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School of Medicine

Dr Brian Bigger PhD

Senior Research Fellow

Stem Cell & Neurotherapies Laboratory
Faculty of Medical and Human Sciences
3.721 Stopford Building
University of Manchester
Manchester M13 9PT, UK

 

Role

Group leader Stem Cell & Neurotherapies Laboratory (formerly MPS Stem Cell Research)

 

Memberships of Committees and Professional Bodies

Dr Bigger is a member of the American Society of Gene Therapy, The British Society of Gene Therapy, The International Society of Experimental Haematology and The Manchester Stem Cell Network.

Research

Neurodegenerative metabolic diseases mainly affect children and often lack effective treatments.  Some, such as the lysosomal storage disease, Mucopolysaccharidosis (MPS) I, can already be partly treated by allogeneic transplantation of bone marrow or cord blood derived stem cells from a healthy donor, but there is often a high associated risk of morbidity and mortality when using mismatched transplants.

Formerly the MPS Stem cell reserch lab, Dr Bigger’s Stem Cell & Neurotherapies laboratory uses a multidisciplinary approach to investigate stem cell and gene therapies for neurological diseases. It consists of two programmes

 

MPS lysosomal disease group

  1. Comparative neuropathology and mechanisms of neurodegeneration in models of MPS disease
  2. Clinical development of novel stem cell and gene therapies in neurodegenerative lysosomal diseases
  3. Biomarker development
  4. The therapeutic use of haematopoietic stem cell transplantation in neurodegenerative disease
  5. The use of substrate reducing agents to ameliorate mucopolysaccharide diseases.

 

The Brain Tumour group

  1. Brain tumour stem cell biology and their interaction with Microglia in vivo
  2. Novel therapies for brain tumours

We are primarily a research laboratory but have close clinical links, with both the MPS and metabolic disease patients and neurosurgical patients.

News

 

Methodological Knowledge

Main Research Areas

  • Neuropathology and treatment of neurodegenerative lysosomal diseases

  • Stem cell biology and treatment of primary brain tumours

  • Haematopoetic stem cell gene therapy and tolerance induction

  • Haematopoietic cell migration and interactions within bone marrow and neurological niches

  • Clinical translation of gene and cell therapies
    Section through the bone of a female mouse

    Above: Section through the bone of a female mouse transplanted with male haematopoietic stem cells that have been transduced with a lentiviral vector expressing eGFP, using a reduced toxicity conditioning regimen. Blue - nuclei, Red - eGFP immunostaining, Green - Y probe. Six weeks after transplant, male (Y+) donor cells populate approximately 60% of the bone marrow, with eGFP expressing male donor cells making up around 60% of those.

Funders

The laboratory is funded by a programme grant and several subsidiary grants from the UK Society for Mucopolysaccharide (MPS) diseases to Dr Bigger as well as the Christopher Clarke Cancer Research Foundation Fellowship awarded to Mr Omar Pathmanaban.

We gratefully acknowledge grant support from:

The Lady Shauna Gosling Trust,

Lois Gosling

The Ollie G Ball,

The National MPS Society (US),

The Irish MPS society,

The Sanfilippo Children's Research Foundation (Canada),

The Children's Bone Marrow Trust,

BBSRC,

The Manchester Biomedical Research Centre,

Department of Health,

CMFT NHS trust endowments

The Association for Glycogen Storage Disorders

as well as contributions from the MPS societies of Austria, Canada, Germany, Ireland, Japan, Netherlands, Spain, Sweden, Switzerland, UK and USA.

