HMB204 Lecture 6: What Kills Us? PDF

HMB204 | Introduction to Human Biology What kills us? The pathophysiology of common human diseases Lecture 6 James Hong, PhD Not Tested Format of lectures Ask questions anytime! I encourage all students to ask many questions during the lecture so that all the other students can benefit from the answ...

HMB204 | Introduction to Human Biology What kills us? The pathophysiology of common human diseases Lecture 6 James Hong, PhD Not Tested Format of lectures Ask questions anytime! I encourage all students to ask many questions during the lecture so that all the other students can benefit from the answers Is it tested? These labels will help you know: Tested Not Tested This does not mean that the non-tested material doesn’t help with understanding testable material, it just means memorization of the specifics is not required Not Tested Mini bio Scientific Associate at UHN Run the spinal cord injury program at Dr. Michael Fehlings’ lab Founder of Verismo Health Inc. Clinic management firm (70 primary care practices in Ontario) AI-driven software solutions to streamline medical practice Lecturer at UofT Not Tested Intro to human bio is a bit vague Human biology: the scientific study of the structure, function, and behavior of the human body exploration and understanding of the biological processes and mechanisms In essence, every department in the faculty of medicine But, since they all have their own courses, I would like to teach you about how and why we study human biology Tested So how do we study human bio? We use human samples (this is termed clinical research): Biological fluids Post-mortem (after death) tissue donation Imaging data from human tissue (CT, MRI, Ultrasound …) Population research But sometimes, especially in the context of human disease (i.e. pathology) we cannot readily harvest the tissue during disease progression Not Tested Take spinal cord injury as an example A 19-year old boy dives into the shallow end of a pool head first, and fractures his cervical (neck) vertebrae. How do we better understand what happens to the spinal cord here? Clinical research: Imaging, analysis of the blood and cerebrospinal fluid, injury prevention at population level We cannot readily harvest this individual’s (or any other individual’s) spinal cord How can we understand the molecular and cellular processes that underpin this trauma in this individual? Translational research. Translational research as a pillar to medical advancement Most people would refer to this as “pre-clinical” research How does it differ from basic science research? It is focused on understanding human biology, especially pertaining to disease Basic research focuses on understanding the general molecular underpinnings of phenomena – how does the transcription factor STAT3 bind to its downstream response elements in the nucleus? Basic research can often serve as the foundation for translational research Tested Not Tested Example with spinal cord injury Basic science research: Studying how stem cells in the lamprey are capable of spontaneous regeneration after injury Outcome informs lamprey biology and general vertebrate central nervous system molecular biology Translational research: Using the foundation set by basic science and our understanding of the molecular underpinnings Use a drug that emulates that same molecular change as what occurs in lampreys on human stem cells See if they behave the same when transplanted into a mouse with an injured spine Outcome informs human biology (to a greater extent) and advances therapeutic understanding in the setting of injury Not Tested Overarching objective of my lectures To get you all to think like scientists and clinical investigators in terms of experimental design in the area of translational research Specific aims: 1. Give you an understanding of the highest research priorities in the field 2. Give you the tools to be able to study them 3. Do so without getting beat up on my course evaluations PICO: A framework for human research It consists of four components: Patient (P), Intervention (I), Comparison (C), and Outcome (O) P specifies the characteristics of the patient population under investigation I refers to the specific treatment or intervention being evaluated C involves comparing the primary intervention with alternative or control interventions O defines the measurable outcomes used to assess the effectiveness or impact of the interventions Tested Not Tested Examples of different PiCO questions Patient Problem or Population Intervention or Exposure Comparison or Control Example Outcome Measure s Therapy (Treatment) Patient's disease or condition. A therapeutic measure, e.g. medication, surgical intervention, or life style change. Standard care, another intervention, or a placebo. Mortality rate, number of days off work, pain, disability. Prevention Patient's risk factors and general health condition. A preventive