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Cambridge Institute for Medical Research

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COVID-19 UPDATE

The CIMR has reopened for research on Monday June 15th, following detailed, University-approved protocols to protect our staff and students, who are the heart of our institution. We will continue to work from home whenever possible, but critical lab experiments are now starting again. We are pleased to see some normality return, but also recognise that the COVID-19 crisis and its impacts are far from over, and we will continue to adjust working practice in the weeks and months ahead. Deliveries aside, our building remains closed to external visitors. For general enquiries, please use cimr-reception@lists.cam.ac.uk or phone 01223 762322. Email continues to be the best way to contact other CIMR staff and students. COVID-19 has demonstrated on a global scale the impact that disease has on patients, on families and communities. Our research contributes to understanding the molecular mechanisms of a range of human diseases, and these diseases have not paused during lockdown. We are delighted that our talented researchers can now resume their critical work at the lab bench again. Thanks to all our staff and students for the amazing support and community spirit and support during this difficult time.


Our strategy

CIMR is a unique partnership between basic and clinical research, aiming to understand the cellular basis of disease. Our goal is to create an inspiring environment in which outstanding scientists can excel. By providing state-of-the-art core facilities and support for our researchers, we foster new collaborations that spark discoveries about fundamental cellular processes and their relevance in disease.

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Research Advance

Publishing in the Journal of Cell Biology, Dr Hirst in the Robinson lab and co-authors show that recruitment of the AP-5 complex (that includes SPG11 and SPG15) is by coincidence detection, requiring both phosphatidylinositol 3-phosphate and Rag GTPases. The requirement for Rag GTPases places the AP-5 complex right at the heart of the signalling network that governs the cell’s response to starvation, uncovering an important link between the AP-5 complex and the mTORC1 pathway. These findings provide new insights into both the function of the AP-5 complex in normal cells and why its absence leads to spastic paraplegia, and could potentially open up new therapeutic approaches.

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Research Advance

mTORC2 is a protein complex in a network which transduces extracellular signals from growth factors into cellular responses such as growth, proliferation and nutrient metabolism. The precise mechanisms of this process are unclear. However, Dr Lidia Wrobel and colleagues from CIMR’s Rubinsztein lab demonstrate in Cell Reports that growth factors stimulate the expression of the protease USP9X, which then has a role in activating mTORC2 and downstream signalling. The protein RICTOR is needed to form the mTORC2 complex, but it can’t do so when ‘tagged’ with polyubiquitin at K274. USP9X removes the ubiquitin ‘tags’ from RICTOR, enabling the deubiquitinated RICTOR to form an active mTORC2 complex with other components. Dysregulated mTORC2 is a feature of some metabolic disorders and cancers; new mechanistic insights such as this may contribute towards understanding of these diseases and potentially guide new therapeutic approaches.

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Research advance

The Integrated Stress Response (ISR) is a protective mechanism used by cells when they detect adverse conditions. However, prolonged activation of the ISR can occur in, and contribute to some disease states. Dampening the ISR is therefore a potential treatment strategy for such conditions. ISRIB, is an experimental tool compound that does this, and a new paper from the Ron lab at CIMR and the Ito lab at RIKEN, Japan sheds new light on its mechanism of action. Publishing in Molecular Cell, Alisa Zyryanova, Kazuhiro Kashiwagi and colleagues demonstrate that ISRIB binds a protein called eIF2B, affecting its interactions with active and inactive forms of its target, eIF2, thereby attenuating the ISR.

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Research advance

A new paper in The American Journal of Human Genetics has been published by a UK-Italian collaboration co-led by CIMR’s Dr Evan Reid and Prof. Lucy Raymond, together with Dr Marco Tartaglia (ICRCC, Rome). Rapid whole genome sequencing of children in neonatal intensive care, combined with detailed analyses of genomic databases identified patients with a novel severe neurodevelopmental syndrome (termed CIMDAG), who all had mutations in the VPS4A gene. Dr Catherine Rodger and Dr Rachel Allison from the Reid Lab then undertook detailed molecular and cellular modelling of these mutations, including in stem cell-derived human neurons. VPS4A is a master regulator of the ‘endosomal sorting complexes required for transport’ (ESCRTs), cellular machinery that is active in many different membrane fission processes. The VPS4A mutations disrupted key cellular processes including endosomal trafficking and cell division. This research illustrates how the causes of devastating diseases can be understood by combining powerful genomics with cellular and molecular biology.

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Research Advance

Over the centuries, malaria has selected for many natural human genetic variants such as sickle haemoglobin that provide protection against severe disease. One such variant, Dantu, codes for an unusual hybrid glycophorin protein on the surface of red blood cells and is only found at high frequency in coastal East Africa. Determining how Dantu protects against malaria is the focus of a new paper published in Nature by a multidisciplinary team featuring multiple CIMR authors from the Rayner and Weekes labs, together with researchers from Cambridge’s Cavendish Laboratory, the KEMRI Research Institute (Kenya) and the Wellcome Sanger Institute. The paper’s key finding is that membranes of red blood cells from people carrying the Dantu variant are under increased biophysical tension, which makes them more resistant to invasion by the malaria parasite. Tension varies naturally across all red blood cells, and this work identifies for the first time a tension threshold above which invasion routinely fails, pointing to novel ways to treat this deadly disease.

