Towards An Ethics of the Human Genome Project

1. Towards An Ethics of the Human Genome Project • Pattle P.Pun, • Department of Biology, • Wheaton College, • Wheaton, IL 60187 • USA Dr. Pattle Pun, Biology, Wheaton College, IL 60187

2. Dr. Pattle Pun, Biology, Wheaton College, IL 60187

3. Human Genome Project Goals:  ■ identify all the approximate 30,000 genes in human DNA, ■ determine the sequences of the 3 billion chemical base pairs that make up human DNA, ■ store this information in databases, ■ improve tools for data analysis, ■ transfer related technologies to the private sector, and ■ address the ethical, legal, and social issues (ELSI) that may arise from the project. Milestones: ■ 1990: Project initiated as joint effort of U.S. Department of Energy and the National Institutes of Health ■ June 2000: Completion of a working draft of the entire human genome ■ February 2001: Analyses of the working draft are published ■ April 2003: HGP sequencing is completed and Project is declared finished two years ahead of schedule Timeline: http://www.dnai.org/timeline/index.html Dr. Pattle Pun, Biology, Wheaton College, IL 60187 U.S. Department of Energy Genome Programs, Genomics and Its Impact on Science and Society, 2003

4. How does the human genome stack up? Dr. Pattle Pun, Biology, Wheaton College, IL 60187

5. Anticipated Benefits of Genome Research Molecular Medicine • improve diagnosis of disease• detect genetic predispositions to disease• create drugs based on molecular information• use gene therapy and control systems as drugs• design “custom drugs” (pharmacogenomics) based on individual genetic profiles Microbial Genomics • rapidly detect and treat pathogens (disease-causing microbes) in clinical practice• develop new energy sources (biofuels)• monitor environments to detect pollutants• protect citizenry from biological and chemical warfare• clean up toxic waste safely and efficiently Dr. Pattle Pun, Biology, Wheaton College, IL 60187 U.S. Department of Energy Genome Programs, Genomics and Its Impact on Science and Society, 2003

6. Anticipated Benefits of Genome Research-cont. Risk Assessment • evaluate the health risks faced by individuals who may be exposed to radiation (including low levels in industrial areas) and to cancer-causing chemicals and toxins Bioarchaeology, Anthropology, Evolution, and Human Migration • study evolution through germline mutations in lineages• study migration of different population groups based on maternal inheritance• study mutations on the Y chromosome to trace lineage and migration of males• compare breakpoints in the evolution of mutations with ages of populations and historical events Dr. Pattle Pun, Biology, Wheaton College, IL 60187 U.S. Department of Energy Genome Programs, Genomics and Its Impact on Science and Society, 2003

7. Anticipated Benefits of Genome Research-cont. DNA Identification (Forensics) • identify potential suspects whose DNA may match evidence left at crime scenes• exonerate persons wrongly accused of crimes• identify crime and catastrophe victims• establish paternity and other family relationships• identify endangered and protected species as an aid to wildlife officials (could be used for prosecuting poachers)• detect bacteria and other organisms that may pollute air, water, soil, and food• match organ donors with recipients in transplant programs• determine pedigree for seed or livestock breeds• authenticate consumables such as caviar and wine Dr. Pattle Pun, Biology, Wheaton College, IL 60187 U.S. Department of Energy Genome Programs, Genomics and Its Impact on Science and Society, 2003

8. Anticipated Benefits of Genome Research-cont. Agriculture, Livestock Breeding, and Bioprocessing • grow disease-, insect-, and drought-resistant crops• breed healthier, more productive, disease-resistant farm animals• grow more nutritious produce• develop biopesticides• incorporate edible vaccines incorporated into food products• develop new environmental cleanup uses for plants like tobacco Dr. Pattle Pun, Biology, Wheaton College, IL 60187 U.S. Department of Energy Genome Programs, Genomics and Its Impact on Science and Society, 2003

9. ELSI: Ethical, Legal, and Social Issues • Privacy and confidentiality of genetic information. • Fairness in the use of genetic information by insurers, employers, courts, schools, adoption agencies, and the military, among others. • Psychological impact, stigmatization, and discrimination due to an individual’s genetic differences. • Reproductive issues including adequate and informed consent and use of genetic information in reproductive decision making. • Clinical issues including the education of doctors and other health-service providers, people identified with genetic conditions, and the general public about capabilities, limitations, and social risks; and implementation of standards and quality‑control measures. Dr. Pattle Pun, Biology, Wheaton College, IL 60187 U.S. Department of Energy Genome Programs, Genomics and Its Impact on Science and Society, 2003

