School of BiosciencesSchool of Biosciences

Ole H PetersenOle H Petersendirector-biosi@cardiff.ac.uk director-biosi@cardiff.ac.uk

Using Using clinical case stories clinical case stories to motivate students to motivate students to study the to study the relevant basic science relevant basic science

Providing links to Providing links to relevant and exciting research relevant and exciting research toto enable students to enable students to understand how progress understand how progress is made is made and how this will and how this will change future clinical change future clinical practicespractices

A great Medical School has great A great Medical School has great TeachersTeachers

Jørn Hess ThaysenJørn Hess ThaysenProfessor of Internal MedicineProfessor of Internal Medicine

University of CopenhagenUniversity of Copenhagen

Professor Niels Anker ThornProfessor Niels Anker ThornProfessor of PhysiologyProfessor of Physiology

University of CopenhagenUniversity of Copenhagen

Meeting at the Royal Danish Academy, Copenhagen, June 1987Meeting at the Royal Danish Academy, Copenhagen, June 1987

17421742

Royal Danish Academy of Sciences & LettersRoyal Danish Academy of Sciences & Letters

Two teachers who had a great influence on me Two teachers who had a great influence on me as an undergraduate medical studentas an undergraduate medical student

(here seen ~20 years later)(here seen ~20 years later)Jørn Hess Thaysen, the top clinician at ‘The Jørn Hess Thaysen, the top clinician at ‘The

Kingdom’ in Copenhagen, was a tireless Kingdom’ in Copenhagen, was a tireless defender and supporter of physiology as the defender and supporter of physiology as the

essential basis of medicineessential basis of medicine

Sir Richard Doll FRSSir Richard Doll FRSRegius Professor of Regius Professor of

Medicine, University of Medicine, University of Oxford, 1969-1979Oxford, 1969-1979

As External Examiner in the Oxford As External Examiner in the Oxford Prelims in the late 1970s, I was Prelims in the late 1970s, I was impressed by the fact that Sir impressed by the fact that Sir

Richard spent a great deal of time Richard spent a great deal of time participating in the basic science participating in the basic science examinations, including the vivas, examinations, including the vivas,

always insisting on thealways insisting on the highest highest standards.standards.

CredoCredo::

●●Physiology and pathophysiology are Physiology and pathophysiology are the basis of Medicine the basis of Medicine

●●All diseases are due to malfunction of All diseases are due to malfunction of one or more cell typesone or more cell types

●●Textbooks are importantTextbooks are important

●●It is a duty (for both educators and It is a duty (for both educators and students) to be competent, but students) to be competent, but unfortunately nobody is sufficiently unfortunately nobody is sufficiently competent. Dedication makes up the competent. Dedication makes up the deficitdeficit

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

C21:C21:

The core Values are: The core Values are: Teaching Teaching ExcellenceExcellence, Patient Safety, Scholarship, , Patient Safety, Scholarship, Science and ServiceScience and Service

To me the most important point about teaching excellence is To me the most important point about teaching excellence is COMPETENCE in the relevant subject matter COMPETENCE in the relevant subject matter

Interdisciplinarity IS important, but the quality of Interdisciplinarity IS important, but the quality of interdisciplinary teaching (and indeed research) is totally interdisciplinary teaching (and indeed research) is totally dependent on competence in the eductor’s own (primary) dependent on competence in the eductor’s own (primary)

disciplinediscipline

Learning initiated and inspired by specific case Learning initiated and inspired by specific case studiesstudies

An example: Acute pancreatitis (AP)An example: Acute pancreatitis (AP)Why chose a relatively minor (infrequent) disease?Why chose a relatively minor (infrequent) disease?

