Recent Projects

Quote from Chris Day

(VC of Newcastle University)

The JGW Patterson has made a very substantial contribution to Newcastle University. Since 2001 they have been the 15th largest single funder of grant awards to Newcastle University and the 7th largest of our charity funders. The value of the long-term funding, despite several economic recessions, has benefitted us in many ways. Many of their awards have been to our early career researchers, often supported by more experienced investigators. This has underpinned our strategy of recruiting outstanding Newcastle University Research Fellows (NURFs) and Faculty Fellows and several of these have gone on to receive further funding having built up their track records on the outcomes of their JGW Patterson-funded research. In retrospect, I am sure, that JGW Patterson funding will have proved pivotal in their long-term careers. When funding for a lectureship (now Professor) and the currently funded PhD studentships are also taken into consideration the role of the JGW Patterson Foundation in individual careers and for capacity building at Newcastle have been crucial as well as the benefits that accrue to the public, patients and the economy from their research findings.

Chris Day – VC of Newcastle University

Newcastle is particularly proud of the many external awards it has received for infrastructure funding and there can be little doubt that the underpinning awards from the JGW Patterson will have played their part in our gaining the large Centres and Programme Awards such as for musculoskeletal research: the jointly MRC and ARUK-funded Centre for Integrated Research into Musculoskeletal Ageing (CIMA) with Liverpool and Sheffield Universities and for our Northern Institute for Cancer Research (NICR) being awarded Cancer Centre status from CRUK and also one of the CRUK and Health Departments Experimental Cancer Medicine Centres and LLR/Bloodwise programme grant funding for our world-leading Leukaemia Research Group.

Newcastle University, working in close partnership with Newcastle upon Tyne Hospitals NHS Foundation Trust and Northumberland, Tyne and Wear NHS Foundation Trust is known for its translational research and again several of our investigators obtaining MRC Developmental Pathway Funding Scheme or NIHR Invention for Innovation (i4i) funding or other translational research funding streams have done so after receiving feasibility funding from the JGW Patterson Foundation.

"We are very fortunate in the UK to have such a strong charity structure and we are particularly blessed in the North East to work with the JGW Patterson Foundation"

Studentship title:

The Andrew Walker PhD Arthritis Studentship 2015 – 2019

Project title:

Joining the dots” between genetic risk and joint inflammation in rheumatoid arthritis to find better treatments

Student:

Alex Clark

Supervisors:

Dr Arthur Pratt and Dr Louise Reynar

In rheumatoid arthritis (RA), “misdirected” cells of the immune system attack the joints, causing pain, stiffness and disability – but quite what causes this to happen remains poorly understood. Much has recently been learned about how variations in a person’s inherited genetic code may influence his or her risk of developing RA. For example, over 100 “risky” variations in the code have been found near genes that make proteins often used by immune cells. However, it is challenging to decipher precisely which proteins are most influenced by these risky variations, whose altered function might in turn misdirect the immune system. Doing so could better guide scientists to focus their efforts on biological processes that are most important in driving disease – and those that could most beneficially be targeted with drugs to improve the lives of people with RA in the future.

In our project, patient volunteers with newly diagnosed arthritis donated their blood for genetic studies aimed at addressing this challenge. Our research team used a combination of technologies together with statistical techniques to refine understanding of which proteins might be most influenced by variations in the genetic code that put people at risk of RA. Our results provide important clues as to some of the the precise immune processes scientists should now focus on to understand the cause of RA in more detail.  Interestingly, it looks as though some of the processes our work highlights may be just as important in causing other diseases of the immune system, so the implications of our findings are potentially far-reaching.

"The funding we received from the JGW Patterson Foundation made this work possible. It also provided an important spring-board for a talented young scientist, who not only gained a PhD qualification as a result of his work, but successfully applied for a post as a junior scientist at the NIH Maryland, USA."

Some members of the study team

Arthur Pratt

(PI, supervisor)

Alex Clark

(Student)

Louise Reynard

(PI, supervisor)

Original papers arising from this funding

  • Clark AD et al. Lymphocyte DNA methylation mediates genetic risk at shared immune-mediated disease loci. Journal of Allergy and Clinical Immunology 2020; 145:1438-51.
  • Anderson AE et al. Expression of STAT3-regulated genes in circulating CD4+ T cells discriminates rheumatoid arthritis independently of clinical parameters in early arthritis. Rheumatology 2019;58:1250-8
  • Thalayasingam N et al. CD4+ and B lymphocyte expression quantitative traits at rheumatoid arthritis risk loci in patients with untreated early arthritis: implications for causal gene identification. Arthritis & Rheumatology 1018; 70:361-70

Studentship title:

The Andrew Walker Cancer PhD studentship 2015 – 2019

Project title:

Small molecule modulators of cyclin-dependent kinase 2 activity and regulation

Supervisor:

Prof Jane Endicott

Department:

The CRUK Newcastle Drug Discovery Unit

The cyclin-dependent kinases (CDKs) bind to members of the cyclin protein family to form complexes that regulate cell proliferation. Just as CDK-cyclins are important in normal cells, so they can also contribute to the development of disease when they do not function properly. Using insights from structural biology we can describe the three-dimensional form of CDK complexes to understand how they work and are regulated and importantly how their dysregulation might contribute to cancer. Historically the development of CDK inhibitors has targeted the CDK ATP-binding site. However, this approach cannot distinguish the different activities of their CDK target, which may depend on the complexes in which they are found. Consequently, ATP-competitive inhibitors can have unwanted effects that limit their use as drugs. This studentship has helped to further understand the structural differences between closely related CDKs in order to better target CDK inhibitors1. To improve the safety and increase the robustness of clinical response to CDK inhibitors this studentship has also helped to develop “FragLites”2. These small molecules can be used to identify potential drug binding sites on the CDK-cyclin surface and are starting points to develop inhibitors that bind to sites other than the CDK active site.  Overall, the studentship has provided biological insights, and actionable approaches to novel ways of inhibiting CDKs for drug design. The student received training in many key techniques and gained experience of the chemistry/biology interface that underpins modern drug discovery. He has since taken up a post-doc position in Germany.