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Research Advance

Hypoxia-inducible factor (HIF) 1α is a key orchestrator of a wide range of responses to changes in cellular oxygen levels. Dr Natalie Burrows and colleagues from Prof. Patrick Maxwell’s lab at CIMR, together with other co-authors, have reported in Nature Immunology an essential role for HIF1α in the early development of B cells. Deep inside bone marrow, elevated HIF1α activity acts a developmental brake within immature B cells- which is released upon their transition to a less hypoxic state, enabling their subsequent departure from the bone marrow and development. This involves a key tolerance mechanism, a process that limits the survival of B cells that recognise self. Additional experiments in mice using a pharmacological activator of the HIF pathway support this link further, opening up potential therapeutic applications in certain autoimmune conditions or B cell malignancies.

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Research Advance

A powerful example of how researching rare genetic variants can provide much wider insights was published recently in a multi-disciplinary, Cambridge-led study of childbirth pain. Together with Dr Michael Lee and colleagues at the Dept. of Anaesthetics, Prof. Geoff Woods’ CIMR team found a rare variant of the KCNG4 gene which was over-represented in a group of women who asked for no pain relief during labour. KCNG4 encodes for the voltage-gated potassium channel subunit Kv6.4. Dr Ewan St. John Smith’s group at the Dept. of Pharmacology then discovered that Kv6.4 was almost exclusively expressed in uterine nociceptors, and that the rare variant of Kv6.4 modulated potassium channels resulting in reduced nociceptor activity. Labour pain is the usual reason given by women for the increasing rates of epidurals for delivery and elective Caesarean sections; this work suggests that systemic delivery of Kv6.4 antagonist could be useful analgesic for labour – without the adverse effects associated with currently available local anaesthetics which occur even when administered via the epidural route.

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Research Advance

Programmed cell death pathways can be activated as a defence mechanism in cells infected with viruses to reduce further viral spread. These pathways can be either necroptotic (which trigger local inflammatory responses) or apoptotic (which are non-inflammatory), but both can be targeted by viral inhibitor proteins. Final-year CIMR PhD student Alice Fletcher-Etherington in the Weekes lab, together with other colleagues have published in PNAS on how human cytomegalovirus (HCMV) can subvert host cell death pathways to enhance its cellular infectivity. From proteomic screens, this new paper shows how the HCMV protein pUL36 targets MLKL, a key human cell regulator of necroptosis, for proteasome degradation. This mechanism is combined with pUL36’s anti-apoptotic action, making it a ‘dual-death inhibitor’ and a potential target for anti-HCMV therapy.

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CIMR researcher recognised in 2021 New Year Honours

Congratulations to Dr Mike Weekes who was awarded a British Empire Medal for services to the NHS during the COVID-19 pandemic. Dr Weekes developed a comprehensive COVID-19 screening programme for all Cambridge University Hospitals healthcare workers, and Cambridge University staff and students with symptoms of COVID-19. He simultaneously continued to lead his laboratory research at CIMR on how viruses evade intracellular defences.


Multidisciplinary funding award for CIMR early career researcher

Congratulations to Dr Jonathon Nixon-Abell (Sir Henry Wellcome Fellow at CIMR with Prof. Peter St George Hyslop FRS) and Dr Georg Krainer (Marie Skłodowska-Curie Fellow with Prof. Tuomas Knowles at the Department of Chemistry) who have jointly secured a Pump Priming Grant from the Cambridge Centre for Physical Biology. This annual funding scheme supports new collaborations between early career researchers with complementary expertise, thereby promoting multidisciplinary research in the field of physical biology in the University. Jonathan’s and Georg’s award will allow them to develop high-throughput methods of studying biomolecular condensates of protein and nucleic acid which can form inside cells – and which may have a role in neurodegenerative diseases.

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CIMR experts comment on a major advance in protein research

There has been wide interest in AlphaFold2, a program from Google’s DeepMind Artificial Intelligence (AI) network which was reported as having solved a long-standing challenge in biology. The incredible range of different behaviour and functions found across proteins depends upon their 3D structures - in turn, largely determined by protein amino acid sequences. Working out precisely how a protein chain folds from just knowing its amino acid sequence has been a major goal for decades - but now may be within reach using this AI program.

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CIMR at RAREfest2020

We’re pleased to be taking part in RAREfest2020 on Saturday 28th November. CIMR’s Prof. Stefan Marciniak and colleagues from his team Dr Jenny Dickens, Eimear Rutherford and Nikita Zubkov will be discussing their research on rare lung diseases between 12:45 – 13:30. The programme is online and registration is free, via this link: https://www.eventbrite.co.uk/e/rarefest20-virtual-science-technology-advocacy-arts-festival-tickets-82941617611


CIMR Principal Investigator recognised as 'highly-cited researcher' in 2020

Professor David Rubinsztein FRS has been highlighted by the Web of Science Group as a 2020 ‘Highly Cited Researcher’ for his research on mechanisms of autophagy and neurodegeneration. This reflects analysis by Web of Science of Prof. Rubinsztein’s research publications in the years 2009 – 2019, many of which rank in the top 1% by citations for a given research field or fields. The University of Cambridge was the second highest ranking UK University by numbers of highly cited researchers from the 2020 analysis.


