1. Pathogenesis How, when and why do body systems fail?
Nancy Long Sieber, Ph.D.
August 30, 2010

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. Genetics Will analyzing your genotype foretell your future?

4. Recall the “Central Dogma”
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

8. The change of a single base-pair causes one change in the amino acid sequence of the hemoglobin molecule

9. Normal vs. Sickle Cell Hemoglobin

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 risk but other factors are also involved

12. Breast Cancer Genes
from

13. BRCA genes and increased cancer risk
Type of Cancer
General Population That Will Develop Disease
Women With BRCA1 or BRCA2 Mutation Who Will Develop Disease
Breast
13.2%
36-85%
Ovarian
1.7% 
16-60%
BRCA2 is also associated with increased risk of prostate cancer,
male breast cancer, and pancreatic cancer.
Source: National Cancer Institute (

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

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 Methylation One mechanism of epigenetic change

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.

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 ; 261:

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

29. Malnutrition weakens defenses against many kinds of diseases.

30. Inflammation

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?
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. An increase in muscle mass in response to exercise
Adaptive Changes:
An increase in muscle mass in response to exercise

36. Adaptive Changes: Weight-bearing exercise increases bone density

37. Adaptive Changes: Calluses on your feet

38. Cilia on the respiratory epithelium
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

40. How Cells Die Necrosis vs. Apoptosis

41. Necrosis vs Apoptosis Necrosis Apoptosis
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

43. Developing hand after web apoptosis

44. Ischemic Stroke

45. Apoptosis of Irreversible Injured Cells
Damage Control
Apoptosis of Irreversible Injured Cells
                                            
. . Area of necrotic (dead) tissue Cells in the surrounding area are commonly irreversibly damaged.
Cells in this region often undergo apoptosis in the hours after the stroke.
Modified from:

46. http://www. wirednewyork

47. 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
From: Jared Diamond “Quantitative Evolutionary Design’ J. Physiol 2002, 542:

49. Inflammation

50. Common Allergens

51. Allergen binds to IgE, which links to mast cells, triggering release of histamine.
                                                                                              

52. Autoimmune Diseases

53. Mechanisms of Autoimmunity
Modification of a molecule on the host cell
Molecular mimicry
Exposure of a sequestered antigen to the immune system
Inappropriate activation of lymphocytes that should be “tolerant
Imbalance of suppressor T cells, which inhibit the immune response, and helper T cells, which promote it.
Genetic factors – the risk of autoimmune disease runs in families.

54. The Development of Cancer

57. Lupus