10. ELSI Issues (cont.) • Uncertainties associated with gene tests for susceptibilities and complex conditions (e.g., heart disease, diabetes, and Alzheimer’s disease). • Fairness in access to advanced genomic technologies. • Conceptual and philosophical implications regarding human responsibility, free will vs genetic determinism, and concepts of health and disease. • Health and environmental issues concerning genetically modified (GM) foods and microbes. • Commercialization of products including property rights (patents, copyrights, and trade secrets) and accessibility of data and materials. Dr. Pattle Pun, Biology, Wheaton College, IL 60187 U.S. Department of Energy Genome Programs, Genomics and Its Impact on Science and Society, 2003

11. Huntington Disease (HD)and Cystic Fibrosis (CF) • How are HD and CF inherited? What are the patterns of inheritance? • What is the cause of HD? Of CF? What’s wrong with the HD or CF genes? • What is the predictive reliability of the genetic test that determines whether an individual carries a gene for HD? For CF? Dr. Pattle Pun, Biology, Wheaton College, IL 60187

12. What is the clinical course of HD? • HD is typically a late manifesting autosomal dominant neurodegenerative disorder. It is characterized by motor disturbances, loss of cognitive functions, and psychiatric manifestations. HD patients present with loss of coordination, worsening gait, constant uncontrolled movements (chorea) and personality changes. Dr. Pattle Pun, Biology, Wheaton College, IL 60187

13. After diagnosis, HD patients require medical intervention and as the disease worsens patients invariably require specialized care in long-term nursing facilities. Death comes within 15 years after the initial clinical diagnosis of HD. Dr. Pattle Pun, Biology, Wheaton College, IL 60187

14. What is the HD gene? • The HD gene is represented by a segment of DNA (approximately 300,000 letters) found on human chromosome 4. • Approximately 3% of the letters of the HD gene are expressed as the HD protein, which has been named huntingtin. • Although HD is relatively rare (both inherited and de novo case), every human possesses two alleles of the HD gene. Dr. Pattle Pun, Biology, Wheaton College, IL 60187

15. What’s wrong with the HD gene? • The variant HD alleles which cause HD have a molecular abnormality consisting of an expanding triplet repeat (CAG). • The expanding triplet repeat causes extra glutamine amino acids to be placed within the front end of the huntingtin protein, making huntington bigger. Dr. Pattle Pun, Biology, Wheaton College, IL 60187

16. The genetic test that measures the presence of the HD disease alleles. • The original HD test was based on genetic markers that were close to the HD gene. These tests were about 95% reliable (sometimes crossing over would “break” the linkage). • The current test is based on the direct assessment of the exact size of the “expanding triplet repeat” region of the HD gene. This is a much more reliable test, more than 99.5% accurate. Dr. Pattle Pun, Biology, Wheaton College, IL 60187

17. The genetic test that measures the presence of the HD disease alleles. • Alleles of HD which have between 10 and 35 (CAG) repeats never cause HD. • Alleles of HD which have more than 40 (CAG) repeats always cause HD. • Alleles of HD which have between 36 and 39 (CAG) repeats almost always causes HD. Dr. Pattle Pun, Biology, Wheaton College, IL 60187

18. Clinical Diagnosis of CF • Typical pulmonary manifestations. • Typical gastrointestinal manifestations. • A history of cystic fibrosis in the immediate family. • Sweat chloride concentrations greater than a baseline value. • Identification of pathological CFTR mutations on both CFTR alleles. • Occasionally, CF is uncovered by a discovery of “male infertility”. Dr. Pattle Pun, Biology, Wheaton College, IL 60187

19. Consequence of CF • CF patients have greatly shortened life expectancy. The mean age of death now is around 30. • There is no cure for cystic fibrosis. • Cystic fibrosis is a fatal disease. Dr. Pattle Pun, Biology, Wheaton College, IL 60187

20. Inheritance of CF • Cystic Fibrosis is a autosomal recessive disease. It is caused by a single gene defect which is inherited in a autosomal recessive mendelian fashion. Both alleles of the CF gene must be “affected” to be at risk of CF. Having a single allele of the “CF gene” makes the individual a carrier, but does not produce CF. Dr. Pattle Pun, Biology, Wheaton College, IL 60187

21. Identification of the CF gene • The CF gene, now called CFTR, was identified in 1989 by several groups, including Francis Collins, the former director of the NIH Human Genome Institute. Dr. Pattle Pun, Biology, Wheaton College, IL 60187

22. Genotype and Phenotype correlation in CF • Many symptoms are common to all CF patients, such as salty sweat. • There is a reasonably good correlation of genotype (particular CF alleles) and pancreatic function. • There is little or no correlation of genotype and severity of lung disease or other clinical symptoms. Lack of concordance in twin studies. Dr. Pattle Pun, Biology, Wheaton College, IL 60187

