CHEME 355

1. CHEME 355 Genotype - Phenotype Correlation 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

2. CHEME 355 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.

3. CHEME 355 Genotype - 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.

4. CHEME 355 Genotype - 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 birth genotype database Through a decision support system, the physician may prescribe a personal immunization and screening schedule or recommend specific preventive measures

5. CHEME 355 Genotype - 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.

6. CHEME 355 Genotype - 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.

7. CHEME 355 McKeown, T. The Origins of Human Disease. (Blackwell, Oxford, UK, 1988) pp. 233.

8. CHEME 355 Hunting and Gathering 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.

9. CHEME 355 Hunting 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

10. CHEME 355 Hunting 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.

11. CHEME 355 Hunting 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 BC Leprosy from ~500 AD Syphilis from ~1500 AD Osteoarthritis Osteomyelitis Sinusitis Colle’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.

12. CHEME 355 Agriculture 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.

13. CHEME 355 Agriculture 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.

14. CHEME 355 Agriculture 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.

15. CHEME 355 Agriculture 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.

16. CHEME 355 Industry 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.

17. Mortality Rate Population Growth CHEME 355 Industry

18. CHEME 355 Industry Industrialists: • Sedentary lifestyle • Longer life • Abundant food • Processed food • Degraded environment • Increase in medical technology

19. CHEME 355 Industry 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.

20. CHEME 355 Industry

21. CHEME 355 Disease origins • 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.

22. CHEME 355 Prenatal diseases • 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)

23. CHEME 355 Postnatal 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

24. CHEME 355 Postnatal 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

25. CHEME 355 Postnatal diseases -- diseases of affluence 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.

26. CHEME 355 Summary: 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 birth genotype database Through a decision support system, the physician may prescribe a personal immunization and screening schedule or recommend specific preventive measures

27. CHEME 355 Postnatal and Prenatal Disease Examples

28. CHEME 355 Atherosclerotic Cardiovascular Disease Survival curves and life expectancy at birth for females in the United States (1900, 1995, and projected).

29. 1900 1910 1948 1949 CHEME 355 Atherosclerotic Cardiovascular Disease

30. 1960 1970 1980 1990 CHEME 355 Atherosclerotic Cardiovascular Disease

31. CHEME 355 Atherosclerotic Cardiovascular Disease 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.

32. 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.

33. CHEME 355 Atherosclerotic Cardiovascular Disease

34. CHEME 355 Atherosclerotic Cardiovascular Disease LDL Cholesterol OX-LDL Endothelial dysfunction Inflammation Macrophage activation Thrombosis Loss of control of vascular tone

35. CHEME 355 Atherosclerotic Cardiovascular Disease

36. CHEME 355 Osteogenesis imperfecta Clinical Forms OI Type I OI Type II OI Type III OI Type IV

37. CHEME 355 Osteogenesis imperfecta Demographics Incidence Gender Distribution

38. Post-mortem photo Post-mortem x-ray image CHEME 355 Phenotype, OI type II

39. CHEME 355 Bone structure & function A decalcified bone Post-mortem x-ray OI type II Human femur

40. CHEME 355 Collagen structure & biosynthesis / biomineralization Structure Biosynthesis

41. Two Classes of Mutation Structural and Null CHEME 355

42. 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 Gly Asp G A T C G A T C

43. CHEME 355 Gly Asp ? G A T C G A T C Post-mortem x-ray image