Genomics Applications in Public Health Across All Populations, Environment, and Work Settings Genomic Epidemiology/Inter

1. Genomics Applications in Public Health Across All Populations, Environment, and Work Settings Genomic Epidemiology/International Health American public Health Association Conference Philadelphia, Pennsylvania December 10, 2005 William Ebomoyi, Ph.D. Professor & International Health Consultant (APHA) Community Health College of Natural and Health Sciences University of Northern Colorado Greeley, Colorado William.ebomoyi@unco.edu

2. What is genomics? • View point of the Institute of Medicine (21st Century) • In Genomics and the Public’s Health: “the study of the entire human genome”1. • potential benefits of genomics: • improving the health of the public (not only the actions of single genes, but also the interactions of multiple genes with each other and with the environments1) • differentiating genomics from genetics (functions and effects of single genes). Harwell’s definition of genomics is “the study of the whole genome” • development and application of more effective mapping, sequencing and bio-informatics computational tools • Genomicists – molecular techniques for linkage analysis, physical mapping, and the sequencing of genomes to generate detailed data which are subjected to analysis using high-speed computer facility • A typical genome is the entire collection of chromosomes which are present in the nucleus of each cell of an individual organism2.

3. Statement of Purpose & Institute Overview • Milestones accomplished in sequencing the human genome & with genomics technology • public health careers will become the pre-eminent discipline in neonatal screening for genetic, and in chronic and degenerative diseases • monumental role in environmental health • enabling scientists to identify microbial agents which can sequester carbon dioxide gas (predominant greenhouse gas) • enhance the physical, emotional and cognitive development of children

4. Sequencing of the Human Genome • 1990s – International Scientific Community Sequenced the Human Genome • 2003 – Completed draft • Deciphering – profound understanding of the structure of genes and their functions • Creativity – understanding of gene structure and the complex network of cells • Benefits of advances – revolutionized the epidemiological knowledge about the etiology of a broad spectrum of diseases their progression and preventive medicine • Understanding – amplified the biochemical constituents of biological cells, tissues and fluids which are relevant in explaining disease pathways • Improvement in technology for biochemical analysis – facilitated knowledge about the incipient signs of diseases, diagnosis, treatment and preventive services. • Recently developed technologies – chromatography and electrophoresis, gene amplifications and polymerase chain reaction tests and micro arrays sequencing

5. US Department of Energy & NIH • International collaborators – identification of 30,000 genes in human • Sequencing of the human DNA revealed 3 billion chemical base pairs • Astonishing data: • 1) The human genome contains 3 billion chemical nucleotide bases (adenine (A), cytosine (C), thymine(T) and guanine(G)) • 2) an average gene contains 3000 bases and 3) almost (99.0%) of the nucleotide bases are identical in all humans4

6. Relevance of Human Genome Project to Public Health • CDC’s definition of public health genomics – the study and application of knowledge about the element of the human genome and their functions, including interactions with the environment, in relation to health and disease in population5 • Used to diagnose & understanding of single & multi-factorial genetic disorders: • Chromatography • Radiometry • enzyme and immunoassay • 1985-1986 – United States National Academy of Science and the Nation Research Council’s proposal “map first & sequence later”6. • Scientific breakthrough of locating specific chromosomes & identification of genes for inherited disorders

7. Relevance of Human Genome Project to Public Health • Possibility to develop cures for several single and multi-factorial genetic diseases • Potential breakthroughs: • gene-replacement therapy to correct those genes associated with sickle hemoglobinopathies • Human gene transfer could assist people with genetic disorders that result from inherited errors in a single gene • comprehensive list of some single gene defects are listed in • detect mutations for a handful of more complex diseases such as breast, ovarian and colon cancers • Rapid progress will: • Improve diagnosis of disease • Detect genetic predispositions to disease • Create drug based on molecular information • Use gene therapy and control systems as drugs and • Design “custom drugs” (pharmacogenomics) ased on individual genetic profiles7

8. Genomics in Neonatal Screening • Early identification of disease for which timely intervention can lead to reduction and possible elimination of morbidity of diseases • Neonatal Screening is now performed for 4 million infants each year in United States • Successful & Cost effective