One of the major factors responsible for AP is alcohol abuse; the second-One of the major factors responsible for AP is alcohol abuse; the second-leading cause of preventable death in the UKleading cause of preventable death in the UK

AP is due to malfunction of pancreatic acinar cells. This cell type has been, 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 and continues to be, used as one of the most important cell biological models. Studies of pancreatic acinar cells have been fundamental in models. Studies of pancreatic acinar cells have been fundamental in

establishing:establishing:

[1] [1] The basis for our understanding of intracellular protein synthesis, The basis for our understanding of intracellular protein synthesis, processing and secretionprocessing and secretion (Palade, Nobel Prize 1974) (Palade, Nobel Prize 1974)

[2] [2] The basis for our understanding of intracellular signalling, by the The basis for our understanding of intracellular signalling, by the discovery of the ubiquitous intracellular messenger function of the Cadiscovery of the ubiquitous intracellular messenger function of the Ca2+2+--releasing agent inositol trisphosphate releasing agent inositol trisphosphate (Sir Michael Berridge FRS, Lasker (Sir Michael Berridge FRS, Lasker

Award 1989)Award 1989)

Acute pancreatitis (AP) – a case studyAcute pancreatitis (AP) – a case studyhttp://www.nhs.uk/Conditions/Pancreatitis/Pages/Introduction.aspxhttp://www.nhs.uk/Conditions/Pancreatitis/Pages/Introduction.aspx

Stephanie Atts was diagnosed with pancreatitis when she was 24. She Stephanie Atts was diagnosed with pancreatitis when she was 24. She has given up drinking but the condition still causes her pain.has given up drinking but the condition still causes her pain.

 “ “I kept going into hospital back in 2002 because I was suffering from 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 severe stomach pain. But the doctors couldn’t find anything wrong with me.” me.”

““They took some blood tests. They said they had my results and it was 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 something quite serious. When they told me it was pancreatitis, I was really shocked and upset.” really shocked and upset.”

““Pancreatitis is incredibly painful. The stomach pain just comes on all of a 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 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 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 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 there’s no position where you can get comfortable. It’s so bad you can barely move.”barely move.”

““They did some more tests to find out the extent of the damage and found 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 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 drinking immediately, which I did. I had been drinking heavily for about eight months, which is what caused the pancreatitis.”eight months, which is what caused the pancreatitis.”

Themes to explore (Themes to explore (selectionselection):):●● How does the body deal with alcohol (ethanol) (How does the body deal with alcohol (ethanol) (basicsbasics: absorption, metabolism, : absorption, metabolism, elimination – quantitative approach) elimination – quantitative approach) Biochemistry/PhysiologyBiochemistry/Physiology

●● Mechanisms of cellular action of ethanol (and metabolites) (Mechanisms of cellular action of ethanol (and metabolites) (basicsbasics: ion channels : ion channels in plasma membrane and organelle membranes; in plasma membrane and organelle membranes; research liresearch linknk: molecular : molecular mechanisms of alcohol actions) mechanisms of alcohol actions) Physiology/Pathophysiology/NeurophysiologyPhysiology/Pathophysiology/Neurophysiology

●● How could actions on ion channel opening and closure in nerve cell membranes How could actions on ion channel opening and closure in nerve cell membranes affect behaviour? (affect behaviour? (research linkresearch link: molecular neurobiology and behavioural studies) : molecular neurobiology and behavioural studies) Neurophysiology/Psychology/PsychiatryNeurophysiology/Psychology/Psychiatry

●● AP is initiated by activation of digestive pro-enzymes (particularly proteases such AP is initiated by activation of digestive pro-enzymes (particularly proteases such as trypsinogen) inside the pancreatic acinar cells (as trypsinogen) inside the pancreatic acinar cells (basicsbasics: intracellular processing of : intracellular processing of proteins and secretion). How can ethanol or ethanol products induce such proteins and secretion). How can ethanol or ethanol products induce such inappropriate activation (inappropriate activation (research linkresearch link: live cell imaging of protease activation, : live cell imaging of protease activation, gene deletion studies)? gene deletion studies)? Physiology/Pathophysiology/Cell BiologyPhysiology/Pathophysiology/Cell Biology

●● Disease progression: How does AP become chronic pancreatitis and why does Disease progression: How does AP become chronic pancreatitis and why does chronic pancreatitis predispose to pancreatic cancer (chronic pancreatitis predispose to pancreatic cancer (basicsbasics: stellate cells and : stellate cells and fibrosis; fibrosis; research linkresearch link: the cancer-promoting intercellular matrix)? : the cancer-promoting intercellular matrix)? Cell Cell Biology/Cancer BiologyBiology/Cancer Biology

