School of Biosciences

1. School of Biosciences Ole H Petersen director-biosi@cardiff.ac.uk Using clinical case stories to motivate students to study the relevant basic science Providing links to relevant and exciting research toenable students to understand how progress is made and how this will change future clinical practices

2. A great Medical School has great Teachers Two teachers who had a great influence on me as an undergraduate medical student (here seen ~20 years later) Jørn Hess Thaysen, the top clinician at ‘The Kingdom’ in Copenhagen, was a tireless defender and supporter of physiology as the essential basis of medicine 1742 Royal Danish Academy of Sciences & Letters Professor Niels Anker Thorn Professor of Physiology University of Copenhagen Jørn Hess Thaysen Professor of Internal Medicine University of Copenhagen Meeting at the Royal Danish Academy, Copenhagen, June 1987

3. As External Examiner in the Oxford Prelims in the late 1970s, I was impressed by the fact that Sir Richard spent a great deal of time participating in the basic science examinations, including the vivas, always insisting on thehighest standards. Sir Richard Doll FRS Regius Professor of Medicine, University of Oxford, 1969-1979

4. Credo: ●Physiology and pathophysiology are the basis of Medicine ●All diseases are due to malfunction of one or more cell types ●Textbooks are important ●It is a duty (for both educators and students) to be competent, but unfortunately nobody is sufficiently competent. Dedication makes up the deficit

5. These are, in my view, by far the most serious challenges

7. C21: The core Values are: Teaching Excellence, Patient Safety, Scholarship, Science and Service To me the most important point about teaching excellence is COMPETENCE in the relevant subject matter Interdisciplinarity IS important, but the quality of interdisciplinary teaching (and indeed research) is totally dependent on competence in the eductor’s own (primary) discipline

8. Learning initiated and inspired by specific case studies An example: Acute pancreatitis (AP) Why chose a relatively minor (infrequent) disease? One of the major factors responsible for AP is alcohol abuse; the second-leading cause of preventable death in the UK AP is due to malfunction of pancreatic acinar cells. This cell type has been, and continues to be, used as one of the most important cell biological models. Studies of pancreatic acinar cells have been fundamental in establishing: [1] The basis for our understanding of intracellular protein synthesis, processing and secretion (Palade, Nobel Prize 1974) [2] The basis for our understanding of intracellular signalling, by the discovery of the ubiquitous intracellular messenger function of the Ca2+-releasing agent inositoltrisphosphate(Sir Michael Berridge FRS, Lasker Award 1989)

10. Acute pancreatitis (AP) – a case study http://www.nhs.uk/Conditions/Pancreatitis/Pages/Introduction.aspx Stephanie Atts was diagnosed with pancreatitis when she was 24. She has given up drinking but the condition still causes her pain.  “I kept going into hospital back in 2002 because I was suffering from severe stomach pain. But the doctors couldn’t find anything wrong with me.” “They took some blood tests. They said they had my results and it was something quite serious. When they told me it was pancreatitis, I was really shocked and upset.” “Pancreatitis is incredibly painful. The stomach pain just comes on all of a sudden. There’s no run-up to it, it just hits you. It starts in my guts and moves round to my back, then I throw up. It’s hard to describe how bad the pain is. It's worse than being in labour, which is saying something. And there’s no position where you can get comfortable. It’s so bad you can barely move.” “They did some more tests to find out the extent of the damage and found that a quarter of my pancreas was terminally damaged. I was told to stop drinking immediately, which I did. I had been drinking heavily for about eight months, which is what caused the pancreatitis.”

11. Themes to explore (selection): ● How does the body deal with alcohol (ethanol) (basics: absorption, metabolism, elimination – quantitative approach) Biochemistry/Physiology ● Mechanisms of cellular action of ethanol (and metabolites) (basics: ion channels in plasma membrane and organelle membranes; research link: molecular mechanisms of alcohol actions) Physiology/Pathophysiology/Neurophysiology ● How could actions on ion channel opening and closure in nerve cell membranes affect behaviour? (research link: molecular neurobiology and behavioural studies) Neurophysiology/Psychology/Psychiatry ● AP is initiated by activation of digestive pro-enzymes (particularly proteases such as trypsinogen) inside the pancreatic acinar cells (basics: intracellular processing of proteins and secretion). How can ethanol or ethanol products induce such inappropriate activation (research link: live cell imaging of protease activation, gene deletion studies)? Physiology/Pathophysiology/Cell Biology ● Disease progression: How does AP become chronic pancreatitis and why does chronic pancreatitis predispose to pancreatic cancer (basics: stellate cells and fibrosis; research link: the cancer-promoting intercellular matrix)? Cell Biology/Cancer Biology ● Other causes of AP (gallstones, high lipid concentration in blood) (basics: anatomy/phsyiology of biliary and pancreatic systems) (fat-alcohol interactions) (research link: cellularmechanisms of action of bile acids). Anatomy/Physiology/Biochemistry ● Prevention and treatment of AP (dealing with excessive use of alcohol, dietary advice, exploration of ways to diminish intracellular protease activation) (basics and many research links). General Practice/Psychiatry/Sociology/Pathophysiology/Pharmacology/Pharmacy

