Transcript Enhancement in sport - Research Ethics Program

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
(germ-line 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,
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
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somatic cell
germ cell
therapy?
enhancement
therapy
enhancement
LeRoy 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
lmo2
integrated lmo2
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
- IGF1,
• enhance skeletal and cardiac muscle function - GH,
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
Qu i c k Ti m e ™ a n d a
An i m a ti o n d e c o m p re s s o r
a re n e e d e d to s e e th i s p i c tu re .
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 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?