Beyond TherapyBeyond Therapy - - The President’s The President’s Council on Bioethics; Council on Bioethics; www.bioethics.gov

Enhancing Human Traits: Ethical and Enhancing Human Traits: Ethical and Social Implications, Social Implications, Eric Parens, ed. Eric Parens, ed.

Georgetown U. Press, 1998Georgetown U. Press, 1998

Wondergenes: Genetic enhancement and Wondergenes: Genetic enhancement and the future of society, M. Mehlman, the future of society, M. Mehlman,

Indiana U. Press, 2003Indiana U. Press, 2003

The ethical issues of human genetic The ethical issues of human genetic modificationmodification

1.1. can/should human beings be modified can/should human beings be modified genetically to treat or prevent disease?genetically to treat or prevent disease?

2.2. can/should human beings be modified can/should human beings be modified genetically to affect non-disease traits genetically to affect non-disease traits (enhancement)? What traits?(enhancement)? What traits?

3.3. can/should inherited genetic modification be can/should inherited genetic modification be carried out to affect future generations carried out to affect future generations (germ-line modification)? What traits? (germ-line modification)? What traits?

Enhancement - higher, faster, stronger

Underlying principlesUnderlying principles

• attempts at enhancement in sport are attempts at enhancement in sport are ancient, inherent in goal of victoryancient, inherent in goal of victory

• enhancement in sport is cheating, enhancement in sport is cheating, inconsistent with ideal of fairness, honest inconsistent with ideal of fairness, honest competition, equity, concept of rules; competition, equity, concept of rules; corruption of human excellence (IOC, corruption of human excellence (IOC, WADA, Kass) WADA, Kass)

• use of some drugs (steroids) in sport is use of some drugs (steroids) in sport is not a medical or moral threat (Fost)not a medical or moral threat (Fost)

ConsensusConsensus

• drug use in sport drug use in sport isis social concern, in its social concern, in its own right and as paradigm for other own right and as paradigm for other forms of enhancement of human behaviorforms of enhancement of human behavior

• requires oversight and controlrequires oversight and control

Monitoring and testing of drug use in Monitoring and testing of drug use in sportsport

• IOC and individual sports federationsIOC and individual sports federations• World Anti-Doping Agency (WADA) - World Anti-Doping Agency (WADA) -

jointly supported by IOC and national jointly supported by IOC and national governmentsgovernments

• national anti-doping agencies (USADA)national anti-doping agencies (USADA)

Enhancement in sport - banned drugs Enhancement in sport - banned drugs (WADA)(WADA)

• hormones - epo (oxygen carrying capacity), growth hormones (GH, IGF-1) (muscle strength, repair)

• anabolic steroids - muscle strength• stimulants and narcoticsnarcotics- amphetamines,

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

Gene-based dopingGene-based doping

• many aspects of human biology, normal and many aspects of human biology, normal and pathological, are genetically determined - genetic pathological, are genetically determined - genetic basis of disease, behavior and cognition, social basis of disease, behavior and cognition, social behavior (“sociogenomics”)behavior (“sociogenomics”)

• designed genetic change in human beings is designed genetic change in human beings is becoming a realitybecoming a reality– treatment, prevention of disease (gene therapy)treatment, prevention of disease (gene therapy)– non-disease traits - “enhancement”non-disease traits - “enhancement”– athletic enhancement an early model for enhancement athletic enhancement an early model for enhancement

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therapy?somatic cell

germ cell therapy

enhancement

enhancement

LeRoy WaltersKennedy Institute, Georgetown

Gene therapy for X-SCIDGene therapy for X-SCID

• X-SCID - gene on the X chromosome that X-SCID - gene on the X chromosome that encodes encodes c protein - required for development c protein - required for development and function of immune cells (T, NK, B cells) and function of immune cells (T, NK, B cells)

• bone marrow cells treated with virus vector bone marrow cells treated with virus vector carrying normal version of carrying normal version of c gene. c gene.

• return corrected cells to patients - normalized return corrected cells to patients - normalized cells have growth advantage, overtake bone cells have growth advantage, overtake bone marrowmarrow

• ?restore immune cells and their function?restore immune cells and their function

Clinical result of X-SCID studyClinical result of X-SCID study

• 15-16 patients treated (France, England), 13-14 15-16 patients treated (France, England), 13-14 markedly improved - ?cured of their genetic diseasemarkedly improved - ?cured of their genetic disease– in school, playing with friends, require no supportive in school, playing with friends, require no supportive

therapy, recover from lethal infections (e.g., chicken pox)therapy, recover from lethal infections (e.g., chicken pox)

• 3 patients have developed life-threatening leukemia 3 patients have developed life-threatening leukemia up to 6 years after treatment - one deathup to 6 years after treatment - one death

• French study on clinical “hold”, English study French study on clinical “hold”, English study proceeding, U.S. studies under re-review by FDA, proceeding, U.S. studies under re-review by FDA, some have had “clinical hold” removedsome have had “clinical hold” removed

lmo2lmo2

vectorvector

integratedintegratedprovirusprovirus

lmo2lmo2

chromosome 11chromosome 11

Why leukemia?Why leukemia?