Royal Society Dorothy Hodgkin Research Fellowship for CIMR early-career researcher

Congratulations to Dr Janin Lautenschlaeger, who will start as Royal Society Dorothy Hodgkin Research Fellow at CIMR. Her project, entitled ‘Liquid-liquid phase separation of alpha-synuclein at the presynaptic terminal’ will be carried out in Prof. Peter St George-Hyslop’s lab and focus on the recently-discovered property of the protein to form liquid condensates. Janin will study how these protein condensates are implicated in the synaptic function of alpha-synuclein, a protein important in Parkinson’s and some other, rarer neurodegenerative diseases.


Award for rare disease research at CIMR

Congratulations to Dr Joseph Chambers of the Marciniak Lab, one of two winners of the 18th Annual Alpha-1-Antitrypsin Laurell’s Training Award. This global award is to support early-career researchers working on alpha-1-antitrypsin deficiency. Joseph’s project is entitled ‘Effects of alpha-1 antitrypsin polymerisation on organelle structure and fluidity in hepatocytes’, and will be supported with €50,000 from Grifols S.A.

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CIMR spin-out company starts first clinical trial

Z Factor Ltd have announced that dosing has begun in a Phase I study of ZF874, their first-in-class, small molecule drug. This was discovered from research at Prof. Jim Huntington's laboratory in CIMR as a potential treatment for alpha-1-antitrypsin deficiency (AATD). Most forms of this genetic disease are caused by the misfolding and accumulation of the Z variant of alpha-1-antitrypsin in liver cells. As well as liver disease, there is also downstream lung damage in AATD. ZF874 is designed specifically to correct the misfolding of Z-AAT. Once the first stage of this safety and dosing study is complete in healthy volunteers, it will be extended to AATD patients. Results are expected by the end of 2020.

Coronavirus

Postgraduate Open Day

New publications

Rubinsztein lab (Cell Reports, 2020)
mTORC2 Assembly Is Regulated by USP9X-Mediated Deubiquitination of RICTOR

Ron lab (eLife, 2020)
Calcium depletion challenges endoplasmic reticulum proteostasis by destabilising BiP-substrate complexes

Ron lab in collaboration with the Ito lab, RIKEN (Molecular Cell, 2020)
ISRIB blunts the Integrated Stress Response by allosterically antagonising the inhibitory effect of phosphorylated eIF2 on eIF2B

Raymond and Reid labs (American Journal of Human Genetics, 2020)
De Novo VPS4A Mutations Cause Multisystem Disease with Abnormal Neurodevelopment

Rayner lab (Nature, 2020)
Red blood cell tension protects against severe malaria in the Dantu blood group

Maxwell lab (Nature Immunology, 2020)
Dynamic regulation of hypoxia-inducible factor-1α activity is essential for normal B cell development

Weekes lab (PNAS, 2020)
Human cytomegalovirus protein pUL36: A dual cell death pathway inhibitor

Woods lab (Cell Reports, 2020)
Human Labor Pain Is Influenced by the Voltage-Gated Potassium Channel KV6.4 Subunit

Deane lab (Nature Communications, 2020)
The receptor PTPRU is a redox sensitive pseudophosphatase

Rubinsztein lab (Nature Communications, 2020)
Leucine regulates autophagy via acetylation of the mTORC1 component raptor

Rubinsztein lab in collaboration with the Goldberg lab, Harvard (PNAS, 2020)
cGMP via PKG activates 26S proteasomes and enhances degradation of proteins, including ones that cause neurodegenerative diseases

Griffiths lab (eLife, 2020)
Stimulation strength controls the rate of initiation but not the molecular organization of TCR-induced signalling

Buss lab (Journal of Cell Science, 2020)
OPTN recruitment to a Golgi-proximal compartment regulates immune signalling and cytokine secretion

Rubinsztein lab (Developmental Cell, 2020)
A DNM2 Centronuclear Myopathy Mutation Reveals a Link between Recycling Endosome Scission and Autophagy

Buss lab (Biology of Reproduction, 2020)
Myosin VI maintains the actin-dependent organization of the tubulobulbar complexes required for endocytosis during mouse spermiogenesis

Weekes lab (Scientific Reports, 2020)
Comprehensive cell surface proteomics defines markers of classical, intermediate and non-classical monocytes

Buss lab (Traffic, 2020)
Ultrastructural insights into pathogen clearance by autophagy

Read lab (Acta Crystallographica Section D, 2020)
Measuring and Using Information Gained by Observing Diffraction Data

Read lab (Acta Crystallographica Section D, 2020)
Factors influencing estimates of coordinate error for molecular replacement