Developing non-invasive pathology for the delivery of precision anti-cancer medicine

Developing non-invasive pathology for the delivery of precision anti-cancer medicine

As part of a Rosetrees Trust-funded PhD studentship project at The Institute of Cancer Research (ICR), Dr. Simon Robinson, Dr. Yann Jamin, and Konstantinos Zormpas-Petridis, are working to bridge the gap between two clinically useful disciplines to demonstrate that MRI can complement diagnostic molecular pathology, and develop MRI as a non-invasive tool to characterise tumour heterogeneity and evolution in situ.

The focus of this project is childhood neuroblastoma, a pathology-rich disease with a very wide range of clinical outcomes. In their latest research, using their image analysis framework, the team have demonstrated that the clinically available MRI technique called T1-mapping is sensitive to the underlying neuroblastoma pathology. Published in Cancer Research, this non-invasive scanning technique can detect and map the presence of active (including resistant) disease, and can subsequently inform on the response to treatment in a specific model of neuroblastoma, including promising MYCN-targeted treatment.

The team will move to initiating the translation of their MRI scans into the neuroblastoma clinic. Through a clinical and biological study within standard-of-care- induction chemotherapy, the aim now will be to use their approach to help identify active disease in children with neuroblastoma and help enhance response assessment, surgical planning, and biopsies guidance, for improved genomic characterisation.

Written by: Dr. Rebecca Downing

Dr. David Kent, Dr. Nina Öbro, and Dr. Jacob Grinfeld: Getting to know Rosetrees researchers

Dr. David Kent, Dr. Nina Öbro, and Dr. Jacob Grinfeld: Getting to know Rosetrees researchers

Rosetrees researcher profile: Dr. David Kent, Dr. Nina Öbro, and Dr. Jacob Grinfeld, University of Cambridge

Who Rosetrees Trust is funding

Postdoctoral fellow, Dr. Nina Öbro, and clinical PhD student, Dr. Jacob Grinfeld, led this project with the aim of identifying new biomarkers in the early stages of blood cancer. The work was carried out in the research laboratory of Dr. David Kent, where work focuses on understanding how single blood stem cells are subverted to drive blood cancers. Many blood cancers are thought to arise from a series of mutations in blood stem cells, that cause an overproduction of blood cells, eventually leading to cancer. However, comparatively little is understood about the role played by the environment in which these cells reside, especially in the early stages of cancer development. This project therefore undertook an investigation of the proteins present in serum samples from patients with diseases known as chronic myeloproliferative neoplasms (MPNs) a powerful disease model for studying the early stages of tumours. Their approach was to identify novel biomarkers associated with cancer progression, and to uncover the biological role of these biomarkers in the emergence of blood cancer stem cells.

David said: “The recent explosion of genetic data in patients has led to some incredible advances in diagnosis and treatment, but it is very clear that mutations in genes cannot explain all the differences between patients. This project therefore set out to understand the cellular context in which these mutated cells reside – asking the question of whether specific proteins in the blood correlated with or drive disease progression.”

Dr. David Kent

The Kent lab has now relocated to the York Biomedical Research Institute in the Department of Biology at The University of York where researchers continues to pursue the goal of understanding the disease evolution of blood cancers. Jacob is now a consultant in Leeds and Nina has undertaken a new position as Senior Researcher at Rigshospitalet in Copenhagen.

How Rosetrees Trust have supported Dr. David Kent, Dr. Nina Öbro, and Dr. Jacob Grinfeld

The Kent Lab received funding for this research grant from 2016 to 2019, and it was Nina and Jacob who drove this project. The funds from the Rosetrees Trust allowed the team to purchase the necessary laboratory reagents to monitor changes in protein biomarkers at diagnosis and throughout the disease.

