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Lecture Synopsis

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.

Michaelmas Term Metabolism in Health and Disease

Dr G Yeo: Prologue - Diabetes (2)

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.

Lecture 1

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.

Lecture 2

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 H R Mott:  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 F 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.

Glycolysis.

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 b-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. 

Dr Marc de la Roche:  Membrane Dynamics And Cellular Signalling (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 R 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 also have a brief look at leptin and mechanisms regulating appetite and energy expenditure.

 

Lent Term

Lent Term: The Genome in Health and Disease

Dr T Littlewood: Prologue:  Cancer as A Molecular Disease (1)

The lecture provides a general introduction to cancer and the types of molecules that are involved.

Cancer epidemiology and tumour development

  • Changes in cancer incidence 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.
  • Cancer is primarily a genetic disease.
  • The relevance of DNA repair mechanisms in cancer
  • 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 The Genome (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.

Centromeres.

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.

Dr 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        

Elongation

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.

Professor C Watson: Control of Proliferation and Death in Cancer Cells (3)

Lectures 1 and 2: 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

Checkpoints

The licensing of DNA replication

Re-replication block

Two types of cell division: mitosis and meiosis

Stages of mitosis

Spindle assembly checkpoint

Chromosome separation

Cytokinesis

Aberrant cell division can lead to cancer

Lecture 3:  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

Prof A Ferguson-Smith, Dr E Murchison – Introduction to Medical and Veterinary Genetics

The aim of these lectures is to introduce you to genetics in human and animal health, including a framework for cancer genetics, and will 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 and foundations

Introduction to the course

Karyotypes and the architecture of chromosomes

Pedigrees and kinship

Mendel’s Laws and some exceptions

Meiosis and crossing over

Lecture 2 – Disease mapping and inheritance

Genetic linkage

Recombination frequency and linkage maps

Mapping traits, genes and diseases

Single gene disorders

Exome sequencing

Autosomal dominant diseases

Autosomal recessive diseases

Lecture 3 – Chromosome aberrations, mechanisms and diagnosis

Numerical and structural aberrations

Copy number variation

Diagnosis of chromosome aberrations

Chromosome abnormalities in disease

Lecture 4 – Sex-linked disorders and X inactivation

Thomas Hunt Morgan and the white gene

Sex linked disorders

X inactivation and introduction to epigenetics

Epigenetic modifications to DNA and chromatin and their function

Lecture 5 – Cancer Genetics

Somatic evolution of cancer - overview

Driver and passenger mutations

Cancer genes

Germline genetic variation and inherited cancer risk

Types of somatic mutation

Mutation signatures

Epigenetic changes in cancer

Viruses and cancer

Transmissible cancers

Lecture 6 – Epigenetics, environment and disease

Genomic imprinting and imprinted disorders

Gene-environment interactions and disease – non-genetic inheritance

Twin studies

Mitochondrial disease

Lecture 7 – Introduction to genetics in populations

Hardy-Weinberg equilibrium

Allele-frequencies in populations

Founder effects and bottlenecks

Selection

Genetic variants in populations

Genetic selection and livestock breeding

Lecture 8 – Genetics revision lecture – see Easter term

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.

Prof A Venkitamaran: 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?

Easter Term

Translating biochemistry and genetics to the clinic

Dr Alan Wright:  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.

Parallel lecture (1) –details to be given later in the year Professor N. Wareham: Nutrition and Preventive Medicine

Dr P. Watson: Clinical Aspects of Energy Metabolism in Small Animals

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?

Professor A Ferguson-Smith: Genetics revision session and preparation for exams (1)

Lecture 8

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 genetics 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.