PathogenesisHow, when and why do body

systems fail?

Nancy Long Sieber, Ph.D.September 10, 2012

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

http://cellbio.utmb.edu/cellbio/DNA-RNA.jpg

Recall the “Central Dogma”

Shape of proteins gives

rise to function.

Small errors can result in dysfunctional

proteins

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?

MutationA 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

http://evolution.berkeley.edu/evolibrary/images/evo/hemoglobin.gif

Normal vs. Sickle Cell Hemoglobin

What else can go wrong?

Certain genes increase risk of diseaseEg: 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 riskbut other factors are also involved

http://www.dnadirect.com/img/content_images/tests/breast_cancer/percentage_breast_cancer.gif

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

Breast Cancer Genes

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%

Source: National Cancer Institute (http://www.cancer.gov)

BRCA2 is also associated with increased risk of prostate cancer,male breast cancer, and pancreatic cancer.

BRCA genes and increased cancer risk

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

http://www.humanillnesses.com/original/images/hdc_0001_0001_0_img0082.jpg

Type 1 diabeticslack insulin

Type 2 diabeticsare insulinresistant

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 environmentsAmong 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 adultwas 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 ahigher risk of obesityhigher levels of lipids in the bloodstream3-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)

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.

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

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 disordersAssociated 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

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

Inflammation

Signs of InflammationRubor (redness)Tumor (swelling)Calor (heat)Dolor (pain)

These changes result from Increased blood flow to affected area Increased capillary permeabilityMovement of phagocytic cells into

site of injury

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

Normal Cell or Tissue

Injury

Adaptive Changes

Maladaptive Changes(generally reversible)

Irreversible Damage(cell death by

necrosis)

How do Cells and Tissues Respond to Stress?

http://www.angelfire.com/ab7/mystro157/year/arnold3.jpg

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

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

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.

Some adaptive changes come at a cost

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

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

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

                                     

       

.

.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.

Damage Control Apoptosis of Irreversible Injured Cells

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

http://www.gkivdo.com/gkii/wire_3.jpg

Elevator cable for passenger elevators has a safety factor of about 11

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

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

Inflammation

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

Common Allergens

http://www.euromeds.co.uk/allergy-treatment-information.htm

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

                                                                                              

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.

http://www.wellesley.edu/Chemistry/chem227/nucleicfunction/cancer/cancergrowth.gif

The Development of Cancer

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

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

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

Lupus

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