BISC 307L 2nd Edition Lecture 2 Current Lecture Why do we get sick There are 2 ways to analyze this question 1 Proximate Reasons Pathophysiology The traditional way looking at the immediate cause of the disease the way doctors do Examples Hypertension is due to an increase in vascular resistance Sickle cell anemia is due to mutation in hemoglobin gene Cerebral palsy is due to asphyxia during birth Cystic fibrosis is due to mutation in chloride channel gene 2 Ultimate Reasons Evolutionary Medicine This is a new approach asks Why has evolution left our bodies vulnerable to disease The first formulations of people in this field resulted in the following four points 1 Selection is about fitness not health well being or strength 2 Constraints and trade offs are inevitable Evolution only works on pre existing things resulting in evolutionary holdovers term often used for this is BISLAGIATT but it seemed like a good idea at the time 3 Human evolution is too slow to cope with challenges especially the challenges of a changing environment 4 Our evolved defenses may be harmful or seem harmful Evolution is too slow to cope Evolution can only optimize within an environment Figure on right graphs time from 9k years BC to 2000 showing population of earth in millions Shows that the change in environment was relatively slow up until the agricultural revolution when human population took off But while environmental changes have been rapid our human evolutionary change has been relatively slower This has lead to mismatches between human adaptations and the challenges of our environment Example 1 lactose intolerance All babies can digest lactose but after childhood there is repression of the lactase gene because early on in human history we accumulated mutations to make it nonfunctional But with the advent of domestication of animals there were secondary mutations that inactivated the repressor of the lactase gene so it continued to be expressed Example 2 food availability and food storage In the past to survive we had to evolve the ability to take advantage of food when it was available and convert it to stored fat as insurance against the next period of starvation Now there s a mismatch high calorie foods and low activity lifestyle conflict with our ability to efficiently store fat Evolved Defenses May Be Harmful Evolution has left us susceptible to disease in that our evolved defenses may be harmful It has given us powerful immune defenses but excessive reactions can cause harm Fever pyrexia can cause seizures brain damage Allergies inappropriate immune reaction asthma anaphylaxis Autoimmune disease long list of disease in which the immune system inappropriately attacks tissues of your own body Immune system like the central nervous system experiences developmental plasticity the environment during early life could shape the development of the immune system Example In undeveloped countries where people experience malnutrition at an early age even after overcoming this problem these individuals are much more susceptible to disease than their contemporaries who did not experience early malnutrition Specifically if you look at the thymus gland houses T lymphocytes during final stage of development it is undeveloped in these individuals These individuals maximized their survival at the expense of developing the immune system by focusing on survival instead of full development in utero Graph below shows incidence of certain diseases as function of time Left common infectious diseases Starting in the 50 s these had high incidence but have been plummeting due to improved health care sanitation vaccinations etc On right is the incidence of inflammatory autoimmune disorders They are increasing Why Hygiene hypothesis suggests co evolution with microbiota Study looked at adults in Sweden who lived in cities vs adults who were raised on farms as children Found that incidence of autoimmune disorders was much higher in children raised in cities vs individuals raised on farms In order for the immune system to develop its regulatory mechanisms it has to undergo certain environmental exposures and activities like interacting with dirt and other microbes In clean cities the regulation of immune system activity is not properly developed resulting in autoimmune symptoms Proof If you take mice and raise them in germ free conditions you get mice with messed up immune systems If you reintroduce normal bacteria to mice later in life they quickly resume development of their immune systems Proof 2 Parasitic worms humans used to have them but not anymore Human immune response is nonvigorous because defense mechanism is an antibody which cannot kill a multicellular organism like a worm but instead controls it Infection stimulates activity of B lymphocytes to secrete IgE which attacks the parasitic worm Its other function is to bind to the surface of mast cells and sensitize them to antigens known as allergens and cause allergic reactions by activating histamine release Studies have occurred where individuals with autoimmune disease Crohn s disease were given worms that infect but don t cause damage and the symptoms were alleviated Methods of transport across membranes Diffusion is affected by Conc entra tion Dista nce Temp erature Molecular Size C S Area Lipid Solubility Facilitated Diffusion One example would be the glucose transporter GLUT GLUT can exist open to the outside or inside It has a binding site for glucose and when glucose binds it causes the transporter to undergo a conformational change These are passive transporters that don t use any ATP and are facilitated because the molecule they assist cannot cross the membrane by itself GLUT is especially important because most cells use glucose as a substrate for production of immediate energy The figure below shows the 5 types of Glut that transport the common hectoses high affinity transporter low affinity little or no affinity Glut 2 has low affinity for all 3 sugars but has high capacity meaning it can transport large amounts across the membrane over time In the small intestine it is responsible for absorption of sugar from the lumen of the intestine back into blood In the liver it allows glucose to enter leave the liver at high rates as necessary For example it can take up glucose quickly from the blood and ECF into the cell to feed the process of glycogenesis It is also responsible for glucose entry into pancreatic beta cells which secrete insulin Glut 3