●● Other causes of AP (gallstones, high lipid concentration in blood) (Other causes of AP (gallstones, high lipid concentration in blood) (basicsbasics: : anatomy/phsyiology of biliary and pancreatic systems) (fat-alcohol interactions) anatomy/phsyiology of biliary and pancreatic systems) (fat-alcohol interactions) ((research linkresearch link: : cellularcellular mechanisms of action of bile acids). mechanisms of action of bile acids). Anatomy/Physiology/BiochemistryAnatomy/Physiology/Biochemistry

●● Prevention and treatment of AP (dealing with excessive use of alcohol, dietary Prevention and treatment of AP (dealing with excessive use of alcohol, dietary advice, exploration of ways to diminish intracellular protease activation) (advice, exploration of ways to diminish intracellular protease activation) (basicsbasics and many and many research linksresearch links). ). General General Practice/Psychiatry/Sociology/Pathophysiology/Pharmacology/PharmacyPractice/Psychiatry/Sociology/Pathophysiology/Pharmacology/Pharmacy

Time course of BAL in a man weighing 79 kg after intake of 36.8 g alcohol (at Time course of BAL in a man weighing 79 kg after intake of 36.8 g alcohol (at time 0)time 0)

[For historical reasons blood alcohol concentrations are calculated as g/kg blood plasma [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 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 LDmg/dl corresponds to 4.060/00; (this is close to LD5050 of ethanol in humans)] of ethanol in humans)]

BAL

min

Blood Alcohol Level (BAL) as a function of Blood Alcohol Level (BAL) as a function of time after intake of single alcohol dosetime after intake of single alcohol dose

Absorption from G-I TractAbsorption from G-I Tract

Elimination by oxidation in liverElimination by oxidation in liver

Example of one set of Learning Outcomes, arising from Example of one set of Learning Outcomes, arising from critical considerations of a simple quantitative experiment:critical considerations of a simple quantitative experiment:

Time course of BAL in a man weighing 79 kg after intake of 36.8 g alcohol (at Time course of BAL in a man weighing 79 kg after intake of 36.8 g alcohol (at time 0)time 0)

[For historical reasons blood alcohol concentrations are calculated as g/kg blood plasma [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 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 LDmg/dl corresponds to 4.060/00; (this is close to LD5050 of ethanol in humans)] of ethanol in humans)]

BAL

min

[[11] Alcohol is absorbed relatively quickly from the G-I tract. [] Alcohol is absorbed relatively quickly from the G-I tract. [22] After appearance in blood ] After appearance in blood it is rapidly distributed in a fluid volume corresponding to ~50 - 70 % of the body weight. it is rapidly distributed in a fluid volume corresponding to ~50 - 70 % of the body weight. [[33] At BAL > 0.1] At BAL > 0.10/000/00,, alcohol is metabolized at a constant rate (mostly by oxidation) of ~7 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 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 [and low levels of this enzyme will decrease alcohol tolerance [44] Alcohol is excreted via ] Alcohol is excreted via lung ventilation (concentration in alveolar air ~1/2000 of BAL) and in the urine (~same lung ventilation (concentration in alveolar air ~1/2000 of BAL) and in the urine (~same concentration as in plasma). [concentration as in plasma). [55] The rate of elimination of alcohol via the lungs and urine ] 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 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 substantial part of oxidation in the liver is only partial to acetate, which can then be further broken down in extra-hepatic tissues). [further broken down in extra-hepatic tissues). [66] The rate of alcohol oxidation in the ] The rate of alcohol oxidation in the liver is rate limiting for disposal of alcohol from the whole body. Increased energy 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 consumption by skeletal muscles (physical work), for example, will therefore NOT affect the rate of elimination.the rate of elimination. Blood Alcohol Level (BAL) as a function of Blood Alcohol Level (BAL) as a function of

time after intake of single alcohol dosetime after intake of single alcohol dose

Absorption from G-I TractAbsorption from G-I Tract

Elimination by oxidation in liverElimination by oxidation in liver

Example of Required Core KnowledgeExample of Required Core Knowledge

How to assess the Blood Alcohol Level (BAL) at the time of an accident on the How to assess the Blood Alcohol Level (BAL) at the time of an accident on the basis of later repeated measurements of BAL and extrapolationbasis of later repeated measurements of BAL and extrapolation

Time course of BAL in a man weighing 79 kg after intake of 36.8 g alcohol (at Time course of BAL in a man weighing 79 kg after intake of 36.8 g alcohol (at time 0)time 0)

