Mitochondrial Genetics

Lead Research Organisation: Medical Research Council

Abstract

In eukaryotic organisms almost all genetic information is encoded in DNA present in the nucleus of the cell, but a small DNA molecule inhabits mitochondria, cellular structures that provide energy from food for the cells to use. Mitochondrial DNA contains genes that are vital for the physiological functioning of the cell. Defects that directly or indirectly affect mitochondrial genes cause human diseases. We are still do not know how mitochondrial genes work exactly. One of the ways to investigate the role of a gene, or to discover its biological function, it to change or disrupt DNA, and then to look for the effect on cultured cells, or on the whole organism. These methods of genetic modification are often powerful ways of studying disease genes encoded in the nucleus, but they cannot be applied to mammalian mitochondrial DNA. Therefore, our research goals are to identify new genes regulating mitochondria, define how these mitochondrial genes operate and to provide the technology to allow mammalian mitochondrial DNA to be modified genetically. It could be an invaluable way of understanding mitochondrial diseases and for advancing the quest for therapies.

Technical Summary

Human mitochondria have their own genome (mtDNA) that is two hundred thousand times smaller that the nuclear genome (nDNA) and encodes only thirteen essential subunits of the oxidative phosphorylation (OXPHOS) machinery. Given the relatively small size of the mitochondrial genome our detailed understanding of the molecular mechanism that govern mitochondrial gene maintenance and expression is still surprisingly sketchy. Defects of mtDNA and nDNA are well-recognised cause of genetic disorders that have diverse clinical manifestations ranging from progressive muscle weakness to fatal infantile disease. Much of our understanding of mitochondrial molecular genetics has come from studying rare mitochondrial disorders. Currently there are no effective treatments for these diseases and there are very few animal models for them. The slow progress in gathering more data on how mitochondrial genome is regulated is, in large part, owing to our current inability to edit mtDNA. Genome engineering techniques, analogous to the ones routinely used to modify the nuclear DNA, are not in hand, so we are unable to interrogate the role of cis-acting elements for RNA expression as well as transcription or replication. Furthermore, we are still unable to introduce pathogenic mtDNA mutations at will so their effect could be studied in animal models.

In particular, the programme focuses on:

(i) Studying the basic mechanisms of mitochondrial genome regulation with the main focus on
the novel proteins responsible for nuclolytic processing of precursor mitochondrial RNA, polyadenylation of mitochondrial messenger RNA, post-transcriptional nucleotide modification of mitochondrial RNA and mitoribosome biogenesis.

(ii) The analysis of the key aspects of mitochondrial genome regulation in samples derived from patients affected with mitochondrial disease. This analysis is a source of valuable insights into the pathomechanisms of human disease, and also into basic mitochondrial molecular genetics. Importantly. They provide patients with a molecular diagnosis for prevention (prenatal genetic diagnosis) and counselling.

(iii) Developing new approaches for the genetic modification of mitochondria of living cells.
The key long-term aim is to establish routine methods of genetic modification of mammalian mitochondria. Enzymatic methods are being developed to modify the mitochondrial genome e.g. engineered zinc finger nucleases are delivered to mitochondria in order to deplete cells selectively of specific mtDNA variants.

Publications

10 25 50
 
Description Diagnosis of mitochondrial disease
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical reviews
Impact improvements in clinical service delivery via e.g. pre-natal diagnosis
 
Description Pre-clinical approach to treatment of mtDNA disease
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical reviews
 
Description Biochemical Society General Travel Grant
Amount £450 (GBP)
Organisation Biochemical Society 
Sector Learned Society
Country United Kingdom
Start 06/2017 
End 06/2017
 
Description Boehringer Ingelheim Fonds Travel Grant
Amount € 1,060 (EUR)
Organisation Boehringer Ingelheim 
Department Boehringer Ingelheim Fonds
Sector Charity/Non Profit
Country Germany
Start 04/2017 
End 04/2017
 
Description CGAT pump priming proposal
Amount £14,000 (GBP)
Organisation Medical Research Council (MRC) 
Department MRC Functional Genomics Unit
Sector Public
Country United Kingdom
Start 03/2012 
End 03/2014
 
Description Clare college - travel grant
Amount £300 (GBP)
Organisation University of Cambridge 
Sector Academic/University
Country United Kingdom
Start 05/2012 
End 06/2012
 
Description EMBO Long Term Fellowship
Amount £60,000 (GBP)
Organisation European Molecular Biology Organisation 
Sector Learned Society
Country European Union (EU)
Start 10/2013 
End 10/2015
 
Description EMBO Short Term fellowship
Amount € 7,646 (EUR)
Funding ID ASTF 564 - 2015 
Organisation European Molecular Biology Organisation 
Sector Learned Society
Country European Union (EU)
Start 12/2015 
End 02/2016
 
Description FEBS YTF
Amount £500 (GBP)
Organisation Federation of European Biochemical Societies (FEBS) 
Sector Charity/Non Profit
Country European Union (EU)
Start 05/2012 
End 06/2012
 
Description GAABA
Amount € 85,000 (EUR)
Organisation Portuguese Foundation for Science and Technology (Portugal) 
Sector Public
Country Portugal
Start 09/2015 
End 09/2019
 
Description Homerton College Research Grant
Amount £400 (GBP)
Organisation University of Cambridge 
Sector Academic/University
Country United Kingdom
Start 06/2017 
End 06/2017
 
Description Methods for genetic transformation of mitochondria: providing tools for studying mitochondrial myopathies
Amount £50,000 (GBP)
Organisation French Muscular Dystrophy Association (AFM) 
Sector Charity/Non Profit
Country France
Start 04/2010 
End 03/2012
 
Description REMIX ITN
Amount € 3,920,000 (EUR)
Funding ID 727217 
Organisation Marie Sklodowska-Curie Actions 
Sector Academic/University
Country Global
Start 10/2017 
End 10/2020
 
Description The Champ Foundation Grant
Amount $100,000 (USD)
Organisation The Champ Foundation 
Start 05/2017 
End 05/2019
 
Title High-throughput detection of f5C in RNA 
Description Reduced Bisulfite RNA sequencing (RedBS RNA-Seq) that relies on the chemical reduction of f5C to hm5C by NaBH4, with the resulting hm5C being subsequently detected by RNA BS. The second protocol, 5-formylcytosine Chemically Assisted Bisulfite RNA sequencing (fCAB RNA-Seq) is based upon O-ethylhydroxylamine protection of f5C from bisulfite conversion. [Nat. comm Lindsey Van Haute et al. 2016] 
Type Of Material Technology assay or reagent 
Year Produced 2016 
Provided To Others? Yes  
Impact These two new, straightforward methods allow base-resolution mapping of f5C in transcriptomes and are expected to facilitate the search for new 5-formylated cytosines, reveal their functional role in both cytoplasmic and mitochondrial RNA therefore assist further expansion of epitranscriptome research. 
 
Title In vivo mtDNA manipulation using programmable nucleases 
Description Over the past decade mitochondrial DNA (mtDNA) has transitioned to broader relevance across diverse fields in biology and medicine. This has largely been thanks to the recognition of mitochondria as a major biochemical hub, the discovery of mitochondrial dysfunction in various diseases and a number of high-profile attempts at preventing hereditary mitochondrial disease using three-parent in vitro fertilisation, or mitochondrial replacement therapy (1-4). Mitochondrial diseases are a genetically diverse group of hereditary, multi-system disorders that are incurable and largely untreatable, with heterogeneous penetrance, presentation and prognosis. The majority of mitochondrial diseases are transmitted through maternally inherited mutations in mtDNA, and patients suffering with these disorders present a substantial disease burden (5). Mitochondrial DNA is a small, circular genome, encoding 13 essential protein subunits of the respiratory chain complexes and ATP synthase. As the mitochondrial genome is multi-copy, with anything from 100-10,000 copies per cell depending on tissue type, mutated mtDNA co-exists with healthy wild-type mtDNA in most patients suffering from mitochondrial disease, a phenomenon known as heteroplasmy. Patient symptoms and outcomes are closely correlated with the extent of mutation load, and approaches to treatment of mtDNA disease by shifting the heteroplasmic ratio in favour of wild-type mtDNA have long been desired and pursued. As mtDNA engineering lags many decades behind its nuclear counterpart, owing to various technical challenges (6) that likely negate the possibility of a functional CRISPR/Cas9 platform in mammalian mitochondria (7), it has not been possible to produce animal models of mtDNA disease until recently. The m.5024C>T tRNAALA strain is the only available mouse model of heteroplasmic mtDNA disease, bearing a pathogenic point mutation that results in biochemical hallmarks of mtDNA disease (diminished steady-state levels of the affected mt-tRNAALA) at high levels of mutant heteroplasmy in cardiac tissue (8). The mouse m.5024C>T mutation is equivalent to the human m.5591G>A mutation in mt-tRNAALA, associated with an adult-onset mitochondrial disease (9). This animal model is also, more broadly, clinically relevant to a large number of mtDNA diseases caused by mutations in mitochondrial tRNAs. In past work from our laboratory, we have engineered a new class of programmable, mitochondria-specific nuclease: the mitochondrially-targeted zinc finger-nuclease (mtZFN), which we have demonstrated can specifically eliminate mutated mtDNA in patient-derived cell models, resulting in recovery of associated cellular dysfunction (10-11). Aspects of this work are protected by the MRC patent on mtZFNs (US9139628 B2). In our recent work we achieved the successful translation of mtZFN technology from in vitro studies to the disease-relevant m.5024C>T tRNAALA mouse model. Through the experiments presented in the manuscript, we demonstrate that: 1) mtZFNs can be engineered to selectively eliminate m.5024C>T mutation with single nucleotide specificity. 2) When delivered systemically by adeno-associated virus (AAV), mtZFNs are capable of robustly manipulating mtDNA heteroplasmy of the targeted tissue. 3) Treatment-induced shifts in mtDNA heteroplasmy are accompanied by recovery of molecular and biochemical phenotypes in cardiac tissue of the m.5024C>T tRNAALA mouse model. 4) We conclude that mtZFNs are an effective tool for the treatment of heteroplasmic mitochondrial disease in mammalian animal models, with potential for development as a new class of therapy. References: [1] Craven L, et al. 2010. Nature. 465: 82-5. [2] Tachibana M, et al. 2013. Nature. 493: 627-31. [3] Hyslop LA, et al. 2016. Nature. 534: 383-6. [4] Kang E, et al. 2016. Nature. 540: 270-275. [5] Gorman GS, et al. 2015. Ann. Neurol. 77: 753-9. [6] Patananan AN, et al. 2016. Cell Metab. 23: 785-96. [7] Gammage PA, et al., 2018. Trends. Genet. in press [8] Kauppila JHK, et al., 2016. Cell Rep. 16: 2980-90. [9] Swalwell H, et al. 2006. Neurology. 66: 447-9. [10] Gammage PA, et al. 2014. EMBO Mol. Med. 6: 458-66. [11] Gammage PA, et al. 2016. Nucleic Acids Res. 44: 7804-16. 
Type Of Material Technology assay or reagent 
Year Produced 2017 
Provided To Others? No  
Impact Taken together, this study constitute proof-of-principle that a potential cure for all heteroplasmic mitochondrial disease using mtZFNs. We describe possibly universal therapeutic for heteroplasmic mtDNA disease represent a potential transformation in the future prospects of mitochondrial disease, bringing the promise of a cure to an area of medicine that lacks efficacious treatments, let alone curative therapy. Additionally, the existence of viable therapeutics, such as mtZFN, could alter the balance of ethical arguments surrounding the use mitochondrial replacement therapy techniques (1-4), which are controversial and have been licensed partially on the basis of the desperate state of mitochondrial medicine at present. 
URL http://www.mrc-mbu.cam.ac.uk/projects/2308/genetic-modification-mitochondrial-genome
 