What the outcomes are of Rosetrees Trust-funded research from Dr. David Kent, Dr. Nina Öbro, and Dr. Jacob Grinfeld

The first research paper to emerge from this project has now been published in the European Hematology Association’s new journal Hemasphere. Nina and Jacob’s results, from a comprehensive serum cytokine profile of more than 400 MPN patient samples, identified an essential thrombocythemia (ET)-specific inflammatory cytokine signature consisting of Eotaxin, GRO-α, and EGF. Their data implicates the immune cell microenvironment as a significant player in ET disease evolution, and also illustrates the utility of using cytokines as biomarkers for reaching beyond genomic classification for disease stratification and monitoring.

Written by: Dr. Rebecca Downing and Dr. David Kent

An Introduction to the Physics of Medicine Network

An Introduction to the Physics of Medicine Network

The Physics of Medicine (2020-2023) is an exciting new Rosetrees Trust-funded project that has recently launched, representing a new partnership with the well-established Physics of Life network.

The Physics of Life network is a community driven network consisting of researchers from the physical and life sciences, which first started in 2012. During that time, the network has successfully attracted engagement from UK wide based researchers, through delivering an impressive number of student bursaries, pump priming funding and events, such as workshops. It was the second iteration, PoLNET2, which worked with UKRI (EPSRC, BBSRC and MRC) to help formulate a £30M investment under a new funding call, ‘Building Collaborations at the Physics of Life Interface’, split across two calls (in 2019 and 2021). UKRI (EPSRC, BBSRC, MRC) have continued to recognise the success of this network, and are now supporting the network into its third iteration (PoLNET3; 2020-2023), led by Professor Tom McLeish, FRS.

The third phase of the network further broadened its ambitions, to specifically encourage engagement from clinical and medical communities. This resulted in the formation of a new, separate arm to the network ‘Physics of Medicine, 2020-2023’, led by Professor Stephen Smye, OBE.

Professor Stephen Smye, OBE, said: “The contribution of the physical sciences to medicine is long-standing and significant, not least in the development of new technologies, but there are many new and surprising opportunities for further fruitful and exciting interdisciplinary approaches to tackle some of the major research questions in medicine. The Rosetrees Physics of Medicine network will promote novel collaborations between clinicians, biological and physical scientists by seeing how techniques and approaches developed in apparently disparate areas can be brought to bear on some of the major clinical challenges, including antimicrobial resistance, precision treatments for cancer and virus dynamics.”

Physics of Medicine aims to significantly enhance clinical participation into the Physics of Life network. The objective is to create a sustainable, clinically-focused, Physics of Medicine network community – as part of the wider Physics of Life network, by delivering a 3-year programme of multidisciplinary workshops linked to major clinical and biological challenges.

Physics of Medicine will therefore deliver a short series of ‘Rosetrees Interdisciplinary Challenge Workshops’ over the next 3 years, covering key clinical challenges from the perspective of the Physics of Life, including but not limited to; Anti-microbial resistance, Metastasis and resistance, Neurodegenerative disease, Gut disorders, Joint degeneration and Heart disease. In each case, the workshop will be jointly organised with cognate national research charities and other funders including NIHR, UKRI, and the Wellcome Trust.

There are many ways to get involved with the Physics of Medicine, the community is OPEN and available for everyone to join!

You can get involved in the following ways:

• Become a member by signing up to the Physics of Life newsletter for FREE. This will enable you to be up to date with all available opportunities.

• Apply for funding from Physics of Life or Physics of Medicine – both are relevant to the medical and clinical communities (support is available for workshops, sandpits support, summer student bursaries and pump priming, calls to follow).

• Attend one of our many events over the next 3 years (Workshops, Sandpits, Summer Schools) – virtually or physically!

• Follow the Physics of Life on Twitter! @PhysicsOfLifeUK

• Look out for the next linked funding call; UKRI Physics of Life Strategic Priority: ‘Building Collaborations at the Physics of Life Interface’.

• Visit the Physics of Life website which is regularly being updated to provide the latest information on their funding opportunities.

