Stem Cells: A Pathway Through the Maze

Course summary

  • Wed 09 Dec 2015 to Fri 11 Dec 2015
  • Rewley House, Oxford, OX1 2JA
  • £995.00
  • Course code O15C496C1Y
  • Closed to new applications

Stem Cells: A Pathway Through the Maze


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This course is intended to dispel the myths behind stem cell biology and introduce delegates to the science behind the headlines, the pitfalls as well as the promises.

Bringing together eighteen leading experts in the field to explore this cutting-edge technology, this course is designed for those who have little prior knowledge or understanding of stem cells, so as to provide as broad an overview of the subject as possible.

This will include not only the science underlying the subject, but also related issues such as the ethics and regulatory infrastructure and commercialisation of regenerative medicine.

This course can be combined with the new practical workshop course, Pluripotent Stem Cell Technology, to offer a complete overview of stem cell technology.

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Note: This is a two-day course held over three days - from lunchtime on Wednesday until lunchtime on Friday.

Few topics have captured the imagination of the general public quite as dramatically as stem cells, both for the potential they offer regenerative medicine and the ethical sensitivities they create.

Although the course will assume basic knowledge of the biomedical sciences, no previous understanding of stem cell biology will be required.

“The course is designed for those who have little prior knowledge or understanding of stem cells, so as to provide as broad an overview of the subject as possible. This will include not only the science underlying the subject but related issues such as the ethics and regulatory infrastructure and commercialisation of regenerative medicine.

Many of the lecturers will undoubtedly present some of their more cutting-edge insights which will, we hope, be of relevance to those with a particular interest in the field and who already come with specialist knowledge. In essence, we therefore hope to cater for the range of people we anticipate will be attracted to the course."

Professor Paul Fairchild, Co-Director, Oxford Stem Cell Institute, University of Oxford



What people say about the course…


Well-organised, very valuable and scientifically interesting. Gives materials for future in-depth study.
- Carla Martino, Scientific Administrator, The European Medicines Agency (EMEA)

Fantastic review of current status of field in an informative and understandable format.
- Rebecca Dias, Head of In Vivo Pharmacology, Pfizer Ltd

An excellent overview of the field.
- Una Riekstina, University of Latvia

An interesting and stimulating course - helps me understand the current position of stem cell research.
- Pilar Vazquez, D.Phil student, University of Oxford


Programme details

The course will begin by introducing key concepts in the field which will form the basis for exploring the properties of selected populations of adult and embryonic stem cells.

Later sessions will be devoted to applied topics that are essential to the therapeutic application of stem cell biology before focussing on ethical and regulatory issues and surveying the landscape for patenting and marketing of stem cell therapies.

The taught component of the course will draw on the varied expertise available within the University of Oxford, with contributions from outside experts, where appropriate.

This course is led by Professor Paul Fairchild, Co-Director, Oxford Stem Cell Institute, Sir William Dunn School of Pathology, University of Oxford.


2015 Schedule

This course was previously offered in 2015. Please note that the course programme, along with the course presenters may be subject to change when the course is next offered.


Day 1: Afternoon Session - Basics of Stem Cell Biology

14:00 Stem Cells: Definitions and Principles
Professor Paul Fairchild, Sir William Dunn School of Pathology, University of Oxford

14:40 The Planarian flatworm as a model for the study of stem cells
Professor Aziz Aboobaker , Department of Zoology, University of Oxford

15:20 The Stem Cell Niche
Dr Carolyn Carr, Department of Physiology, Anatomy and Genetics, University of Oxford

16:00 Afternoon tea/coffee

16:20 Molecular Mechanisms of Pluripotency
Dr Ita Costello, Sir William Dunn School of Pathology, University of Oxford

17:00 Is Cancer a Stem Disease?
Professor Colin Goding, Ludwig Institute

17:40 Finish


Day 2: Morning Session - Stem Cell Populations: Adult versus Embryonic

9:00 Embryonic Stem Cells
Dr Frances Brook, Radcliffe Department of Cardiovascular Medicine

09:40 Induced Pluripotent Stem Cells
Dr Sally Cowley, James Martin Stem Cell Facility

10:20 Hematopoietic Stem Cells
Dr Marella de Bruijn, Weatherall Institute of Molecular Medicine