 

Biography

Dr Bigger was awarded a Bachelors degree from the University of Bath in Applied Biology. His PhD was conducted in the Gene Therapy Research Group, Imperial College, London, where he worked with Professor Charles Coutelle on developing a gene delivery vehicle for mitochondrial gene therapy. On completion of his PhD in 2000, Dr Bigger joined Dr Mike Themis, Imperial College, London to work on a Wellcome Trust collaborative project with Cancer Research UK, investigating gene delivery to stem cells for liver diseases. In 2004 he joined Dr Suzanne Watt’s group in Oxford University and the National Blood Service as a Senior Research Scientist to work on mechanisms of stem cell homing. In 2006 Dr Bigger set up the MPS Stem Cell Research laboratory at the University of Manchester and the Royal Manchester Children's hospital. Recently, the lab has been renamed the Stem Cell & Neurotherapies laboratory to reflect its wider remit in developing stem cell gene therapy and other treatments for neudegenerative lysosomal diseases and also for primary brain tumours.

 

Qualifications


 

Collaborators and affiliated staff

Group Members and Affiliated Staff

  • Dr Rob Wynn - Consultant, Head of Bone Marrow Transplantation Unit
  • Dr Ed Wraith - Consultant, Head of Biochemical Genetics Unit
  • Dr Simon Jones - Consultant, Biochemical Genetics Unit
  • Dr Fiona Wilkinson - Senior Postdoctoral Associate
  • Mr Omar Pathmanaban - CCCRF Clinical Research Fellow, Speciality Registrar Neurosurgery/PhD student
  • Dr Muhammad Saif, Speciality Registrar Haematology, PhD student
  • Miss Kia Langford - Research Technician/PhD student
  • Ms Karen Brookes - Research Technician
  • Miss Ai Yin Liao - Research Technician
  • Mr Alex Smith - PhD Student
  • Miss Ana Sergijenko - Manchester BRC Fellow/PhD student
  • Miss Soumya Badrinath - MRes student

Collaborators

  • Dr Cathy Merry, University of Manchester. Heparan sulphate and cellular interactions in neurodegenerative diseases
  • Dr Maria Canal, University of Manchester. Circadian profiling in MPS
  • Professsor Nancy Rothwell, University of Manchester. Microglial interactions with brain tumours
  • Professor Adrian Thrasher and Professor Bobby Gaspar, UCL. Lentiviral mediated stem cell gene therapy for lysosomal diseases
  • Dr Jon Cooper, Kings College London. Neurodegeneration in MPS.

Job Opportunities

We offer laboratory placements for motivated high quality project students on Manchester University Medical undergraduate or postgraduate MSc and MRes courses and will consider self-funded internships for excellent non-clinical or clinical candidates wishing to gain laboratory experience in the field.

 

Publications

2011

  • Bigger, B., Liao, A., Sergijenko, A. & Coutelle, C (2011). Trial and Error: How the Unclonable Human Mitochondrial Genome was Cloned in Yeast. Pharm Res, 28(11), 2863-70. eScholarID:133434 | PMID:21739320 | DOI:10.1007/s11095-011-0527-1
  • Holley, R., Deligny, A., Wei, W., Watson, H., Ninonuevo, M., Dagalv, A., Leary, J., Bigger, B., Kjellen, L. & Merry, C (2011). Mucopolysaccharidosis type I: Unique structure of accumulated heparan sulfate and increased N-sulfotransferase activity in mice lacking alpha-L-iduronidase. J Biol Chem, eScholarID:133433 | PMID:21873421 | DOI:10.1074/jbc.M111.287474
  • Langford-Smith, A., Langford-Smith, K., Jones, S., Wynn, R., Wraith, J., Wilkinson, F. & Bigger, B (2011). Female mucopolysaccharidosis IIIA mice exhibit hyperactivity and a reduced sense of danger in the open field test. PLoS One, 6(10), e25717. eScholarID:141828 | PMID:22028789 | DOI:10.1371/journal.pone.0025717
  • Langford-Smith, A., Malinowska, M., Langford-Smith, K., Wegrzyn, G., Jones, S., Wynn, R., Ed Wraith, J., Wilkinson, F. & Bigger, B (2011). Hyperactive behaviour in the mouse model of Mucopolysaccharidosis IIIB in the open field and home cage environments. Genes Brain Behav, eScholarID:124493 | PMID:21635693 | DOI:10.1111/j.1601-183X.2011.00706.x
  • Langford-Smith, K., Mercer, J., Petty, J., Tylee, K., Church, H., Roberts, J., Moss, G., Jones, S., Wynn, R., Wraith, J. & Bigger, B (2011). Heparin cofactor II-thrombin complex and dermatan sulphate:chondroitin sulphate ratio are biomarkers of short- and long-term treatment effects in mucopolysaccharide diseases. J Inherit Metab Dis, 34(2), 499-508. eScholarID:124491 | PMID:21170681 | DOI:10.1007/s10545-010-9254-8
  • Saif, M., Bonney, D., Bigger, B., Forsythe, L., Williams, N., Page, J., Babiker, Z., Guiver, M., Turner, A., Hughes, S. & Wynn, R (2011). Chronic norovirus infection in pediatric hematopoietic stem cell transplant recipients: A cause of prolonged intestinal failure requiring intensive nutritional support. Pediatr Transplant, eScholarID:124492 | PMID:21504523 | DOI:10.1111/j.1399-3046.2011.01500.x