9. Human Genome Project (HGP) • 3 tools: • Diagnose • Treat • Prevent various diseases

10. Sickle Cell Disease • Recessive hereditary disorder • “This disease involves the possession of two abnormal allelemorphic genes related to hemoglobin formation, at least one of which is the sickle cell gene, the genotype constituting sickle cell disease b being SS, Sc, S Thal, SE, SF high gene and SD”8 • Sickle cell disease is caused by a change in just one nucleotide of our six billion cells. • The clinical abnormality caused by sickle cell anemia includes manifestations of sever pain, leg ulcers, swelling of the joints, pains in the abdomen, arms, fatigue, and sometimes death9,10. • sickle cell disease vs. sickle cell trait (SCI) • quantity of erythrocytes of sickle cell trait and sickle cell disease • involvement of greater reduction in the partial pressure of oxygen (required for a significant quantity of trait to sickle than sickle cell disease) • sickle cell trait – one normal hemoglobin gene (A) inherited from one parent and one abnormal gene (S) from the other parent • sickle cell disease – two abnormal genes are inherited, one from each parent

11. Sickle Cell Disorder – Reasons for Screening • Reasons for Screening • No known cure. • Consensus Conference report12, hemoglobinopathies represent one of the significant public health problems in the United States • Sickle cell disease – most common genetic dysfunction in some populations • one of every 400 African-American newborns affected • In other countries the technology for screening infants for hemoglobinopathis in the newborn may not be efficient • United States – widespread adoption of screening was not instituted, some reasons are: • inertia about who to test • lack of overt improvement in outcome with early diagnosis • technical difficulties arising from the increased level of fetal hemoglobin in the neonate • unresolved issues about obligation to those diagnosed as carriers of the sickling genes12

12. Reasons for Neonatal Screening – Sickle Cell • Prevention of unnecessary mortality among infants • prompt referral of diagnosed children to tertiary health care centers • Life-threatening complications associated with sickle cell disease: • acute splenic sequestration crisis • bacterial infection (Streptococcus pneumonia) – most severe in children under 3 years of age • Identify infants with SCD is necessary to enable health care providers to institute effective measures of prophylaxis and intervention. • High pressure liquid chromatography (HPLC) – very sensitive & rapid • Differentiates between hemoglobinpathies13 • “solubility testing procedures are not satisfactory for screenign purposes.14 • cellulose acetate accompanied by citrate agar electrophoresis remains the method

13. Medical Management of Sickle Cell Disease • No effective treatment of sickle cell disease • Individuals suffering from SCD are encouraged to avoid low oxygen tension which occurs during flight in an unpressurized aircraft • Patients are kept well hydrated if an episode of crisis occures14 • blood transfusion becomes advisable in some cases • SCD tolerate hemoglobin levels of 5 to 6 g/100 ml blood adequately

14. Indicators of Sickle Cell Disease • Initial clinical tests • paked cell volume (PCV) • reticulocyte cou nt on blood film • white cell and differential counts • Urinalysis • hemoglobin electrophoresis • x-ray of the chest to determine the size of the heart and X-ray fo the asffected bone if observed uring crisis. • Common signs of SCD • inactive crises • anemic crisis • susceptibility to bacteria infections (streptococcus pneumonia1,15).

16. Public Health Workforce • Unprecedented tasks of meeting the needs of the society • visual impairment • hearing and cognitive deficits • School Health Curriculum – infused with genomics science information • health services – appraisal, preventive screening, & remedial activities • health instruction – planned instruction, integrated learning & incidental instruction • healthful school living – physical environment • Genomic applications in school health curriculum transcend the three components of school health program. But by far most crucial are the various screening programs to prepare the elementary-school child for meaningful cognitive ventures.