Title MPAT-Seq: Next-generation sequencing-based analysis of RNA polyadenylation 
Description MPAT-Seq approach allowes to perform the transcriptome-wide parallel assessment of 3' ends of mitochondrial tRNAs. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact The further application of this technique may be useful to determine the regulation of the 3' end RNA metabolism in other studies 
 
Title Quantitative gradient fractionation mass spectrometry (qGFMS) 
Description This method is based on SILAC proteomics and sucrose density gradient separation of mitoribosomal subunits 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact Pending 
 
Title Zinc-finger nucleases for manipulation of mtDNA 
Description We reported an improved version of mitochondrially-targeted engineered zinc-finger nucleases (mtZFNs) designed to eliminate human mtDNA molecules with pathogenic point mutations and large-scale deletions. Expression of mtZFNs successfully led to a reduction in the mutant mtDNA haplotype load, and subsequent repopulation of wildtype mtDNA was found to restore mitochondrial respiratory function in a cybrid cell model. This research was highlighted by: Moraes C. T. (2014) A magic bullet to specifically eliminate mutated mitochondrial genomes from patients' cells. EMBO Mol. Med. 6, 434-435 Gammage, P.A., Rorbach, J., Vincent, A.I., Rebar, E.J, Minczuk, M. (2014) Mitochondrially-targeted ZFNs for selective degradation of pathogenic mitochondrial genomes bearing large-scale deletions or point mutations. EMBO Mol Med 6, 458-466 
Type Of Material Technology assay or reagent 
Year Produced 2014 
Provided To Others? Yes  
Impact Mutations and rearrangements of mitochondrial DNA (mtDNA) are a common cause of human disease, where they often coexist with wildtype mtDNA within a single cell. Mitochondrially targeted engineered zinc finger nucleases (mtZFNs) can phenotypically rescue a severe mtDNAmediated dysfunction and show future therapeutic potential. Previously reported mtZFN constructs were redesigned, greatly improving target specificity and allowing their safe use in human mitochondria. The capacity of the novel mtZFN design was validated by selectively degrading point mutant mtDNA associated with neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP) and maternally inherited Leigh syndrome (MILS). The use of the novel mtZFNs was expanded by selectively degrading mtDNA harbouring a pathogenic largescale deletion associated with adultonset chronic progressive external ophthalmoplegia (CPEO) and, less frequently, KearnsSayre syndrome (KSS) and Pearson's marrow pancreas syndrome. Data are provided demonstrating that elimination of deleted, pathogenic mtDNA molecules by mtZFNs is sufficient for full recovery of oxidative phosphorylation in a disease model cell line. 
URL http://embomolmed.embopress.org/content/6/4/458.long
 
Title mTUNE 
Description We developed cell model with defined levels of m.8993T>G mutation heteroplasmy, mTUNE, to investigate the metabolic underpinnings of mitochondrial dysfunction 
Type Of Material Cell line 
Year Produced 2018 
Provided To Others? Yes  
Impact We uncovered a novel link between glycolysis and mitochondrial dysfunction mediated by reductive carboxylation of glutamine. 
 
Description Analysis of a novel nuclease in patients presenting combined OXPHOS deficiencies. 
Organisation Columbia University
Department College of Physicians & Surgeons
Country United States 
Sector Academic/University 
PI Contribution In 2010 we identified a novel mitochondrial deoxyribonuclease. In order to understand its function in human mtDNA maintenance we have studied the phenotypes of gene inactivation by RNAi and overexpression and analysed the biochemical activity of the recombinant enzyme. In 2011 we started a collaboration with five other groups as they had identified a mutation in the coding gene in six individuals from three unrelated families presenting combined OXPHOS deficiency. Currently, we are confirming the phenotypes observed in the RNAi experiments using patient-derived fibroblasts and performing complementation studies. New patients identified in 2016
Collaborator Contribution following the family clinical history and provided clinical data identified mutations
Impact The project is multidisciplinary as it involves collaboration between neurologists and molecular biologists. Two papers published: Loss-of-function mutations in MGME1 impair mtDNA replication and cause multisystemic mitochondrial disease. Kornblum C, Nicholls TJ, Haack TB, Schöler S, Peeva V, Danhauser K, Hallmann K, Zsurka G, Rorbach J, Iuso A, Wieland T, Sciacco M, Ronchi D, Comi GP, Moggio M, Quinzii CM, DiMauro S, Calvo SE, Mootha VK, Klopstock T, Strom TM, Meitinger T, Minczuk M, Kunz WS, Prokisch H. Nat Genet. 2013 Feb;45(2):214-9. doi: 10.1038/ng.2501. Linear mtDNA fragments and unusual mtDNA rearrangements associated with pathological deficiency of MGME1 exonuclease. Nicholls TJ, Zsurka G, Peeva V, Schöler S, Szczesny RJ, Cysewski D, Reyes A, Kornblum C, Sciacco M, Moggio M, Dziembowski A, Kunz WS, Minczuk M. Hum Mol Genet. 2014 Dec 1;23(23):6147-62. doi: 10.1093/hmg/ddu336. We identified a new disease gene which is now routinely screened in patients with mitochondrial disease
Start Year 2011
 
Description Analysis of a novel nuclease in patients presenting combined OXPHOS deficiencies. 
Organisation Harvard University
Department Harvard Medical School
Country United States 
Sector Academic/University 
PI Contribution In 2010 we identified a novel mitochondrial deoxyribonuclease. In order to understand its function in human mtDNA maintenance we have studied the phenotypes of gene inactivation by RNAi and overexpression and analysed the biochemical activity of the recombinant enzyme. In 2011 we started a collaboration with five other groups as they had identified a mutation in the coding gene in six individuals from three unrelated families presenting combined OXPHOS deficiency. Currently, we are confirming the phenotypes observed in the RNAi experiments using patient-derived fibroblasts and performing complementation studies. New patients identified in 2016
Collaborator Contribution following the family clinical history and provided clinical data identified mutations
Impact The project is multidisciplinary as it involves collaboration between neurologists and molecular biologists. Two papers published: Loss-of-function mutations in MGME1 impair mtDNA replication and cause multisystemic mitochondrial disease. Kornblum C, Nicholls TJ, Haack TB, Schöler S, Peeva V, Danhauser K, Hallmann K, Zsurka G, Rorbach J, Iuso A, Wieland T, Sciacco M, Ronchi D, Comi GP, Moggio M, Quinzii CM, DiMauro S, Calvo SE, Mootha VK, Klopstock T, Strom TM, Meitinger T, Minczuk M, Kunz WS, Prokisch H. Nat Genet. 2013 Feb;45(2):214-9. doi: 10.1038/ng.2501. Linear mtDNA fragments and unusual mtDNA rearrangements associated with pathological deficiency of MGME1 exonuclease. Nicholls TJ, Zsurka G, Peeva V, Schöler S, Szczesny RJ, Cysewski D, Reyes A, Kornblum C, Sciacco M, Moggio M, Dziembowski A, Kunz WS, Minczuk M. Hum Mol Genet. 2014 Dec 1;23(23):6147-62. doi: 10.1093/hmg/ddu336. We identified a new disease gene which is now routinely screened in patients with mitochondrial disease
Start Year 2011
 