2010

  • Archer, L., Langford, K., Bigger, B. & Fildes, J (2010). Immune activation or immunomodulation in the brains of MPS IIIB mice? Commentary on "Innate and adaptive immune activation in the brain of MPS IIIB mouse model". J Neurosci Res, 88(2), 233. eScholarID:80170 | PMID:19746428 | DOI:10.1002/jnr.22211
  • Bonney, D., O'Meara, A., Shabani, A., Imrie, J., Bigger, B., Jones, S., Wraith, J. & Wynn, R (2010). Successful allogeneic bone marrow transplant for Niemann-Pick disease type C2 is likely to be associated with a severe 'graft versus substrate' effect. J Inherit Metab Dis, eScholarID:80167 | PMID:20393800 | DOI:10.1007/s10545-010-9060-3
  • Canal, M., Wilkinson, F., Cooper, J., Ed Wraith, J., Wynn, R. & Bigger, B (2010). Circadian rhythm and suprachiasmatic nucleus alterations in the mouse model of mucopolysaccharidosis IIIB. Behav Brain Res, 209(2), 212-20. eScholarID:80168 | PMID:20138090 | DOI:10.1016/j.bbr.2010.01.045
  • Langford-Smith, K., Arasaradnam, M., Wraith, J., Wynn, R. & Bigger, B (2010). Evaluation of heparin cofactor II-thrombin complex as a biomarker on blood spots from mucopolysaccharidosis I, IIIA and IIIB mice. Mol Genet Metab, 99(3), 269-74. eScholarID:80169 | PMID:19926322 | DOI:10.1016/j.ymgme.2009.10.175
  • Marcelina Malinowska, Fiona L. Wilkinson, Kia J. Langford-Smith, Alex Langford-Smith, Jillian R. Brown, Brett E. Crawford, Marie T. Vanier, Grzegorz Grynkiewicz, Rob F. Wynn, J. Ed Wraith, Grzegorz Wegrzyn, Brian W. Bigger. (2010). Genistein Improves Neuropathology and Corrects Behaviour in a Mouse Model of Neurodegenerative Metabolic Disease. PLoSONE, 5(12), eScholarID:98028 | DOI:10.1371/journal.pone.0014192

2009

  • Malinowska, M., Wilkinson, F., Bennett, W., Langford-Smith, K., O'Leary, H., Jakobkiewicz-Banecka, J., Wynn, R., Wraith, J., Wegrzyn, G. & Bigger, B (2009). Genistein reduces lysosomal storage in peripheral tissues of mucopolysaccharide IIIB mice. Mol Genet Metab, 98(3), 235-42. eScholarID:80171 | PMID:19632871 | DOI:10.1016/j.ymgme.2009.06.013
  • Wynn RF, Stubbs M, Ozyilmaz N, Wraith JE, Bigger B. (2009). Cellular therapy of lysosomal storage disorders: Current status and future prospects. Curr Ped Reviews, 5(3), 15. eScholarID:84833 | DOI:10.2174/157339609789007187
  • Wynn, R., Wraith, J., Mercer, J., O'Meara, A., Tylee, K., Thornley, M., Church, H. & Bigger, B (2009). Improved metabolic correction in patients with lysosomal storage disease treated with hematopoietic stem cell transplant compared with enzyme replacement therapy. J Pediatr, 154(4), 609-11. eScholarID:80172 | PMID:19324223 | DOI:10.1016/j.jpeds.2008.11.005

