Outline of the MIMS lecture course
Important note. This information is provided at the beginning of the year for your guidance and that of your supervisors. It is not intended to be a comprehensive list of contents. Lecturers will all issue their own handouts, and may vary the topics and the order in which they are presented.
Metabolism in Health and Disease
Dr G Yeo: Prologue - Diabetes Mellitus as a Metabollic Disease
The aim of the Prologue is to illustrate the molecular basis of medicine, to anticipate the main topics covered in the first term's lectures and to introduce terminology, within the context of diabetes as a common metabolic disease.
- Case studies, illustrating typical presentation of diabetes.
- Definition of diabetes in terms of hyperglycaemia; diagnosis by glucose tolerance test.
- Classification, causes and treatment of type 1 (juvenile) and type 2 (maturity onset) diabetes; other forms of diabetes; diabetes in animals.
- Historical perspective on Banting and Best and the discovery of insulin.
- Acute manifestation of diabetes as a metabolic problem reflecting lack of insulin action.
- Long term complications of diabetes resulting from chronic hyperglycaemia
- Statistics on prevalence of diabetes and obesity and cost implications for health care.
- Structure of insulin, as an example of a small protein.
- Carbohydrates and lipids as fuels; metabolic pathways for their oxidation.
- Introduction to regulation of metabolic pathways by cellular energy charge or hormonal signals ; allosteric regulation and covalent modification of enzymes.
- Insulin biosynthesis and secretion.
- Actions of insulin on carbohydrate, lipid and protein metabolism.
- Insulin receptors and glucose transporters as examples of membrane proteins.
- Introduction to mechanism of insulin action & signalling via protein kinase cascades.
- Obesity, insulin resistance and type 2 diabetes; why is insulin action impaired by obesity?
Dr Mott: Introcution to Biological Macromolecules, Protein Structure And Enzyme Catalysis (6)
After an introduction to macromolecules, the lectures concern understanding of the structure of proteins and how the structure governs the function. We will study examples of the structures of medically relevant proteins and enzymes. We will then focus on enzymes, studying how they catalyse reactions and how this activity is controlled.
Lecture 1: Introduction to Macromolecules
Sugars, nucleic acids and proteins
Lectures 2-3: Protein Structure and Function
- Methods for studying macromolecules.
- The levels of protein structure.
- The amino acids and peptide bond formation.
- Prediction of function from sequence information.
- Bond formation in the development of protein structure.
- How proteins fold.
- Protein misfolding and disease
- The structure of a protein is determined by the amino acid sequence.
- The role of prosthetic groups and cofactors.
- Case study - how protein structure leads to function in haemoglobin.
- Membrane proteins.
- Antibody structure and function.
Lectures 4-6: Enzyme Function and Control
- Energetics of enzyme-catalysed reactions
- Catalysis of a reaction by transition state stabilisation.
- How the structure of an enzyme active site causes catalysis.
- Classification and characterisation of enzymes.
- Michaelis-Menten kinetics.
- Enzyme inhibition
- Alteration of activity by covalent modification.
- Allosteric control and conformational change.
- Cooperativity of multimeric enzymes.
- Case study - development of HIV protease inhibitors.
Dr. R. W. Broadhurst, Prof. P. Leadlay: Bioenergetics And Metabolism (8)
The Metabolic Fates of Glucose and Fat After Feeding
- Importance of blood glucose concentration and insulin.
- Cameos of fuel economies of gut, liver, muscle, adipose tissue, brain.
- Uptake of glucose and its conversion to fuel stores.
- Formation of acetyl-CoA from pyruvate.
- Biosynthesis of fatty acids from acetyl-CoA.
- Biosynthesis of triacylglycerols ('fat').
- Digestion of dietary fat: formation and fate of chylomicrons.
- Role of other lipoproteins in transferring triacylglycerol from liver to adipose tissue.
The Fuelling of Muscle Contraction by Carbohydrate and Lipids
- Mobilisation of glycogen: glycogenolysis.
- Fates of pyruvate: reduction to lactate (anaerobic) and oxidation to CO2 (aerobic)
- Mobilisation of triacylglycerol: lipolysis.
- Fatty acid transport to muscle and -oxidation to acetyl-CoA.
- Citric acid cycle and oxidation of acetyl-CoA to complete carbohydrate and fat oxidation.
- Formation and use of ketone bodies.
Control of Fuel Storage and Oxidation
- The interplay of insulin and the catabolic hormones glucagon and adrenaline.
- Principles of metabolic control.
- Control of glycogen synthesis and breakdown.