Description Analysis of a novel nuclease in patients presenting combined OXPHOS deficiencies. 
Organisation Ludwig Maximilian University of Munich (LMU Munich)
Department Department of Human Genetics
Country Germany 
Sector Academic/University 
PI Contribution In 2010 we identified a novel mitochondrial deoxyribonuclease. In order to understand its function in human mtDNA maintenance we have studied the phenotypes of gene inactivation by RNAi and overexpression and analysed the biochemical activity of the recombinant enzyme. In 2011 we started a collaboration with five other groups as they had identified a mutation in the coding gene in six individuals from three unrelated families presenting combined OXPHOS deficiency. Currently, we are confirming the phenotypes observed in the RNAi experiments using patient-derived fibroblasts and performing complementation studies. New patients identified in 2016
Collaborator Contribution following the family clinical history and provided clinical data identified mutations
Impact The project is multidisciplinary as it involves collaboration between neurologists and molecular biologists. Two papers published: Loss-of-function mutations in MGME1 impair mtDNA replication and cause multisystemic mitochondrial disease. Kornblum C, Nicholls TJ, Haack TB, Schöler S, Peeva V, Danhauser K, Hallmann K, Zsurka G, Rorbach J, Iuso A, Wieland T, Sciacco M, Ronchi D, Comi GP, Moggio M, Quinzii CM, DiMauro S, Calvo SE, Mootha VK, Klopstock T, Strom TM, Meitinger T, Minczuk M, Kunz WS, Prokisch H. Nat Genet. 2013 Feb;45(2):214-9. doi: 10.1038/ng.2501. Linear mtDNA fragments and unusual mtDNA rearrangements associated with pathological deficiency of MGME1 exonuclease. Nicholls TJ, Zsurka G, Peeva V, Schöler S, Szczesny RJ, Cysewski D, Reyes A, Kornblum C, Sciacco M, Moggio M, Dziembowski A, Kunz WS, Minczuk M. Hum Mol Genet. 2014 Dec 1;23(23):6147-62. doi: 10.1093/hmg/ddu336. We identified a new disease gene which is now routinely screened in patients with mitochondrial disease
Start Year 2011
 
Description Analysis of a novel nuclease in patients presenting combined OXPHOS deficiencies. 
Organisation Oslo University Hospital
Department Department of Medical Genetics
Country Norway 
Sector Hospitals 
PI Contribution In 2010 we identified a novel mitochondrial deoxyribonuclease. In order to understand its function in human mtDNA maintenance we have studied the phenotypes of gene inactivation by RNAi and overexpression and analysed the biochemical activity of the recombinant enzyme. In 2011 we started a collaboration with five other groups as they had identified a mutation in the coding gene in six individuals from three unrelated families presenting combined OXPHOS deficiency. Currently, we are confirming the phenotypes observed in the RNAi experiments using patient-derived fibroblasts and performing complementation studies. New patients identified in 2016
Collaborator Contribution following the family clinical history and provided clinical data identified mutations
Impact The project is multidisciplinary as it involves collaboration between neurologists and molecular biologists. Two papers published: Loss-of-function mutations in MGME1 impair mtDNA replication and cause multisystemic mitochondrial disease. Kornblum C, Nicholls TJ, Haack TB, Schöler S, Peeva V, Danhauser K, Hallmann K, Zsurka G, Rorbach J, Iuso A, Wieland T, Sciacco M, Ronchi D, Comi GP, Moggio M, Quinzii CM, DiMauro S, Calvo SE, Mootha VK, Klopstock T, Strom TM, Meitinger T, Minczuk M, Kunz WS, Prokisch H. Nat Genet. 2013 Feb;45(2):214-9. doi: 10.1038/ng.2501. Linear mtDNA fragments and unusual mtDNA rearrangements associated with pathological deficiency of MGME1 exonuclease. Nicholls TJ, Zsurka G, Peeva V, Schöler S, Szczesny RJ, Cysewski D, Reyes A, Kornblum C, Sciacco M, Moggio M, Dziembowski A, Kunz WS, Minczuk M. Hum Mol Genet. 2014 Dec 1;23(23):6147-62. doi: 10.1093/hmg/ddu336. We identified a new disease gene which is now routinely screened in patients with mitochondrial disease
Start Year 2011
 
Description Analysis of a novel nuclease in patients presenting combined OXPHOS deficiencies. 
Organisation University Hospital Bonn
Department Department of Epileptology
Country Germany 
Sector Hospitals 
PI Contribution In 2010 we identified a novel mitochondrial deoxyribonuclease. In order to understand its function in human mtDNA maintenance we have studied the phenotypes of gene inactivation by RNAi and overexpression and analysed the biochemical activity of the recombinant enzyme. In 2011 we started a collaboration with five other groups as they had identified a mutation in the coding gene in six individuals from three unrelated families presenting combined OXPHOS deficiency. Currently, we are confirming the phenotypes observed in the RNAi experiments using patient-derived fibroblasts and performing complementation studies. New patients identified in 2016
Collaborator Contribution following the family clinical history and provided clinical data identified mutations
Impact The project is multidisciplinary as it involves collaboration between neurologists and molecular biologists. Two papers published: Loss-of-function mutations in MGME1 impair mtDNA replication and cause multisystemic mitochondrial disease. Kornblum C, Nicholls TJ, Haack TB, Schöler S, Peeva V, Danhauser K, Hallmann K, Zsurka G, Rorbach J, Iuso A, Wieland T, Sciacco M, Ronchi D, Comi GP, Moggio M, Quinzii CM, DiMauro S, Calvo SE, Mootha VK, Klopstock T, Strom TM, Meitinger T, Minczuk M, Kunz WS, Prokisch H. Nat Genet. 2013 Feb;45(2):214-9. doi: 10.1038/ng.2501. Linear mtDNA fragments and unusual mtDNA rearrangements associated with pathological deficiency of MGME1 exonuclease. Nicholls TJ, Zsurka G, Peeva V, Schöler S, Szczesny RJ, Cysewski D, Reyes A, Kornblum C, Sciacco M, Moggio M, Dziembowski A, Kunz WS, Minczuk M. Hum Mol Genet. 2014 Dec 1;23(23):6147-62. doi: 10.1093/hmg/ddu336. We identified a new disease gene which is now routinely screened in patients with mitochondrial disease
Start Year 2011
 
Description Analysis of a novel nuclease in patients presenting combined OXPHOS deficiencies. 
Organisation University of Milan
Department Department of Neurology
Country Italy 
Sector Academic/University 
PI Contribution In 2010 we identified a novel mitochondrial deoxyribonuclease. In order to understand its function in human mtDNA maintenance we have studied the phenotypes of gene inactivation by RNAi and overexpression and analysed the biochemical activity of the recombinant enzyme. In 2011 we started a collaboration with five other groups as they had identified a mutation in the coding gene in six individuals from three unrelated families presenting combined OXPHOS deficiency. Currently, we are confirming the phenotypes observed in the RNAi experiments using patient-derived fibroblasts and performing complementation studies. New patients identified in 2016
Collaborator Contribution following the family clinical history and provided clinical data identified mutations
Impact The project is multidisciplinary as it involves collaboration between neurologists and molecular biologists. Two papers published: Loss-of-function mutations in MGME1 impair mtDNA replication and cause multisystemic mitochondrial disease. Kornblum C, Nicholls TJ, Haack TB, Schöler S, Peeva V, Danhauser K, Hallmann K, Zsurka G, Rorbach J, Iuso A, Wieland T, Sciacco M, Ronchi D, Comi GP, Moggio M, Quinzii CM, DiMauro S, Calvo SE, Mootha VK, Klopstock T, Strom TM, Meitinger T, Minczuk M, Kunz WS, Prokisch H. Nat Genet. 2013 Feb;45(2):214-9. doi: 10.1038/ng.2501. Linear mtDNA fragments and unusual mtDNA rearrangements associated with pathological deficiency of MGME1 exonuclease. Nicholls TJ, Zsurka G, Peeva V, Schöler S, Szczesny RJ, Cysewski D, Reyes A, Kornblum C, Sciacco M, Moggio M, Dziembowski A, Kunz WS, Minczuk M. Hum Mol Genet. 2014 Dec 1;23(23):6147-62. doi: 10.1093/hmg/ddu336. We identified a new disease gene which is now routinely screened in patients with mitochondrial disease
Start Year 2011
 
Description Analysis of protein localisation depending on mtDNA content 
Organisation University of Kent
Country United Kingdom 
Sector Academic/University 
PI Contribution Providing inducible human cell line for allowing for controlled reduction of the copy number of mitochondrial DNA
Collaborator Contribution Analysis of protein localisation in conditions of reduced mtDNA copy number
Impact Unknown
Start Year 2012
 
