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

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)

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

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

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.

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.

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

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

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

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.

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

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

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 (http://www.cancer.gov)

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

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

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

“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)

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

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.

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

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

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.

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)

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.

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.

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.

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

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

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

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

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

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

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

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)

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

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

Adaptive Changes: Calluses on your feet

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.

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

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

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

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

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

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

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: http://www.chrononhotonthologos.com/inactive/strokedr/hbothera.htm

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

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

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

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

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

Allergen binds to IgE, which links to mast cells, triggering release of histamine.                                                                                                http://www.euromeds.co.uk/allergy-treatment-information.htm

Autoimmune Diseases http://www.theintellectualdevotional.com/blog/2010/01/25/autoimmune-diseases-basically-an-epic-body-fail/

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.

The Development of Cancer http://www.wellesley.edu/Chemistry/chem227/nucleicfunction/cancer/cancergrowth.gif

http://www.wellesley.edu/Chemistry/chem227/nucleicfunction/cancer/cancer.html

http://www.wellesley.edu/Chemistry/chem227/nucleicfunction/cancer/cancer.html

Lupus http://www.medicinenet.com/images/illustrations/butterfly_rash.jpg

http://www.naturosante.ch/B.L.-lupus-evolution-1.jpg