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The ethical issues of human genetic modification

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

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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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