23. Gene therapy for cystic fibrosis • Gene therapy for cystic fibrosis has been evaluated in several human clinical trials. Dr. Pattle Pun, Biology, Wheaton College, IL 60187

24. Behavior is Multifactorial Sin? Environment Genes Development Behavior Dr. Pattle Pun, Biology, Wheaton College, IL 60187

25. The Number of Genes Involved in Particular Behaviors is Unknown gene 1 environment gene 6 or ? gene1 environment Dr. Pattle Pun, Biology, Wheaton College, IL 60187 gene 100

26. The Advent of Genomic Medicine • The science of genomics rests on direct experimental access to the entire human genome and applies to common conditions, such as breast cancer and colorectal cancer, human immunodeficiency virus (HIV) infection, tuberculosis, Parkinson's disease, and Alzheimer's disease. Dr. Pattle Pun, Biology, Wheaton College, IL 60187

27. Iceland’s experiment • Iceland has decided to become the first country in the world to sell the rights to the entire population’s genetic code to a biotechnology company, deCODE Genetics. • Iceland’s parliament has passed a law to allow deCODE to hold an unusual 12-year monopoly on the data marketing rights of her people. • The striking uniform DNA of Iceland’s population of 270,000 has provided an invaluable resource for studying human genetics, leading to the discovery of the genetic bases for some hereditary diseases such as Alzheimer’s, Schizophrenia and Osteoporosis. Dr. Pattle Pun, Biology, Wheaton College, IL 60187

28. case vignette : • Thirty-four-year-old Kathleen becomes pregnant and sees a new physician for her first prenatal visit. • Her medical history is remarkable for an episode of deep venous thrombosis five years earlier while she was taking oral contraceptives; • her mother had had deep venous thrombosis when pregnant with Kathleen. • Her physician suspects that Kathleen has a hereditary thrombophilia and obtains blood tests to screen for a genetic predisposition to thrombosis. • Kathleen proves to be among the approximately 4 percent of Americans who are heterozygous for a mutation in factor V known as factor V Leiden that increases the risk of thrombotic events. • On the basis of this knowledge and her history of possibly estrogen-related thromboembolism, she is treated with prophylactic subcutaneous heparin for the balance of her pregnancy. She remains asymptomatic and delivers a healthy, term infant. Dr. Pattle Pun, Biology, Wheaton College, IL 60187

29. The Cypriot ParadigmThe Journal of Medicine and Philosophy     Volume 23, Number 3 / July 1998   Pages:  274 - 287 Geneticization: The Cyprus Paradigm • Genetic Testing for Thalassemia for Greek Cypriots: • Government and church cooperate in public education, counseling and clinical service. • Small, homogeneous population • Fairly high living standard • High literacy rate. • Within One Generation, disease rate fell from 1/1000 births to 0 in 1986. • No more reported case as of 1992. Dr. Pattle Pun, Biology, Wheaton College, IL 60187

30. Sustained Correction of X-Linked Severe Combined Immunodeficiency by ex Vivo Gene Therapy, NEJM 346:1185-1193 April 18, 2002 • Methods • CD34+ bone marrow cells from five boys with X-linked severe combined immunodeficiency were transduced ex vivo with the use of a defective retroviral vector. Integration and expression of the c transgene and development of lymphocyte subgroups and their functions were sequentially analyzed over a period of up to 2.5 years after gene transfer. Dr. Pattle Pun, Biology, Wheaton College, IL 60187

31. Sustained Correction of X-Linked Severe Combined Immunodeficiency by ex Vivo Gene Therapy • Results • No adverse effects resulted from the procedure. Transduced T cells and natural killer cells appeared in the blood of four of the five patients within four months. The numbers and phenotypes of T cells, the repertoire of T-cell receptors, and the in vitro proliferative responses of T cells to several antigens after immunization were nearly normal up to two years after treatment. Thymopoiesis was documented by the presence of naive T cells and T-cell antigen-receptor episomes and the development of a normal-sized thymus gland. The frequency of transduced B cells was low, but serum immunoglobulin levels and antibody production after immunization were sufficient to avoid the need for intravenous immunoglobulin. Correction of the immunodeficiency eradicated established infections and allowed patients to have a normal life. Dr. Pattle Pun, Biology, Wheaton College, IL 60187

32. The case of Jesse Gelsinger Dr. Pattle Pun, Biology, Wheaton College, IL 60187

33. The Case (1)Jesse Gelsinger was born with an X-linked recessive error of metabolism, ornithine transcarbamylase deficiency (OTC). This disease causes a life threatening buildup of ammonia. Half of the youngsters born with the disease die within hours of birth. Jesse’s case was relatively mild and was controlled with drugs. Even so, he had experienced one serious episode of coma. Dr. Pattle Pun, Biology, Wheaton College, IL 60187