Papers:

  1. Differences in the conformational energy landscape of CDK1 and CDK2 suggest a mechanism for achieving selective CDK inhibition. Wood DJ, Korolchuk S, Tatum NJ, Wang LZ, Endicott JA, Noble MEM, Martin MP. Cell Chem Biol. (2019) 26:121-130.e5. doi: 10.1016/j.chembiol.2018.10.015. (13 citations)
  1. FragLites-minimal, halogenated fragments displaying pharmacophore doublets. An efficient approach to druggability assessment and hit generation. Wood DJ, Lopez-Fernandez JD, Knight LE, Al-Khawaldeh I, Gai C, Lin S, Martin MP, Miller DC, Cano C, Endicott JA, Hardcastle IR, Noble MEM, Waring MJ. J Med Chem. (2019) 62:3741-3752. doi: 10.1021/acs.jmedchem.9b00304. (12 citations)

Review:

Structural insights into the functional diversity of the CDK-cyclin family. Wood DJ, Endicott JA. Open Biol. (2018) 8:180112. doi: 10.1098/rsob.180112. (37 citations)

FragLite binding to CDK2

The CRUK Newcastle Drug Discovery Unit

Studentship title:

The Peter May Arthritis PhD Studentship 2015 – 2019

Project title:

Biomechanical sensing in cartilage ageing and disease

Student:

Thais de las Heras Ruiz

Supervisors:

Dr Arthur Pratt

Thais de las Heras Ruiz has developed a model of cartilage in a dish, which we will use as a tool to investigate rare skeletal conditions and cartilage ageing. Developing this exciting model would not be possible without the generous support of the JGW Patterson Foundation who have also previously funded the purchase of the state of the art Flexcell FX500 TM compression system that enables us to culture our mini-cartilages under the right physiological cues. Thais was able to show that culturing cells in agar hydrogel promotes cartilage formation and that the cells can indeed respond to compression – a major step for modelling cartilage diseases in a dish. This project opened up a new collaboration with the School of Engineering and Agriculture at Newcastle University and with Liverpool University and we will continue to refine the model, and use it to study cartilage ageing and disease. Thais successfully defended her thesis in November 2020.

Thais de las Heras Ruiz

"Developing this exciting model would not be possible without the generous support of the JGW Patterson Foundation who have also previously funded the purchase of the state of the art Flexcell FX500 TM compression system that enables us to culture our mini-cartilages under the right physiological cues."

Cells embedded in the gel (on the left) and scanning electron microscopy image of the gel structure.

Studentship title:

The Peter May Cancer PhD studentship 2015 – 2019

Project title:

Investigating the pre-T Cell Receptor (pTCR) pathway as a potential new drug target in T-cell Acute Lymphoblastic Leukaemia

Student:

Melanie C Beckett

Supervisors:

Dr A Krippner-Heidenreich, Dr FW van Delft

T-cell Acute Lymphoblastic Leukaemia (T-ALL) affects 90 children and adolescents per year in the United Kingdom. Although current treatment cures 80% of patients, the outcome for patients with drug resistant or recurrent leukaemia is usually unfavourable. Leukaemia, which remains detectable after 4 weeks of VXLD treatment, is associated with poor outcomes. The reasons for poor treatment response remain poorly understood, which in turn hampers our efforts to improve survival rates.

The JGWP PhD studentship allowed us to develop a model system in which to simulate poor response to treatment and use this to develop new treatments. Mice with human T-ALL received chemotherapy treatment and underwent a genetic screen. Data analysis has already identified several processes that are likely involved in drug resistance and we have initiated confirmatory studies. Once completed, we aim to publish this research and share our model with the wider community. The data will form the basis for further grant and PhD studentship applications. The valuable system we have developed will allow us to continue to investigate mechanisms underlying drug resistance with the ultimate aim to improve treatment and outcomes.

"The JGWP PhD studentship allowed us to develop a model system in which to simulate poor response to treatment and use this to develop new treatments."

Melanie successfully gained her PhD degree in 2020 based on the research described. Subsequently she was appointed as Higher Scientific Officer in the team led by Dr Alejandra Bruna at the Institute of Cancer Research.

Studentship title:

The Andrew Walker Arthritis PhD studentship 2019 – 2023

Project title:

Predicting and Understanding Flare in Rheumatoid Arthritis

Student:

Jasmine Sim

Supervisors:

Dr Ken Baker, Prof John Isaacs

Department:

Newcastle University Translational and Clinical Research Institute

Rheumatoid arthritis is a common condition affecting 1 in 100 UK adults, and characterised by inflammation in the joints causing pain, swelling and disability. Thankfully, many patients can now achieve an excellent control of their arthritis (called ‘remission’) with modern disease modifying anti-rheumatic drug (DMARDs) therapy. However, DMARDs carry the risk of potentially severe drug side-effects, the need for regular blood tests, and the expense of drug prescribing. Patients and their doctors are thus faced with an uncertain dilemma – when is it safe to reduce or stop DMARDs once remission is achieved?

In our recent clinical trial (Biomarkers of Remission in Rheumatoid Arthritis – BioRRA), 44 patients with RA in remission stopped DMARD treatment and were reviewed for 6 months. Half (23/44) of patients maintained drug-free remission, which could be predicted by the activation of specific genes within a type of white blood cell (CD4+ T cell).

In this JGW Patterson Foundation PhD Studentship, we aim to confirm these findings using blood samples from a larger study of DMARD cessation (the BIO-FLARE study). We then aim to identify ways in which these findings can be translated to a laboratory test suitable for clinical use in future research projects. Such a test, if successfully validated, would help to identify those patients who can safely reduce or stop their DMARD therapy. This would reduce the occurrence of drug side-effects, reduce healthcare costs, and ultimately improve the quality of life of patients living with RA.