Why is this result so important?Why is this result so important?

• first rigorous demonstration that gene transfer can first rigorous demonstration that gene transfer can bebe therapeutictherapeutic, although at severe cost, although at severe cost

• all previous gene transfer studies, benefits have beenall previous gene transfer studies, benefits have been potential or marginalpotential or marginal; risks; risks theoreticaltheoretical

• X-SCID - benefitsX-SCID - benefits quantifiablequantifiable and unambiguous, and unambiguous, risksrisks inherentinherent in a successful technology in a successful technology

• with X-SCID study, “gene therapy” rises to level of with X-SCID study, “gene therapy” rises to level of rigorousrigorous clinical researchclinical research with quantifiable with quantifiable risk/benefit ratio - a new epoch for human geneticsrisk/benefit ratio - a new epoch for human genetics

therapy - therapy - OKOK somatic cellsomatic cell

germ cellgerm cell therapytherapy

enhancement?enhancement?

enhancementenhancement

Therapy vs. enhancement?Therapy vs. enhancement?

• modify trait or raise performance from “normal” to modify trait or raise performance from “normal” to “better than normal”, toward “ideal”“better than normal”, toward “ideal”

• indistinct boundary between indistinct boundary between normalnormal and and abnormalabnormal– height - should normal but small children be treated with GH?height - should normal but small children be treated with GH?– intelligence and cognition - what is normal, desirable for normal intelligence and cognition - what is normal, desirable for normal

human function?human function?– beauty - whose concept of beauty? beauty - whose concept of beauty?

• indistinct boundary between indistinct boundary between healthhealth and and diseasedisease– depression - is all depression pathological, require therapy?depression - is all depression pathological, require therapy?– memory deficit in Alzheimer’s disease. When does “I forgot where memory deficit in Alzheimer’s disease. When does “I forgot where

I put my keys” become “I forget where I live”I put my keys” become “I forget where I live”– muscle wasting in aging, etc. - is feebleness in the elderly normal muscle wasting in aging, etc. - is feebleness in the elderly normal

or disease, requireor disease, require treatment?treatment?

Some enhancementSome enhancement is socially and is socially and ethically “acceptable, sought out” ethically “acceptable, sought out”

• common in modern medicinecommon in modern medicine• cosmetic surgery - spectrum from lipoplasty, botox and cosmetic surgery - spectrum from lipoplasty, botox and

breast implants to congenital malformations breast implants to congenital malformations • therapy of serious psychiatric disease and “deviant” therapy of serious psychiatric disease and “deviant”

behaviorbehavior– antidepressants, tranquilizers, mood enhancers (benzodiazepines, antidepressants, tranquilizers, mood enhancers (benzodiazepines,

SSRIs, etc.) SSRIs, etc.) – Ritalin for attention deficit hyperactivity disorder, etc.Ritalin for attention deficit hyperactivity disorder, etc.

• social and recreational drug use - mood and performance-social and recreational drug use - mood and performance-enhancingenhancing– alcohol, caffeine, marijuana, cocaine, etc.alcohol, caffeine, marijuana, cocaine, etc. – do we really think National Football League players and NASCAR do we really think National Football League players and NASCAR

drivers have higher incidence of erectile dysfunction? drivers have higher incidence of erectile dysfunction?

So, if enhancement, why not gene-So, if enhancement, why not gene-based enhancement?based enhancement?

• genetic modification for therapy is a realitygenetic modification for therapy is a reality• physical (height, strength, etc.) and complex physical (height, strength, etc.) and complex

behavioral and social traits (intelligence, personality behavioral and social traits (intelligence, personality traits, cognition, mating and sexual behavior, etc.) traits, cognition, mating and sexual behavior, etc.) are partially genetically determinedare partially genetically determined

• modern genomics, genetics are identifying role of modern genomics, genetics are identifying role of genes in many non-disease traits genes in many non-disease traits

• same genetic modification methods used for therapy same genetic modification methods used for therapy will be applicable to non-disease traitswill be applicable to non-disease traits

Sport as an early model for gene-based Sport as an early model for gene-based enhancementenhancement