measure, e.g., A lifestyle change or medication. Another preventative measure Mortality rate, number of days off work, disease incidence. Diagnosis Specific disease or condition. A diagnostic test or procedure. Current "reference standard" or "gold standard" test for that disease or condition. Measures of the test utility, i.e. sensitivity, specificity, odds ratio. Question Type Sometimes there is no comparison Not Tested Examples with spinal cord injury Question Type Patient Problem or Population Intervention or Exposure Comparison or Control Outcome Measure Therapy In a mouse model of spinal cord injury is stem cell therapy more effective than Traditional decompression surgery in promoting functional recovery? Prevention In young adults does the use of injury prevention education compared to no injury prevention education reduce the risk of spinal cord injuries in the future? Diagnosis For spinal cord injury Does monthly bloodwork compared to imaging every 6 months lead to more accurate prognosis of recovery? So let’s start with P – the Patient, the why “A patient is an individual who seeks or receives medical or healthcare services for the diagnosis, treatment, or management of a health condition, injury, or illness.” – ChatGPT, 2023 As a translational researcher your focus first is then to find a disease to tackle, how do you decide? Not Tested Not Tested What disease to study? Personal motivation Curiosity But all else being equal, you may choose to focus on the diseases that are having the greatest impact on us as a species Tested Assessing impact Few things to consider How deadly it is How common it is How much it impacts quality of life To prioritize research as a species, we should focus on diseases that have: a high impact on quality of life (e.g. disability or death) is relatively common Tested Epidemiology The study of the patterns, causes, and effects of health and disease conditions in populations Where, when and how a disease impacts us as a species Tested Common epidemiological measures Incidence rate Prevalence rate Morbidity Mortality rate Tested Incidence rate Measure used describe the occurrence of new cases of a specific disease or condition within a defined population during a specified time period Incidence rate = number of newly diagnosed cases of a diseases / midperiod total population at risk As population changes, the number of persons at midyear is generally used as an approximation Not Tested Example of incidence rate Let's consider a population of 10,000 individuals in a community. During a one-year period, 200 new cases of a respiratory infection were diagnosed among them. The population at risk during that time was 8,000 individuals (after excluding individuals who had the infection at the beginning of the year and are no longer susceptible). Using the formula: Incidence = (200 new cases) / (8,000 population at risk) x 1,000 Incidence = 25 per 1,000 population at risk This means that during the specified time period, there were 25 new cases of the respiratory infection per 1,000 individuals at risk in the population. Tested Prevalence rate Determines a person’s likelihood of having a disease, not just the new cases, but all cases (including existing cases) Prevalence rate = Number of new and existing cases in that period / midperiod total population at risk If we talk about someone being cured from a disease in a given year, the incidence will not change as it only logs new cases, but the prevalence would as it also logs existing cases Not Tested Example of prevalence rate Let's consider a population of 10,000 individuals living in a particular city. Suppose that, in the year 2022, there are 500 individuals in that population who have been diagnosed with diabetes and another 2,000 which are currently living with the condition. Prevalence rate = (2,500 new and existing cases) / (10,000 population at risk) x 1,000 Prevalence rate = 250 per 1,000 population at risk This means that during the specified time period, there were 2,500 new and existing cases of diabetes per 1,000 individuals at risk in the population. Tested Morbidity Also known as illness A person can have several morbidities (e.g. several illnesses) simultaneously, this is referred to as co-morbidities Morbidities can be low impact like an arm sprain or high impact like traumatic brain injury Morbidities are not referring to deaths but that is not to say they are not deadly Prevalence is a measure often used to determine the level of morbidity in a population (how many people have the illness) Tested Mortality Means death Annual mortality rate (per 100,000 population) = Total number of deaths from all causes in 1 year / number of persons in the population at midyear x 100,000 Like incidence rate, mortality rate should always be accompanied by a specific time range Tested Is mortality rate the best determinant? What if a disease kills you when you are young? What if a disease