View
221
Download
0
Category
Tags:
Preview:
Citation preview
CHEME 355
4 Lectures
Oct 28: Human Disease Patterns / Prenatal and Postnatal Disease (Examples)
Oct 30: Gene / Etiology of Prenatal Disease (Osteogenesis Imperfecta)
Nov 6: Genetic Flow of Information/ Intracellular Pathogenesis of Osteogenesis Imperfecta
Nov 13 : Body Plan / Tissue Pathogenesis of Osteogenesis Imperfecta /
Adaptation
2 Labs
Nov 4: Genotype-Phenotype Correlations and the Internet
Nov 18: Methodological Approaches to Studying Human Disease & Treatment
Genotype - Phenotype Correlation
Biologists, as they consider the genome’s impact on their work, are also moved by the prospect of doing science in new ways.
…In vitro…In vivo
There is now a third: in silico, meaning biology that is done by querying genome data in databases.
As a consequence of this revolution, biology in the 21st century is rapidly becoming an information science.
CHEME 355Genotype - Phenotype Correlation
In a few years, genomics will make possible a test of quite different power. The search for human gene variants, and the technology of testing for thousands of gene variants with a single microarray, are both progressing so rapidly that it should soon be possible to scan the entire human genome.
Such a scan in essence would predict all the diseases a person might suffer in the course of a life, with an implicit forecast of lifespan and likely cause of death.
CHEME 355Genotype - Phenotype Correlation
“Personalized therapy is supported by an expanded spectrum of drugs developed to target particular disease subtypes on a particular genetic background. Molecular profiling is used to monitor the progress of the disease, and therapy may be adjusted flexibly. This scenario is most likely to apply to life-threatening diseases and to those for which disease disposition and response to therapy are known to vary considerably between individuals, such as cancer and heart and brain disease. Overall, the primary goal of personalized medicine should be to increase the quality of life first, and life-span second.”
Sander, C. (2000) Science 287:1977
Through a decision support system, the physician may prescribe a personal immunization and screening schedule or recommend specific preventive measures
birth
genotype
database
CHEME 355Genotype - Phenotype Correlation
“The April 1998 issue of Life magazine ran a cover story, complete with a double-helix spanning the length of the page, boldly titled "Were You Born That Way?" The subtitle left no doubt about the answer: "Personality, temperament, even life choices. New studies show it's mostly in your genes.””
Allen, G.E. (2001) Is a new eugenics afoot? Science 294: 59-61.
CHEME 355Genotype - Phenotype Correlation
With the human genome in hand, as well as those of pathogenic viruses and bacteria, will any identifiable barrier remain to curing all human disease?
If and when all disease is conquered, a great goal of medicine will have been attained.
People will live out their natural lifespan in full health.
Genomic knowledge may show us not only how to correct the degenerative diseases of aging from which evolution has neglected to protect us, but also how to unlock mechanisms that determine lifespan.
CHEME 355Genotype - Phenotype Correlation
CHEME 355
McKeown, T. The Origins of Human Disease. (Blackwell, Oxford, UK, 1988) pp. 233.
Homo sapiens is identified ~600,000-years ago, about the time when use of fire is discovered.
~100,000-years ago, archaic Homo sapiens merges into Neanderthal man. About this time, cooperative hunting, burial of the dead, use of tools, use of clothing, and use of fire are commonly practiced.
Acquisition of these abilities/tools enlarges the human habitat.
CHEME 355Hunting and Gathering
Hunter-gatherers:
• Live in conditions that minimize exposure to human infection (small groups of 25 to 50)
• Do not degrade environment
• Do not enhance environment
• Live as nomads: men obtaining food by hunting, women obtained food by gathering
• Diet consists of insects, vegetables, fruit
CHEME 355Hunting and Gathering
Hunter-gatherer populations may have been actively restrained:
• It was common practice to eliminate a substantial proportion (15- to 50%) of normal children.
• It also appears to be common to eliminate children who were handicapped.
This may have been an attempt to titrate population size with available resources, but the point is controversial.
CHEME 355Hunting and Gathering
Hunter-gatherer health and disease:
• Life was short, death rates were high.
• Main causes of death include: accidents, food shortage, predation, parasitic disease.
TB from ~ 3000 BCLeprosy from ~500 ADSyphilis from ~1500 ADOsteoarthritisOsteomyelitisSinusitisColle’s fracture
• Relationship between food shortage and parasitic disease.