11:00 Morning tea/coffee

11:30 Neural Stem Cells
Professor Francis Szele, Department of Physiology, Anatomy and Genetics, University of Oxford

12:10 Cardiac Stem Cells
Professor Paul Riley, Department of Physiology, Anatomy and Genetics, University of Oxford

12:50 Lunch

Day 2: Afternoon Session - Enabling Technologies in Stem Cell Biology

14:00 Reprogramming Technologies and Genome Editing
Dr Kenny Moore, Sir William Dunn School of Pathology

14:40 Stem Cells and Gene Therapy
Professor Len Seymour, Department of Oncology, University of Oxford

15:20 Stem Cells and Epigenetics
Professor Udo Oppermann, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences

16:00 Afternoon tea/coffee

16:20 Small Molecule Manipulation of Stem Cell Fate
Professor Angela Russell , Department of Chemistry, University of Oxford

17:00 Immunological Tolerance in Stem Cell Therapies
Professor Paul Fairchild, Sir William Dunn School of Pathology

17:40 Finish


Day 3: Morning Session - The Societal Context of Stem Cell Biology

9:00 Population Aging: The Motivation behind Regenerative Medicine
Professor Sarah Harper, Oxford Institute for Population Aging

9:40 The Ethics of Stem Cell Research
Dr Jonathan Pugh,Programme on Ethics of the New Biosciences

10:20 Intellectual Property Rights and Patenting of Stem Cells
Lee Chapman, J A Kemp & Co Chartered Patent Attorneys, London

11:00 Morning tea/coffee

11:30 Commercialisation of Stem Cell Biology and Regenerative Medicine
Bill Shingleton, GE Healthcare

12:10 Legal and Regulatory Aspects of Stem Cell Biology
Professor Glyn Stacey, UK Stem Cell Bank, South Mimms

12:50 Finish



Participants who attend the full course will receive a Certificate of Attendance. The sample shown is an illustration only and the wording will reflect the course and dates attended.


Accommodation is available at the Rewley House Residential Centre, within the Department for Continuing Education, in central Oxford. The comfortable, en-suite, study-bedrooms have been rated as 4-Star Campus accommodation under the Quality In Tourism scheme, and come with tea- and coffee-making facilities, free Wi-Fi access and Freeview TV. Guests can take advantage of the excellent dining facilities and common room bar, where they may relax and network with others on the programme.


Standard course fee: £995.00


Fees include course materials, tuition, refreshments and lunches. The price does not include accommodation.

All courses are VAT exempt.


Dr Paul Fairchild


Co-Director, Oxford Stem Cell Institute, Sir William Dunn School of Pathology, University of Oxford

After obtaining a first class degree and an award for top graduate in the Biological Sciences, Paul Fairchild began his research career in Oxford, where he studied for a DPhil within the Nuffield Department of Surgery, focussing on the immune response to organ allografts.

After spending five years as a Post-Doctoral Fellow in the Department of Pathology, University of Cambridge, he returned to Oxford where he is currently a Lecturer and RCUK Academic Fellow within the Sir William Dunn School of Pathology. Here, he has applied his immunological training to the emerging field of cell replacement therapy and regenerative medicine to investigate the immune response to tissues differentiated from embryonic stem cells, the rejection of which threatens to undermine the success of regenerative medicine in the future.

He has developed technologies which may help promote the indefinite survival of stem cell-derived grafts, which forms the basis of a patent, licensed by Geron Corporation with whom he collaborates scientifically. He has published widely in the field and is a frequent speaker at international conferences.

Dr Frances Brook


Nuffield Dept of Obstetrics and Gynaecology, University of Oxford

Dr Brook completed a D.Phil at Oxford in the Department of Agricultural Sciences, studying ovarian structure and function in the wood mouse, Apodemus sylvaticus. Following a post-doctoral position at Washington University in St. Louis she returned to Oxford to work on post-implantation mouse embryo development with Dr Andrew Copp. Subsequently she joined the laboratory of Professor Sir Richard Gardner to study the biology of mouse embryonic stem cells, work that involved the derivation of numerous new ES cell lines. She then moved to the in Nuffield Department of Obstetrics & Gynaecology to work in the laboratory of Professor Helen Mardon on a project to derive human embryonic stem cells. Currently she is in the Department of Cardiovascular Medicine in Professor Hugh Watkins’ group working on a project to derive patient-specific iPS cells and to differentiate these into cardiomyocytes.