cripples someone? Early mortality: No opportunity to have experienced life Crippled: Little to no quality of life None of the previous metrics could capture these impacts So, we introduce two new metrics: Years of potential life lost (YPLL) – also known as years of life lost (YLL) Disability-adjusted life years (DALY) Tested Years of potential life lost (YPLL) Deceased person's age at death is subtracted from a predetermined age at death In the United States, this predetermined “standard” age is usually 75 years An infant dying at 1 year of age has lost 74 years of life (75 − 1), but a person dying at 50 years of age has lost 25 years of life (75 − 50) YPLL = ∑(Standard Life Expectancy – Age at Death) When interpreting YPLL its important to know what predetermined standard age has been selected Not Tested Example of YPLL Let's consider a population of a specific community and the ages at which individuals passed away. We will assume a life expectancy of 75 years for simplicity. Age at death: 45, 60, 70, 80, 55, respectively. To calculate YPLL, follow these steps: 1. Subtract the age at death from the life expectancy for each individual to determine the potential years of life lost for each case: 45 years old: 75 (life expectancy) - 45 = 30 YPLL 60 years old: 75 - 60 = 15 YPLL 70 years old: 75 - 70 = 5 YPLL 80 years old: 75 - 80 = 0 YPLL (no potential years of life lost, as they lived beyond life expectancy) 55 years old: 75 - 55 = 20 YPLL 2. Sum up the YPLL for all cases: 30 + 15 + 5 + 0 + 20 = 70 YPLL In this example, the total Years of Potential Life Lost (YPLL) for the given population is 70 years. This indicates the loss of 70 potential years of life due to premature mortality within the community. Tested Disability adjusted life years (DALY) Most diseases have a major impact on the afflicted individuals above and beyond mortality Diseases that may not be lethal may be associated with considerable physical and emotional suffering resulting from disability associated with the illness DALY = YPLL + YLD YLD = Years lived with disability YLD = ∑(Number of Cases × Disability Weight (a constant) × Average Duration of Condition until remission or death) Currently accepted as the most comprehensive method at quantifying the impact of a disease on our species Not Tested Example of DALY A female patient develops severe alcohol use disorder (DW = 0.55) at age 40 and dies at age 60. YLD = 1 x (60-40) x 0.55 = 11 YPLL = (75-60) = 15 DALY = 11 + 15 = loss of 26 healthy years Tested Ranking DALYs – the GBD study First published in 1996 The most comprehensive and consistent set of estimates of mortality and morbidity yet produced WHO now regularly develops GBD estimates at regional and global levels for a set of more than 135 causes of disease and injury A GBD study aims to quantify the burden of premature mortality and disability for major diseases or disease groups Uses the DALY to combine estimates of the years of life lost and years lived with disabilities Data broken down by age, sex and region Not Tested Our focus this week: DALY Rankings The Lancet, GBD 2019 Non-communicable diseases: Not a physical injury Not transmissible Not infections 10 min health break Questions? Come up! Not Tested Going back to the PiCO Framework Patient (P), Intervention (I), Comparison (C), and Outcome (O) For P, we can use the highest DALY score diseases as a start For I, in order to understand how to intervene, we must understand the cellular or molecular basis of disease – this is the bulk of the work We will now provide three non-communicable disease examples of how we lay the groundwork for the first two sections of the PICO framework Tested Understanding human disease Common themes: Inflammation Oxidative Stress Fighting infection vs. Septic shock Exercise vs. Stroke When in balance, these processes are naturally occurring and keep us alive When imbalance they fuel each other in a pathological way Cell Death Natural turnover vs. cancer Tested Oxidative stress in health and disease Mitochondria are the primary source of reactive oxygen species (ROS) Normal: Exercise can lead to transient ROS rises, which stimulates adaptive responses including improved antioxidant capacity and mitochondrial biogenesis Pathology: During ischemia/hypoxia, reduced oxygen availability impairs the electron transport chain, leading to electron leakage and the generation of superoxide radicals This contributes to mitochondrial dysfunction and exacerbates tissue damage Tested Cell death is necessary Cell death is a fundamental biological process that occurs in multicellular organisms to maintain tissue homeostasis, eliminate damaged or unwanted cells, and regulate development There are different types of cell death, including apoptosis, necrosis, and autophagy, each characterized by distinct morphological and molecular features Tested Apoptosis – programmed cell death Characteristics: Cell shrinkage, chromatin