Jasmine Sim

Studentship title:

The Andrew Walker Cancer PhD Studentship 2019-2023

Project title:

Understanding the mechanisms of chromothripsis in cancer

Student:

Connor Gilkes-Imeson

Supervisors:

Jonathan Higgins, Christine Harrison, Diana Papini

Chromothripsis is an event in which a chromosome is shattered into many pieces and then randomly reassembled. This dramatic event can promote the development of cancer. Although chromothripsis is currently a hot topic in the scientific community, little is understood about its role in cancer. Patients with a type of leukaemia named iAMP21-ALL are known to have a chromosome that undergoes chromothripsis. A subgroup of iAMP21-ALL patients are born with an abnormal chromosome (pictured) that causes an increased risk of developing this cancer. We studying this cancer to gain a better understanding of the events which lead to chromothripsis. The outcomes of this project will provide us with knowledge of how certain cancers arise to inform future diagnosis and treatment. The project brings together cell biologists in the laboratory of Jonathan Higgins and cancer researchers in the laboratory of Christine Harrison to provide an excellent multidisciplinary training environment for a PhD student, Connor Gilkes-Imeson.

Studentship title:

The Peter May Cancer PhD Studentship 2019-2023

Project title:

The Monitoring immunE DysregulAtion foLLowIng checkpOint inhibitioN study (MEDALLION)

Student:

Kristian Williams

Supervisors:

Dr Arthur Pratt, Dr Amy Anderson & Professor Ruth Plummer

The immune system is highly effective at protecting our bodies from harm. It also plays a part in protecting us from cancer by recognising and destroying harmful cells of our own bodies. But, for about 5% of people, the immune system itself causes disease. Immune mediated diseases (IMDs) are long-term conditions in which the immune system attacks parts of an otherwise healthy body as if it were harmful. Until now, studying the “initiation phase” of IMDs including inflammatory bowel disease and rheumatoid arthritis has been difficult because it typically begins before patients even develop symptoms. Use of a new class of drugs in the field of cancer medicine, called immune checkpoint inhibitors (CPIs), offers a way of overcoming this barrier for the first time. CPIs work by interfering with signals transmitted by the body’s cells that tell its immune system they are harmless. Cancer cells sometimes take advantage of these signals, using them as “decoys” to fool the immune system into ignoring them, even though they are harmful. By blocking the ability of cancer cells to do this, CPIs help the immune system to attack and kill the cancer cells. This approach has transformed the outlook of many cancer patients, but the strategy also makes the body’s harmless cells vulnerable to attack, and many patients treated with recommended CPI-drugs develop side effects that look similar to IMDs – called immune-related adverse events (irAEs).

In order to open a window on the beginnings of IMDs, and gain a better understanding of how irAEs develop, we propose close monitoring of the immune system in patients being started on CPI drugs as part of their routine care. We will identify how the changes that occur for the ensuing 9 months differ between patients who go on to experience irAEs in this period and those who do not. To achieve all this we will ask patients to donate blood for research at each routinely scheduled visit to hospital during the first 9 months of their treatment. The student will look for signs of the immune system becoming unbalanced in the run-up to irAE development by carrying out detailed measurements on blood cells. Resultant insights should suggest new treatments to prevent IMDs, as well as tools to help predict and treat irAEs in cancer patients.

Some members of the study team

Arthur Pratt

(PI, supervisor)

Amy Anderson

(PI, supervisor)

Kristian Williams

(Student)

Ruth Plummer

(PI, supervisor)

Related Work

  • Matched support from the Cancer Research UK (CRUK) Newcastle Centre is funding a clinical PhD student to work closely with the Peter May Fellow, adding substantial value to the project.
  • Because of this work we are participating in a multi-site collaborative effort to pool resources and thereby maximise outputs of this and similar investigations into irAEs with colleagues nationally. Dr. Pratt and Professor Plummer are co-applicant in an MRC Experimental Medicine funding application.
  • This work was also integral to a parallel funding application, led by Drs. Pratt and Anderson (in collaboration with Professor Plummer), to investigate mechanisms of immune-mediated arthritis specifically, and this is also under review.

Marie Curie – examples of grants given to Marie Curie Hospice, Newcastle

A hospice has received grants totalling more than £120,000 from a regional charitable foundation, to allow it to upgrade its facilities for the benefit of people living with terminal illnesses from across the North East.

The Marie Curie Hospice Newcastle has received six major donations from The JGW Patterson Foundation in the past eight years, which have allowed the hospice to update a number of areas of the building.

The most recent donation of £26,840 from the Foundation – which was founded in 2002 – has enabled the hospice to update many essential pieces of kitchen equipment.

Previous donations have enabled upgrades to areas of the hospice – the region’s only Marie Curie facility, which offers in-patient and day therapy services to people living with any terminal illness, including cancer, across the North East – including its Education Centre.

The JGW Patterson Foundation was established by the late philanthropist John George William Patterson, from Jesmond, Newcastle, who bequeathed his entire portfolio of commercial and residential properties to the Foundation.

The main objectives of the Foundation are to fund research into, and purchase equipment and caring services for, the relief of cancer, arthritis and rheumatology. It makes grants extensively to the Universities, hospices and charities across the region.

The board of Trustees is made up of some of the most prominent professionals in the city – nationally-renowned paediatrician Professor Sir Alan Craft; Professor Tim Cawston, former Dean of Research at Newcastle University; Stephen Gilroy, retired Partner with Lambert Smith Hampton; David Gold, Partner with Joseph Miller & Co; and Jim Dias, retired Chairman of Sintons LLP. All of the professional services firms represented on the board were trusted advisors used by Mr Patterson during his life.

Pippa Aitken, Company Secretary of the JGW Patterson Foundation and Senior Associate at Sintons LLP, said: “It was the wish of Mr Patterson that the ongoing income from his property portfolio would be used for the benefit of his home city, namely to fund life-changing medical research and to support hospices and other medical institutions which provide vital care for people.

“To make such an ongoing impact is an incredible legacy, and it gives myself and the Trustees great joy to be able to make grants on behalf of the JGW Patterson Foundation which we know will do such good.

“We are delighted to have been able to support the Marie Curie Hospice Newcastle over the years, and have seen for ourselves the difference the grants have made for the benefit of patients and their families.”

Helen Forrow, Hospice Manager at Marie Curie, said: “When you are living with a terminal illness you want to make the most of the time you have left. Quite often, it can be the little things that mean the most to people – like fish and chips on a Friday. And thanks to the recent renovations to our kitchen that were funded by the JGW Patterson Foundation’s contribution, this is something we are able to offer and it’s a huge hit with patients and their families.

“Being able to bring a sense of normality to people when they are facing such difficult times is a big part of what we try to do at the hospice. And we simply couldn’t do it without the generosity of our supporters and partners like the JGW Patterson Foundation.”