Description Designing mitochondrial zinc finger nucleases 
Organisation Sangamo Biosciences, Inc
Country United States 
Sector Private 
PI Contribution Developing mitochondrially-targeted engineered nucleases to eliminate human mtDNA molecules with pathogenic point mutations and large-scale deletions
Collaborator Contribution Assembling and validating zinc finger proteins
Impact Several papers e.g. Minczuk, M., Kolasinska-Zwierz, P., Murphy, M.P., Papworth, M.A. (2010) Construction and testing of engineered zinc-finger proteins for sequence-specific modification of mtDNA. Nat Protoc 5, 342-56 Gammage, P.A., Rorbach, J., Vincent, A.I., Rebar, E.J, Minczuk, M. (2014) Mitochondrially-targeted ZFNs for selective degradation of pathogenic mitochondrial genomes bearing large-scale deletions or point mutations. EMBO Mol Med 6, 458-466 In this paper we are reporting an improved version of mitochondrially-targeted engineered zinc-finger nucleases (mtZFNs) designed to eliminate human mtDNA molecules with pathogenic point mutations and large-scale deletions. Expression of mtZFNs successfully led to a reduction in the mutant mtDNA haplotype load, and subsequent repopulation of wildtype mtDNA was found to restore mitochondrial respiratory function in a cybrid cell model. This research was highlighted by: Moraes C. T. (2014) A magic bullet to specifically eliminate mutated mitochondrial genomes from patients' cells. EMBO Mol. Med. 6, 434-435 Gammage, P.A., Van Haute, L., Minczuk, M. (2015) Engineered mtZFNs for manipulation of human mitochondrial DNA heteroplasmy Methods Mol. Biol. Mitochondrial DNA McKenzie, M (Ed)
Start Year 2009
 
Description Manipulating mtDNA heteroplasmy in vivo using engineered nucleases 
Organisation Max Planck Society
Department Max Planck Institute for the Biology of Ageing
Country Germany 
Sector Academic/University 
PI Contribution We have generated a mtZFN library specific to mtDNA mutation present in a model strain, tested them in mouse embryonic fibroblasts (MEF) from the mt-tRNAAla mouse line and identified constructs capable of effective reduction of mutant load. We will deliver these ZFNs affected mice with optimal mtZFN constructs by organtropic, recombinant adeno-associated viruses (AAVs). We will also manipulte mtDNA heteroplasmy in germline using mtZFN and mitoTALENs (the latter obtained in collaboration with Uni of Miami)
Collaborator Contribution Providing mouse model, help and expertise in mtZFN research that may led to generation of pre-clinical data useful for a development of an effective treatment of mtDNA disease in the future.
Impact pending, likely to be societal. Some protocols for generation of mtZFN published: Gammage PA, Van Haute L, Minczuk M. Engineered mtZFNs for Manipulation of Human Mitochondrial DNA Heteroplasmy. Methods Mol Biol. 2016;1351:145-62. doi: 10.1007/978-1-4939-3040-1_11 Vectors available at Addgen
Start Year 2015
 
Description Manipulating mtDNA heteroplasmy in vivo using engineered nucleases 
Organisation University of Miami
Country United States 
Sector Academic/University 
PI Contribution We have generated a mtZFN library specific to mtDNA mutation present in a model strain, tested them in mouse embryonic fibroblasts (MEF) from the mt-tRNAAla mouse line and identified constructs capable of effective reduction of mutant load. We will deliver these ZFNs affected mice with optimal mtZFN constructs by organtropic, recombinant adeno-associated viruses (AAVs). We will also manipulte mtDNA heteroplasmy in germline using mtZFN and mitoTALENs (the latter obtained in collaboration with Uni of Miami)
Collaborator Contribution Providing mouse model, help and expertise in mtZFN research that may led to generation of pre-clinical data useful for a development of an effective treatment of mtDNA disease in the future.
Impact pending, likely to be societal. Some protocols for generation of mtZFN published: Gammage PA, Van Haute L, Minczuk M. Engineered mtZFNs for Manipulation of Human Mitochondrial DNA Heteroplasmy. Methods Mol Biol. 2016;1351:145-62. doi: 10.1007/978-1-4939-3040-1_11 Vectors available at Addgen
Start Year 2015
 
Description Mitochondria in drug toxicity 
Organisation AstraZeneca
Department Research and Development AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution Hosting and training a collaborative post-doc
Collaborator Contribution Providing access to a high-throughput measurements of mitochondrial function.
Impact ongoing
Start Year 2014
 
Description Mitochondrial RNA metabolism and human disease 
Organisation Carlo Besta Neurological Institute
Country Italy 
Sector Public 
PI Contribution We analyse molecular phenotypes associated with mutations in muclaer genes involved in mitochondrial RNA processing and post-transcriptional modification.
Collaborator Contribution Identification of mutations by next-generation exome sequencing in patients with combined OXPHOS defects
Impact Several papers e.g: Van Haute L, Dietmann S, Kremer L, Hussain S, Pearce SF, Powell CA, Rorbach J, Lantaff R, Blanco S, Sauer S, Kotzaeridou U, Hoffmann GF, Memari Y, Kolb-Kokocinski A, Durbin R, Mayr JA, Frye M, Prokisch H, Minczuk M.Deficient methylation and formylation of mt-tRNA(Met) wobble cytosine in a patient carrying mutations in NSUN3. Nat Commun. 2016 Jun 30;7:12039. doi: 10.1038/ncomms12039. Haack, T.B.*, Kopajtich, R.*, Freisinger, P.*, Wieland, T., Rorbach, J, Nicholls, T.J., Enrico Baruffini, E., Walther, A., Danhauser, K., Zimmermann, F.A., Husain, R.A., Schum, J., Mundy, H., Ferrero, I., Strom, T.M., Meitinger, T., Taylor, R.W., Minczuk, M**., Mayr, J.A., Prokisch, H.** (2013) ELAC2 Mutations Cause a Mitochondrial RNA Processing Defect Associated with Hypertrophic Cardiomyopathy. Am J Hum Genet 93, 211-223 Kopajtich, R.,* Nicholls, T.J.,* Rorbach, J.,* Freisinger, P., Mandel, H., Vanlander, A., Ghezzi, D., Carrozzo, R., Taylor, R.W., Marquard, K., Murayama, K., Wieland, T., Schwarzmayr, T., Mayr, J.A., Pearce, S. F., Powell, C. Saada, A., Ohtake, A., Invernizzi, F., Lamantea, E., Sommerville, E. W., Pyle, A., Chinnery, P. F., Crushell, E., Okazaki, Y., Kohda, M., Kishita, Y., Tokuzawa, Y., Smet, J., Régal, L., Lorber, A., Khoury, A., Zeviani, M., Strom, T. M., Meitinger, T., Bertini, E. S., Van Coster, R., Klopstock, T., Haack, T. B., Minczuk, M.,** Prokisch, H.** (-) Mutations in GTPBP3 cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis and encephalopathy Am J Hum Genet 95, 708-20 Vanlander, A.V., Menten, B., Smet, J., De Meirleir, L., Sante, T., De Paepe, B., Seneca, S., Pearce, S.F., Powell, C.A., Vergult, S., Michotte, A., De Latter, E., Vantomme, L., Minczuk, M. and Van Coster, R. (-) Two siblings with homozygous pathogenic splice site mutation in mitochondrial asparaginyl-tRNA synthetase (NARS2) Hum. Mutat Mutat 36, 222-231 Powell, C.A.*, Kopajtich, R.*, D'Souza, A.R., Rorbach, J., Dallabona, C., Donnini, C., Alston, C.L., Griffin, H., Pyle, A., Chinnery, P.F., Strom, T.M., Meitinger, T., Rodenburg, R.J., Schottmann, G., Schuelke, M., Romain, N., Haller, R., Ferrero, I., Haack, T.B., Taylor, R.W., Prokisch, H.**, Minczuk, M. (2015) Mutations in TRMT5 cause a defect in post-transcriptional modification of mitochondrial tRNA associated with multiple respiratory-chain deficiencies. Am J Hum Genet. 97,319-328 Coughlin, C.R. Scharer, G.H., Friederich, M.W., Yu, H.C., Geiger, E.A., Creadon-Swindell, G., Collins, A.E., Vanlander, A.V., Coster, R.V., Powell, C.A., Swanson, M.A., Minczuk, M., Van Hove, J.L., Shaikh, T.H. (2015) Mutations in the mitochondrial cysteinyl-tRNA synthase gene, CARS2, lead to a severe epileptic encephalopathy and complex movement disorder. J Med Genet. 52,532-540 and more
Start Year 2011
 