• Non-communicable diseases (cancer, ASCVD, obesity, diabetes, hypertension) are rare to non-existent.
• Early nomads lived in small bands, infrequently contacting others. Numbers were not large enough -- and bands were not dense enough -- to maintain (spread) acutely infectious diseases, e.g. measles, smallpox, whooping cough, polio, enteric infections, respiratory infections, either by fomites or by zoonoses.
CHEME 355Hunting and Gathering
The switch from hunter-gatherer to agriculturalist occurred over a period of ~8,000-years.
Agriculture is thought to have offered one principle advantage — providing a greater amount of food per unit area of land — which could feed a larger population.
Pattern of events in various parts of the world is consistent with a picture of continuous population growth and population pressure. Was expansion a stimulus for technological change?
Beginning about 6000-years ago, man’s first attempts to control the environment — the domestication of plants and animals — is associated with (a) transition from a nomadic to a settled way of life, (b) an increase in food supply, (c) expansion of populations, and (d) creation of first ‘urban’ areas with large populations in continuous close contact.
CHEME 355Agriculture
Agriculturalists:
• Lacked mechanized power
• Were physically active
• Domesticated plants and animals
Diet was different from that of hunter-gatherer, but still based mainly on unrefined plant foods. Dairy products consumed for the first time.
CHEME 355Agriculture
Population growth:
• 10,000-years ago, < 10 mil.
• 1800, 1 bil.
• Even allowing for gross inaccuracy of the figures, there is little doubt that human populations grew more rapidly in the first few thousand years following the agricultural revolution than in the few million years preceding it.
CHEME 355Agriculture
Agriculturalist health and disease:
• Life was short, death rates were high.
• Main causes of death include: acute infectious disease, accidents, food shortage, parasitic disease, dietary insufficiency.
• Relationship between food shortage and parasitic/infectious disease.
• Non-communicable diseases (cancer, ASCVD, obesity, diabetes, hypertension) are rare to non-existent.
• Acutely infectious diseases, e.g. measles, smallpox, whooping cough, polio, enteric infections, respiratory infections, are spread either by fomites or by zoonoses.
• Connection between public health and infection control/spread.
CHEME 355Agriculture
Change from agriculture to industry takes place over a few hundred years. Effect on health is profound, with the decline of infectious disease and the rise on non-communicable disease.
Modern rise in population is distinguished from all previous increases by its size, continuity and duration.
A major contributor is the decline in death rate -- increase in normal longevity -- of modern man.
CHEME 355Industry
CHEME 355Industry
Population GrowthMortality Rate
Industrialists:
• Sedentary lifestyle
• Longer life
• Abundant food
• Processed food
• Degraded environment
• Increase in medical technology
CHEME 355Industry
Industrialist health and disease:
• Life is extended, death rates fall significantly. For the first time in history a mother knows that the loss of one of her children before maturity is an unlikely event.
• Main causes of death include: non-communicable diseases (cancer, ASCVD, obesity, diabetes, hypertension) .
• Although much in decline, acutely infectious diseases are spread either by fomites or by zoonoses.
• Connection between public health and infection control/spread.
• Acute infections decline because of improved public health, improved medical treatment, increased resistance to infection.
CHEME 355Industry
CHEME 355Industry
Classification scheme that includes:
• Diseases determined at the time of fertilization. Genes (gene defects) are both necessary and sufficient requirements for disease manifestations to arise.
• Diseases that require environmental influences for their manifestation. These include diseases of poverty and diseases of affluence. Concept of diseases due to maladaption.
Prenatal diseases are considered separately from postnatal diseases because experience suggests that they are essentially different in character, e.g. prenatal diseases do not respond to improvements in living conditions.
CHEME 355Disease origins
Common gene abnormalities are said to be determined at fertilization:
• Chromosomal defects - Can be seen in the microscope - 7- to 10% of embryos - 5- to 6-per 1000 births(e.g. Down’s Syndrome)
• Single-gene disorders - Inheritance can be predicted on Mendelian principles - Autosomal dominant, autosomal recessive, X-linked - 2- to 9-per 1000 births(e.g. Thalassemia, PKU, cystic fibrosis, muscular dystrophy, osteogenesis imperfecta)
CHEME 355Prenatal diseases
Postnatal diseases are multifactorial, which means that disease is caused by the interaction over time of multiple environmental and genetic influences.