17. School health program Health Services Health Instruction Healthful living • Appraisal Aspects • Health examination, dental examination, teacher health assessment, vision testing, hearing testing, height and weight measurement, cleanliness inspection, guidance and supervision, teacher health • Planned Instruction • Practices, attitudes, knowledge • Physical environment • Site, plant plan, heating, ventilation, lighting, water, lunch room facilities, sewage disposal 2.Correlated instruction Arts, social studies, sciences 2. Mentally healthy environment Pupil status, pupil-teacher relationships, provision for individual differences, curriculum adaptation, atmosphere of mutual respect 3.Integrated learning Personal experiences, pupil-teacher relationships, classroom experiences, school experiences… 2.Preventive aspects Communicable disease control, safety, emergency care, first aid… 4.Incidental instruction Personal experiences, classroom experiences, school activity, community events… 3.Remedial Aspects Follow-up services, correction of remediable defects, practitioner services, school functions 3. Practices Schedules, time allotments, activity and rest, fire protection safety, inspection, housekeeping… Public Health Workforce Source: Creswell WH, School Health Practice, St. Louis, Mosby Press 1993; P.40

18. Genomics in Chronic & Degenerative Diseases • Genomics in Chronic and Degenerative Diseases • Cardiovascular diseases – leading cause of death worldwide • 1st time in 65 years – is not leading in U.S.

19. Genomics in Chronic & Degenerative Diseases • Public health interventions which yielded positive epidemiological outcomes have been • Abstaining from tobaccco • Health promotion initiative prohibiting smoking in public places across the nation • Education of the public about diet modification • Encouragement of physical activities • Avoidance of excessive alcohol • Of the ten leading causes of death in United States, nine of them are associated with genetic etiologies. Although there is no evidence that accidents have genetic link, the major causes of death in United States continue to be heart disease, cancer, cardiovascular disease, chronic lower respiratory disease, diabetes, pneumonia/influenza, kidney disease and septicemia. • Genetic susceptibility, the environment, immune status and behavioral patterns play major role in the onset of many of the leading causes of death in United States.

20. Genomics in Environmental Health • Environment - physical and biological characteristics of an area • microbial organisms • bioremediation • environmentally induced diseases • nature’s most abundant, simplest organisms ubiquitous – able to thrive under extreme conditions (heat, cold, pressure, radiation) • It is therefore axiomatic that the ability of this planet to sustain life is mainly dependent on microbes, which to a large extent are not pathogenic.21

21. Genomics in Environmental Health (cont). • United States Department of Energy • microbes are the foundation of the biosphere (lithosphere, atmosphere, and hydrosphere) • Microbes control: • earth’s natural biogeochemical cycling • affect the nutrient level and productivity of the soil, quality of water • stability of global climate • They can be used to • transform various waste products • organic matter • cycling nutrients • converting sunlight energy • storing carbon dioxide from the atmosphere22.

22. Genomics in Environmental Health (cont). • Microbial genomics: • application of bacterial and other microbial agents • environmental health problems • Toxic waste sites – contain a myriad of contaminates • possible to develop “designer bacteria” to degrade those compounds in these wasteland/landfills • Rapid detection and treatment of environmentally induced microbial diseases • Development of new energy sources (biofuels) • Monitoring of air, land, and water environment to isolate pollutants • Protection of citizenry from biological and chemical warfare and clean up of toxic waste safely and efficiently23.

23. Integration of Genomic Science into Statewide Public Health Programs • Statewide offices of public health • Essential components of such units: • administrative leadership care • environmental health • maternal and child health • clinical laboratory services • health promotion units • demographic units where vital statistical records on births, marriages and death records are stored • The Institute of Medicine (IOM) in the Future of Public Health outlined the process of integration of genomics into public health through policy development, assessment of programs and assurance of services.

24. Integration of Genomic Science into Statewide Public Health Programs • The integration of genomics must include: • regular systematic collection • Assembly • Analysis of health status information • dissemination of health status information • Genomic data are used judiciously • Genetic tests are used to meet the national goal of promoting healthy living • System management • Capacity building • An eclectic initiative involving data elicitation from all program staff can create meaningful insights about how best to integrate genomics into public health services.

25. Prospects for Genomic Science Applications • Genetic variation can be characterized and charted for many ethnic groups • Microbial genomes can be explored for: • protein machines that perform critical life functions • Bioinformatics could be integrated, understood and the copious data derived used to model complex biological systems.