2007

  • Katrangi, E., D'Souza, G., Boddapati, S., Kulawiec, M., Singh, K., Bigger, B. & Weissig, V (2007). Xenogenic transfer of isolated murine mitochondria into human rho0 cells can improve respiratory function. Rejuvenation Res, 10(4), 561-70. eScholarID:142239 | PMID:18069915 | DOI:10.1089/rej.2007.0575
  • Siapati, E., Bigger, B., Kashofer, K., Themis, M., Thrasher, A. & Bonnet, D (2007). Murine leukemia following irradiation conditioning for transplantation of lentivirally-modified hematopoietic stem cells. Eur J Haematol, 78(4), 303-13. eScholarID:56465 | PMID:17378892 | DOI:10.1111/j.1600-0609.2006.00813.x

2006

  • Bigger, B., Siapati, E., Mistry, A., Waddington, S., Nivsarkar, M., Jacobs, L., Perrett, R., Holder, M., Ridler, C., Kemball-Cook, G., Ali, R., Forbes, S., Coutelle, C., Wright, N., Alison, M., Thrasher, A., Bonnet, D. & Themis, M (2006). Permanent partial phenotypic correction and tolerance in a mouse model of hemophilia B by stem cell gene delivery of human factor IX. Gene Ther, 13(2), 117-26. eScholarID:56473 | PMID:16163377 | DOI:10.1038/sj.gt.3302638
  • Russo, F., Alison, M., Bigger, B., Amofah, E., Florou, A., Amin, F., Bou-Gharios, G., Jeffery, R., Iredale, J. & Forbes, S (2006). The bone marrow functionally contributes to liver fibrosis. Gastroenterology, 130(6), 1807-21. eScholarID:56466 | PMID:16697743 | DOI:10.1053/j.gastro.2006.01.036
  • Tolmachov O, Palaszewski I, Bigger B, Coutelle C. (2006). RecET driven chromosomal gene targeting to generate a RecA deficient Escherichia coli strain for Cre mediated production of minicircle DNA. BMC Biotechnol, 6, eScholarID:1d13202

2005

  • O Tolmachov, R Harbottle, B W Bigger and C Coutelle. (2005). Minimised, CpG-depleted and methylated DNA vectors: Towards perfection in non-viral gene therapy. In M Schleef (Ed.), DNA-Pharmaceuticals: Formulation and delivery in gene therapy, DNA vaccination and immunotherapy. (pp. -). Cambridge, UK: Wiley. eScholarID:46442
  • Bigger B, Siapati E, Miskin J, Chipchase D, Parsley K, Mitrophanous K, Themis M, Thrasher A, Bonnet D. (2005). Comparison of HIV- and EIAV-based vectors on their efficiency in transducing murine and human hematopoietic repopulating cells. Molecular Therapy, 12( 3), eScholarID:1d26981
  • Themis, M, Waddington, S, Schmidt, M, von Kalle, C, Wang, Y, Al-Allaf, F, Gregory, L, Nivsarkar, M, Themis, M, Holder, M, Buckley, S, Dighe, N, Ruthe, A, Mistry, A, Bigger, B, Rahim, A, Nguyen, T, Trono, D, Thrasher, A, Coutelle, C. (2005). Oncogenesis following delivery of a nonprimate lentiviral gene therapy vector to fetal and neonatal mice. Molecular Therapy, 12( 4), 763-71. eScholarID:1d26982