Effects of B-cell depletion on bone turnover in Rheumatoid Arthritis

Rheumatoid arthritis is associated not only with joint damage, but generalised bone loss which ultimately can result in osteoporosis and an increased risk of fractures. This bone loss is driven by a variety of factors, including loss of mobility and inflammation which activate bone cells to break down (resorption) more bone than they form. There is also growing evidence that there is close interaction between immune cells and bone cells. Many immune cells produce molecules which stimulate both the inflammation underlying rheumatoid arthritis and bone breakdown. One such cell is a white cell known as the B-cell. Recently, a new and successful treatment for rheumatoid arthritis called Rituximab has been developed which destroys B-cells.

The Foundation funded a recent study to see if the removal of B-cells would also improve bone quality which was led by Roger Francis and Stephen Tuck. Preliminary evidence was sought by measuring markers of bone cell activity using stored blood from a previous study of 46 patients who had been given Rituximab every 6 months. Bone cell activity could be measured in blood prior to being given Rituximab and the effects 6 and 12 months after starting Rituximab. We found that B-cell depletion by Rituximab increased bone formation and decreased bone resorption. This suggests that there may be an improvement in bone density over time, which could help to prevent osteoporosis and fractures. The study has just been published in Osteoporosis International (Osteoporosis Int. 2011; 22:3067-3072). The success of this study has enabled us to obtain a further £150,000 in funding from the Pharmaceutical Company Roche to undertake a prospective study to measure bone density and confirm these findings.

Dr David Young

The first grant awarded by the JGWP Foundation allowed us to recruit a new member of academic staff, Dr David Young, to the Musculoskeletal Research Group in Newcastle University. His brief was to develop a new research laboratory that focused on osteoarthritis.

Osteoarthritis (OA) is a disabling joint disease predominantly affecting older people. The cartilage, which allows pain free movement of the joints, becomes degraded leading to pain and disability for patients. The cartilage tissue is produced by cells called chondrocytes. If the removal of cartilage components by these cells exceeds the building up of new cartilage, then the tissue will be gradually destroyed. This is what happens in OA cartilage.

This early JGWP grant has allowed David Young to establish a research group of 9 researchers that aims to understand the cellular processes occurring in OA. He is a co applicant on a prestigious Arthritis Research-UK programme grant for £1.1 million that aims to understand how new factors called microRNAs control the behaviour of chondrocytes and contribute to the cartilage destruction seen in osteoarthritis and therefore provide potential new treatments for this disabling disease. The Newcastle component of this 5 year award plays to one of our main strengths in the North East, access to human tissue, kindly donated by patients at joint replacement surgery. Using this and human stem cells we’re developing models of cartilage in the laboratory. We then use these models to determine what microRNAs are important when cartilage breaks down, as in diseases like OA. Along with this we want to know what microRNAs are important for cartilage to form in the first instance and so allow us to “engineer” cartilage in the lab to be used to replace damaged cartilage in a patient.

Drug Discovery and Imaging Group

One of the important aims of the work undertaken by both Dr Williamson and Dr Heer is the identification of new targets for anti-cancer drug development. One of the strengths of the Northern Institute of Cancer Research at Newcastle University is the capacity to link these kinds of findings to an in-house team of medicinal chemists. Headed by Professors Roger Griffin and Herbie Newell, the Drug Discovery and Imaging Group has had a number of notable successes in developing very effective anti-cancer drugs.

Funding from the JGW Patterson Foundation is being used to support PhD students in the group such as Andrew Shouksmith who is designing drugs to inhibit the SKP2 protein – a molecule which interferes with the normal breaks in place to control cell division. In some forms of cancer the levels of this protein are abnormally high leading to rapid tumour growth. As well as producing important information in its own right, support for PhD students such as Andrew is vital to ensure that talented young scientists join the work-force in the future.

Dr Rakesh Heer

Another example of the way in which support from the Foundation has been used to generate new data. Dr Rakesh Heer, an academic urological surgeon based at the NICR, has collected samples from bladder cancers to generate a tissue micro array containing 400 clinical cases. This will enable him to compare tumours for the presence of microscopic features which will predict how well an individual patient is likely to respond to drug treatment, surgery or treatment with X-rays.

He will link these findings to the results of highly sophisticated tests on the genetic code of the tumours and to a database of clinical information.

Dr Dan Williamson

In a project supported by the Foundation since 2010, Dr Dan Williamson has been looking at tumours arising in the brain using state-of-the art techniques which can examine the entire genetic code for the damage which can lead to cancer. Using this information he will be able to devise tests that can determine the best treatment, tailored for an individual child based on his or her tumour type. This will help to eliminate unnecessary damage to normal brain tissue-a particular problem in the developing brain.

The results produced by this project have enabled Dr Williamson, working with his colleagues Professor Clifford and Dr Bailey, to attract more than £1m pounds of additional funding from a national charity to continue their studies in this important area of research.

Contributon towards the purchase of stereoscopic microscope

The JGW Patterson Foundation has contributed to the purchase of several items of complex, and very expensive, specialist equipment including a sophisticated stereoscopic microscope fitted with minute tools for the dissection of tissues. Using this equipment Professor Debbie Tweddle and her research team are using stem cells to model the normal development of the sympathetic nervous system which gives rise to a form of childhood cancer called neuroblastoma which, when advanced, can be very difficult to treat. Detailed knowledge of how and why neuroblastomas arise will enable her to suggest new forms of treatment.

Daft as a Brush Cancer Patient Care

Daft as a Brush provide a free transfer service to and from the Freeman/RVI Hospitals for outpatient undergoing chemotherapy and /or radiotherapy treatment. The JGW Patterson foundation have purchased two ambulances for them which they have named Speedy Squirrel and Busee Bee.

St. Oswald's Hospice

‘Thank you all, once again, for your kindness and support. Improving our kitchen facilities and nutritional expertise will make a very positive difference to all patients who use St Oswald’s services. This work would not be possible without your assistance.’