Please contact Network Coordinator, Karis Baker (k.h.baker@dur.ac.uk), for any enquiries related to Physics of Medicine.

Dr. Nicky Whiffin: Getting to know Rosetrees researchers

Dr. Nicky Whiffin: Getting to know Rosetrees researchers

Rosetrees researcher profile: Dr. Nicky Whiffin, Imperial College London

Who Rosetrees Trust is funding

Dr. Nicky Whiffin is a research fellow in the National Heart and Lung Institute, at Imperial College London. Her research focuses on exploring genetic variants that cause rare diseases. Although individually rare, these diseases collectively affect >250 million people worldwide. Genetic testing is widespread in the clinical management of rare diseases, but current strategies only find a genetic cause for ~50% of cases.

Nicky is part of the Cardiovascular Genetics and Genomics team at Imperial College, led by her fellowship sponsor Dr. James Ware. The group focuses on a specific class of rare diseases called inherited cardiomyopathies. These conditions are diseases of the heart muscle, resulting in heart failure and often sudden death.

To date, much of genetic research into rare disease has focused on regions of the DNA that code directly for proteins, which accounts for ~1.5% of the genome, and these regions have been the traditional focus in clinical diagnostic settings. This is because studies of ‘non-coding’ DNA, rich in functional elements that regulate protein production, have certain limitations including the requirement for large sample sizes, and difficulties in interpreting the effect of any individual variant. Despite these challenges, there is strong supporting evidence indicating that variants in non-coding DNA cause disease.

Nicky is using state-of-the-art techniques to narrow down the 98.5% of the genome that is non-coding to identify small regions and individual variants that cause rare diseases. The data output from this project will enable investigation of the contribution of rare non-coding variants to the pathogenesis of rare diseases, including cardiomyopathies. Nicky’s research is also highly translational, because it will inform genetic testing and impact patient care.

Nicky said: To a patient with a rare disease, knowing the precise genetic cause is invaluable. This genetic diagnosis can be used to screen other family members to identify those also at risk of disease, to suggest personalised treatment approaches and can often end a long ‘diagnostic odyssey’ for patients and their families. This research is increasing our understanding of non-coding variants that cause rare diseases and how they do so. Ultimately this will enable more patients to receive a valuable genetic diagnosis.

Dr. Nicky Whiffin

How Rosetrees Trust have supported Dr. Nicky Whiffin

Nicky is a Rosetrees/Stoneygate 2018 Imperial College Research Fellow, receiving funding for her fellowship from 2018 to 2022, under the sponsorship of Dr. James Ware. This springboard award has enabled Nicky to build her independent research program and foster a strong collaboration with Dr. Daniel MacArthur and researchers at the Broad Institute in Boston where she is a visiting scientist.

What the outcomes are of Rosetrees Trust-/Stoneygate-funded research from Dr. Nicky Whiffin

Nicky is a member of the analysis team of the Genome Aggregation Database (gnomAD), a collaboration of >100 principle investigators spearheaded by Dr. MacArthur. GnomAD is used across the globe, by both researchers and for clinical diagnostics, and is central to the analysis for this project.

Briefly, gnomAD is a population reference dataset that brings together exome and genome sequencing data from largescale sequencing projects, accessible to the wider scientific community. The resource gives us an accurate picture of which genetic variants exist naturally in the population, helping us to identify those which are unlikely to cause rare diseases. Nicky and James are members of the gnomAD consortium, contributing to the creation and analysis of the data. This database is continuously being scaled-up, growing from sequencing data of ~60,000 individuals (as the precursor ExAC database) to more than 140,000 individuals (~15,000 whole-genomes). The latest release contains whole-genome sequencing data for >70,000 individuals.

Today, the gnomAD consortium released a package of 7 publications in Nature Journals (Whiffin et al., 2020a; Whiffin et al., 2020b; Karczewski et al., 2020; Collins et al., 2020; Cummings et al., 2020; Wang et al., 2020; Minikel et al., 2020). Nicky led the analysis for two of the papers, published in Nature Communications (Whiffin et al., 2020a) and Nature Medicine (Whiffin et al., 2020b).

