Science 2010 Friedmann 647 8 PDF

Download as pdf or txt
Download as pdf or txt
You are on page 1of 2

www.sciencemag.

org SCIENCE VOL 327 5 FEBRUARY 2010 647


POLICYFORUM
Gene Doping and Sport
ETHICS
Theodore Friedmann,
1
* Olivier Rabin,
2
Mark S. Frankel
3

W
e humans have long sought to
enhance ourselves beyond nor-
mal through cosmetic surgery
and drugs. Science is increasingly becoming
humanitys partner and handmaiden in those
efforts ( 1) and has added genetic manipulation
to our enhancement tool kit. Many forms of
human enhancement are becoming more fea-
sible, sought-after, and even justiable in the
quest for healthier, happier, and longer lives.
Around the world, people have been
exposed to the notion of human enhancement
through sport, as some athletes seek a boost to
success, stardom, and nancial reward. In the
past, doping and cheating in sport have been
enabled by advances in pharmacology and
physiology. Recently, the successful develop-
ment of gene therapy has provided the con-
cepts, tools, opportunity, and, for some, justi-
cation for genetic modication of functions
that affect normal human traits, including
athletic performance. This intersection of sci-
ence and sport raises fundamental ethical and
policy issues that neither domain can resolve
absent a broader societal conversation ( 2). As
science progresses and sport and antidoping
authorities express increasing concerns, the
time is right to look at how advances in genet-
ics are affecting sport in ways unexpected just
a decade ago.
Genetic Manipulation for Doping
Some early experimental studies illustrate
the potential of gene therapy for treating dis-
eases ( 3 8). Although most gene therapy
approaches involve gain-of-function expres-
sion of exogenous transgenes, other methods
for genetic modication have also emerged
( 9 15). A denitive approach to genetic mod-
ication for therapy would involve an emerg-
ing technology of site-specific sequence
correction of disease-causing mutations, as
through the use of zinc fingerassociated
recombinational methods ( 16).
Although highly effective in some mod-
els, these gene therapy techniques are imper-
fect and still highly risky, as demonstrated by
severe adverse events such as
treatment-induced leukemia,
or even deaths ( 17 19). Nev-
ertheless, it is inevitable that,
as the science and techniques
mature, these same methods
and concepts will be applied
to broader nontherapeutic
uses, including gene-based
enhancement of human
traits linked to sport.
Toward that end, genetic methods have
been used, for instance, to demonstrate
enhanced muscle function from the insulin-
like growth factor (IGF-1) or follistatin trans-
genes ( 20, 21) and stably increased, regulat-
able, erythropoietin-enhanced blood pro-
duction in primates ( 22). One of the most
widely discussed transcriptional modula-
tion approaches has involved small molecule
modulators of peroxisomal proliferator-acti-
vated receptor delta (PPAR-), which regu-
lates expression of genes involved in lipid
metabolism, energy utilization, and insulin
action and that increases the production of
slow twitch oxidative energy-efcient mus-
cle bers. These effects have important impli-
cations for therapy of diabetes, obesity, and
muscle disease. Furthermore, mice overex-
pressing a PPAR- transgene or treated with
a PPAR- agonist show enhanced endurance
performance ( 23).
Not surprisingly, these scientif ic
approaches are known in sport communities
and are coming temptingly close to human
doping. A German athletic coach was found
attempting to obtain Repoxygen, a gene-
transfer vector that induces expression of the
erythropoietin gene ( 24). A Chinese genet-
ics laboratory reportedly offered gene-based
manipulations before the 2008 Olympic
Games in Beijing ( 25). It is not clear whether
these or other similar attempts reached the
stage of actual use in human athletes, but
there seem to be few technical barriers stand-
ing in the way.
Genetic Tools for Doping Detection
Traditional approaches to detection of dop-
ing in sport have been based on chemical or
molecular detection of the doping agent or of
markers reecting the physiological or met-
abolic effect(s) of the agent (e.g., chemical
assays for steroids and stimulants, molecu-
lar identication of foreign erythropoietin,
and detection of abnormally high erythro-
cyte production following exogenous eryth-
ropoietin exposure). Although this is the
most direct approach, new assays are con-
stantly needed to respond to chemical modi-
cations that make some drugs more dif-
cult to detect, and therefore more prone to
doping abuse.
A potentially more powerful detection
method has emerged, based on the concept
that chemical, biological, or genetic dop-
ing agents are likely to produce broad meta-
bolic, genetic, and proteomic changes. These
changes are now detectable by techniques
such as microarray- or sequence-based tran-
scriptional profiling and proteomic and
metabolomic analyses that can dene molec-
ular signatures of exposure to specic dop-
ing agents, or families of drugs, or methods.
Such signatures may be used to identify per-
turbed physiological systems, even in the
absence of knowledge of, or assays for, spe-
cic doping agents. This approach is similar
to that commonly used in searches for molec-
ular signatures of oncogenesis, developmen-
tal disorders, and so on ( 26, 27).
Highly concerned by the risk of gene dop-
ing, the World Anti-Doping Agency (WADA)
( 28), which has retained gene doping in its list
of prohibited substances and methods since
2004, has sponsored international research
teams with early results providing growing
credence to the utility of molecular signatures
in doping detection. For instance, exposure of
murine myoblasts to IGF-1 has been shown to
induce transcriptional and proteomic changes
that may eventually constitute a signature
specic for exogenous IGF-1 exposure ( 29,
30). Of course, the application of these kinds
of global assays would require rigorous vali-
dation of a connection with specic doping
agents or methods.
Marketing Gene Doping
The challenges posed to sports organizations
concerned with gene doping are compounded
by the ubiquity of the Internet, relatively
unconstrained by geographical boundaries,
which, when fueled with private commer-
cial interests, creates a powerful marketing
tool for promotion and distribution of per-
formance-enhancing agents. An industry has
emerged to cater to the desire of athletes and C
R
E
D
I
T
:

A
D
A
P
T
E
D

F
R
O
M

I
S
T
O
C
K
P
H
O
T
O
.
C
O
M
*T.F. is chair of WADAs Gene Doping Expert Group
and has performed research sponsored by WADA.
Author for correspondence. E-mail: [email protected]
1
University of California at San Diego, La Jolla, CA 92093,
USA.
2
World Anti-Doping Agency (WADA), Montreal, Que-
bec H4Z 1B7, Canada.
3
American Association for the
Advancement of Science, Washington, DC 20005, USA.
Advances in gene therapy set the stage for the
next generation of illegal doping, and doping
detection, in sport.
Published by AAAS

o
n

J
u
n
e

1
7
,

2
0
1
3
w
w
w
.
s
c
i
e
n
c
e
m
a
g
.
o
r
g
D
o
w
n
l
o
a
d
e
d

f
r
o
m

5 FEBRUARY 2010 VOL 327 SCIENCE www.sciencemag.org 648
POLICYFORUM
their coaches to nd a competitive edge.
Athletes are an especially vulnerable
population in the marketing of performance
enhancement ( 31). Reputable athletes or
coaches with little knowledge of genetics are at
a disadvantage in assessing scientic claims
that appear in advertisements. Marketing is
particularly worrisome when the science is
still a work in progress, when a persons health
can be adversely affected, and when consumer
knowledge about genetics is low. Although
advertisements promoting products that prom-
ise to enhance athletic performance have per-
vaded the Internet for many years, recently it
has become home for advertisements that pro-
mote products to alter muscle genesby acti-
vating your genetic machinery ( 32), or that
state your genetic limitations are a thing of the
past! ( 33) or Finally, every bodybuilder can
be genetically gifted! ( 34).
Conclusion
The stakes are high in competitive sport.
Enter the science of genetics and the increas-
ing ability to modify genes for medical and
performance enhancement purposes. As a
result, the former chairman of WADA pro-
claimed that You would have to be blind not
to see that the next generation of doping will
be genetic ( 35). As others have observed,
What is clear is just how impatient some
coaches and athletes are to nd new and inge-
nious ways to cheat. First it was steroids, then
EPO [erythropoietin], then human growth
hormoneand now the illicit grail seems to
be gene therapy ( 36). The global market-
place is ready to meet the demand in ways
that will inevitably include untested, and per-
haps unregulated, products and exaggerated
claims. Although commercial Web sites may
be biased, and unreliable by rigorous sci-
entic standards, they are a principal source
of information for many athletes and should
be monitored when looking for evidence of
developing trends in doping ( 37).
Accompanying those developments is the
emergence of a community that alleges short-
comings in the testing process and blames the
antidoping effort for stimulating an arms
race between regulators and the cheats ( 38).
Others question why certain enhancement
technologies are banned while others remain
legal and argue that athletes should be free to
use virtually any enhancing agents that sci-
ence makes available to them ( 39). Scientists
are not mere bystanders in these matters. The
2010 Winter Olympic Games and other major
sport events present good opportunities for
researchers to reafrm their responsibilities to
conduct and report their work by means con-
sistent with international ethics codes of clini-
cal research. They also must be aware that
some athletes and coaches will be tempted,
prematurely and unwisely, to take advantage
of results packaged by some as performance
enhancement breakthroughs, even if they
are untested in humans and the only break-
through is faster or stronger mice ( 40, 41).
