Cambridge Institute for Medical Research

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.

Research Advance

The ability of cells to clear unwanted proteins and organelles through autophagy is a requirement across biology. Conversely, the accumulation of misfolded, toxic proteins inside cells is a hallmark of a number of human diseases. In the CIMR, Professor David Rubinsztein’s lab researches autophagy and how it relates to neurodegenerative diseases such as Huntington’s, Alzheimer’s and Parkinson’s. A new paper published in eLife uncovers a regulatory mechanism common to mammalian cells and C.elegans worms: the role of the microRNA miR-1, which activates autophagy through reducing expression of a Rab GTPase-activating protein known as TBC-7 in the worm and TBC1D15 in mammals. The reduction in TBC-7 / TBC1D15 in turn increases the activity of Rab7, a positive regulator of autophagy. This mechanism was tested in a worm model of Huntingtin polyQ toxicity by collaborators in Prof. Roger Pocock’s lab, from the Monash Biomedicine Discovery Institute, and in mammalian cells by Prof. Rubinsztein’s lab. Interferon-beta was shown to activate this process in the latter model, with the potential for therapeutic application.

Research Advance

Cytotoxic T lymphocytes (CTLs) play a critical role in the immune system, recognising and destroying virally infected and cancer targets with remarkable specificity. CTLs are particularly important right now, with new immunotherapies focused on harnessing the cytotoxic potential of these cells to combat cancer. Research in the Griffiths lab aims to identify the multitude of genes that control killing and to understand the underlying cell biology that addresses the question: what makes a good killer? The lab’s most recent paper in the Journal of Clinical Investigation follows the identification of a small number of immunodeficient patients who carry mutations in the gene for actin-related protein complex 1B (ARPC1B) and are susceptible to severe infections. Dr Lyra Randzavola and colleagues show that CTLs require ARPC1B for normal growth and proliferation during an immune response. These findings could explain why patients lacking ARPC1B struggle with chronic viral infections, and shed light on the complex interplay between the actin cytoskeleton and vesicle trafficking in CTLs.

Research Advance

Professor David Ron’s lab researches how cells react to stresses in protein homeostasis via the Integrated Stress Response (ISR). Dr Heather Harding and colleagues from the Ron Lab, together with collaborators at the Wellcome Trust Sanger Institute and MRC Laboratory of Molecular Biology have published in eLife on how mammalian cells activate the ISR when being starved of amino acids. Using genetic screens and in vitro biochemistry, the authors show that under amino acid starvation, the P-stalk (a ribosome component) activates the protein kinase GCN2, which then phosphorylates eIF2 alpha, resulting in the downstream ISR pathway towards cellular recovery.

Research Advance

Mutations in the spastin gene are a principal cause of hereditary spastic paraplegia (HSP). Research from the Reid lab has provided new insights into the normal function of spastin, a microtubule-severing ATPase, and the cellular consequences of its loss in HSP. Publishing in Cellular and Molecular Life Sciences, Connell et al show, in cellular models, that spastin interacts with the ESCRT-III-associated proteins IST1 or CHMP1B to prevent cell-polarising membrane protrusions from forming. The protrusions are driven by protrudin, another spastin-interactor. This regulatory control of spastin over protrudin is lost in the absence of spastin, and therefore may contribute to HSP disease pathology.

Research Advance

The advent of CRISPR/Cas9 technology has opened up a growing number of possibilities in genome editing. Paul Manna and Luther Davis from the Robinson and Luzio labs have published a new methodology, CRISPR/Cas9-mediated Homology-independent PCR-product Integration (CHoP-In), in the journal Traffic. Their method enables the generation of 'knock-in' cell lines expressing target proteins N-, C- or internally-tagged with EmGFP / mCherry, without a requirement for donor vectors. Instead, the reporter fusions were generated by PCR and co-transfected directly with the gRNA / Cas9 vector targeting the genes of interest. Positively-expressing cells were separated by flow cytometry and characterised (above left). This method will be used further in the Robinson lab and has already received some wider interest.

Research Advance

Unfolded Protein Response (UPR) effector proteins respond to changing conditions in the endoplasmic reticulum (ER). For example, the ER chaperone BiP is inactivated when AMPylated by FICD, an enzyme which also catalyses BiP’s deAMPylation. In the EMBO Journal, Luke Perera, Steffen Preissler and other colleagues from the Ron and Read labs show that in response to an increase in ER ADP/ATP ratio, FICD switches reversibly from a monomeric AMPylator of BiP to a dimeric state which deAMPylates and thereby activates BiP.

2019 CIMR Research Retreat

CIMR held its research retreat on November 29th at the Wellcome Genome Campus Conference Centre. The scientific programme was delivered by our excellent PhD students and post-doctoral research associates. Congratulations to the prize winners, and thanks to all who took part and made it a success.

CIMR researcher receives recognition for influential publication output

Professor David Rubinsztein FRS has recently been highlighted by the Web of Science Group as a 2019 ‘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 2008 – 2018, many of which rank in the top 1% by citations for a given research field or fields. The University of Cambridge was the highest ranking UK University by numbers of highly cited researchers from the 2019 analysis.

Prestigious award for CIMR PhD student

Congratulations to Alexandra Davies, a former CIMR PhD Student who has been awarded the 2018-2019 Milo Keynes Prize for Outstanding Dissertation by the Cambridge School of Clinical Medicine Degree Committee. The prize is named in honour of Dr Milo Keynes, a clinician and author who had links to Cambridge during his lifetime, and who bequeathed funds to the University to support prizes for exceptional research. Alexandra’s PhD thesis is entitled ‘An investigation of the function of adaptor protein complex 4 (AP-4): Discovering a role for AP-4 in the spatial control of autophagy’, and was supervised by Professor Margaret Robinson FRS.

Another step forward for CIMR research into blood clotting disorders

The goal of CIMR is to understand the cellular mechanisms of disease in order to improve human health. Translating laboratory discoveries to new treatments is a challenging process with many complex steps. One outstanding example of navigating that path comes from a collaboration on blood clotting disorders which combines the biochemistry and drug discovery expertise of the CIMR’s Prof. Jim Huntington with the clinical knowledge of haematologist Dr Trevor Baglin (formerly of Cambridge University Hospitals). Their collaborative research led to the formation of ApcinteX Ltd in 2014, and this week they announced the successful delivery of the first dose of their drug SerpinPC in a first in human Phase I/II clinical trial. SerpinPC acts by prolonging the activity of the protein complex which generates thrombin through covalent inhibition of Activated Protein C. SerpinPC’s mechanism of action therefore makes it potentially suitable to treat all forms of haemophilia as a once-monthly subcutaneous prophylactic injection. This first clinical study of SerpinPC will focus on safety, tolerability and dosing, with reduction in bleeding as an exploratory endpoint when dosing moves from healthy volunteers to haemophilia patients. This critical step for the company and its founders reflects the commitment of the CIMR to translate our laboratory research into benefits for patients.

http://www.apcintex.com/