heart but it has not changed its fundamentals. Hence, we’re able to learn a lot about ourselves by studying this simple, yet very sophisticated, little insect.
The heart of an insect.
A £100,000 Wellcome Trust Seed Award has been granted to fund a project using fruit flies (Drosophila) to examine an important yet poorly understood aspect of human heart physiology.
The heart senses and adapts to its own highly dynamic mechanical environment. This environment changes beat-by-beat, as well as over longer timescales, due to altered physiology or as a consequence of disease. Failure to detect and adjust cardiac performance accordingly is associated with arrhythmias and sudden cardiac death. The mechanism for this adaptation is not known.
The goal is to study the cellular and molecular basis of this mechanism using the Drosophila heart as a simple model. Preliminary data obtained for an Honours project suggests that stretch-activated mechanosensitive ion channels are key components.
Research supported by Paul Hartley’s lab here at Bournemouth University and led by Dr Barry Denholm (University of Edinburgh) will investigate the hypothesis that these channels provide a direct link to convert physical force (stretch of the cardiac tissue) into biochemical signal (ion flux), which in turn regulates heart physiology and function (contractility).
Bournemouth’s biomedical research features in this season’s Kidney Research UK ‘Update’ magazine (page 13). We share this issue with Lauren Laverne (sort of)!
KRUK is one of Britain’s leading kidney research charities and has awarded us an Innovation Award to identify genes that underpin the development of chronic kidney disease (CKD) in diabetes. The innovative part of the research is that it uses the fruit fly Drosophila – a novel tool in the research armoury that has helped us understand the genetic basis of human development and behaviour as well as cardiovascular disease. Research at Bournemouth will use unique genetic tools to establish how insulin signalling maintains the expression of evolutionarily conserved genes that regulate kidney function in both flies and humans. This simple model organism has enormous power to help us identify new pathways of clinical significance to CKD – a condition that affects and kills thousands of people every year in the UK.
If you are keen to learn more about the research – email me at firstname.lastname@example.org