Poverty vs. Affluence
CHEME 355Postnatal diseases
CHEME 355Postnatal diseases -- diseases of poverty
‘Third world’ & Diseases of Poverty:
• Natural resource development• New diseases• Civil war• Public health• Lack of food• Political instability• Population growth
Striking replacement of infectious disease that kills early in life with non-communicable disease that kills late.
New diseases in human history caused by conditions of life arising during the industrial period (smoking example).
Small changes in genome; large changes in environment/living conditions, e.g. population growth, cities, technology, diet, reproductive patterns, habits, exercise, substance abuse (maladaptation idea).
‘Wear and tear’ idea: The programmed end is often preceded by a period of ill health caused by the breakdown of non-essential organs such as the eyes, ears and joints, or by the partial collapse of an essential organ such as brain, heart, kidney.
Examples include cancer, ASCVD, obesity, diabetes, hypertension, osteoporosis, etc.
CHEME 355Postnatal diseases -- diseases of affluence
CHEME 355Summary: Genotype - phenotype correlations
“Personalized therapy is supported by an expanded spectrum of drugs developed to target particular disease subtypes on a particular genetic background. Molecular profiling is used to monitor the progress of the disease, and therapy may be adjusted flexibly. This scenario is most likely to apply to life-threatening diseases and to those for which disease disposition and response to therapy are known to vary considerably between individuals, such as cancer and heart and brain disease. Overall, the primary goal of personalized medicine should be to increase the quality of life first, and life-span second.”
Sander, C. (2000) Science 287:1977
Through a decision support system, the physician may prescribe a personal immunization and screening schedule or recommend specific preventive measures
birth
genotype
database
CHEME 355
Postnatal and Prenatal Disease Examples
CHEME 355
Atherosclerotic Cardiovascular Disease
Survival curves and life expectancy at birth for females in the United States (1900, 1995, and projected).
CHEME 355
Atherosclerotic Cardiovascular Disease
1900
1910
1948
1949
CHEME 355
Atherosclerotic Cardiovascular Disease
1960
1970
1980
1990
The reduction in cardiovascular mortality in the past three decades has increased the life expectancy in the United States by an average of five years.
Cardiovascular disease remains by far the leading cause of death in industrialized nations. It has been projected that cardiovascular disease worldwide will climb from the 2nd most common cause of death to 1st, with >36% of all deaths in 2020. Thus, for the first time in human history, cardiovascular disease is likely to become the most common cause of death worldwide.
Two new epidemics of cardiovascular disease are emerging: heart failure and atrial fibrillation.
CHEME 355
Atherosclerotic Cardiovascular Disease
Atherosclerosis is an inflammatory disease. The lesion of atherosclerosis results from several highly specific cellular and molecular responses to injury of the artery wall.
Atherosclerosis is a progressive disease characterized by the accumulation of lipid and fibrous extracellular matrix in large- and medium-sized arteries.
CHEME 355
Atherosclerotic Cardiovascular Disease
CHEME 355
Atherosclerotic Cardiovascular Disease
OX-LDL
Endothelialdysfunction
Inflammation
LDL Cholesterol
Thrombosis
Loss of control of vascular tone
Macrophageactivation
CHEME 355
Atherosclerotic Cardiovascular Disease
CHEME 355
Atherosclerotic Cardiovascular Disease
Clinical Forms
OI Type I
OI Type II
OI Type III
OI Type IV
CHEME 355
Osteogenesis imperfecta
Demographics
Incidence
Gender
Distribution
CHEME 355
Osteogenesis imperfecta
Phenotype, OI type II
Post-mortem photo
Post-mortem x-ray image
CHEME 355
Human femur
A decalcified bonePost-mortem x-ray
OI type II
Bone structure & function
CHEME 355
Structure
Biosynthesis
Collagen structure & biosynthesis / biomineralization
CHEME 355
Two Classes of Mutation
Structural and Null
CHEME 355
G A T C G A T C
Gly Asp
Glycine mutations are the most common structural mutations
-Gly - X - Y - Gly - X - Y
Ala, Asp, Arg, Ser, Cyc, Trp, Val, Tyr, Term
CHEME 355
G A T C G A T C
Gly Asp
Post-mortem x-ray image
?
CHEME 355
Recommended