Description Mitochondrial RNA metabolism and human disease 
Organisation Columbia University Medical Center
Country United States 
Sector Academic/University 
PI Contribution We analyse molecular phenotypes associated with mutations in muclaer genes involved in mitochondrial RNA processing and post-transcriptional modification.
Collaborator Contribution Identification of mutations by next-generation exome sequencing in patients with combined OXPHOS defects
Impact Several papers e.g: Van Haute L, Dietmann S, Kremer L, Hussain S, Pearce SF, Powell CA, Rorbach J, Lantaff R, Blanco S, Sauer S, Kotzaeridou U, Hoffmann GF, Memari Y, Kolb-Kokocinski A, Durbin R, Mayr JA, Frye M, Prokisch H, Minczuk M.Deficient methylation and formylation of mt-tRNA(Met) wobble cytosine in a patient carrying mutations in NSUN3. Nat Commun. 2016 Jun 30;7:12039. doi: 10.1038/ncomms12039. Haack, T.B.*, Kopajtich, R.*, Freisinger, P.*, Wieland, T., Rorbach, J, Nicholls, T.J., Enrico Baruffini, E., Walther, A., Danhauser, K., Zimmermann, F.A., Husain, R.A., Schum, J., Mundy, H., Ferrero, I., Strom, T.M., Meitinger, T., Taylor, R.W., Minczuk, M**., Mayr, J.A., Prokisch, H.** (2013) ELAC2 Mutations Cause a Mitochondrial RNA Processing Defect Associated with Hypertrophic Cardiomyopathy. Am J Hum Genet 93, 211-223 Kopajtich, R.,* Nicholls, T.J.,* Rorbach, J.,* Freisinger, P., Mandel, H., Vanlander, A., Ghezzi, D., Carrozzo, R., Taylor, R.W., Marquard, K., Murayama, K., Wieland, T., Schwarzmayr, T., Mayr, J.A., Pearce, S. F., Powell, C. Saada, A., Ohtake, A., Invernizzi, F., Lamantea, E., Sommerville, E. W., Pyle, A., Chinnery, P. F., Crushell, E., Okazaki, Y., Kohda, M., Kishita, Y., Tokuzawa, Y., Smet, J., Régal, L., Lorber, A., Khoury, A., Zeviani, M., Strom, T. M., Meitinger, T., Bertini, E. S., Van Coster, R., Klopstock, T., Haack, T. B., Minczuk, M.,** Prokisch, H.** (-) Mutations in GTPBP3 cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis and encephalopathy Am J Hum Genet 95, 708-20 Vanlander, A.V., Menten, B., Smet, J., De Meirleir, L., Sante, T., De Paepe, B., Seneca, S., Pearce, S.F., Powell, C.A., Vergult, S., Michotte, A., De Latter, E., Vantomme, L., Minczuk, M. and Van Coster, R. (-) Two siblings with homozygous pathogenic splice site mutation in mitochondrial asparaginyl-tRNA synthetase (NARS2) Hum. Mutat Mutat 36, 222-231 Powell, C.A.*, Kopajtich, R.*, D'Souza, A.R., Rorbach, J., Dallabona, C., Donnini, C., Alston, C.L., Griffin, H., Pyle, A., Chinnery, P.F., Strom, T.M., Meitinger, T., Rodenburg, R.J., Schottmann, G., Schuelke, M., Romain, N., Haller, R., Ferrero, I., Haack, T.B., Taylor, R.W., Prokisch, H.**, Minczuk, M. (2015) Mutations in TRMT5 cause a defect in post-transcriptional modification of mitochondrial tRNA associated with multiple respiratory-chain deficiencies. Am J Hum Genet. 97,319-328 Coughlin, C.R. Scharer, G.H., Friederich, M.W., Yu, H.C., Geiger, E.A., Creadon-Swindell, G., Collins, A.E., Vanlander, A.V., Coster, R.V., Powell, C.A., Swanson, M.A., Minczuk, M., Van Hove, J.L., Shaikh, T.H. (2015) Mutations in the mitochondrial cysteinyl-tRNA synthase gene, CARS2, lead to a severe epileptic encephalopathy and complex movement disorder. J Med Genet. 52,532-540 and more
Start Year 2011
 
Description Mitochondrial RNA metabolism and human disease 
Organisation Helmholtz Zentrum München
Department Institute of Human Genetics
Country Germany 
Sector Public 
PI Contribution We analyse molecular phenotypes associated with mutations in muclaer genes involved in mitochondrial RNA processing and post-transcriptional modification.
Collaborator Contribution Identification of mutations by next-generation exome sequencing in patients with combined OXPHOS defects
Impact Several papers e.g: Van Haute L, Dietmann S, Kremer L, Hussain S, Pearce SF, Powell CA, Rorbach J, Lantaff R, Blanco S, Sauer S, Kotzaeridou U, Hoffmann GF, Memari Y, Kolb-Kokocinski A, Durbin R, Mayr JA, Frye M, Prokisch H, Minczuk M.Deficient methylation and formylation of mt-tRNA(Met) wobble cytosine in a patient carrying mutations in NSUN3. Nat Commun. 2016 Jun 30;7:12039. doi: 10.1038/ncomms12039. Haack, T.B.*, Kopajtich, R.*, Freisinger, P.*, Wieland, T., Rorbach, J, Nicholls, T.J., Enrico Baruffini, E., Walther, A., Danhauser, K., Zimmermann, F.A., Husain, R.A., Schum, J., Mundy, H., Ferrero, I., Strom, T.M., Meitinger, T., Taylor, R.W., Minczuk, M**., Mayr, J.A., Prokisch, H.** (2013) ELAC2 Mutations Cause a Mitochondrial RNA Processing Defect Associated with Hypertrophic Cardiomyopathy. Am J Hum Genet 93, 211-223 Kopajtich, R.,* Nicholls, T.J.,* Rorbach, J.,* Freisinger, P., Mandel, H., Vanlander, A., Ghezzi, D., Carrozzo, R., Taylor, R.W., Marquard, K., Murayama, K., Wieland, T., Schwarzmayr, T., Mayr, J.A., Pearce, S. F., Powell, C. Saada, A., Ohtake, A., Invernizzi, F., Lamantea, E., Sommerville, E. W., Pyle, A., Chinnery, P. F., Crushell, E., Okazaki, Y., Kohda, M., Kishita, Y., Tokuzawa, Y., Smet, J., Régal, L., Lorber, A., Khoury, A., Zeviani, M., Strom, T. M., Meitinger, T., Bertini, E. S., Van Coster, R., Klopstock, T., Haack, T. B., Minczuk, M.,** Prokisch, H.** (-) Mutations in GTPBP3 cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis and encephalopathy Am J Hum Genet 95, 708-20 Vanlander, A.V., Menten, B., Smet, J., De Meirleir, L., Sante, T., De Paepe, B., Seneca, S., Pearce, S.F., Powell, C.A., Vergult, S., Michotte, A., De Latter, E., Vantomme, L., Minczuk, M. and Van Coster, R. (-) Two siblings with homozygous pathogenic splice site mutation in mitochondrial asparaginyl-tRNA synthetase (NARS2) Hum. Mutat Mutat 36, 222-231 Powell, C.A.*, Kopajtich, R.*, D'Souza, A.R., Rorbach, J., Dallabona, C., Donnini, C., Alston, C.L., Griffin, H., Pyle, A., Chinnery, P.F., Strom, T.M., Meitinger, T., Rodenburg, R.J., Schottmann, G., Schuelke, M., Romain, N., Haller, R., Ferrero, I., Haack, T.B., Taylor, R.W., Prokisch, H.**, Minczuk, M. (2015) Mutations in TRMT5 cause a defect in post-transcriptional modification of mitochondrial tRNA associated with multiple respiratory-chain deficiencies. Am J Hum Genet. 97,319-328 Coughlin, C.R. Scharer, G.H., Friederich, M.W., Yu, H.C., Geiger, E.A., Creadon-Swindell, G., Collins, A.E., Vanlander, A.V., Coster, R.V., Powell, C.A., Swanson, M.A., Minczuk, M., Van Hove, J.L., Shaikh, T.H. (2015) Mutations in the mitochondrial cysteinyl-tRNA synthase gene, CARS2, lead to a severe epileptic encephalopathy and complex movement disorder. J Med Genet. 52,532-540 and more
Start Year 2011
 
Description Mitochondrial RNA metabolism and human disease 
Organisation Newcastle University
Department School of Biomedical Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution We analyse molecular phenotypes associated with mutations in muclaer genes involved in mitochondrial RNA processing and post-transcriptional modification.
Collaborator Contribution Identification of mutations by next-generation exome sequencing in patients with combined OXPHOS defects
Impact Several papers e.g: Van Haute L, Dietmann S, Kremer L, Hussain S, Pearce SF, Powell CA, Rorbach J, Lantaff R, Blanco S, Sauer S, Kotzaeridou U, Hoffmann GF, Memari Y, Kolb-Kokocinski A, Durbin R, Mayr JA, Frye M, Prokisch H, Minczuk M.Deficient methylation and formylation of mt-tRNA(Met) wobble cytosine in a patient carrying mutations in NSUN3. Nat Commun. 2016 Jun 30;7:12039. doi: 10.1038/ncomms12039. Haack, T.B.*, Kopajtich, R.*, Freisinger, P.*, Wieland, T., Rorbach, J, Nicholls, T.J., Enrico Baruffini, E., Walther, A., Danhauser, K., Zimmermann, F.A., Husain, R.A., Schum, J., Mundy, H., Ferrero, I., Strom, T.M., Meitinger, T., Taylor, R.W., Minczuk, M**., Mayr, J.A., Prokisch, H.** (2013) ELAC2 Mutations Cause a Mitochondrial RNA Processing Defect Associated with Hypertrophic Cardiomyopathy. Am J Hum Genet 93, 211-223 Kopajtich, R.,* Nicholls, T.J.,* Rorbach, J.,* Freisinger, P., Mandel, H., Vanlander, A., Ghezzi, D., Carrozzo, R., Taylor, R.W., Marquard, K., Murayama, K., Wieland, T., Schwarzmayr, T., Mayr, J.A., Pearce, S. F., Powell, C. Saada, A., Ohtake, A., Invernizzi, F., Lamantea, E., Sommerville, E. W., Pyle, A., Chinnery, P. F., Crushell, E., Okazaki, Y., Kohda, M., Kishita, Y., Tokuzawa, Y., Smet, J., Régal, L., Lorber, A., Khoury, A., Zeviani, M., Strom, T. M., Meitinger, T., Bertini, E. S., Van Coster, R., Klopstock, T., Haack, T. B., Minczuk, M.,** Prokisch, H.** (-) Mutations in GTPBP3 cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis and encephalopathy Am J Hum Genet 95, 708-20 Vanlander, A.V., Menten, B., Smet, J., De Meirleir, L., Sante, T., De Paepe, B., Seneca, S., Pearce, S.F., Powell, C.A., Vergult, S., Michotte, A., De Latter, E., Vantomme, L., Minczuk, M. and Van Coster, R. (-) Two siblings with homozygous pathogenic splice site mutation in mitochondrial asparaginyl-tRNA synthetase (NARS2) Hum. Mutat Mutat 36, 222-231 Powell, C.A.*, Kopajtich, R.*, D'Souza, A.R., Rorbach, J., Dallabona, C., Donnini, C., Alston, C.L., Griffin, H., Pyle, A., Chinnery, P.F., Strom, T.M., Meitinger, T., Rodenburg, R.J., Schottmann, G., Schuelke, M., Romain, N., Haller, R., Ferrero, I., Haack, T.B., Taylor, R.W., Prokisch, H.**, Minczuk, M. (2015) Mutations in TRMT5 cause a defect in post-transcriptional modification of mitochondrial tRNA associated with multiple respiratory-chain deficiencies. Am J Hum Genet. 97,319-328 Coughlin, C.R. Scharer, G.H., Friederich, M.W., Yu, H.C., Geiger, E.A., Creadon-Swindell, G., Collins, A.E., Vanlander, A.V., Coster, R.V., Powell, C.A., Swanson, M.A., Minczuk, M., Van Hove, J.L., Shaikh, T.H. (2015) Mutations in the mitochondrial cysteinyl-tRNA synthase gene, CARS2, lead to a severe epileptic encephalopathy and complex movement disorder. J Med Genet. 52,532-540 and more
Start Year 2011
 