References and Notes
1. E. A. Williams, Good, Better, Best: The Human Quest
for Enhancement, Washington, DC, 1 and 2 June 2006
(Workshop summary report, AAAS, Washington, DC,
2007); www.aaas.org/spp/sfrl/projects/human_enhance-
ment/pdfs/HESummaryReport.pdf.
2. There have long been divergent views of sport doping
and the value of antidoping regulation ( 41). Some com-
mentators have addressed how the use of performance-
enhancing drugs in sports and their regulation have
adversely affected fair competition ( 42). Others have
suggested that drug- or gene-based doping causes little
or no harm to athletes, sport, and public policy and that
the controversies surrounding doping could readily be
obviated by simply carrying out doping under medical
supervision ( 43).
3. D. B. Kohn, F. Candotti, Gene therapy fullling its prom-
ise. N. Engl. J. Med. 360, 518 (2009).
4. S. Hacein-Bey-Abina et al., Sustained correction of
X-linked severe combined immunodeciency by ex vivo
gene therapy. N. Engl. J. Med. 346, 1185 (2002).
5. A. Aiuti et al., Gene therapy for immunodeciency due to
adenosine deaminase deciency. N. Engl. J. Med. 360,
447 (2009).
6. A. M. Maguire et al., Safety and efcacy of gene transfer
for Lebers congenital amaurosis. N. Engl. J. Med. 358,
2240 (2008).
7. N. Cartier et al., Hematopoietic stem cell gene therapy
with a lentiviral vector in X-linked adrenoleukodystrophy.
Science 326, 818 (2009).
8. M. K. Brenner, Developing T-cell therapies for cancer
in an academic setting. Adv. Exp. Med. Biol. 610, 88
(2008).
9. E. R. Barton-Davis, L. Cordier, D. I. Shoturma, S. E.
Leland, H. L. Sweeney, Aminoglycoside antibiotics restore
dystrophin function to skeletal muscles of mdx mice. J.
Clin. Invest. 104, 375 (1999).
10. A. Aartsma-Rus et al., Exploring the frontiers of thera-
peutic exon skipping for Duchenne muscular dystrophy
by double targeting within one or multiple exons. Mol.
Ther. 14, 401 (2006).
11. G. McClorey, H. M. Moulton, P. L. Iversen, S. Fletcher, S.
D. Wilton, Antisense oligonucleotide-induced exon skip-
ping restores dystrophin expression in vitro in a canine
model of DMD. Gene Ther. 13, 1373 (2006).
12. E. Abranches et al., Neural differentiation of embryonic
stem cells in vitro: A road map to neurogenesis in the
embryo. PLoS ONE 4, e6286 (2009).
13. J. Alper, Geron gets green light for human trial of ES cell-
derived product. Nat. Biotechnol. 27, 213 (2009).
14. U. Dressel et al., The peroxisome proliferator-activated
receptor beta/delta agonist, GW501516, regulates the
expression of genes involved in lipid catabolism and
energy uncoupling in skeletal muscle cells. Mol. Endo-
crinol. 17, 2477 (2003).
15. D. Grimm, M. A. Kay, Therapeutic application of RNAi: Is
mRNA targeting nally ready for prime time? Clin. Inves-
tig. 117, 3633 (2007).
16. D. Carroll, Progress and prospects: zinc-nger nucleases
as gene therapy agents. Gene Ther. 15, 1463 (2008).
17. S. Hacein-Bey-Abina et al., A serious adverse event after
successful gene therapy for X-linked severe combined
immunodeciency. N. Engl. J. Med. 348, 255 (2003).
18. B. C. Engel et al., Prolonged pancytopenia in a gene
therapy patient with ADA-decient SCID and trisomy 8
mosaicism: A case report. Blood 109, 503 (2007).
19. A. J. Thrasher et al., Gene therapy: X-SCID transgene leu-
kaemogenicity. Nature 443, E5 (2006).
20. S. Lee, E. R. Barton, H. L. Sweeney, R. P. Farrar, Viral
expression of insulin-like growth factor-I enhances
muscle hypertrophy in resistance-trained rats. J. Appl.
Physiol. 96, 1097 (2004).
21. J. Kota et al, Sci. Transl. Med. 1, 6ra15 (2009).