condensation, nuclear fragmentation (pyknosis), formation of apoptotic bodies Mechanism: Mediated by caspases, protease enzymes Extrinsic pathway: Initiated by death ligands binding to death receptors (e.g. Fas) Intrinsic pathway: Triggered by cellular stressors like DNA damage or oxidative stress, involves mitochondrial outer membrane permeabilization Role: Tissue remodeling during development, Immune system regulation and elimination of damaged cells Dysregulation linked to diseases like cancer, neurodegenerative disorders, and autoimmune diseases. Tested Necrosis – uncontrolled cell death Caused by injury, pathogen etc. Characteristics: Rapid loss of membrane integrity, swelling of organelles and release of cellular contents, triggering inflammation Consequences: Triggers inflammation and tissue damage Release of pro-inflammatory molecules and DAMPs (damage associated molecular patterning molecules – like mitochondrial DNA, heat shock proteins) Activates the innate immune system Tested Inflammation in health and disease Healthy Inflammation: Normal physiological response to injury or infection Protective mechanism to remove harmful stimuli and initiate tissue repair Controlled and self-limiting Involves recruitment of immune cells, release of cytokines, and activation of inflammatory pathways Pathological Inflammation: Dysregulated immune response Chronic inflammation can lead to tissue damage and contribute to various diseases Associated with conditions like autoimmune disorders, chronic infections, and metabolic syndrome Involves sustained activation of inflammatory pathways and impaired resolution mechanisms Implications: Healthy inflammation promotes healing and tissue repair Pathological inflammation can result in tissue destruction and organ dysfunction Ischemic heart disease or coronary heart disease (CHD) Belongs in a class of diseases known as atherosclerotic cardiovascular disease (CVD) which includes: CHD Hypertension Stroke Comprise the #1 cause of death globally In 2015, 17M people died from CVD Not Tested Tested Atherosclerosis: the basis of CHD A chronic progressive disease characterized by the buildup of fatty deposits, cholesterol, cellular waste products, calcium, and other substances within the walls of arteries This process leads to the formation of plaques, which can narrow and harden the arteries, impairing blood flow to organs and tissues Atherosclerosis is a major underlying cause of cardiovascular diseases such as coronary artery disease, stroke, and peripheral artery disease Tested Understanding the vasculature Normal artery wall has a three-layer structure enclosing the lumen and are Tie2+ (an endothelial cell marker) Tunica intima: a single layer of endothelial cells positioned on subendothelial extracellular matrix circularly arranged elastic bands called the internal elastic lamina Tunica media: extracellular matrix smooth muscle cells (SMCs) thick elastic band called external elastic lamina Tunica adventitia: connective tissue with interspersed fibroblasts and stem/progenitor cells nerve endings nutrient capillaries (vasa vasorum) Inside Outside Tested Atherosclerosis: Three Phases 1. Initiation: Low density lipoprotein (LDL) accumulation 2. Progression: foam cell formation 3. Complications: plaque formation and rupture Tested Phase 1: Initiation 1. The low-density lipoprotein (LDL) accumulates through Scarb1mediated transcytosis (uptake and secretion) across the endothelium 2. Classic Iba1+ monocytes enter the intima through transendothelial migration 3. These monocytes mature into macrophages once in the intima 4. Macrophages express scavenger receptors such as Lrp6 that bind to LDL particles and become foam cells 5. CD4+ T lymphocytes also enter the intima and regulate the functions of the innate immune cells as well as the endothelial and Acta2+ smooth muscle cells 6. Smooth muscle cells from the media become activated and migrate into the intima in response to macrophages Tested Phase 2: Progression Resident and recruited smooth muscle cells produce ECM molecules such as Col1a1 and Fn1 (collagen and fibronectin) that contribute to thickening of the intima CD4+ T cells secret Ifng which impair the ability of the SMC to synthesize collagen Activated macrophages show increased production of collagenase (Mmp8) enzymes that degrade the collagen Thinning and structural weakening of the collagen-rich cap increases the susceptibility of the plaque to rupture As the lesion develops, foam cells and smooth muscle cells undergo apoptosis which accumulates cellular debris forming the necrotic lipid rich core of the atheroma Tested Phase 3: Complications Rupture The fracture of the fibrous cap of the atheroma permits blood coagulation Pro-coagulant substances like tissue factor (TF) can trigger thrombosis which can cause occlusion of the vessel and lead to an acute ischemic event Many thrombi may not totally occlude the vessel or undergo lysis due to endogenous