- Control of fatty acid and triacylglycerol synthesis.
- Interplay of short-term acute control and longer term adaptive control.
- Control of lipolysis in adipose tissue.
- Control of glycolysis and citric acid cycle.
- Amphibolic role of citric acid cycle.
Fasting and Gluconeogenesis; Aspects of Amino Acid Metabolism
- Fuel needs of brain and how met in fasting by liver making glucose and ketone bodies.
- Amino acids in gluconeogenesis and ketogenesis.
- Control of gluconeogenesis.
- Ketosis and diabetes.
- Overview of metabolic roles of amino acids and of amino acid catabolism.
- The importance of aminotransferases and glutamate dehydrogenase.
- The urea cycle.
- Amino acids and the supply of methyl groups and other 'one-carbon' fragments for biosynthesis.
Mitochondrial respiration and oxidative phosphorylation
- ATP couples exergonic catabolism to endergonic anabolism.
- How oxidation is coupled to phosphorylation by mitochondria.
- Overview of the electron-transport chain.
- Some comments on individual redox cofactors.
- Experimental background to the ordering of the electron-transport chain.
- Structure and function of the complexes of the electron-transport chain.
- How the proton motive force drives the ATP synthase to make ATP.
- How the proton motive force drives transport in and out of mitochondria.
Professor C Taylor: Membrane Dynamics And Cellular Function Signalling by Hormones (5)
Lecture 1: Protein Trafficking, Secretion and Endocytosis.
- Secretion and endocytosis.
- Importance of protein trafficking for maintenance and synthesis of intracellular structures.
- The diabetes context: insulin synthesis and secretion.
- Structure of the endoplasmic reticulum, Golgi apparatus and plasma membrane, emphasising their dynamic nature and interrelationship.
- Secretion - Concept of targeting sequences. Consideration of organelle-specific targeting, protein processing, role of cytoskeleton and motor proteins. Outline of molecular events in secretion.
- Endocytosis - Pinocytosis and endocytosis in coated pits leading to lysosomes or recycling to plasma membrane. Example of LDL receptors.
Lectures 2-5: Hormonal Signalling
- Recognition of water-soluble hormones by surface receptors generates a signal inside the cell. The lectures will give an understanding of the key elements of the nature of some of the signals, how they are generated and removed, and how the cell interprets them as a part of its function.
- The three basic types of receptor, how they work and why: ligand-gated ion channels, G-protein coupled (7 transmembrane domain), and tyrosine kinase.
- The role of trimeric G-proteins in signal transduction, illustrated by control of adenylyl cyclase activity to produce the 2nd messenger cyclic AMP. Actions of cyclic AMP to illustrate protein phosphorylation as a transducing mechanism.
- Simple introduction to cyclic GMP and nitric oxide.
- Hormonal activation of phosphoinositide hydrolysis and elevation of Ca2+ concentration by inositol trisphosphate.
- Action of diacylglycerol to activate protein kinase C.
- Phosphatidylinositol 3,4,5-trisphosphate as another lipid second messenger.
- A brief outline of Ca2+ regulation and its importance as a 2nd messenger.
- The operation of tyrosine kinase receptors, illustrated by the (typical) PDGF receptor and the insulin receptor.
- Receptor families and the concept of more complex signal transduction cascades involving protein kinases. A complex signal transduction cascade exemplified by the pathway from the insulin receptor to the stimulation of glycogen synthesis.
Dr H Mott: Molecular Recognition & Drug Design (2)
The aim of these lectures is to understand how molecules interact with one another within the cell. We will consider the basic principles of molecular recognition, focusing on examples from growth factor response pathways. We will then go on to see how knowledge of protein structure and function helps to develop inhibitors that act as drug molecules
Lecture 1: Principles of Molecular Recognition
- How the structure of a protein allows it to perform molecular recognition.
- Bond formation in recognition.
- Conformational changes and reversible covalent modification.
- Protein-protein and protein-DNA recognition in growth factor response pathways
- Measuring binding affinities and finding new interactions
Lecture 2: Principles of Drug Design
- Design of enzyme inhibitors as drug molecules.
- How monoclonal antibodies are produced experimentally.
- Use of monoclonal antibodies in cancer therapy.
Dr G Yeo: Epilogue (1)
I will use the opportunity to tie together the information covered in the PBL, and will discuss the obesity epidemic: a major threat to public health.
We will also have a brief look at leptin and mechanisms regulating appetite and energy expenditure.
The Genome in Health and Disease
Dr T Littlewood: Prologue - Cancer As A Molecular Disease (1)
The lectures provide a general introduction to cancer and the molecules that are involved.