Description Mitochondrial RNA metabolism and human disease 
Organisation Radboud University Nijmegen
Country Netherlands 
Sector Academic/University 
PI Contribution We analyse molecular phenotypes associated with mutations in muclaer genes involved in mitochondrial RNA processing and post-transcriptional modification.
Collaborator Contribution Identification of mutations by next-generation exome sequencing in patients with combined OXPHOS defects
Impact Several papers e.g: Van Haute L, Dietmann S, Kremer L, Hussain S, Pearce SF, Powell CA, Rorbach J, Lantaff R, Blanco S, Sauer S, Kotzaeridou U, Hoffmann GF, Memari Y, Kolb-Kokocinski A, Durbin R, Mayr JA, Frye M, Prokisch H, Minczuk M.Deficient methylation and formylation of mt-tRNA(Met) wobble cytosine in a patient carrying mutations in NSUN3. Nat Commun. 2016 Jun 30;7:12039. doi: 10.1038/ncomms12039. Haack, T.B.*, Kopajtich, R.*, Freisinger, P.*, Wieland, T., Rorbach, J, Nicholls, T.J., Enrico Baruffini, E., Walther, A., Danhauser, K., Zimmermann, F.A., Husain, R.A., Schum, J., Mundy, H., Ferrero, I., Strom, T.M., Meitinger, T., Taylor, R.W., Minczuk, M**., Mayr, J.A., Prokisch, H.** (2013) ELAC2 Mutations Cause a Mitochondrial RNA Processing Defect Associated with Hypertrophic Cardiomyopathy. Am J Hum Genet 93, 211-223 Kopajtich, R.,* Nicholls, T.J.,* Rorbach, J.,* Freisinger, P., Mandel, H., Vanlander, A., Ghezzi, D., Carrozzo, R., Taylor, R.W., Marquard, K., Murayama, K., Wieland, T., Schwarzmayr, T., Mayr, J.A., Pearce, S. F., Powell, C. Saada, A., Ohtake, A., Invernizzi, F., Lamantea, E., Sommerville, E. W., Pyle, A., Chinnery, P. F., Crushell, E., Okazaki, Y., Kohda, M., Kishita, Y., Tokuzawa, Y., Smet, J., Régal, L., Lorber, A., Khoury, A., Zeviani, M., Strom, T. M., Meitinger, T., Bertini, E. S., Van Coster, R., Klopstock, T., Haack, T. B., Minczuk, M.,** Prokisch, H.** (-) Mutations in GTPBP3 cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis and encephalopathy Am J Hum Genet 95, 708-20 Vanlander, A.V., Menten, B., Smet, J., De Meirleir, L., Sante, T., De Paepe, B., Seneca, S., Pearce, S.F., Powell, C.A., Vergult, S., Michotte, A., De Latter, E., Vantomme, L., Minczuk, M. and Van Coster, R. (-) Two siblings with homozygous pathogenic splice site mutation in mitochondrial asparaginyl-tRNA synthetase (NARS2) Hum. Mutat Mutat 36, 222-231 Powell, C.A.*, Kopajtich, R.*, D'Souza, A.R., Rorbach, J., Dallabona, C., Donnini, C., Alston, C.L., Griffin, H., Pyle, A., Chinnery, P.F., Strom, T.M., Meitinger, T., Rodenburg, R.J., Schottmann, G., Schuelke, M., Romain, N., Haller, R., Ferrero, I., Haack, T.B., Taylor, R.W., Prokisch, H.**, Minczuk, M. (2015) Mutations in TRMT5 cause a defect in post-transcriptional modification of mitochondrial tRNA associated with multiple respiratory-chain deficiencies. Am J Hum Genet. 97,319-328 Coughlin, C.R. Scharer, G.H., Friederich, M.W., Yu, H.C., Geiger, E.A., Creadon-Swindell, G., Collins, A.E., Vanlander, A.V., Coster, R.V., Powell, C.A., Swanson, M.A., Minczuk, M., Van Hove, J.L., Shaikh, T.H. (2015) Mutations in the mitochondrial cysteinyl-tRNA synthase gene, CARS2, lead to a severe epileptic encephalopathy and complex movement disorder. J Med Genet. 52,532-540 and more
Start Year 2011
 
Description Mitochondrial RNA metabolism and human disease 
Organisation South Australian Clinical Genetics Service
Country Australia 
Sector Hospitals 
PI Contribution We analyse molecular phenotypes associated with mutations in muclaer genes involved in mitochondrial RNA processing and post-transcriptional modification.
Collaborator Contribution Identification of mutations by next-generation exome sequencing in patients with combined OXPHOS defects
Impact Several papers e.g: Van Haute L, Dietmann S, Kremer L, Hussain S, Pearce SF, Powell CA, Rorbach J, Lantaff R, Blanco S, Sauer S, Kotzaeridou U, Hoffmann GF, Memari Y, Kolb-Kokocinski A, Durbin R, Mayr JA, Frye M, Prokisch H, Minczuk M.Deficient methylation and formylation of mt-tRNA(Met) wobble cytosine in a patient carrying mutations in NSUN3. Nat Commun. 2016 Jun 30;7:12039. doi: 10.1038/ncomms12039. Haack, T.B.*, Kopajtich, R.*, Freisinger, P.*, Wieland, T., Rorbach, J, Nicholls, T.J., Enrico Baruffini, E., Walther, A., Danhauser, K., Zimmermann, F.A., Husain, R.A., Schum, J., Mundy, H., Ferrero, I., Strom, T.M., Meitinger, T., Taylor, R.W., Minczuk, M**., Mayr, J.A., Prokisch, H.** (2013) ELAC2 Mutations Cause a Mitochondrial RNA Processing Defect Associated with Hypertrophic Cardiomyopathy. Am J Hum Genet 93, 211-223 Kopajtich, R.,* Nicholls, T.J.,* Rorbach, J.,* Freisinger, P., Mandel, H., Vanlander, A., Ghezzi, D., Carrozzo, R., Taylor, R.W., Marquard, K., Murayama, K., Wieland, T., Schwarzmayr, T., Mayr, J.A., Pearce, S. F., Powell, C. Saada, A., Ohtake, A., Invernizzi, F., Lamantea, E., Sommerville, E. W., Pyle, A., Chinnery, P. F., Crushell, E., Okazaki, Y., Kohda, M., Kishita, Y., Tokuzawa, Y., Smet, J., Régal, L., Lorber, A., Khoury, A., Zeviani, M., Strom, T. M., Meitinger, T., Bertini, E. S., Van Coster, R., Klopstock, T., Haack, T. B., Minczuk, M.,** Prokisch, H.** (-) Mutations in GTPBP3 cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis and encephalopathy Am J Hum Genet 95, 708-20 Vanlander, A.V., Menten, B., Smet, J., De Meirleir, L., Sante, T., De Paepe, B., Seneca, S., Pearce, S.F., Powell, C.A., Vergult, S., Michotte, A., De Latter, E., Vantomme, L., Minczuk, M. and Van Coster, R. (-) Two siblings with homozygous pathogenic splice site mutation in mitochondrial asparaginyl-tRNA synthetase (NARS2) Hum. Mutat Mutat 36, 222-231 Powell, C.A.*, Kopajtich, R.*, D'Souza, A.R., Rorbach, J., Dallabona, C., Donnini, C., Alston, C.L., Griffin, H., Pyle, A., Chinnery, P.F., Strom, T.M., Meitinger, T., Rodenburg, R.J., Schottmann, G., Schuelke, M., Romain, N., Haller, R., Ferrero, I., Haack, T.B., Taylor, R.W., Prokisch, H.**, Minczuk, M. (2015) Mutations in TRMT5 cause a defect in post-transcriptional modification of mitochondrial tRNA associated with multiple respiratory-chain deficiencies. Am J Hum Genet. 97,319-328 Coughlin, C.R. Scharer, G.H., Friederich, M.W., Yu, H.C., Geiger, E.A., Creadon-Swindell, G., Collins, A.E., Vanlander, A.V., Coster, R.V., Powell, C.A., Swanson, M.A., Minczuk, M., Van Hove, J.L., Shaikh, T.H. (2015) Mutations in the mitochondrial cysteinyl-tRNA synthase gene, CARS2, lead to a severe epileptic encephalopathy and complex movement disorder. J Med Genet. 52,532-540 and more
Start Year 2011
 