St. Cuthbert's Hospice

St. Cuthberts Hospice, Durham, reclining chairs purchased by JGW Patterson Foundation

Daft as a Brush Cancer Patient Care

Daft as a Brush provide a free transfer service to and from the Freeman/RVI Hospitals for outpatient undergoing chemotherapy and /or radiotherapy treatment. The JGW Patterson foundation have purchased two ambulances for them which they have named Speedy Squirrel and Busee Bee.

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St. Oswald's Hospice

‘Thank you all, once again, for your kindness and support. Improving our kitchen facilities and nutritional expertise will make a very positive difference to all patients who use St Oswald’s services. This work would not be possible without your assistance.’

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Quote from Chris Day

(VC of Newcastle University)

The JGW Patterson has made a very substantial contribution to Newcastle University. Since 2001 they have been the 15th largest single funder of grant awards to Newcastle University and the 7th largest of our charity funders. The value of the long-term funding, despite several economic recessions, has benefitted us in many ways. Many of their awards have been to our early career researchers, often supported by more experienced investigators. This has underpinned our strategy of recruiting outstanding Newcastle University Research Fellows (NURFs) and Faculty Fellows and several of these have gone on to receive further funding having built up their track records on the outcomes of their JGW Patterson-funded research (we could name David Llobet-Navas and Ruth Rodriguez here if you wanted to). In retrospect, I am sure, that JGW Patterson funding will have proved pivotal in their long-term careers. When funding for a lectureship (now Professor) and the currently funded PhD studentships are also taken into consideration the role of the JGW Patterson Foundation in individual careers and for capacity building at Newcastle have been crucial as well as the benefits that accrue to the public, patients and the economy from their research findings.

Chris Day – VC of Newcastle University

Newcastle is particularly proud of the many external awards it has received for infrastructure funding and there can be little doubt that the underpinning awards from the JGW Patterson will have played their part in our gaining the large Centres and Programme Awards such as for musculoskeletal research: the jointly MRC and ARUK-funded Centre for Integrated Research into Musculoskeletal Ageing (CIMA) with Liverpool and Sheffield Universities and for our Northern Institute for Cancer Research (NICR) being awarded Cancer Centre status from CRUK and also one of the CRUK and Health Departments Experimental Cancer Medicine Centres and LLR/Bloodwise programme grant funding for our world-leading Leukaemia Research Group.

Newcastle University, working in close partnership with Newcastle upon Tyne Hospitals NHS Foundation Trust and Northumberland, Tyne and Wear NHS Foundation Trust is known for its translational research and again several of our investigators obtaining MRC Developmental Pathway Funding Scheme or NIHR Invention for Innovation (i4i) funding or other translational research funding streams have done so after receiving feasibility funding from the JGW Patterson Foundation.

"We are very fortunate in the UK to have such a strong charity structure and we are particularly blessed in the North East to work with the JGW Patterson Foundation"

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Marie Curie – examples of grants given to Marie Curie Hospice, Newcastle

A hospice has received grants totalling more than £120,000 from a regional charitable foundation, to allow it to upgrade its facilities for the benefit of people living with terminal illnesses from across the North East.

The Marie Curie Hospice Newcastle has received six major donations from The JGW Patterson Foundation in the past eight years, which have allowed the hospice to update a number of areas of the building.

The most recent donation of £26,840 from the Foundation – which was founded in 2002 – has enabled the hospice to update many essential pieces of kitchen equipment.

Previous donations have enabled upgrades to areas of the hospice – the region’s only Marie Curie facility, which offers in-patient and day therapy services to people living with any terminal illness, including cancer, across the North East – including its Education Centre.

The JGW Patterson Foundation was established by the late philanthropist John George William Patterson, from Jesmond, Newcastle, who bequeathed his entire portfolio of commercial and residential properties to the Foundation.

The main objectives of the Foundation are to fund research into, and purchase equipment and caring services for, the relief of cancer, arthritis and rheumatology. It makes grants extensively to the Universities, hospices and charities across the region.

The board of Trustees is made up of some of the most prominent professionals in the city – nationally-renowned paediatrician Professor Sir Alan Craft; Professor Tim Cawston, former Dean of Research at Newcastle University; Stephen Gilroy, retired Partner with Lambert Smith Hampton; David Gold, Partner with Joseph Miller & Co; and Jim Dias, retired Chairman of Sintons LLP. All of the professional services firms represented on the board were trusted advisors used by Mr Patterson during his life.

Pippa Aitken, Company Secretary of the JGW Patterson Foundation and Senior Associate at Sintons LLP, said: “It was the wish of Mr Patterson that the ongoing income from his property portfolio would be used for the benefit of his home city, namely to fund life-changing medical research and to support hospices and other medical institutions which provide vital care for people.

“To make such an ongoing impact is an incredible legacy, and it gives myself and the Trustees great joy to be able to make grants on behalf of the JGW Patterson Foundation which we know will do such good.

“We are delighted to have been able to support the Marie Curie Hospice Newcastle over the years, and have seen for ourselves the difference the grants have made for the benefit of patients and their families.”

Helen Forrow, Hospice Manager at Marie Curie, said: “When you are living with a terminal illness you want to make the most of the time you have left. Quite often, it can be the little things that mean the most to people – like fish and chips on a Friday. And thanks to the recent renovations to our kitchen that were funded by the JGW Patterson Foundation’s contribution, this is something we are able to offer and it’s a huge hit with patients and their families.

“Being able to bring a sense of normality to people when they are facing such difficult times is a big part of what we try to do at the hospice. And we simply couldn’t do it without the generosity of our supporters and partners like the JGW Patterson Foundation.”

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St. Cuthbert's Hospice

St. Cuthberts Hospice, Durham, reclining chairs purchased by JGW Patterson Foundation

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Effects of B-cell depletion on bone turnover in Rheumatoid Arthritis

Rheumatoid arthritis is associated not only with joint damage, but generalised bone loss which ultimately can result in osteoporosis and an increased risk of fractures. This bone loss is driven by a variety of factors, including loss of mobility and inflammation which activate bone cells to break down (resorption) more bone than they form. There is also growing evidence that there is close interaction between immune cells and bone cells. Many immune cells produce molecules which stimulate both the inflammation underlying rheumatoid arthritis and bone breakdown. One such cell is a white cell known as the B-cell. Recently, a new and successful treatment for rheumatoid arthritis called Rituximab has been developed which destroys B-cells.

