Pathogenesis How, when and why do body systems fail?

1. PathogenesisHow, when and why do body systems fail? Nancy Long Sieber, Ph.D. September 10, 2012

2. Factors that Contribute to Disease • Genes • Genetic diseases • Genetic risk factors • Gene – environment interactions • Epigenetic changes – altered expression of genes due to environment during development • Nutrition • Injury and Toxicity • Infection • Immune Dysfunction • Neoplasia (cancer)

3. GeneticsWill analyzing your genotype foretell your future? http://wildcat.arizona.edu/papers/98/135/01_7_1.jpg

4. Recall the “Central Dogma” http://cellbio.utmb.edu/cellbio/DNA-RNA.jpg Shape of proteins gives rise to function. Small errors can result in dysfunctional proteins

5. In any given cell type, physiologic or environmental challenges cause changes in gene expression. • Example: When you have an infection, the genes for proteins that help you fight the infection are turned on. • This allows you to adapt to changing conditions inside and outside the body.

6. What can go wrong?Mutation • A mutation is an error in the genetic code, causing you to make an incorrect form of the protein • This gives rise to genetic diseases, such as cystic fibrosis and sickle cell anemia.

7. Sickle Cell Disease http://www.sciencemuseum.org.uk/exhibitions/genes/images/1-3-5-1-4-2-1-3-1-0-0.jpg

8. The change of a single base-pair causes one change in the amino acid sequence of the hemoglobin molecule http://www.wasdarwinright.com/images/sickle%20cell%20DNA.gif

9. Normal vs. Sickle Cell Hemoglobin http://evolution.berkeley.edu/evolibrary/images/evo/hemoglobin.gif

10. What else can go wrong?Certain genes increase risk of disease • Eg: breast cancer • Some people are at high genetic risk for breast cancer. Environment and lifestyle may not make much difference in these cases. • However, most cases occur in people with no strong family history.

11. Genes influence breast cancer riskbut other factors are also involved http://www.dnadirect.com/img/content_images/tests/breast_cancer/percentage_breast_cancer.gif

12. Breast Cancer Genes http://en.wikipedia.org/wiki/Image:BRCA_Genes-location_of_BRCA1_and_BRCA2_on_chromosomes_13_and_17.giffrom http://press2.nci.nih.gov/sciencebehind/cioc/survival/49.1.htm

13. BRCA genes and increased cancer risk BRCA2 is also associated with increased risk of prostate cancer, male breast cancer, and pancreatic cancer. Source: National Cancer Institute (http://www.cancer.gov)

14. What else can go wrong?Gene-environment interactions • Some genes promote disease, but only under certain environmental conditions. • This is probably the most common scenario for disease – nature and nurture. • Eg: Obesity and type II diabetes

15. Insulin is necessary to transport glucose from the blood into cells Type 1 diabetics lack insulin Type 2 diabetics are insulin resistant http://www.humanillnesses.com/original/images/hdc_0001_0001_0_img0082.jpg

16. Certain ethnic groups are at greater risk of type II diabetes. Eg: Pima Indians of North America

17. “Thrifty genes” plus Western eating habits increase the risk of obesity and diabetes among Pima Indians Luis Morago, a noted scout for the U.S. Army in 1872 (Smithsonian Institution)

18. Pima Indians appear to have genes that favor obesity, but only become obese in certain environments • Among Pima Indians living in the US • 75% of Adult Pima Indians are obese • 50% have type II diabetes, a common consequence of obesity. • Among Pima Indians living a more traditional lifestyle in Mexico • Most are not obese • About 10% have diabetes

19. Long-term Changes in Gene Expression:Epigenetics • Altered expression of genes based on environment during critical periods of development. • Can explain discrepancy between genotype (what genes you have) and phenotype (what characteristics you express). • Can be persist for generations • May also explain why adult lifestyle and genetic background alone fail to predict who is at greatest risk of heart disease and other conditions.

20. DNA MethylationOne mechanism of epigenetic change https://www.hgu.mrc.ac.uk/Research/Meehan/images/4.jpg

21. The Dutch Famine of 1944 During the Dutch Famine, the average caloric intake for an adult was about 400 – 800 calories, compared to 1800 calories before the famine. http://www.beeldbank.leidenuniv.nl/ImageDisplay.php?uid=FT083778&thumbed=5

22. Studies of people who were in early gestation during the Dutch Famine showed a • higher risk of obesity • higher levels of lipids in the bloodstream • 3-fold higher risk of cardiovascular disease than people who were not exposed to the famine. Also: higher risk of schizophrenia and addictions.