Description Mitochondrial RNA metabolism and human disease 
Organisation University College London
Department Faculty of Medical Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution We analyse molecular phenotypes associated with mutations in muclaer genes involved in mitochondrial RNA processing and post-transcriptional modification.
Collaborator Contribution Identification of mutations by next-generation exome sequencing in patients with combined OXPHOS defects
Impact Several papers e.g: Van Haute L, Dietmann S, Kremer L, Hussain S, Pearce SF, Powell CA, Rorbach J, Lantaff R, Blanco S, Sauer S, Kotzaeridou U, Hoffmann GF, Memari Y, Kolb-Kokocinski A, Durbin R, Mayr JA, Frye M, Prokisch H, Minczuk M.Deficient methylation and formylation of mt-tRNA(Met) wobble cytosine in a patient carrying mutations in NSUN3. Nat Commun. 2016 Jun 30;7:12039. doi: 10.1038/ncomms12039. Haack, T.B.*, Kopajtich, R.*, Freisinger, P.*, Wieland, T., Rorbach, J, Nicholls, T.J., Enrico Baruffini, E., Walther, A., Danhauser, K., Zimmermann, F.A., Husain, R.A., Schum, J., Mundy, H., Ferrero, I., Strom, T.M., Meitinger, T., Taylor, R.W., Minczuk, M**., Mayr, J.A., Prokisch, H.** (2013) ELAC2 Mutations Cause a Mitochondrial RNA Processing Defect Associated with Hypertrophic Cardiomyopathy. Am J Hum Genet 93, 211-223 Kopajtich, R.,* Nicholls, T.J.,* Rorbach, J.,* Freisinger, P., Mandel, H., Vanlander, A., Ghezzi, D., Carrozzo, R., Taylor, R.W., Marquard, K., Murayama, K., Wieland, T., Schwarzmayr, T., Mayr, J.A., Pearce, S. F., Powell, C. Saada, A., Ohtake, A., Invernizzi, F., Lamantea, E., Sommerville, E. W., Pyle, A., Chinnery, P. F., Crushell, E., Okazaki, Y., Kohda, M., Kishita, Y., Tokuzawa, Y., Smet, J., Régal, L., Lorber, A., Khoury, A., Zeviani, M., Strom, T. M., Meitinger, T., Bertini, E. S., Van Coster, R., Klopstock, T., Haack, T. B., Minczuk, M.,** Prokisch, H.** (-) Mutations in GTPBP3 cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis and encephalopathy Am J Hum Genet 95, 708-20 Vanlander, A.V., Menten, B., Smet, J., De Meirleir, L., Sante, T., De Paepe, B., Seneca, S., Pearce, S.F., Powell, C.A., Vergult, S., Michotte, A., De Latter, E., Vantomme, L., Minczuk, M. and Van Coster, R. (-) Two siblings with homozygous pathogenic splice site mutation in mitochondrial asparaginyl-tRNA synthetase (NARS2) Hum. Mutat Mutat 36, 222-231 Powell, C.A.*, Kopajtich, R.*, D'Souza, A.R., Rorbach, J., Dallabona, C., Donnini, C., Alston, C.L., Griffin, H., Pyle, A., Chinnery, P.F., Strom, T.M., Meitinger, T., Rodenburg, R.J., Schottmann, G., Schuelke, M., Romain, N., Haller, R., Ferrero, I., Haack, T.B., Taylor, R.W., Prokisch, H.**, Minczuk, M. (2015) Mutations in TRMT5 cause a defect in post-transcriptional modification of mitochondrial tRNA associated with multiple respiratory-chain deficiencies. Am J Hum Genet. 97,319-328 Coughlin, C.R. Scharer, G.H., Friederich, M.W., Yu, H.C., Geiger, E.A., Creadon-Swindell, G., Collins, A.E., Vanlander, A.V., Coster, R.V., Powell, C.A., Swanson, M.A., Minczuk, M., Van Hove, J.L., Shaikh, T.H. (2015) Mutations in the mitochondrial cysteinyl-tRNA synthase gene, CARS2, lead to a severe epileptic encephalopathy and complex movement disorder. J Med Genet. 52,532-540 and more
Start Year 2011
 
Description Mitochondrial RNA metabolism and human disease 
Organisation University of Ghent
Country Belgium 
Sector Academic/University 
PI Contribution We analyse molecular phenotypes associated with mutations in muclaer genes involved in mitochondrial RNA processing and post-transcriptional modification.
Collaborator Contribution Identification of mutations by next-generation exome sequencing in patients with combined OXPHOS defects
Impact Several papers e.g: Van Haute L, Dietmann S, Kremer L, Hussain S, Pearce SF, Powell CA, Rorbach J, Lantaff R, Blanco S, Sauer S, Kotzaeridou U, Hoffmann GF, Memari Y, Kolb-Kokocinski A, Durbin R, Mayr JA, Frye M, Prokisch H, Minczuk M.Deficient methylation and formylation of mt-tRNA(Met) wobble cytosine in a patient carrying mutations in NSUN3. Nat Commun. 2016 Jun 30;7:12039. doi: 10.1038/ncomms12039. Haack, T.B.*, Kopajtich, R.*, Freisinger, P.*, Wieland, T., Rorbach, J, Nicholls, T.J., Enrico Baruffini, E., Walther, A., Danhauser, K., Zimmermann, F.A., Husain, R.A., Schum, J., Mundy, H., Ferrero, I., Strom, T.M., Meitinger, T., Taylor, R.W., Minczuk, M**., Mayr, J.A., Prokisch, H.** (2013) ELAC2 Mutations Cause a Mitochondrial RNA Processing Defect Associated with Hypertrophic Cardiomyopathy. Am J Hum Genet 93, 211-223 Kopajtich, R.,* Nicholls, T.J.,* Rorbach, J.,* Freisinger, P., Mandel, H., Vanlander, A., Ghezzi, D., Carrozzo, R., Taylor, R.W., Marquard, K., Murayama, K., Wieland, T., Schwarzmayr, T., Mayr, J.A., Pearce, S. F., Powell, C. Saada, A., Ohtake, A., Invernizzi, F., Lamantea, E., Sommerville, E. W., Pyle, A., Chinnery, P. F., Crushell, E., Okazaki, Y., Kohda, M., Kishita, Y., Tokuzawa, Y., Smet, J., Régal, L., Lorber, A., Khoury, A., Zeviani, M., Strom, T. M., Meitinger, T., Bertini, E. S., Van Coster, R., Klopstock, T., Haack, T. B., Minczuk, M.,** Prokisch, H.** (-) Mutations in GTPBP3 cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis and encephalopathy Am J Hum Genet 95, 708-20 Vanlander, A.V., Menten, B., Smet, J., De Meirleir, L., Sante, T., De Paepe, B., Seneca, S., Pearce, S.F., Powell, C.A., Vergult, S., Michotte, A., De Latter, E., Vantomme, L., Minczuk, M. and Van Coster, R. (-) Two siblings with homozygous pathogenic splice site mutation in mitochondrial asparaginyl-tRNA synthetase (NARS2) Hum. Mutat Mutat 36, 222-231 Powell, C.A.*, Kopajtich, R.*, D'Souza, A.R., Rorbach, J., Dallabona, C., Donnini, C., Alston, C.L., Griffin, H., Pyle, A., Chinnery, P.F., Strom, T.M., Meitinger, T., Rodenburg, R.J., Schottmann, G., Schuelke, M., Romain, N., Haller, R., Ferrero, I., Haack, T.B., Taylor, R.W., Prokisch, H.**, Minczuk, M. (2015) Mutations in TRMT5 cause a defect in post-transcriptional modification of mitochondrial tRNA associated with multiple respiratory-chain deficiencies. Am J Hum Genet. 97,319-328 Coughlin, C.R. Scharer, G.H., Friederich, M.W., Yu, H.C., Geiger, E.A., Creadon-Swindell, G., Collins, A.E., Vanlander, A.V., Coster, R.V., Powell, C.A., Swanson, M.A., Minczuk, M., Van Hove, J.L., Shaikh, T.H. (2015) Mutations in the mitochondrial cysteinyl-tRNA synthase gene, CARS2, lead to a severe epileptic encephalopathy and complex movement disorder. J Med Genet. 52,532-540 and more
Start Year 2011
 
Description RNA polyadenylation in the maintenance and expression of the mitochondrial genome 
Organisation Medical Research Council (MRC)
Department MRC Functional Genomics Unit
Country United Kingdom 
Sector Public 
PI Contribution Establishing how poly(A) tails regulate mt-RNA abundance and mitochondrial protein synthesis Identifying novel proteins that play a role in mitochondrial poly(A) tail metabolism Determining whether poly(U) extensions play a role in RNA surveillance and/or turnover in human mitochondria
Collaborator Contribution Next-generation sequencing and analysis of mitochondrial RNA
Impact finantial support
Start Year 2012
 