The Foundation funded a recent study to see if the removal of B-cells would also improve bone quality which was led by Roger Francis and Stephen Tuck. Preliminary evidence was sought by measuring markers of bone cell activity using stored blood from a previous study of 46 patients who had been given Rituximab every 6 months. Bone cell activity could be measured in blood prior to being given Rituximab and the effects 6 and 12 months after starting Rituximab. We found that B-cell depletion by Rituximab increased bone formation and decreased bone resorption. This suggests that there may be an improvement in bone density over time, which could help to prevent osteoporosis and fractures. The study has just been published in Osteoporosis International (Osteoporosis Int. 2011; 22:3067-3072). The success of this study has enabled us to obtain a further £150,000 in funding from the Pharmaceutical Company Roche to undertake a prospective study to measure bone density and confirm these findings.

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Dr David Young

The first grant awarded by the JGWP Foundation allowed us to recruit a new member of academic staff, Dr David Young, to the Musculoskeletal Research Group in Newcastle University. His brief was to develop a new research laboratory that focused on osteoarthritis.

Osteoarthritis (OA) is a disabling joint disease predominantly affecting older people. The cartilage, which allows pain free movement of the joints, becomes degraded leading to pain and disability for patients. The cartilage tissue is produced by cells called chondrocytes. If the removal of cartilage components by these cells exceeds the building up of new cartilage, then the tissue will be gradually destroyed. This is what happens in OA cartilage.

This early JGWP grant has allowed David Young to establish a research group of 9 researchers that aims to understand the cellular processes occurring in OA. He is a co applicant on a prestigious Arthritis Research-UK programme grant for £1.1 million that aims to understand how new factors called microRNAs control the behaviour of chondrocytes and contribute to the cartilage destruction seen in osteoarthritis and therefore provide potential new treatments for this disabling disease. The Newcastle component of this 5 year award plays to one of our main strengths in the North East, access to human tissue, kindly donated by patients at joint replacement surgery. Using this and human stem cells we’re developing models of cartilage in the laboratory. We then use these models to determine what microRNAs are important when cartilage breaks down, as in diseases like OA. Along with this we want to know what microRNAs are important for cartilage to form in the first instance and so allow us to “engineer” cartilage in the lab to be used to replace damaged cartilage in a patient.

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Drug Discovery and Imaging Group

One of the important aims of the work undertaken by both Dr Williamson and Dr Heer is the identification of new targets for anti-cancer drug development. One of the strengths of the Northern Institute of Cancer Research at Newcastle University is the capacity to link these kinds of findings to an in-house team of medicinal chemists. Headed by Professors Roger Griffin and Herbie Newell, the Drug Discovery and Imaging Group has had a number of notable successes in developing very effective anti-cancer drugs.

Funding from the JGW Patterson Foundation is being used to support PhD students in the group such as Andrew Shouksmith who is designing drugs to inhibit the SKP2 protein – a molecule which interferes with the normal breaks in place to control cell division. In some forms of cancer the levels of this protein are abnormally high leading to rapid tumour growth. As well as producing important information in its own right, support for PhD students such as Andrew is vital to ensure that talented young scientists join the work-force in the future.

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Dr Rakesh Heer

Another example of the way in which support from the Foundation has been used to generate new data. Dr Rakesh Heer, an academic urological surgeon based at the NICR, has collected samples from bladder cancers to generate a tissue micro array containing 400 clinical cases. This will enable him to compare tumours for the presence of microscopic features which will predict how well an individual patient is likely to respond to drug treatment, surgery or treatment with X-rays.

He will link these findings to the results of highly sophisticated tests on the genetic code of the tumours and to a database of clinical information.

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Dr Dan Williamson

In a project supported by the Foundation since 2010, Dr Dan Williamson has been looking at tumours arising in the brain using state-of-the art techniques which can examine the entire genetic code for the damage which can lead to cancer. Using this information he will be able to devise tests that can determine the best treatment, tailored for an individual child based on his or her tumour type. This will help to eliminate unnecessary damage to normal brain tissue-a particular problem in the developing brain.

The results produced by this project have enabled Dr Williamson, working with his colleagues Professor Clifford and Dr Bailey, to attract more than £1m pounds of additional funding from a national charity to continue their studies in this important area of research.

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Contributon towards the purchase of stereoscopic microscope

The JGW Patterson Foundation has contributed to the purchase of several items of complex, and very expensive, specialist equipment including a sophisticated stereoscopic microscope fitted with minute tools for the dissection of tissues. Using this equipment Professor Debbie Tweddle and her research team are using stem cells to model the normal development of the sympathetic nervous system which gives rise to a form of childhood cancer called neuroblastoma which, when advanced, can be very difficult to treat. Detailed knowledge of how and why neuroblastomas arise will enable her to suggest new forms of treatment.

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Studentship title:

The Andrew Walker PhD Arthritis Studentship 2015 – 2019

Project title:

Joining the dots” between genetic risk and joint inflammation in rheumatoid arthritis to find better treatments

Student:

Alex Clark

Supervisors:

Dr Arthur Pratt and Dr Louise Reynar

In rheumatoid arthritis (RA), “misdirected” cells of the immune system attack the joints, causing pain, stiffness and disability – but quite what causes this to happen remains poorly understood. Much has recently been learned about how variations in a person’s inherited genetic code may influence his or her risk of developing RA. For example, over 100 “risky” variations in the code have been found near genes that make proteins often used by immune cells. However, it is challenging to decipher precisely which proteins are most influenced by these risky variations, whose altered function might in turn misdirect the immune system. Doing so could better guide scientists to focus their efforts on biological processes that are most important in driving disease – and those that could most beneficially be targeted with drugs to improve the lives of people with RA in the future.

In our project, patient volunteers with newly diagnosed arthritis donated their blood for genetic studies aimed at addressing this challenge. Our research team used a combination of technologies together with statistical techniques to refine understanding of which proteins might be most influenced by variations in the genetic code that put people at risk of RA. Our results provide important clues as to some of the the precise immune processes scientists should now focus on to understand the cause of RA in more detail.  Interestingly, it looks as though some of the processes our work highlights may be just as important in causing other diseases of the immune system, so the implications of our findings are potentially far-reaching.