26. Ethical, Legal, & Social Implications • James Watson25, the first director of NIH genomic center • first biologist to advocate the relevance of the ethical, legal and social issues about advances in genomic technology • NIH, United States and the Department of Energy, Genome programs • adhere to stringent and sanctimonious principles • Seek genetic information from potential clients

27. Ethical, Legal, & Social Implications • Collectively, their resolutions enforced: • Maintaining privacy and confidentiality of genetic information. • Adoption of fairness in the use of genetic information by insurance companies, employers, court, schools, the military, adoption agencies and health associations among others. • Avoidance of social stigmatization status and discrimination against an individual due to a person’s genetic differences. • Ensuring that researchers seek adequate and informed consent while working with patients with specific genetic defects.

28. Ethical, Legal, & Social Implications • Resolutions (cont.) • Education of physicians, other clinicians, health service providers about clients identities with genetic conditions and the general public about the capabilities, limitations and social risks associated with certain disorders and the implementation of standards and quality control measure at all laboratories and counseling centers. • Use of experiences geneticists and other clinicians to explain the uncertainties associated with gene tests for susceptibility, particularly for multi-factorial complex diseases such as heart disease, diabetes and Alzheimer’s disease. • Ensuring that there is fairness in access to advanced genomic technology and other pertinent philosophical and conceptual leanings of clients.

29. Acknowledgements The author would like to express his gratitude to the late professor William H. Creswell, Jr. formerly the University of Illinois at Urbana-Champaign and Dr. Flora F. Cherry, my preceptor at the Tulane Medical School in New Orleans and the late professor Emmanuel Shapiro, a medical geneticist who made his lab available to me while undergoing NIH post-doctoral training at the Tulane Medical Center. Without the assistance from The National Institutes of Health and Ms. Anita Johnson of United States Department of Energy, this report would not have been completed. The author thanks Dr. Freddie Asinor and Ms. Karon Moody and Dona Wright for coordinating the Continuing Education Institute for the American Public Health Association.

30. References • Institute of Medicine (IOM) Implications of genomics for public health. Washington, DC The National Academy Press, 2005. • Hartwell LL, et al. Genetics from genes to genomes Boston, McGraw Hill Higher Education, 2004. • US Department of Energy Joint Genome Institute and the Technical & Electronic Information Department, Lawrence Berkeley National Laboratory genomics The human genome and beyond (poster). • United States Department of Energy, Office of Science Genomics and its impact on science and society. Oak Ridge Tenessee, Oak Ridge National Laboratory February, 2004. • CDC A guide to public Health http://www.genomicstoolkit.org, 2005 • Marchi, E. China at 50: A test for functional genetics ABL 2000, 18, 1-14. • United States Department of Energy, Office of Science Genomics and its impact on science and society. Oak Ridge Tenessee, Oak Ridge National Laboratory. February 2004 p.7. • Konotey-Ahulu FID The sicle cell disease clinical manifestation including the sickle crisis. Arch. International Medicine 1974, 1133, 611-619. • Ohene-Frampong K. Selected testing of Newborns for sickle cell disease. Pediatric Supplement 1989, 879-880. • Ebomoyi EW Community Medicine A global perspoective Belmont CA Star Press, 1998. • Pauling L. et al. Sickle cell anemia: A molecular disease Science 1949, 543-548. • Consensus conference, Newborn screening for sickle cell disease and other hemoglobinpathies JAMA 1987, 258, 1205-1209. • Ebomoyi, EW and Cherry FF Control of hereditary disorders in Ebomoyi, EW (ed.) Community medicine a global perspective. Belmont CA 1998, 257-287. • McCarthy M. USA Reocmmends universal sickle cell screening Lancet 1993 34: 1209 • Consensus conference, ibid • Creswell WH and Newman IM School health practice St. Louis MI Times Mirror/Mosby college publishing 1989. • Ibid,7, 10, 35-40, 35-42, 114-129, & 115-130 • United States Department of Energy (DOE) Genomics: GTL Exploring microbial genomics for energy and environment http://www.ornl.gov/hgmis/publicat/primer • Institute of Medicine (IOM) Future of public health Washington DC the National academy Press, 2005 20. Watson J. DNA the Secret of life. New Yor Alfred A. Knopf, 2004.