Dr Carolyn Carr


Senior Post Doctoral Research Fellow, Department of Physiology, Anatomy and Genetics, University of Oxford

Carolyn Carr is a senior post-doctoral research fellow in the Department of Physiology, Anatomy and Genetics at the University of Oxford. She has a DPhil in Chemistry from Oxford and has worked with NMR spectroscopy and mass spectrometry both within the Chemistry Department at Oxford and also in industry for Kodak Ltd and Synaptica Ltd. She had a career break of 10 years to spend time with her children and returned to science with a Daphen Jackson Returner’s Fellowship. Since joining Professor Kieran Clarke’s group in 2003 she has progressed from Chemistry to Biology, as she now runs their BHF funded project, studying stem cell therapy for the infarcted heart. She uses her MR skills to measure cardiac function before and after stem cell therapy and to track the cells in vivo. As well as presenting her work at conferences, she enjoys giving ‘public understanding of science’ lectures about stem cell therapy.

Dr Lee Chapman


Partner and Patent Attorney, J A Kemp & Co Chartered Patent Attorneys, London

Dr Lee Chapman has a Degree in Physiological Sciences from the University of Oxford and was awarded his DPhil from the same institution, focusing on the endocrine regulation of reproduction during stress. He joined J A Kemp & Co in 2002 and qualified as a patent attorney in 2005.

Lee deals with a wide variety of biotechnology subject matter, with areas of particular expertise including stem cells, therapeutic cloning, Alzheimer's disease, molecular biology, multiplex assays and diagnostics. He has experience in various patent-related matters, including drafting patent applications, prosecution of patent applications in Europe and other territories, and European Patent Office (EPO) oppositions and appeals. Lee also has experience in carrying out freedom to operate and due diligence exercises. Lee was part of the team that represented WARF in front of the Enlarged Board of Appeal of the EPO. He often works from J A Kemp & Co’s Oxford office where his clients include Isis Innovation Ltd and Oxford Nanopore Technologies Ltd.

Dr Ita Costello


Sir William Dunn School of Pathology, University of Oxford

I attended the National University of Ireland, Galway where I obtained a B.Sc (Hons) degree in Biotechnology. Following this I undertook a four-year Wellcome Trust funded PhD in the cellular and molecular basis of disease at the University of Edinburgh. After completing my M.Sc. degree in my first year, I conducted my PhD at the Institute of Stem Cell Research.

My PhD research focused on the area of transcriptional regulation in embryonic stem cell maintenance, in particular the role chromatin remodeling and histone modifications plays in ES cell pluripotency and in early mammalian development.

I joined the lab of Prof. Elizabeth Robertson at the Sir William Dunn School of Pathology, University of Oxford in 2008, where my post-doctoral research has focused on exploiting mouse genetics to investigate the molecular mechanisms underlying mammalian development, specifically understanding the transcriptional control of early lineage decisions.

Dr Sally Cowley


Head, James Martin Stem Cell Facility

A graduate of Natural Sciences at Cambridge, Sally began her research career working on host-pathogen interactions (Ph.D 1990 University of London, and later at AHRI, Ethiopia). Her post-doctoral work (New England Deaconess Hospital, Harvard, Boston, and Institute of Cancer Research, London) centred around signal transduction pathways involved in differentiation: She identified and cloned a novel tyrosine kinase, MATK, implicated in megakaryocyte differentiation; and was the first to demonstrate that the protein kinase MEK (/MKK) is critical for signal transduction pathways leading to differentiation and to tumorigenic transformation.

Following a career break to raise children, she obtained a Wellcome Trust Career Re-entry fellowship and joined the Sir William Dunn School of Pathology in 2007, where she established and Heads the James Martin Stem Cell Facility. The Facility has expertise in human induced Pluripotent Stem (iPS) cell derivation, culture, genetic modification and differentiation. iPS cells derived from patients with genetic disease offers a new, hugely exciting opportunity to model human diseases ‘in a dish’, and this is particularly important for modelling neurological conditions, where patient material is generally unavailable until after death. The JMSCF has generated panels of iPS cells from Parkinson’s Disease patients as part of a large scale Oxford Parkinson’s Disease Centre research programme funded by Parkinson’s UK (in collaboration with Richard Wade-Martins), and Sally is a key member of StemBANCC, an EU-wide collaborative programme to develop iPSc disease models as drug-screening platforms.