"The funding we received from the JGW Patterson Foundation made this work possible. It also provided an important spring-board for a talented young scientist, who not only gained a PhD qualification as a result of his work, but successfully applied for a post as a junior scientist at the NIH Maryland, USA."

Some members of the study team

Arthur Pratt

(PI, supervisor)

Alex Clark

(Student)

Louise Reynard

(PI, supervisor)

Original papers arising from this funding

  • Clark AD et al. Lymphocyte DNA methylation mediates genetic risk at shared immune-mediated disease loci. Journal of Allergy and Clinical Immunology 2020; 145:1438-51.
  • Anderson AE et al. Expression of STAT3-regulated genes in circulating CD4+ T cells discriminates rheumatoid arthritis independently of clinical parameters in early arthritis. Rheumatology 2019;58:1250-8
  • Thalayasingam N et al. CD4+ and B lymphocyte expression quantitative traits at rheumatoid arthritis risk loci in patients with untreated early arthritis: implications for causal gene identification. Arthritis & Rheumatology 1018; 70:361-70
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Studentship title:

The Andrew Walker Cancer PhD studentship 2015 – 2019

Project title:

Small molecule modulators of cyclin-dependent kinase 2 activity and regulation

Supervisor:

Prof Jane Endicott

Department:

The CRUK Newcastle Drug Discovery Unit

The cyclin-dependent kinases (CDKs) bind to members of the cyclin protein family to form complexes that regulate cell proliferation. Just as CDK-cyclins are important in normal cells, so they can also contribute to the development of disease when they do not function properly. Using insights from structural biology we can describe the three-dimensional form of CDK complexes to understand how they work and are regulated and importantly how their dysregulation might contribute to cancer. Historically the development of CDK inhibitors has targeted the CDK ATP-binding site. However, this approach cannot distinguish the different activities of their CDK target, which may depend on the complexes in which they are found. Consequently, ATP-competitive inhibitors can have unwanted effects that limit their use as drugs. This studentship has helped to further understand the structural differences between closely related CDKs in order to better target CDK inhibitors1. To improve the safety and increase the robustness of clinical response to CDK inhibitors this studentship has also helped to develop “FragLites”2. These small molecules can be used to identify potential drug binding sites on the CDK-cyclin surface and are starting points to develop inhibitors that bind to sites other than the CDK active site.  Overall, the studentship has provided biological insights, and actionable approaches to novel ways of inhibiting CDKs for drug design. The student received training in many key techniques and gained experience of the chemistry/biology interface that underpins modern drug discovery. He has since taken up a post-doc position in Germany.

Papers:

  1. Differences in the conformational energy landscape of CDK1 and CDK2 suggest a mechanism for achieving selective CDK inhibition. Wood DJ, Korolchuk S, Tatum NJ, Wang LZ, Endicott JA, Noble MEM, Martin MP. Cell Chem Biol. (2019) 26:121-130.e5. doi: 10.1016/j.chembiol.2018.10.015. (13 citations)
  1. FragLites-minimal, halogenated fragments displaying pharmacophore doublets. An efficient approach to druggability assessment and hit generation. Wood DJ, Lopez-Fernandez JD, Knight LE, Al-Khawaldeh I, Gai C, Lin S, Martin MP, Miller DC, Cano C, Endicott JA, Hardcastle IR, Noble MEM, Waring MJ. J Med Chem. (2019) 62:3741-3752. doi: 10.1021/acs.jmedchem.9b00304. (12 citations)

Review:

Structural insights into the functional diversity of the CDK-cyclin family. Wood DJ, Endicott JA. Open Biol. (2018) 8:180112. doi: 10.1098/rsob.180112. (37 citations)

FragLite binding to CDK2

The CRUK Newcastle Drug Discovery Unit

Studentship title:

The Peter May Arthritis PhD Studentship 2015 – 2019

Project title:

Biomechanical sensing in cartilage ageing and disease

Student:

Thais de las Heras Ruiz

Supervisors:

Dr Arthur Pratt

Thais de las Heras Ruiz has developed a model of cartilage in a dish, which we will use as a tool to investigate rare skeletal conditions and cartilage ageing. Developing this exciting model would not be possible without the generous support of the JGW Patterson Foundation who have also previously funded the purchase of the state of the art Flexcell FX500 TM compression system that enables us to culture our mini-cartilages under the right physiological cues. Thais was able to show that culturing cells in agar hydrogel promotes cartilage formation and that the cells can indeed respond to compression – a major step for modelling cartilage diseases in a dish. This project opened up a new collaboration with the School of Engineering and Agriculture at Newcastle University and with Liverpool University and we will continue to refine the model, and use it to study cartilage ageing and disease. Thais successfully defended her thesis in November 2020.

Thais de las Heras Ruiz

"Developing this exciting model would not be possible without the generous support of the JGW Patterson Foundation who have also previously funded the purchase of the state of the art Flexcell FX500 TM compression system that enables us to culture our mini-cartilages under the right physiological cues."

Cells embedded in the gel (on the left) and scanning electron microscopy image of the gel structure.

Studentship title:

The Peter May Cancer PhD studentship 2015 – 2019

Project title:

Investigating the pre-T Cell Receptor (pTCR) pathway as a potential new drug target in T-cell Acute Lymphoblastic Leukaemia

Student:

Melanie C Beckett

Supervisors:

Dr A Krippner-Heidenreich, Dr FW van Delft

T-cell Acute Lymphoblastic Leukaemia (T-ALL) affects 90 children and adolescents per year in the United Kingdom. Although current treatment cures 80% of patients, the outcome for patients with drug resistant or recurrent leukaemia is usually unfavourable. Leukaemia, which remains detectable after 4 weeks of VXLD treatment, is associated with poor outcomes. The reasons for poor treatment response remain poorly understood, which in turn hampers our efforts to improve survival rates.

The JGWP PhD studentship allowed us to develop a model system in which to simulate poor response to treatment and use this to develop new treatments. Mice with human T-ALL received chemotherapy treatment and underwent a genetic screen. Data analysis has already identified several processes that are likely involved in drug resistance and we have initiated confirmatory studies. Once completed, we aim to publish this research and share our model with the wider community. The data will form the basis for further grant and PhD studentship applications. The valuable system we have developed will allow us to continue to investigate mechanisms underlying drug resistance with the ultimate aim to improve treatment and outcomes.