• athletes and handlers are risk-takers athletes and handlers are risk-takers • illicit use of drugs for enhanced performance is common in sportillicit use of drugs for enhanced performance is common in sport• tools of gene therapy easily applied to sportstools of gene therapy easily applied to sports• several reviewed therapeutic studies involve genes directly several reviewed therapeutic studies involve genes directly

applicable to sportapplicable to sport• enormous financial and national pressures at all levels of sport - enormous financial and national pressures at all levels of sport -

international elite, national, local international elite, national, local • concern in sports organizations, IOC, World Anti-Doping concern in sports organizations, IOC, World Anti-Doping

Agency (WADA) and U.S. Anti-Doping Agency (USADA)Agency (WADA) and U.S. Anti-Doping Agency (USADA)

Non-disease traits can be modified Non-disease traits can be modified genetically - sports modelsgenetically - sports models

• altered muscle function - growth factors to increase altered muscle function - growth factors to increase muscle size, strength, improve repair of injurymuscle size, strength, improve repair of injury– injection of gene for insulin-like growth factor (IGF-1), other injection of gene for insulin-like growth factor (IGF-1), other

muscle growth factors into muscle. In studies of muscle repair muscle growth factors into muscle. In studies of muscle repair (muscular dystrophy), mice become stronger (muscular dystrophy), mice become stronger (“Schwarzenegger”mice).(“Schwarzenegger”mice).

• improved delivery of oxygen to muscle improved delivery of oxygen to muscle – gene for erythropoietin (epo) into muscle. Studies of anemia gene for erythropoietin (epo) into muscle. Studies of anemia

(cancer, kidney disease), anemia is corrected and oxygen delivery (cancer, kidney disease), anemia is corrected and oxygen delivery improved in miceimproved in mice

Genetic approaches to performance Genetic approaches to performance enhancement in athleticsenhancement in athletics

• increase oxygen carrying capacity of blood - epoincrease oxygen carrying capacity of blood - epo• enhance skeletal and cardiac muscle function - GH, IGF1, enhance skeletal and cardiac muscle function - GH, IGF1,

GHRHGHRH– increase growth and differentiation of myoblasts increase growth and differentiation of myoblasts

– stimulate muscle growth, hypertrophy, anabolic metabolism stimulate muscle growth, hypertrophy, anabolic metabolism

• increase blood flow by stimulating new blood vessel increase blood flow by stimulating new blood vessel formation - i.e., VEGF?formation - i.e., VEGF?

• alter energy utilization - mitochondrial functionalter energy utilization - mitochondrial function• raise pain thresholdraise pain threshold• prevent injury, accelerate healing of injury prevent injury, accelerate healing of injury

-

Sustained epo production and hematocrit Sustained epo production and hematocrit elevationelevation - - Muczynski and Osborne - 2000Muczynski and Osborne - 2000

• to treat anemia of chronic kidney diseaseto treat anemia of chronic kidney disease• genetically modify patient’s (autologous) smooth muscle genetically modify patient’s (autologous) smooth muscle

cells infected cells infected ex vivoex vivo with retrovirus expressing epo, coat with retrovirus expressing epo, coat surface of plastic artery-vein dialysis graft with epo-surface of plastic artery-vein dialysis graft with epo-producing cellsproducing cells

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therapy - OKtherapy - OK somatic cellsomatic cell

germ cellgerm cell therapytherapy??

enhancement -enhancement -inevitableinevitable

enhancementenhancement??

higher, faster, smarter, more beautiful, happier?

Genetic “improvement” beyond sport ?

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

poor science (Charles Davenport - Cold Spring Harbor)poor science (Charles Davenport - Cold Spring Harbor)– genetic basis for poverty, slovenliness, love of the sea (“thalassophilia”)genetic basis for poverty, slovenliness, love of the sea (“thalassophilia”)

– catalyzed restrictive immigration to US, forced sterilization programs (“three catalyzed restrictive immigration to US, forced sterilization programs (“three generations of imbeciles is enough” -Buck v. Bell, 1927 - O.W. Holmes), generations of imbeciles is enough” -Buck v. Bell, 1927 - O.W. Holmes), stimulated Nazi racial policies stimulated Nazi racial policies

• a potential “new” eugenics based on understanding of a potential “new” eugenics based on understanding of genetic components of disease susceptibility, behavior, genetic components of disease susceptibility, behavior, personality - how does “sociogenomics” differ from personality - how does “sociogenomics” differ from Davenport?Davenport?

• new potential for restrictive, discriminatory and unjust new potential for restrictive, discriminatory and unjust social and public policy? social and public policy?