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The ethical issues of human genetic modification

Explore the ethical ramifications of human genetic modification for enhancing traits and preventing diseases. Delve into the principles, consensus, and monitoring of genetic enhancement in sports, including banned drugs. Learn about gene-based doping, gene therapy examples like X-SCID, and the debate between therapy and enhancement. Consider the blurred lines between normal and ideal traits, disease prevention, and the societal acceptance of certain enhancements across various domains.

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The ethical issues of human genetic modification

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  1. Beyond Therapy -The President’s Council on Bioethics; www.bioethics.govEnhancing Human Traits: Ethical and Social Implications, Eric Parens, ed. Georgetown U. Press, 1998Wondergenes: Genetic enhancement and the future of society, M. Mehlman, Indiana U. Press, 2003

  2. The ethical issues of human genetic modification • can/should human beings be modified genetically to treat or prevent disease? • can/should human beings be modified genetically to affect non-disease traits (enhancement)? What traits? • can/should inherited genetic modification be carried out to affect future generations (germ-line modification)? What traits?

  3. Enhancement - higher, faster, stronger

  4. Underlying principles • attempts at enhancement in sport are ancient, inherent in goal of victory • enhancement in sport is cheating, inconsistent with ideal of fairness, honest competition, equity, concept of rules; corruption of human excellence (IOC, WADA, Kass) • use of some drugs (steroids) in sport is not a medical or moral threat (Fost)

  5. Consensus • drug use in sport is social concern, in its own right and as paradigm for other forms of enhancement of human behavior • requires oversight and control

  6. Monitoring and testing of drug use in sport • IOC and individual sports federations • World Anti-Doping Agency (WADA) - jointly supported by IOC and national governments • national anti-doping agencies (USADA)

  7. Enhancement in sport - banned drugs (WADA) • hormones - epo (oxygen carrying capacity), growth hormones (GH, IGF-1) (muscle strength, repair) • anabolic steroids - muscle strength • stimulants and narcotics- amphetamines, pseudoephedrine • narcotics for pain relief • diuretics and plasma expanders • beta blockers (selected sports)

  8. Gene-based doping • many aspects of human biology, normal and pathological, are genetically determined - genetic basis of disease, behavior and cognition, social behavior (“sociogenomics”) • designed genetic change in human beings is becoming a reality • treatment, prevention of disease (gene therapy) • non-disease traits - “enhancement” • athletic enhancement an early model for enhancement

  9. therapy? somatic cell enhancement therapy germ cell enhancement LeRoy Walters Kennedy Institute, Georgetown

  10. Gene therapy for X-SCID • X-SCID - gene on the X chromosome that encodes gc protein - required for development and function of immune cells (T, NK, B cells) • bone marrow cells treated with virus vector carrying normal version of gc gene. • return corrected cells to patients - normalized cells have growth advantage, overtake bone marrow • ?restore immune cells and their function

  11. Clinical result of X-SCID study • 15-16 patients treated (France, England), 13-14 markedly improved - ?cured of their genetic disease • in school, playing with friends, require no supportive therapy, recover from lethal infections (e.g., chicken pox) • 3 patients have developed life-threatening leukemia up to 6 years after treatment - one death • French study on clinical “hold”, English study proceeding, U.S. studies under re-review by FDA, some have had “clinical hold” removed

  12. Why leukemia? vector chromosome 11 integrated provirus lmo2 lmo2

  13. Why is this result so important? • first rigorous demonstration that gene transfer can betherapeutic, although at severe cost • all previous gene transfer studies, benefits have beenpotential or marginal; riskstheoretical • X-SCID - benefitsquantifiableand unambiguous, risksinherentin a successful technology • with X-SCID study, “gene therapy” rises to level of rigorousclinical researchwith quantifiable risk/benefit ratio - a new epoch for human genetics

  14. therapy - OK somatic cell enhancement? therapy germ cell enhancement

  15. Therapy vs. enhancement? • modify trait or raise performance from “normal” to “better than normal”, toward “ideal” • indistinct boundary between normal and abnormal • height - should normal but small children be treated with GH? • intelligence and cognition - what is normal, desirable for normal human function? • beauty - whose concept of beauty? • indistinct boundary between health and disease • depression - is all depression pathological, require therapy? • memory deficit in Alzheimer’s disease. When does “I forgot where I put my keys” become “I forget where I live” • muscle wasting in aging, etc. - is feebleness in the elderly normal or disease, requiretreatment?