"The JGWP PhD studentship allowed us to develop a model system in which to simulate poor response to treatment and use this to develop new treatments."

Melanie successfully gained her PhD degree in 2020 based on the research described. Subsequently she was appointed as Higher Scientific Officer in the team led by Dr Alejandra Bruna at the Institute of Cancer Research.

Studentship title:

The Andrew Walker Arthritis PhD studentship 2019 – 2023

Project title:

Predicting and Understanding Flare in Rheumatoid Arthritis

Student:

Jasmine Sim

Supervisors:

Dr Ken Baker, Prof John Isaacs

Department:

Newcastle University Translational and Clinical Research Institute

Rheumatoid arthritis is a common condition affecting 1 in 100 UK adults, and characterised by inflammation in the joints causing pain, swelling and disability. Thankfully, many patients can now achieve an excellent control of their arthritis (called ‘remission’) with modern disease modifying anti-rheumatic drug (DMARDs) therapy. However, DMARDs carry the risk of potentially severe drug side-effects, the need for regular blood tests, and the expense of drug prescribing. Patients and their doctors are thus faced with an uncertain dilemma – when is it safe to reduce or stop DMARDs once remission is achieved?

In our recent clinical trial (Biomarkers of Remission in Rheumatoid Arthritis – BioRRA), 44 patients with RA in remission stopped DMARD treatment and were reviewed for 6 months. Half (23/44) of patients maintained drug-free remission, which could be predicted by the activation of specific genes within a type of white blood cell (CD4+ T cell).

In this JGW Patterson Foundation PhD Studentship, we aim to confirm these findings using blood samples from a larger study of DMARD cessation (the BIO-FLARE study). We then aim to identify ways in which these findings can be translated to a laboratory test suitable for clinical use in future research projects. Such a test, if successfully validated, would help to identify those patients who can safely reduce or stop their DMARD therapy. This would reduce the occurrence of drug side-effects, reduce healthcare costs, and ultimately improve the quality of life of patients living with RA.

Jasmine Sim

Studentship title:

The Andrew Walker Cancer PhD Studentship 2019-2023

Project title:

Understanding the mechanisms of chromothripsis in cancer

Student:

Connor Gilkes-Imeson

Supervisors:

Jonathan Higgins, Christine Harrison, Diana Papini

Chromothripsis is an event in which a chromosome is shattered into many pieces and then randomly reassembled. This dramatic event can promote the development of cancer. Although chromothripsis is currently a hot topic in the scientific community, little is understood about its role in cancer. Patients with a type of leukaemia named iAMP21-ALL are known to have a chromosome that undergoes chromothripsis. A subgroup of iAMP21-ALL patients are born with an abnormal chromosome (pictured) that causes an increased risk of developing this cancer. We studying this cancer to gain a better understanding of the events which lead to chromothripsis. The outcomes of this project will provide us with knowledge of how certain cancers arise to inform future diagnosis and treatment. The project brings together cell biologists in the laboratory of Jonathan Higgins and cancer researchers in the laboratory of Christine Harrison to provide an excellent multidisciplinary training environment for a PhD student, Connor Gilkes-Imeson.

Studentship title:

The Peter May Cancer PhD Studentship 2019-2023

Project title:

The Monitoring immunE DysregulAtion foLLowIng checkpOint inhibitioN study (MEDALLION)

Student:

Kristian Williams

Supervisors:

Dr Arthur Pratt, Dr Amy Anderson & Professor Ruth Plummer

The immune system is highly effective at protecting our bodies from harm. It also plays a part in protecting us from cancer by recognising and destroying harmful cells of our own bodies. But, for about 5% of people, the immune system itself causes disease. Immune mediated diseases (IMDs) are long-term conditions in which the immune system attacks parts of an otherwise healthy body as if it were harmful. Until now, studying the “initiation phase” of IMDs including inflammatory bowel disease and rheumatoid arthritis has been difficult because it typically begins before patients even develop symptoms. Use of a new class of drugs in the field of cancer medicine, called immune checkpoint inhibitors (CPIs), offers a way of overcoming this barrier for the first time. CPIs work by interfering with signals transmitted by the body’s cells that tell its immune system they are harmless. Cancer cells sometimes take advantage of these signals, using them as “decoys” to fool the immune system into ignoring them, even though they are harmful. By blocking the ability of cancer cells to do this, CPIs help the immune system to attack and kill the cancer cells. This approach has transformed the outlook of many cancer patients, but the strategy also makes the body’s harmless cells vulnerable to attack, and many patients treated with recommended CPI-drugs develop side effects that look similar to IMDs – called immune-related adverse events (irAEs).

In order to open a window on the beginnings of IMDs, and gain a better understanding of how irAEs develop, we propose close monitoring of the immune system in patients being started on CPI drugs as part of their routine care. We will identify how the changes that occur for the ensuing 9 months differ between patients who go on to experience irAEs in this period and those who do not. To achieve all this we will ask patients to donate blood for research at each routinely scheduled visit to hospital during the first 9 months of their treatment. The student will look for signs of the immune system becoming unbalanced in the run-up to irAE development by carrying out detailed measurements on blood cells. Resultant insights should suggest new treatments to prevent IMDs, as well as tools to help predict and treat irAEs in cancer patients.

Some members of the study team

Arthur Pratt

(PI, supervisor)

Amy Anderson

(PI, supervisor)

Kristian Williams

(Student)

Ruth Plummer

(PI, supervisor)

Related Work

  • Matched support from the Cancer Research UK (CRUK) Newcastle Centre is funding a clinical PhD student to work closely with the Peter May Fellow, adding substantial value to the project.
  • Because of this work we are participating in a multi-site collaborative effort to pool resources and thereby maximise outputs of this and similar investigations into irAEs with colleagues nationally. Dr. Pratt and Professor Plummer are co-applicant in an MRC Experimental Medicine funding application.
  • This work was also integral to a parallel funding application, led by Drs. Pratt and Anderson (in collaboration with Professor Plummer), to investigate mechanisms of immune-mediated arthritis specifically, and this is also under review.