fibrinolytic defenses Superficial Erosion Plaques that lack a well-defined lipid core and have abundant rather than sparse ECM can provoke coronary thrombi Endothelial cells that overlay this fibrous plaque can die off and reveal collagen to the lumen, which causes thrombosis The clots associated with superficial erosion have characteristics of plateletrich “white” thrombi; by contrast, “red’ thrombi” are rich in fibrin and trapped RBCs and associate with plaque rupture Healing Advanced plaques show “buried caps” that provide evidence for prior rupture and healing Tested What happens after a clot? If it blocks a coronary vessel = myocardial infarction If it blocks the cerebral artery = stroke Tested Myocardial infarction (Acute) Consequence of a clot Loss of blood supply to the heart Results in: Ischemia/hypoxia Inflammation Cell death (necrosis) Pathophysiology of myocardial infarction (Acute) 1. Coronary artery occlusion: Blockage of a coronary artery by a thrombus or embolus. 2. Ischemia and hypoxia: Reduced blood flow leads to inadequate oxygen supply to the affected myocardium. 3. Cellular metabolic changes: Actn2+ myocardial muscle cells shift to anaerobic metabolism, resulting in lactate accumulation and ATP depletion. 4. Cellular injury: Prolonged ischemia causes cellular dysfunction and impaired contractility. 5. Reactive oxygen species (ROS) generation: Reperfusion injury upon restoration of blood flow exacerbates cellular damage. 6. Inflammatory response: Ischemic injury triggers an inflammatory cascade, further exacerbating tissue damage. 7. Tissue necrosis: Prolonged ischemia leads to irreversible cell death (necrosis) in the affected myocardial tissue. 8. Complications: MI can lead to arrhythmias, myocardial rupture, heart failure, and systemic effects such as cardiogenic shock. Tested Myocardial Infarction Video and Angioplasty / Stent Treatment https://www.youtube.com/watch?v=mLmKq5bQOg0 Not Tested Tested Ischemic Stroke Consequence of a clot Loss of blood supply to the brain Results in: Ischemia/hypoxia Inflammation Cell death (necrosis) Tested Pathophysiology of stroke (Acute) 1. Blood Flow Interruption: Blockage of cerebral artery by thrombus or embolus. 2. Hypoperfusion: Decreased oxygen and glucose delivery, causing hypoxia. 3. Excitotoxicity: Release of excitatory neurotransmitters due to energy failure. 4. Calcium Influx: Overactivation of glutamate receptors leads to calcium influx in Syn1+ neurons, causing cellular damage. 5. Oxidative Stress: Mitochondrial dysfunction and ROS production exacerbate cellular damage. 6. Inflammatory Response: Activation of microglia, astrocytes, and immune cells, releasing pro-inflammatory cytokines. 7. Blood-Brain Barrier Disruption: Inflammation and oxidative stress disrupt the blood-brain barrier, facilitating immune cell infiltration. 8. Cell Death: Prolonged ischemia results in neuronal injury and cell death, predominantly through necrosis and apoptosis. Not Tested Stroke Video – Treatment with tPA https://www.youtube.com/watch?v=bc2_sQ3kK6U Chronic obstructive pulmonary disease (COPD) Prevalence: Approximately 10% globally among adults. Risk Factors: Smoking Occupational exposure Indoor air pollution Genetic factors Global Distribution: High prevalence in low- and middle-income countries. Impact on Mortality: Contributes to 3 million deaths annually. Health Disparities: Higher burden in socioeconomically disadvantaged populations. Tested Tested Pathophysiology of COPD (Chronic) 1. Inhalation of Irritants: Chronic exposure to cigarette smoke, pollution, and occupational hazards. 2. Airway Inflammation: Irritants trigger chronic inflammation in the airways. 3. Mucus Hypersecretion: Inflammatory response leads to excessive mucus production from MUC5AC goblet cells 4. Airway Remodeling: Structural changes occur in the airways, causing narrowing. 5. Emphysema Formation: Destruction of alveolar walls leads to airspace enlargement, Aqp5 alveolar epithelial cells die and regenerative capacity decreases 6. Airflow Limitation: Narrowed airways and reduced lung elasticity impede airflow. 7. Gas Trapping: Incomplete exhalation results in trapped air in the lungs. 8. Hypoxia and Hypercapnia: Reduced oxygen and increased carbon dioxide levels in blood. 9. Secondary Complications: Pulmonary hypertension, respiratory muscle fatigue, systemic inflammation. Not Tested COPD Video https://www.youtube.com/watch?v=sB236fYf_ns Not Tested Back to PiCO Framework For I, in order to understand how to intervene, we must understand the cellular or molecular basis of disease – this is the bulk of the work What is the cellular + molecular basis of the diseases learned today? Atherosclerosis: Cells involved? Mechanisms involved? COPD: Cells involved? Mechanisms involved? Knowing the cellular and molecular mechanisms involved will allow you to devise a therapeutic approach / intervention Next lecture Communicable forms of disease Injuries