[For historical reasons blood alcohol concentrations are calculated as g/kg blood plasma [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 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 LDmg/dl corresponds to 4.060/00; (this is close to LD5050 of ethanol in humans)] of ethanol in humans)]

BAL

min

Measurement period

Accident

A basis for a quantitiative test questionA basis for a quantitiative test question

Research Research Project: Project: Clinically Clinically relevant relevant

pathophysiologpathophysiologyy

Gerasimenko, Lur, Ferdek, Sherwood, Gerasimenko, Lur, Ferdek, Sherwood, Ebisui, Tepikin, Mikoshiba, Petersen, Ebisui, Tepikin, Mikoshiba, Petersen, Gerasimenko Gerasimenko Calmodulin (CaM) protects Calmodulin (CaM) protects against alcohol-induced pancreatic against alcohol-induced pancreatic trypsinogen activation elicited via Catrypsinogen activation elicited via Ca2+2+ release through inositol trisphosphate release through inositol trisphosphate receptors. receptors. Proc. Natl. Acad. Sci. USA (PNAS) Proc. Natl. Acad. Sci. USA (PNAS) 108, 5873-5878, 2011108, 5873-5878, 2011

(MRC press release: (MRC press release: http://www.mrc.ac.uk/Newspublications/Nehttp://www.mrc.ac.uk/Newspublications/News/MRC007775ws/MRC007775) )

  

The intracellular protein calmodulin (CaM) protects against alcohol-related The intracellular protein calmodulin (CaM) protects against alcohol-related pancreatitispancreatitis

Trypsin activityTrypsin activity(ethanol)(ethanol)

Research Research Project: Project: Clinically Clinically relevant relevant

pathophysiologpathophysiologyy

Isolated live Isolated live pancreatic acinar pancreatic acinar

cellcell

Gerasimenko, Lur, Ferdek, Sherwood, Gerasimenko, Lur, Ferdek, Sherwood, Ebisui, Tepikin, Mikoshiba, Petersen, Ebisui, Tepikin, Mikoshiba, Petersen, Gerasimenko Gerasimenko Calmodulin protects against Calmodulin protects against alcohol-induced pancreatic trypsinogen alcohol-induced pancreatic trypsinogen activation elicited via Caactivation elicited via Ca2+2+ release through release through inositol trisphosphate receptors. inositol trisphosphate receptors. Proc. Natl. Proc. Natl. Acad. Sci. USA (PNAS) Acad. Sci. USA (PNAS) 108, 5873-5878, 2011108, 5873-5878, 2011

(MRC press release: (MRC press release: http://www.mrc.ac.uk/Newspublications/Nehttp://www.mrc.ac.uk/Newspublications/News/MRC007775ws/MRC007775) )

  

The intracellular protein calmodulin (CaM) protects against alcohol-related The intracellular protein calmodulin (CaM) protects against alcohol-related pancreatitispancreatitis

CALP-3 is a cell-permeable CALP-3 is a cell-permeable CaM agonistCaM agonist

(Val-Lys-Phe-Gly-Val-Gly-(Val-Lys-Phe-Gly-Val-Gly-Phe-Lys)Phe-Lys)

Trypsin activityTrypsin activity(ethanol)(ethanol)

Research Research Project: Project: Clinically Clinically relevant relevant

pathophysiologpathophysiologyy

Isolated live Isolated live pancreatic acinar pancreatic acinar

cellcell

What is needed to make Phase 1 truly ‘World What is needed to make Phase 1 truly ‘World Class’?Class’?

■■ Use clear clinical case stories to provide stimulation and Use clear clinical case stories to provide stimulation and motivation for the students to work purposefully on the motivation for the students to work purposefully on the relevant basic sciencerelevant basic science

■■ Create an effective Foundation Course in the basic Create an effective Foundation Course in the basic biomedical sciences that will allow students to take full biomedical sciences that will allow students to take full advantage of the case-based studiesadvantage of the case-based studies

■■ Provide clear links to relevant and exciting research Provide clear links to relevant and exciting research enabling students to understand how progress is madeenabling students to understand how progress is made

■■ Above all: employ competent, dedicated and inspirational Above all: employ competent, dedicated and inspirational teachers teachers