BISC 307L 2nd Edition Lecture 2Current LectureWhy 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 gene2. 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 fieldresulted 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 harmfulEvolution is too slow to copeEvolution can only optimize withinan environment. Figure on right graphs time from 9kyears BC to 2000, showingpopulation of earth in millions.Shows that the change inenvironment was relatively slow, upuntil the agricultural revolution,when human population took off. But while environmental changeshave been rapid, our humanevolutionary change has beenrelatively slower. This has lead to mismatches between human adaptations and the challengesof our environment. Example 1: lactose intolerance. All babies can digest lactose, but after childhood, there isrepression of the lactase gene because early on in human history, we accumulated mutations tomake 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 andlow activity lifestyle conflict with our ability to efficiently store fat. Evolved Defenses May Be HarmfulEvolution 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 todisease 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 beenplummeting 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, theyquickly 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:- Concentration- Distance- Temperature- Molecular Size- C-S Area - Lipid SolubilityFacilitated DiffusionOne example would be the glucose transporter GLUTGLUT 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 intoblood. In the liver, it allows glucose to enter/leave the liver at high rates