Dr Marella de Bruijn


Group Head / PI, Grant Holding Senior Scientist and Supervisor, Weatherall Institute of Molecular Medicine, University of Oxford

Marella de Bruijn obtained her PhD from Erasmus University, Rotterdam, the Netherlands, where she trained in immunology and hematology. She then was a post-doctoral fellow in the Department of Cell Biology and Genetics at Erasmus University, and a fellow of the Dutch Cancer Society in the Department of Biochemistry at Dartmouth Medical School, Hanover, NH. She moved to Oxford to join the faculty of the MRC Molecular Haematology Unit in 2003, where she is currently a tenured Group Leader, and an associate of the Oxford Stem Cell Institute. Her research interest is directed towards elucidating the cellular and regulatory processes that give rise to hematopoietic stem cells (HSCs) during embryogenesis, with the aim to better understand the transcriptional network that underlies de novo HSC generation. Her work is relevant to future studies aimed at generating/expanding HSCs in the clinic, and could provide a framework to explore the changes in the network associated with leukemia.

Areas of expertise: Stem cells, developmental hematopoiesis, transcriptional regulation.

Prof Colin Goding


Professor of Oncology, Group Head / PI, Member of Congregation and Supervisor, Oxford Ludwig Institute, University of Oxford

Colin Goding graduated from the University of Leeds, UK after studying microbiology, and subsequently entered the 3 year PhD program at the UK Medical Research Council’s National Institute for Medical Research in Mill Hill, London where he studied adenovirus DNA replication. He then moved to Pierre Chambon’s lab in Strasbourg, France with a Royal Society Fellowship to investigate the mechanisms underlying adenovirus gene expression. His work there led to him being offered a position to run his own lab at the Marie Curie Research Institute in Surrey, UK where he established a program of research examining basic mechanisms of gene expression in S. cerevisiae and cell type-specific gene expression in melanocytes and melanoma. His work has continued on these two parallel research themes on his move in 2008 to the Ludwig Institute for Cancer Research at the University of Oxford UK. He was Editor-in Chief of Pigment Cell and Melanoma Research from 2005-2010, elected to membership of EMBO in 2009, and became co-director of the Oxford Stem Cell Institute in 2011.

Professor Sarah Harper


Dr Kenny Moore


James Martin Stem Cell Research Fellow, James Martin Trust, Brasenose College

Kenny is a James Martin Stem Cell Research Fellow using stem cells to investigate host-pathogen interactions of HIV-1. Genetic manipulation plays an important role in uncovering the function of various proteins in any system, and using stem cell-derived macrophages, a technology developed within the James laboratory, Kenny is creating genetically modified macrophages for the study of HIV-1 infection. Genetic manipulation of stem cells is also of paramount importance for their development as a therapeutic tool and Kenny is also involved in designing new strategies to accomplish this aim. After graduating from Oxford with a degree in Biological Sciences, Kenny studied at Imperial College London, first obtaining a Masters degree in the Molecular Biology of Viruses, and subsequently completing a PhD in Gene Therapy approaches to HBV infection. Kenny then secured a post-doctoral research position within the National Cancer Institute at Frederick, Maryland, within the retrovirology section investigating factors involved in recombination of HIV-1. This lead to the identification of the site and timing of dimerisation of the two strands of HIV-1 genomic RNA that become packaged into the virion ( J Virol 2007 and PLoS Pathog. 2009 ). Upon returning to the UK, Kenny acquired a post-doctoral research position within the James Lab on an NIH funded project to exploit aptamer technology for antiviral microbicides (J Biol Chem 2011) and has subsequently become one of the first James Martin Stem Cell Research Fellows.