In the first of these, Nicky, supported by James and Dr. MacArthur, used the whole-genome sequenced subset of gnomAD to identify and characterise a new class of variants, found outside of protein coding regions, that reduce protein translation and lead to rare disease, published in Nature Communications (Whiffin et al., 2020a). Here, the team demonstrated the power of using large population datasets to identify specific non-coding bases that are under strong selection, using an approach that had previously only been applied to protein-coding variants. When this research was first published on the pre-print sever bioRxiv, Nicky was approached by others in the community who had determined new genetic diagnoses for previously unsolved patients as a direct result of this work.

The second of these papers, published in Nature Medicine (Whiffin et al., 2020b), is a large collaboration between the gnomAD consortium and the direct-to-consumer genetic testing company 23andMe, which also uses the UK Biobank resource. This work was co-led by Irina Armean from the Broad Institute and Aaron Kleinman from 23andMe. Together, they looked specifically at loss-of-function variants in the gene LRRK2. Variants that cause increased LRRK2 kinase function are a known cause of Parkinson’s disease, and drug companies are currently developing LRRK2 inhibitors as a potential treatment strategy. In early model organism studies, however, completely knocking-out LRRK2 resulted in severe side-effects in the lung/liver/kidney. Here, the team looked directly in over 4 million humans, from their three datasets. They assessed the phenotypic impact of a lifelong natural reduction in LRRK2 protein levels, caused by heterozygous loss-of-function variants. The team found no detectable increase in severe disease phenotypes in individuals with these variants, suggesting that reducing LRRK2 protein levels in humans should not cause any severe disease side-effects, at least due to on-target effects. This is promising news for patients with Parkinson’s disease.

What the future holds for Dr. Nicky Whiffin

Nicky has recently been awarded a prestigious Sir Henry Dale fellowship from the Wellcome Trust. Moving from Imperial to the Wellcome Centre for Human Genetics at the University of Oxford, Nicky will become a group leader and continue her research exploring the effect of non-coding variants in rare diseases.

Written by: Dr. Rebecca Downing and Dr. Nicky Whiffin

John Samuels, Medical Research Consultant and familiar face at the Rosetrees Trust, retires

John Samuels, Medical Research Consultant and familiar face at the Rosetrees Trust, retires

After 25 years of meeting our researchers from across the UK, and offering that personal touch from the Rosetrees Trust, John Samuels is now retired. John’s dedication to his role as Medical Research Consultant has seen him attend hundreds of researcher meetings over the years, which has also ensured that the Rosetrees Trust continues to support the best in medical research.

The Rosetrees Trust Team, at the Richard Ross Inaugural Lecture

John’s knowledge and approach has been passed to all members of the Rosetrees Trust team. We will be maintaining our personal touch with all of our researchers, and our community.

John’s retirement lunch, joined by family and friends
Richard and John

Some of John’s other passions in life are travel, art, and wine. He hopes to use his retirement to further explore these with his wife. He will remain in close contact with the Rosetrees Trust team, and keep in touch with the researchers that he has met over the years. We wish John well for the future.

John’s delicious Rosetrees Trust cake made by Sheree
Emergency COVID-19 ultrasensitive point of care diagnostic

Emergency COVID-19 ultrasensitive point of care diagnostic

Professor Molly Stevens, a member of our Scientific Advisory Panel and a Rosetrees Trust-funded researcher, has recently received more than €600,000 in funding for a project that aims to develop an emergency COVID-19 ultrasensitive point of care diagnostic. This project is being supported by the Rosetrees Trust, as well as two other funding sources. These are the EU’s European Institute of Innovation and Technology, where Molly’s team was the only UK-based group to receive funding from EIT Health in its Rapid Response initiative, and Imperial’s COVID-19 Response Fund.