23. Further studies have shown a greater risk of disease in adults who were low birth weight babies, including: • High Blood Pressure • Coronary Artery Disease • Type II Diabetes • Stroke • Dyslipidemia (high cholesterol, fatty acids in blood) • Elevated clotting factors (increasing risk of stroke and heart attack)

24. People born in areas with high infant mortality (most often due to low birth weight) are at high risk of death from heart disease as adults Fig. 1 Standardized mortality ratios for coronary heart disease in England and Wales during 1968–79 and neonatal mortality during 1921–25 (♦ London boroughs; county boroughs; ○ urban districts; □ rural districts) From: DJP Barker, “The Origins of the Developmental Origins Theory. Journal of Internal Medicine. 2007; 261: 412-417.

25. Why do these particular epigenetic changes occur in response to insufficient nutrition? • Some may help the fetus survive in utero. • Some may be adaptations to what appears to be a world without sufficient calories – thus the “thrifty phenotype” . • Some changes may result from having insufficient nutrients to develop properly – brain and heart are prioritized, other organs suffer.

26. What can compromise fetal nutrition in the US today? • Eating disorders • Associated with a doubled risk of having a low birth weight baby, even if the mother was treated before becoming pregnant • Maternal smoking • Associated with smaller babies who are at greater risk of obesity as teens • Nutrient-deficient diets, even if calorically sufficient, may also impede growth.

27. What do we mean by malnutrition? • A diet deficient in essential nutrients. • A diet too low or too high in calories.

28. Malnutrition is most common in Africa and South East Asia http://www.bread.org/learn/global-hunger-issues/maps/malnutrition-hotspots_small.jpg

29. Malnutrition weakens defenses against many kinds of diseases. http://www.usaid.gov/our_work/global_health/nut/images/malnutrition_chart.gif

30. Inflammation http://www.biologymad.com/Immunology/inflammation.jpg

31. Signs of Inflammation • Rubor (redness) • Tumor (swelling) • Calor (heat) • Dolor (pain)

32. These changes result from • Increased blood flow to affected area • Increased capillary permeability • Movement of phagocytic cells into site of injury

33. Is inflammation a good thing or a bad thing? • Good: • Helps with defense against infection • Helps with tissue repair • Bad: • Causes pain • Can damage healthy tissue • Sometimes occurs inappropriately, eg: allergy, autoimmune disease • Chronic inflammation as been implicated in atherosclerosis, which increases risk of heart attack and stroke

34. How do Cells and Tissues Respond to Stress? Adaptive Changes Normal Cell or Tissue Injury Maladaptive Changes (generally reversible) Irreversible Damage (cell death by necrosis)

35. http://www.angelfire.com/ab7/mystro157/year/arnold3.jpg Adaptive Changes: An increase in muscle mass in response to exercise

36. Adaptive Changes:Weight-bearing exercise increases bone density http://www.x-trainers.com/images/bicep%20pull.jpg

37. Adaptive Changes: Calluses on your feet

38. Some adaptive changes come at a cost Cilia on the respiratory epithelium When exposed to cigarette smoke, this tissue adapts by producing epithelial cells that lack cilia. The cells are more likely to survive smoke exposure, but the person loses function.

39. Scarring is generally an adaptive response, but can interfere with organ function http://www.shands.org/health/graphics/images/en/10296.jpg

40. How Cells DieNecrosis vs. Apoptosis http://www.nature.com/labinvest/journal/v83/n4/images/3780641f1.jpg

41. Necrosis vs Apoptosis • Necrosis • Generally a pathological process • Promotes inflammation • Often leads to loss of function • Apoptosis • Often part of normal development • Can minimize the “biological backfire” associated with injury • Minimizes loss of function

42. Developing human hand before web apoptosis http://www.i-am-pregnant.com/img/day48-hand.gif

43. Developing hand after web apoptosis http://www.grg.org/breakingnews2001.htm

44. Ischemic Stroke http://strokecenter.stanford.edu/guide/images/thrombotic.jpg

45. Modified from: http://www.chrononhotonthologos.com/inactive/strokedr/hbothera.htm Damage Control Apoptosis of Irreversible Injured Cells

46. http://www.wirednewyork.com/hotels/marriott_marquis/images/marriott_marquis_elevators.jpghttp://www.wirednewyork.com/hotels/marriott_marquis/images/marriott_marquis_elevators.jpg

47. http://www.gkivdo.com/gkii/wire_3.jpg Elevator cable for passenger elevators has a safety factor of about 11

48. Biological Safety Factors(ratio of capacity to load) • Human Pancreas (enzyme secretion) • About 10 • Human Kidney (plasma filtration) • About 4 • Human Mammary Gland (milk production) • About 3 • Mammalian Lungs (aerobic capacity) • About 1.25 - 2 From: Jared Diamond “Quantitative Evolutionary Design’ J. Physiol 2002, 542: 337-345

49. Inflammation http://www.biologymad.com/Immunology/inflammation.jpg

50. http://www.easterncarolinaent.com/Allergy-Triggers-copy.jpg Common Allergens