Prof Udo Oppermann


Professor in Molecular Biology, Director of Molecular Laboratory Sciences, Botnar Research Centre and Deputy Director of the Institute of Musculoskeletal Sciences, University of Oxford

Professor Udo Oppermann obtained a Diploma in Human Biology in 1990 and PhD in Pharmacology and Toxicology in 1994, both with distinctions from Philipps University Marburg, Germany. He went on to become Associate Professor at Karolinska Institutet, Stockholm, in the Department of Medical Biochemistry and Biophysics where he stayed until 2004. After a sabbatical stay at Yale University, he has been a Principal Investigator of the Structural Genomics Consortium (SGC) in Oxford since its inception in 2003. In 2008 he became Professor in Molecular Biology at the Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, and he is now Deputy Director of the Institute of Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, as well as a Fellow of St Catherine's College.
The research in the Oppermann group focuses on the biology and structure-activity relationships of human metabolic protein families of all types but with emphasis on oxidoreductases such as short- or medium chain dehydrogenases / reductases (SDR, MDR), or oxidative enzymes such as the ketoglutarate dependent oxygenases. The use of chemical biology to understand human biology is a major focus of the group and is currently applied to the field of epigenetic mechanisms in stem cell biology, as well as chronic inflammatory and metabolic diseases.

Dr Jonathan Pugh


Postdoctoral Research Fellow in Applied Moral Philosophy, University of Oxford

Jonathan Pugh is a Postdoctoral Research Fellow in Applied Moral Philosophy at the University of Oxford's Uehiro Centre for Practical Ethics. He is currently working on the Wellcome Trust funded project 'Neurointerventions in Crime Prevention: An Ethical Analysis'. His research focuses on ethical issues surrounding the use of novel biotechnologies, and on personal autonomy in practical ethics. He has published work on the ethics of human embryonic stem cell research, in vitro gametogenesis, and the use of genetic enhancement technologies, amongst other topics.

Prof Paul Riley


Professor of Development and Reproduction & BHF Professor of Regenerative Medicine, Department of Physiology, Anatomy and Genetics, University of Oxford

Paul Riley took up the Chair of Development and Reproduction in the Department of Physiology, Anatomy and Genetics on 1st October 2011, having been awarded a British Heart Foundation Personal Chair of Regenerative Medicine to support this position. He was previously Professor of Molecular Cardiology at the UCL-Institute of Child Health, London, where he was a principal investigator within the Molecular Medicine Unit at UCL-ICH since 1999. Prior to this, he obtained his PhD at UCL (1992-1995) and completed post-doctoral fellowships at the Samuel Lunenfeld Research Institute, Toronto, Canada and the Weatherall Institute of Molecular Medicine, Oxford (1996-1999). In 2008, Professor Riley was awarded the Outstanding Achievement Award of the European Society of Cardiology (ESC) Council on Basic Sciences. The award recognises a landmark discovery in the field of basic cardiovascular science when his team found that Thymosin b4 could mobilise dormant cells from adult epicardium to form new blood vessels in the heart, a major step towards finding a DIY mechanism to repair injury following a heart attack.

Dr Angela Russell


Departmental Research Lecturer and RCUK Fellow in Medicinal Chemistry, Department of Chemistry and Pharmacology, University of Oxford

Angela Russell gained an MChem degree from Oxford University in 2000, which included a Part II project on the synthesis and evaluation of ion channel mimics under the supervision of Paul Beer. She gained her DPhil from Oxford in 2004 under the joint supervision of Steve Davies and Tim Perera from Yamanouchi plc (now Astellas Pharma Inc.). The main focus of her work was using a pharmacophore modelling approach for the development of novel phosphatase inhibitors but also encompassed the development of novel asymmetric methodologies and the synthesis of molecules of biological importance. In March 2006 she became a Departmental Research Lecturer in Organic Chemistry and in August 2007 was awarded an RCUK Fellowship in Medicinal Chemistry jointly between the Departments of Chemistry and Pharmacology in Oxford.

Professor Len Seymour


Professor Len Seymour is a world authority on genetic medicine, with over 120 publications and several patents. Len is Professor of Gene Therapies, and Director of the Section of Clinical Pharmacology at the University of Oxford’s Department of Oncology. He sits on a number of editorial and scientific advisory boards, was the founding President of the British Society for Gene Therapy, and is the current General Secretary of the European Society of Gene and Cell Therapy.

Professor Seymour is also Co-Founder of Oxford Genetics.