  16. Some enhancementis socially and ethically “acceptable, sought out” • common in modern medicine • cosmetic surgery - spectrum from lipoplasty, botox and breast implants to congenital malformations • therapy of serious psychiatric disease and “deviant” behavior • antidepressants, tranquilizers, mood enhancers (benzodiazepines, SSRIs, etc.) • Ritalin for attention deficit hyperactivity disorder, etc. • social and recreational drug use - mood and performance-enhancing • alcohol, caffeine, marijuana, cocaine, etc. • do we really think National Football League players and NASCAR drivers have higher incidence of erectile dysfunction?

  17. So, if enhancement, why not gene-based enhancement? • genetic modification for therapy is a reality • physical (height, strength, etc.) and complex behavioral and social traits (intelligence, personality traits, cognition, mating and sexual behavior, etc.) are partially genetically determined • modern genomics, genetics are identifying role of genes in many non-disease traits • same genetic modification methods used for therapy will be applicable to non-disease traits

  18. Sport as an early model for gene-based enhancement • athletes and handlers are risk-takers • illicit use of drugs for enhanced performance is common in sport • tools of gene therapy easily applied to sports • several reviewed therapeutic studies involve genes directly applicable to sport • enormous financial and national pressures at all levels of sport - international elite, national, local • concern in sports organizations, IOC, World Anti-Doping Agency (WADA) and U.S. Anti-Doping Agency (USADA)

  19. Non-disease traits can be modified genetically - sports models • altered muscle function - growth factors to increase muscle size, strength, improve repair of injury • injection of gene for insulin-like growth factor (IGF-1), other muscle growth factors into muscle. In studies of muscle repair (muscular dystrophy), mice become stronger (“Schwarzenegger”mice). • improved delivery of oxygen to muscle • gene for erythropoietin (epo) into muscle. Studies of anemia (cancer, kidney disease), anemia is corrected and oxygen delivery improved in mice

  20. Genetic approaches to performance enhancement in athletics • increase oxygen carrying capacity of blood - epo • enhance skeletal and cardiac muscle function - GH, IGF1, GHRH • increase growth and differentiation of myoblasts • stimulate muscle growth, hypertrophy, anabolic metabolism • increase blood flow by stimulating new blood vessel formation - i.e., VEGF? • alter energy utilization - mitochondrial function • raise pain threshold • prevent injury, accelerate healing of injury -

  21. Sustained epo production and hematocrit elevation - Muczynski and Osborne - 2000 • to treat anemia of chronic kidney disease • genetically modify patient’s (autologous) smooth muscle cells infected ex vivo with retrovirus expressing epo, coat surface of plastic artery-vein dialysis graft with epo-producing cells

  22. Siprashvili and Khavari, Mol.Ther. 9: 93, 2004

  23. therapy - OK somatic cell enhancement - inevitable therapy? germ cell enhancement?

  24. Genetic “improvement” beyond sport ? higher, faster, smarter, more beautiful, happier?

  25. A potential new “eugenics”? • the “old” eugenics of late 19th-early 20th centuries based on poor science (Charles Davenport - Cold Spring Harbor) • genetic basis for poverty, slovenliness, love of the sea (“thalassophilia”) • catalyzed restrictive immigration to US, forced sterilization programs (“three generations of imbeciles is enough” -Buck v. Bell, 1927 - O.W. Holmes), stimulated Nazi racial policies • a potential “new” eugenics based on understanding of genetic components of disease susceptibility, behavior, personality - how does “sociogenomics” differ from Davenport? • new potential for restrictive, discriminatory and unjust social and public policy?

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