34. Gelsinger (2)When Jesse turned 18, he volunteered for a gene transfer trial at the University of Pennsylvania. The bioethics committee supervising the trial would not accept affected newborns on the grounds that the parents would be too distraught to provide informed consent. Jesse was jubilant on being accepted. “What’s the worst that can happen to me,” he said. “I die and it’s for the babies.” Dr. Pattle Pun, Biology, Wheaton College, IL 60187

35. Gelsinger (3)After two lower dosage trials on other volunteers, Jesse was administered the highest dosage level of an adenovirus vector, with the functional OTC gene stitched into it. This vector had already been safely used in over 80 gene therapy trials involving approximately 1,000 patients. Dr. Pattle Pun, Biology, Wheaton College, IL 60187

36. Gelsinger (4)Jesse entered the hospital on September 13, 1999. Seventeen others in the trial had already been treated and suffered only minor aches and pains. However, Jesse soon suffered a high fever. His ammonia levels skyrocketed and eventually he suffered lung failure and brain death. Dr. Pattle Pun, Biology, Wheaton College, IL 60187

37. Gelsinger (5)Doctors later explained that, because of a previous infection, Jesse had had an acute immune reaction to the adenovirus. In the months following his death, FDA and NIH officials identified a host of procedural irregularities and problems that contributed to Jesse’s death. Dr. Pattle Pun, Biology, Wheaton College, IL 60187

38. Safety and Consent in GT Research: Lessons of the Jesse Gelsinger Case • The risks of this research • The need for better adverse event reporting and fully informed consent Dr. Pattle Pun, Biology, Wheaton College, IL 60187

39. Therapy Enhancement Somatic Germ Line Dr. Pattle Pun, Biology, Wheaton College, IL 60187

40. Sources of Concern • “Insertional mutagenesis” and the iatrogenic creation of genetic disorders • The enduring nature and proliferating potential of such mishaps • The low level of need: prenatal and preimplantation selection and egg or sperm donation obviate most Germ Line GeneTherapy Dr. Pattle Pun, Biology, Wheaton College, IL 60187

41. Can genetic testing be a tool for discrimination by social institutions such as the insurance industry? • What is the limitation of genetic technologies? • By what criteria can we evaluate the use or misuse of human genetic information? Dr. Pattle Pun, Biology, Wheaton College, IL 60187

42. How far should one pursue to improve the human conditions by genetic manipulation? • How can we prevent the abuse of human genetic information? • Does the presence of the genetic defect doom the future of a child's life? • Do parents have a right not to be subject to genetic testing to alleviate anxiety? Dr. Pattle Pun, Biology, Wheaton College, IL 60187

43. Are medical professionals obligated to counsel patients in making these decisions? • Should employers or insurance companies be given free access to the genetic information of potential employees or clients to determine their employability or set the insurance rates? Dr. Pattle Pun, Biology, Wheaton College, IL 60187

44. What professional standards should be set for a physician in regards to the amounts and varieties of genetic testing required for his patients by which malpractice litigation can be measured? • Does a person have a right not to know about his genetic makeup? • Will genetics become a weapon for social discrimination? • Should law enforcement agencies promote universal forensic DNA testing to increase the probability of crime control? Dr. Pattle Pun, Biology, Wheaton College, IL 60187

45. Purdy: • It can sometimes be immoral to have children when we know (or should know) that our offspring may have a genetic disease. Dr. Pattle Pun, Biology, Wheaton College, IL 60187

46. JC Peterson: • Improvement of our genetic heritage is a reflection of God’s gracious redemption if done properly. Dr. Pattle Pun, Biology, Wheaton College, IL 60187

47. Lewontin and Hubbard • DNA Testing does not provide practical benefits for the patients to be warranted since no cure for genetic diseases are available. Dr. Pattle Pun, Biology, Wheaton College, IL 60187

48. Wachbroit • Certain professionals have an obligation to know about their genetic condition and thus to be tested genetically. Medical paternalism in regards to deciding whether genetic testing is given to the patients should be restricted. Dr. Pattle Pun, Biology, Wheaton College, IL 60187

49. Dr. Pattle Pun, Biology, Wheaton College, IL 60187 A. Various Ethical Principles informed by the Christian Worldview:

50. 1. Divine Law of Aquinas and Augustine • The Creator has designed purposes and directions for His creation. This Divine Law can be discovered in Nature. Despite man's sinful nature, God still reveals this Law to man through the Scripture and the Church. The Divine Law is consonant with human nature and can be universally applied. Dr. Pattle Pun, Biology, Wheaton College, IL 60187