Bill Shingleton


Technical Lead, GE Healthcare

Biological scientist, first degree from Bristol Polytechnic, and PhD from Cambridge University, School of Veterinary Medicine. Research focus on connective tissue biology studying the mechanisms inflammation, tissue degradation and ageing. Post-Doctoral position at the University of Newcastle-upon-Tyne, followed by a brief spell in Biotech before joining Unilever’s R&D centre , Bedfordshire. Current role as Technical Lead for GE Healthcare, supporting the Cell Therapy industry through application and development of equipment and processes to enable the manufacture of therapeutic doses of cells.

Prof Glyn Stacey


Director, UK Stem Cell Bank, South Mimms

Glyn Stacey has a background in public health and cancer research and has worked on the development of cell substrates for manufacture of biological medicines. He is currently Head of Division of Cell Biology and Imaging and Director for the UK Stem Cell bank, a licensed clinical tissue bank, at the National Institute for Biological Standards and Control at South Mimms, UK. The work of his group covers safety and quality issues in cell therapy, cells used for manufacturing purposes, development of novel cell-based assays and the development of reference materials for tissue typing and diagnosis of genetic disorders. This work includes the need for scale up of preservation techniques and long term storage of DNA and cell lines of various types including human stem cell lines and cells used in bioassays and vaccine production. Glyn serves on numerous steering groups for organisations promoting and funding regenerative medicine and for many years as a committee member for the Society for Low Temperature Biology. He has also chaired the scientific advisory board for a Public Private Partnership not-for-profit company called Stem Cells for Safer Medicine.

Dr Francis Szele


Dept of Physiology, Anatomy and Genetics, University of Oxford

Francis Szele obtained his PhD at the University of Pennsylvania in Philadelphia where he worked on adult brain plasticity in the laboratory of Marie-Francoise Chesselet. He then moved to Connie Cepko’s laboratory at Harvard Medical School for his postdoctoral fellowship. He examined lineage relationships and migration patterns in the developing forebrain. He established his laboratory in Chicago at Northwestern University, Feinberg School of Medicine in 1999. He has investigated stem cells, neurogenesis, and migration in the postnatal subventricular zone (SVZ). He was appointed to a University Lecturer position at the Department of Physiology, Anatomy and Genetics associated with a Tutorial Fellowship at St Anne's College, Oxford in 2007. Szele’s early studies focusing on animal models of traumatic brain injury (TBI) were the first to show increases in SVZ neurogenesis after injury. His group now seeks to further understand the molecular regulation of SVZ endogenous repair in stroke and multiple sclerosis and to augment it with pharmacological and molecular approaches. The subventricular zone (SVZ) contains stem cells and generates more neurons than any other adult brain region. It is an excellent system to study molecular mechanisms that regulate stem cells and neuronal progenitor cell migration. Szele and colleagues have developed two-photon time-lapse microscopy to study the SVZ and recently discovered that galectin-3 specifically regulates SVZ neuroblast migration. We have also shown that the dopamine D3 receptor is necessary for SVZ neurogenesis. The Szele laboratory uses a large variety of experimental techniques ranging from in vivo approaches and the neurosphere stem cell assay. They collaborate extensively and welcome enquiries from interested scientists and students.


If you would like to discuss your application or any part of the application process before applying, please contact:
Course Administrator
Tel: +44 (0)1865 286958

Level and demands

The course is likely to appeal to research scientists from either industrial or academic sectors, considering entering the stem cell field, together with PhD students wishing to gain a thorough understanding of the field at the outset of their studies.

Furthermore, the course may prove beneficial for healthcare professionals, wishing to explore the likely influence that stem cell biology will have on the practice of medicine in the future, as well as those working for regulatory bodies or in related fields such as journalism, for which a firm understanding of the principles of stem cell biology may facilitate future coverage of developments in the field.

"The course is designed for those who have no prior knowledge or understanding of stem cells, so as to provide as broad an overview of the subject as possible. This will include not only the science underlying the subject but related issues such as the ethics and regulatory infrastructure and commercialisation of regenerative medicine.

Many of the lecturers will undoubtedly present some of their more cutting-edge insights which will, we hope, be of interest to those with a particular interest in the field and who already come with specialist knowledge. In essence, we therefore hope to cater for the range of people we anticipate will be attracted to the course."
Professor Paul Fairchild

If you're uncertain whether this course is suitable for your requirements, please email us with any questions you may have.