22. V. M. Rivera et al., Long-term pharmacologically regu-
lated expression of erythropoietin in primates following
AAV-mediated gene transfer. Blood 105, 1424 (2005).
23. V. A. Narkar et al., AMPK and PPARdelta agonists are
exercise mimetics. Cell 134, 405 (2008).
24. DW-World, Deutsche-Welle, www.dw-world.de/dw/
article/0,2144,1890782,00.html
25. Associated Press, 23 July 2009, www.msnbc.msn.com/
id/25816605/.
26. F. J. Rauscher, 3rd, The year ahead. Cancer Res. 69, 1
(2009).
27. A. Anguiano et al., Gene expression proles of tumor
biology provide a novel approach to prognosis and may
guide the selection of therapeutic targets in multiple
myeloma. J. Clin. Oncol. 27, 4197 (2009).
28. Established in 1999, WADA has been the principal agency
responsible for antidoping activities in sport. Responsive
to initiatives and requests from various stakeholders,
WADA establishes global antidoping rules following
extensive consultation processes with international sports
federations, and governments of the world. More than
600 international sport organizations, including all 33
Olympic federations, have demonstrated their strong sup-
port of antidoping policies by adopting the World Anti-
Doping Code and the related International Standards.
Many active and former elite athletes are members of the
consultative commissions or take part in the work of the
executive boards of international sports federations, and
the nal rules and guidelines issued by WADA reect both
their input and support.
29. C. R. Bhasker, T. Friedmann, Insulin-like growth factor-1
coordinately induces the expression of fatty acid and cho-
lesterol biosynthetic genes in murine C2C12 myoblasts.
BMC Genomics 9, 535 (2008).
30. C. C. King, K. Bouic, T. Friedmann, A fractionation
method to identify qauntitative changes in protein
expression mediated by IGF-1 on the proteome of murine
C2C12 myoblasts. Proteome Sci. 7, 28 (2009).
31. J. M. Tokish, M. S. Kocher, R. J. Hawkins, Ergogenic aids:
A review of basic science, performance, side effects, and
status in sports. Am. J. Sports Med. 32, 1543 (2004).
32. Body Building.com, www.bodybuilding.com/store/vpx/
no.html.
33. Netneutri.com, www.netnutri.com/browse.cfm/4,2954.
html?aff=sh_z&gdftrk=gd.
34. Full Potential Training and Nutrition, www.fptnutrition.
com/framework.cfm?indView=60_0.
35. O. Slot, Times Online (UK), 2 February 2006;
www.timesonline.co.uk/tol/sport/article724765.ece.
36. G. Reynolds, New York Times, 3 June 2007; www.nytimes.
com/2007/06/03/sports/playmagazine/0603play-hot.html.
37. M. N. Fedoruk, J. L. Rupert, Myostatin inhibition: a poten-
tial performance enhancement strategy? Scand. J. Med.
Sci. Sports 18, 123 (2008).
38. Editor, Nature 454, 667 (2008).
39. A. Miah, The Washington Post, 3 August 2008; www.
washingtonpost.com/wp-dyn/content/article/2008/08/01/
AR2008080103060.html.
40. M. Wenner, Sci. Am. Online (15 August 2008); www.
scienticamerican.com/article.cfm?id=olympics-gene-
doping-expert.
41. J. M. Hoberman, Mortal Engines: The Science of Perfor-
mance and the Dehumanization of Sport (Free Press, NY,
1992).
42. D. H. Catlin, T. H. J. Murray, Performance-enhancing
drugs, fair competition, and Olympic sport. JAMA 276,
231 (1996).
43. B. Kayser, A. Mauron, A. Miah, Current anti-doping
policy: A critical appraisal. BMC Med. Ethics 8, 2 (2007).
44. The authors thank the Greenwall Foundation for its sup-
port of this work through a grant to AAAS.
10.1126/science.1177801
Published by AAAS

o
n

J
u
n
e

1
7
,

2
0
1
3
w
w
w
.
s
c
i
e
n
c
e
m
a
g
.
o
r
g
D
o
w
n
l
o
a
d
e
d

f
r
o
m

You might also like