Beyond Therapy — The President s Council on Bioethics

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

The ethical issues of human genetic modification 1. can/should human beings be modified genetically to treat or prevent disease? 2. can/should human beings be modified genetically to affect non-disease traits (enhancement)? What traits? 3. can/should inherited genetic modification be carried out to affect future generations (germline modification)? What traits?

Enhancement - higher, faster, stronger

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)

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

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)

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, narcotics pseudoephedrine • narcotics for pain relief • diuretics and plasma expanders • beta blockers (selected sports)

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

somatic cell germ cell therapy? enhancement therapy enhancement Le. Roy Walters Kennedy Institute, Georgetown

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

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

Why leukemia? vector chromosome 11 lmo 2 integrated lmo 2 provirus

Why is this result so important? • first rigorous demonstration that gene transfer can be therapeutic, although at severe cost • all previous gene transfer studies, benefits have been potential or marginal; risks theoretical • X-SCID - benefits quantifiable and unambiguous, risks inherent in a successful technology • with X-SCID study, “gene therapy” rises to level of rigorous clinical research with quantifiable risk/benefit ratio - a new epoch for human genetics

somatic cell germ cell therapy - OK enhancement? therapy enhancement

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, require treatment?

Some enhancement is 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 performanceenhancing – alcohol, caffeine, marijuana, cocaine, etc. – do we really think National Football League players and NASCAR drivers have higher incidence of erectile dysfunction?

So, if enhancement, why not genebased 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

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)

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

Genetic approaches to performance enhancement in athletics • increase oxygen carrying capacity of blood - epo • enhance skeletal and cardiac muscle function - GH, IGF 1, 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

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 epoproducing cells

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

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

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

A potential new “eugenics”? • the “old” eugenics of late 19 th-early 20 th 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?