2004

  • Alison, M., Vig, P., Russo, F., Bigger, B., Amofah, E., Themis, M. & Forbes, S (2004). Hepatic stem cells: from inside and outside the liver? Cell Prolif, 37(1), 1-21. eScholarID:56477 | PMID:14871234
  • Gregory, L., Waddington, S., Holder, M., Mitrophanous, K., Buckley, S., Mosley, K., Bigger, B., Ellard, F., Walmsley, L., Lawrence, L., Al-Allaf, F., Kingsman, S., Coutelle, C. & Themis, M (2004). Highly efficient EIAV-mediated in utero gene transfer and expression in the major muscle groups affected by Duchenne muscular dystrophy. Gene Ther, 11(14), 1117-25. eScholarID:56476 | PMID:15141156 | DOI:10.1038/sj.gt.3302268
  • Vaysse, L., Harbottle, R., Bigger, B., Bergau, A., Tolmachov, O. & Coutelle, C (2004). Development of a self-assembling nuclear targeting vector system based on the tetracycline repressor protein. J Biol Chem, 279(7), 5555-64. eScholarID:56478 | PMID:14607832 | DOI:10.1074/jbc.M311894200
  • Waddington, S., Nivsarkar, M., Mistry, A., Buckley, S., Kemball-Cook, G., Mosley, K., Mitrophanous, K., Radcliffe, P., Holder, M., Brittan, M., Georgiadis, A., Al-Allaf, F., Bigger, B., Gregory, L., Cook, H., Ali, R., Thrasher, A., Tuddenham, E., Themis, M. & Coutelle, C (2004). Permanent phenotypic correction of hemophilia B in immunocompetent mice by prenatal gene therapy. Blood, 104(9), 2714-21. eScholarID:56474 | PMID:15231566 | DOI:10.1182/blood-2004-02-0627

2003

  • R N Lightowlers, B Bigger, R W Taylor, D Turnbull. (2003). Gene Therapy for Mitochondrial DNA Disorders. In IJ Holt (Ed.), Genetics of Mitochondrial Diseases. (pp. -). Oxford: Oxford University Press. eScholarID:46435
  • Waddington, S., Mitrophanous, K., Ellard, F., Buckley, S., Nivsarkar, M., Lawrence, L., Cook, H., Al-Allaf, F., Bigger, B., Kingsman, S., Coutelle, C. & Themis, M (2003). Long-term transgene expression by administration of a lentivirus-based vector to the fetal circulation of immuno-competent mice. Gene Ther, 10(15), 1234-40. eScholarID:56480 | PMID:12858188 | DOI:10.1038/sj.gt.3301991

2001

  • Bigger, B. & Coutelle, C (2001). Perspectives on gene therapy for cystic fibrosis airway disease. BioDrugs, 15(9), 615-34. eScholarID:56484 | PMID:11580305
  • Bigger, B., Tolmachov, O., Collombet, J., Fragkos, M., Palaszewski, I. & Coutelle, C (2001). An araC-controlled bacterial cre expression system to produce DNA minicircle vectors for nuclear and mitochondrial gene therapy. J Biol Chem, 276(25), 23018-27. eScholarID:56485 | PMID:11304530 | DOI:10.1074/jbc.M010873200
  • Coutelle, C. & Bigger, B (2001). [Gene therapy of cystic fibrosis; review of completed clinical studies]. Internist (Berl), 42(10), 1346-50, 1353-6. eScholarID:56483 | PMID:11688153

2000

  • Bigger, B., Tolmachov, O., Collombet, J. & Coutelle, C (2000). Introduction of chloramphenicol resistance into the modified mouse mitochondrial genome: cloning of unstable sequences by passage through yeast. Anal Biochem, 277(2), 236-42. eScholarID:56489 | PMID:10625512 | DOI:10.1006/abio.1999.4382

1999

  • Bigger, B., Collombet, J. & Coutelle, C (1999). Tipping the scales in favour of mitochondrial gene therapy. Gene Ther, 6(12), 1909-10. eScholarID:56486 | PMID:10637441 | DOI:10.1038/sj.gt.3301090

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