Cancer Epidemiology and Tumour Development
- Changes in the incidence of cancer and mortality in the UK and worldwide
- The causes of cancer
- Cancers occur in many distinct forms but are characterised by common features - the hallmarks of cancer
- The process of tumour development: vascularisation, invasion and metastasis.
The Molecular Biology of Cancer
- The relevance of DNA repair mechanisms in cancer
- Cancer is primarily a genetic disease. There will an introduction to the classes of genes that promote cancer (oncogenes) and those that are involved in suppressing tumour development (tumour suppressors). A small number of examples will be discussed to illustrate the common principles of their molecular functions.
Dr L. Pellegrini: Organisation, Replication And Repair Of Genomes (5)
Lecture 1: Organisation of DNA in the Genome
- DNA is the genetic material.
- Chemistry and structure of the DNA double helix.
- Dimensions and scale of the DNA double helix.
- How do you fit 2 metres of DNA into a 10 micron diameter nucleus?
- Different levels of compaction.
- Nucleosomes, nuclear scaffold, chromosomes.
Lecture 2: How DNA is Replicated
- The double helix as a template. Semiconservative replication.
- DNA polymerases, requirement for substrates, primers and template.
- Ensuring accuracy - proof reading.
- Discontinuous replication and Okazaki fragments.
- Origins of replication - the replication fork.
- How genomes are replicated.
- The problem of linear chromosomes and the solution – telomeres.
- Sequencing DNA – classical methods and massively parallel sequencing.
- Polymerase chain reaction.
Lectures 3-4: Information Content of DNA
- What is a gene?
- What is gene expression – cDNA libraries and microarrays?
- The human and other genome projects – genomic libraries, sequencing and sequence assembly.
- How many genes make a human?
- Differing sizes of genomes.
- Not all DNA encodes genes.
- Junk DNA?
- Repetitive DNA, microsatellites, hypervariability and fingerprints.
- Mobile genetic elements.
Lecture 5: Change and Constancy of DNA
- DNA modifications and epigenetics.
- Mutations and how they arise.
- DNA damage and its consequences.
- Mechanisms of DNA repair.
- DNA repair and cancer.
- How DNA rearrangements can be a good thing.
Prof E Miska: Transcription, Translation And Control (5)
Lecture 1: Transcription in Prokaryotes and its Control
- Course overview – The Central Dogma
- What is a gene? What is mRNA?
- Basic mechanism of RNA synthesis (transcription)
- Regulation of transcription
- The lac repressor and the catabolite activator protein (CAP)
- Antibiotics that inhibit prokaryote transcription
Lecture 2: Transcription in Eukaryotes and its Control
- RNA Polymerases
- Eukaryotic promoters and upstream regulatory elements
- Regulation of transcription
- Roles of chromatin
- Enhancers and response elements
- Tissue-specific and developmentally regulated transcription factors
- Transcription factors and cancer – cFos/c-Jun, p53
Lecture 3: Pre-mRNA Processing - from pre-RNA to Mature mRNA
- 'Polishing' pre-mRNA
- 5' Capping
- Termination and polyadenylation
- RNA splicing
- Alternative splicing
- Anomalous splicing and cancer – Wilms tumour
- Making cDNA and genomic libraries
Lecture 4: Translation - Protein Synthesis
- Control of mRNA stability
- Genetic code
- tRNA structure and charging with amino acids
- Ribosomes and polysomes: structure and function
- Initiation of translation
Lecture 5: Translation Continued – Elongation, Termination, Degradation
- Control and termination of translation
- Antibiotics that target the translational machinery
- Protein degradation – the lysosome and the proteasome, ubiquitin.
- Gene expression studies, arrays and cancer
- MicroRNA, siRNA and RNAi.
Prof A Ferguson-Smith – Genetics in Human and Animal Medicine (8)
The aim of these lectures is to introduce you to the importance of genetics in human and animal health and to focus on many of the basic principles and concepts which form the foundation for understanding genetics in the clinic and in biomedical research today.