Description Role of mitochondria in HCMV infection 
Organisation University of Cambridge
Country United Kingdom 
Sector Academic/University 
PI Contribution Provided analysis of mitochondrial function in cellular model of HCMV infection
Collaborator Contribution Provided HCMV infection model and discovered the link between varial infection and mitochondrial gene expression
Impact publication: Karniely S, Weekes MP, Antrobus R, Rorbach J, Van Haute L, Umrania Y, Smith DL, Stanton RJ, Minczuk M, Lehner P, Sinclair JH (2016) Human cytomegalovirus infection upregulates the mitochondrial transcription and translation machineries.
Start Year 2015
 
Title POLYPEPTIDE TARGETING TO MITOCHONDRIA 
Description Methods for delivering non-mitochondrial proteins to mitochondria are provided. Also provided are nucleic acid constructs comprising a coding sequence encoding a DNA- binding polypeptide, fused to a mitochondrial targeting sequence (MTS) and a nuclear export signal (NES), and the encoded proteins. The construct successfully delivers DNA binding proteins to the mitochondrion. A chimeric methylase based on the above construct is successfully delivered to mitochondria, resulting in modification of mtDNA. 
IP Reference EP1974034 
Protection Patent granted
Year Protection Granted 2013
Licensed No
Impact nil
 
Description "Work in Progress" talk to the Selwyn College MCR Society 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Undergraduate students
Results and Impact A graduate student was invited to give an overview of her studies and her life as a graduate student of the University of Cambridge/MRC MBU.

.
Year(s) Of Engagement Activity 2013
 
Description Biglands Green School visit - Cambridge Outreach event 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact a short talk about general biology was given, folowed by a discusion about science ith an aim to getting them interested in the sciences, and with a hope of inspiring applications to Cambridge in the future.

not measurable yet
Year(s) Of Engagement Activity 2010
 
Description Cambridge Science Festival 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Type Of Presentation Poster Presentation
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Presentations of posters, explanations of mitochondrial processes, movies, interaction with members of the public.

Interest in the Unit's open day.
Year(s) Of Engagement Activity 2013
 
Description Cambridge University Widening Participation Programme 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact PhD student (Payam Gammage) gave a talk to 25 FE college students (doing their A levels) on life as a graduate student at Cambridge and science the MBU. Venue: St. John's College, Cambridge.

Interaction from interested A level students.
Year(s) Of Engagement Activity
 
Description Clare College - Gillespie Conferencing Centre 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Schools
Results and Impact To give advice and share experiences of undergraduate and graduate study with a group of aspiring 17-18 year old biologists (largely Oxbridge applicants) from a deprived area of East London.

not measurable yet
Year(s) Of Engagement Activity 2011
 
Description Clare College STEM Outreach Lecture Series 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Undergraduate students
Results and Impact A graduate student participated in a series of lectures aimed at undergraduates/summer students of the University of Cambridge

Greater awareness of the Unit's activities.
Year(s) Of Engagement Activity 2013
 
Description Dissemination of scientific achievements via the internet 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Dissemination of scientific achievements and publications to the general public, scientists and others via the Unit's website, Twitter and Facebook.

https:/www.facebook.com/mrc-mbu
Twitter - @MRC_MBU
http://www.mrc-mbu.cam.ac.uk
http://www.mrc-mbu.cam.ac.uk/people/michal-minczuk
Year(s) Of Engagement Activity 2015,2016,2017,2018
URL http://www.mrc-mbu.cam.ac.uk/people/michal-minczuk
 
Description Graduate Research Forum 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact talko on general themes in mitochondrial research, the importance of understanding mitochondrial processes (as a key factor in the pathogenesis of many diseases and also in general health/ageing), and on research in our group.

not measurable yet
Year(s) Of Engagement Activity 2011
 
Description Lecture at Clare College Outreach summer school 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Schools
Results and Impact A graduate student gave a lecture on University/MRC life at the Clare College Outreach summer school.

Increased awareness amongst students considering University courses.
Year(s) Of Engagement Activity 2013
 
Description MRC MBU Annual Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Overview of work at the MRC MBU; explanations of how mitochondrial dysfunction causes mitochondrial diseases. Audience: Secondary school students, tutors, general public and scientists from neighbouring institutes. Impact: increased awareness.
Year(s) Of Engagement Activity 2015,2016
URL http://www.mrc-mbu.cam.ac.uk/news/2335/open-day-2015
 
Description Mayfield Primary School, Cambridge 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Members of the MBU visited Mayfield Primary School, Cambridge to participate in their Science Day. This was a classroom based event, with students in Reception (aged 4 and 5 years) rotating around the room. After a short talk, the children interacted with Lego models, pipetting and colouring.
Year(s) Of Engagement Activity 2017
 
Description Opportunities Ahead 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact The event is aimed at school students in years 5 & 6 in the morning followed by students from secondary schools, sixth-forms, recent school and college leavers and parents in the afternoon. The idea is to showcase the wide variety of companies in the Cambridge area and get young people excited about their future.

Signpost 2 Skills is a new service designed to guide students from education and into working life by bringing employers into schools and students into businesses. It is funded by the Greater Cambridge Greater Peterborough LEP and the Greater Cambridge City Deal, and delivered by social enterprise, Form the Future.
Year(s) Of Engagement Activity 2017
URL http://www.mrc-mbu.cam.ac.uk/news/2768/opportunities-ahead-careers-fair-cambridge
 
Description Padova, Italy 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Undergraduate students
Results and Impact Mitochondrial Biology and Genetics Lecture Series: joint initiative between the Galilean School of Higher Education and PhD Courses in Biosciences and Biomedical Sciences of the University of Padova.
Year(s) Of Engagement Activity 2015
 
Description Presentations during the MRC Centenary Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Members of the public attended the Unit's open day to celebrate the MRC's Centenary.

Increased awareness and interest.
Year(s) Of Engagement Activity 2013
 
Description Public Engagement Training 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact A Public Engagement Workshop entitled, "Who are the public and what do they think?" Aimed at:
Understanding body language
Intentions and measuring success
Engagement in practice - case studies/experiences
Places to find further support and methods to engage further
Year(s) Of Engagement Activity 2017
 
Description Queen Edith's Primary School, Cambridge 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Members of the MBU visited Queen Edith's Primary School, Cambridge to participate in their Science Day. This was a carousel-type event, with students in years 1-4 rotating around the room. The demonstrations included Lego models, computer games, pipetting and DNA sequencing puzzles. Feedback: Thank you so much for coming here today. The children have not stopped talking about it since leaving the room.
Year(s) Of Engagement Activity 2017
 
Description SET for BRITAIN 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Exhibition of posters by early-career research scientists, engineers and mathematicians. By competition. MBU participant: Sarah Pearce.

SET for BRITAIN exists to raise the profile of Britain's early-stage researchers at Westminster by engaging Members of both Houses of Parliament with current science, engineering and mathematics research being undertaken in the UK, especially that by their local constituents and in their local University. Few of them have science or technology degrees, but around 100 Parliamentarians usually attend during the day.
Year(s) Of Engagement Activity 2016
URL http://www.setforbritain.org.uk/2016event.asp
 
Description The Norwood School 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Visit to the lab by three year 13 students along with their teacher to discuss the concepts and practicalities of gel electrophoresis, gene technology, and gene manipulation.

Impact: increased awareness
Year(s) Of Engagement Activity 2015
 
Description Visit of Japanese medical students 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Undergraduate students
Results and Impact Visit to Michal Minczuk's laboratory by Japanese medical students. Four members of the research group participated, giving an insight into the work of the Unit, the laboratory and answering questions from the students. Impact - increased awareness.
Year(s) Of Engagement Activity 2015
 
Description Woodhouse College Visit (to MBU) 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Eight year 12 students from Woodhouse College visited on Wednesday, 28th of June for a day focused on gene manipulation. It began with discussions surrounding the ethics and practicalities of genetic engineering followed by a practical on CRISPR-Cas9, PCR, and gel electrophoresis. This was concluded with a session to interpret the results obtained and to discuss their significance. Feedback: It was my first experience in a lab based environment and greatly broadened my perspective of the opportunities available in a career of science.It was an amazing trip, really interesting to see a research scientist's day to day life. In addition participating in a PCR and gel electrophoresis was fascinating and I received advice to help me for my university application. Thanks.The experience we got in the lab was invaluable and the techniques we used were not only relevant to our curriculum but really enjoyable. We got to explore and be a part of a really exciting, cutting-edge development in biomedical science , CRISPR- Cas9! The trip provided an incredible motivation to succeed and aim high. I am incredibly thankful for the opportunity.Visiting a working lab was an exciting opportunity and gave me a great understanding of the techniques biochemists use, including CRISPR/Cas9 which I had heard about in the media, but being so cutting edge I was surprised that the technique was so commonplace in the lab.
Year(s) Of Engagement Activity 2017,2018
 
Description Work Experience 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Visit by three Year 10 students (age 15) to the Unit for a week each - work experience/shadowing in various research groups/environments, chaperoned throughout by individual members of the Unit. Presentation by the visitors at the end of their week.
Year(s) Of Engagement Activity 2016,2017