12. Example of one set of Learning Outcomes, arising from critical considerations of a simple quantitative experiment: BAL Blood Alcohol Level (BAL) as a function of time after intake of single alcohol dose Elimination by oxidation in liver Absorption from G-I Tract min Time course of BAL in a man weighing 79 kg after intake of 36.8 g alcohol (at time 0) [For historical reasons blood alcohol concentrations are calculated as g/kg blood plasma given in percent. Since the specific weight of plasma is 1.23, a BAL of, for example, 500 mg/dl corresponds to 4.060/00; (this is close to LD50 of ethanol in humans)]

13. [1] Alcohol is absorbed relatively quickly from the G-I tract. [2] After appearance in blood it is rapidly distributed in a fluid volume corresponding to ~50 - 70 % of the body weight. [3] At BAL > 0.10/00,alcohol is metabolized at a constant rate (mostly by oxidation) of ~7 g per hour for a person weighing 70 kg. Alcohol dehydrogenase is a key (liver) enzyme and low levels of this enzyme will decrease alcohol tolerance [4] Alcohol is excreted via lung ventilation (concentration in alveolar air ~1/2000 of BAL) and in the urine (~same concentration as in plasma). [5] The rate of elimination of alcohol via the lungs and urine is small compared to elimination by oxidation, which occurs principally in the liver (a substantial part of oxidation in the liver is only partial to acetate, which can then be further broken down in extra-hepatic tissues). [6] The rate of alcohol oxidation in the liver is rate limiting for disposal of alcohol from the whole body. Increased energy consumption by skeletal muscles (physical work), for example, will therefore NOT affect the rate of elimination. BAL Blood Alcohol Level (BAL) as a function of time after intake of single alcohol dose Elimination by oxidation in liver Absorption from G-I Tract min Time course of BAL in a man weighing 79 kg after intake of 36.8 g alcohol (at time 0) [For historical reasons blood alcohol concentrations are calculated as g/kg blood plasma given in percent. Since the specific weight of plasma is 1.23, a BAL of, for example, 500 mg/dl corresponds to 4.060/00; (this is close to LD50 of ethanol in humans)] Example of Required Core Knowledge

14. How to assess the Blood Alcohol Level (BAL) at the time of an accident on the basis of later repeated measurements of BAL and extrapolation A basis for a quantitiative test question BAL Accident Measurement period min Time course of BAL in a man weighing 79 kg after intake of 36.8 g alcohol (at time 0) [For historical reasons blood alcohol concentrations are calculated as g/kg blood plasma given in percent. Since the specific weight of plasma is 1.23, a BAL of, for example, 500 mg/dl corresponds to 4.060/00; (this is close to LD50 of ethanol in humans)]

15. Research Project: Clinically relevant pathophysiology

16. The intracellular protein calmodulin (CaM) protects against alcohol-related pancreatitis Isolated live pancreatic acinar cell Trypsin activity (ethanol) Research Project: Clinically relevant pathophysiology Gerasimenko, Lur, Ferdek, Sherwood, Ebisui, Tepikin, Mikoshiba, Petersen, GerasimenkoCalmodulin (CaM) protects against alcohol-induced pancreatic trypsinogen activation elicited via Ca2+ release through inositoltrisphosphate receptors. Proc. Natl. Acad. Sci. USA (PNAS) 108, 5873-5878, 2011 (MRC press release: http://www.mrc.ac.uk/Newspublications/News/MRC007775)

17. The intracellular protein calmodulin (CaM) protects against alcohol-related pancreatitis Isolated live pancreatic acinar cell Trypsin activity (ethanol) Research Project: Clinically relevant pathophysiology CALP-3 is a cell-permeable CaM agonist (Val-Lys-Phe-Gly-Val-Gly-Phe-Lys) Gerasimenko, Lur, Ferdek, Sherwood, Ebisui, Tepikin, Mikoshiba, Petersen, GerasimenkoCalmodulin protects against alcohol-induced pancreatic trypsinogen activation elicited via Ca2+ release through inositoltrisphosphate receptors. Proc. Natl. Acad. Sci. USA (PNAS) 108, 5873-5878, 2011 (MRC press release: http://www.mrc.ac.uk/Newspublications/News/MRC007775)

18. What is needed to make Phase 1 truly ‘World Class’? ■Use clear clinical case stories to provide stimulation and motivation for the students to work purposefully on the relevant basic science ■Create an effective Foundation Course in the basic biomedical sciences that will allow students to take full advantage of the case-based studies ■Provide clear links to relevant and exciting research enabling students to understand how progress is made ■Above all: employ competent, dedicated and inspirational teachers