Lecture 1: Introduction
- Introduction to the course
- Karyotypes and the architecture of chromosomes
- Mendelian Genetics and the chromosomal basis of inheritance: a historical perspective
Lecture 2: Meiosis and Mapping
- Meiosis and crossing over
- Generation of Recombination maps
- Mutation and mutagenesis
- Mapping traits, genes and diseases
- Disease mapping and exome sequencing
Lecture 3: Pedigrees and the Inheritance of Genetic Disorders in People and Animals
- Numerical and structural aberrations and their diagnosis
- Kinship and pedigree analysis
- Single gene disorders
- Autosomal dominant diseases, examples and mechanisms
- Autosomal recessive diseases, examples and mechanisms
Lecture 4: Sex and Sex chromosomes
- Thomas Hunt Morgan and the white gene
- Sex chromosome abnormalities
- Sex linked disorders
- Sex determination and the Y
- X inactivation
Lecture 5: Environment, Epigenetics and Disease
- Genomic imprinting and parental origin effects
- Epigenetic modifications to DNA and chromatin
- Functions of epigenetic modifications
- Gene-environment interactions
Lecture 6: Other genetic diseases and mechanisms
- Mitochondrial disease and embryological manipulation
- Trinucleotide repeat expansion diseases
- Twin studies
Lecture 7: Behaviour and Analysis of Genes and Variants in Populations
- Hardy-Weinberg equilibrium
- Calculation of allele-frequencies in populations
- Founder effects and bottlenecks
- Sickle cell anemia, malaria and balancing selection
- Genetic variants in populations
Lecture 8: Genomics and the future of medicine
- Introduction to genome-wide association studies
- Variation and quantitative trait loci
- Personalised medicine
- Prognostics, Diagnostics and Therapeutics
- International consortia, big projects and databases.
Professor C Watson: Control Of Proliferation And Death In Cancer Cells (2)
Lecture 1: The Phases of the Cell Cycle and its Regulation
- Why do we need to understand cell proliferation and cell death?
- Phases of the cell cycle: two gap phases (G1 and G2) a DNA replication phase (S) and a cell division phase mitosis (M). Non-dividing cells (Go).
- Regulation of the cell cycle: Cyclins and cyclin-dependent kinases (CDKs) regulate the transition from one phase to the next.
- CDKs are constitutively expressed whereas cyclins are expressed at specific phases of the cell cycle
- Cyclin D and CDK4: G1
- Cyclin E and CDK2: preparing for S phase
- Cyclin B and CDK1: the G2-M transition.
- Regulation of CDK activity
- The licensing of DNA replication
- Re-replication block
- Two types of cell division: mitosis and meiosis
- Stages of mitosis
- Spindle assembly checkpoint
- Chromosome separation
- Aberrant cell division can lead to cancer
Lecture 2. Cell Death in Normal and Cancer Cells
- Two main types of cell death: programmed cell death and necrosis
- Programmed cell death: apoptosis
- Basic mechanisms of apoptosis
- Executioner caspases and their substrates.
- The Bcl2 family
- The intrinsic and extrinsic pathways
- Cancer cells can become resistant to apoptosis
- Cancer drugs that target cell death pathways
Dr T Littlewood: Epilogue: Cancer As A Molecular Disease (1)
- Cancer Genes: Oncogenes and Tumour Suppressor Genes
- What are oncogenes and tumour suppressor genes and where do they operate in biological processes?
- Oncogenes –discovery, mechanisms and consequences of "activation"
- Oncogene cooperation in tumourigenesis
- Tumour suppressor genes – their discovery and the consequences of loss of function
- The molecular basis of the inheritance of genetic predisposition to cancer.
Professor A Venkitaraman: Cancer Therapy (1)
This lecture will draw together information from previous lectures to illustrate how fundamental understanding of the biological basis of cancer is transforming approaches to therapy.
- Cancer pathogenesis and its underlying mechanisms
- Conceptual features and modalities for cancer therapy
- Challenges to the development of new therapies
- Case studies:
– Tackling oncogene addiction
– Unleashing the immune response
– Synthetic lethality: hope or hype?
Translating Biochemistry and Genetics to the Clinic
Professor A Ferguson-Smith: Revision session and preparation for exams (1)
Lecture 9 - Revision session and preparation for exams – it's all yours.
The purpose of this final lecture is to review specific topics that you will choose from the previous 8 lectures, in preparation for the examination. During the Lent term and Easter break, students are encouraged to contact the lecturer if there is a specific area that they would like to see covered in this session.
Professor N. Wareham: Nutrition and Health (1)
This lecture is a new addition to the course. A synopsis will be circulated in advance of the lecture
Professor Kevin Brindle: Imaging Biology in the Cancer Patient (2)
Our growing understanding of the molecular basis of cancer is allowing the design of new clinical imaging methods that provide early disease detection, that give prognostic information and that can detect early treatment response to guide therapy in individual patients. These lectures will outline the physical principles of these methods and show how they can be used to interrogate specific aspects of tumour cell biology in the cancer patient.