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Doping in Sport: From Strychnine to Genetic Enhancement, It’s a Moving Target
Gary I. Wadler, M.D., FACP, FACSM, FACPM, FCP
Associate Professor of Clinical Medicine
New York University School of Medicine
Trustee, The Women’s Sports Foundation
Thank you for that kind introduction.
I want to begin today by taking a moment to recount an event that took place more than 100
years ago.
The year was 1886, a period characterized by the genesis of new industries and the creation of
great wealth. A period when we believed anything was possible. A period, in short, much like
today.
1886 is a significant year for our conference because it marked the first recorded fatality from a
performance enhancing drug.
An English cyclist died of an overdose of what is only known as “trimethyl”, during a race
between Bordeaux and Paris.
Of course, in the more than 100 intervening years, doping in sports, like the rest of technology,
has grown in scientific and ethical complexity.
Indeed, so complex is this issue that we will see later in my remarks how we cannot even agree
on precisely what constitutes doping – and these dueling definitions point to the heart of the
problem.
The multi-stranded nature of the subject of doping is also reflected in the diversity of
backgrounds of the participants here today.
In fact, looking over the list of this conference’s attendees, I noted that only four participants in
this conference are physicians. That’s not as surprising as it might seem on the surface. It
reflects the longstanding traditional orientation of the medical establishment.
Back when I was in medical school, our focus was on how drugs benefitted patients. After all, by
statute, physicians are the ones who write prescriptions. Physicians are the conduit for new drug
development with the scientific community.
Our principle concern, as physicians, was, and is the proper use of drugs, not their abuse.
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Doping in sports was a subject that only a handful of physicians cared about. I suspect we barely
spent 30 seconds on the subject in pharmacology. However, the same as with other forms of
drug abuse, that is, sadly, no longer sufficient.
As my opening story suggests, the use, misuse and abuse of drugs have long shaken the
foundations of both amateur and professional sports.
Competition, at its most basic level, appears to drive athletes to do whatever it takes to win.
Perhaps the need to win at all costs is a Darwinian response, an adaptive mechanism, but we will
leave that thought for another day.
We’ve seen that the problem is not new. History demonstrates that since recorded history began,
athletes sought a competitive advantage by using various substances we call ergogenic aids.
Even as long ago as the 3rd century B.C., the Greeks, inventors of democracy and the Socratic
method, were known to ingest hallucinogenic mushrooms to improve athletic performance. In
the Roman era, gladiators used stimulants in the famed Circus Maximus (circa 600 B.C.) to
overcome fatigue and injury, while other athletes experimented with caffeine, alcohol,
nitroglycerine, opium and even the potent stimulant, strychnine.
Fast forward.
A new inflection point of abuse appeared in the 1950s with anabolic, androgenic steroids.
How prophetic were the words of Olga Fikatova Connolly, when in 1956, she proclaimed: “these
awful drugs (anabolic steroids) have changed the complexion of track and field.”
So did amphetamines change sports.
In the 1960s, the Danish cyclist, Knud Jensen and the English cyclist, Tommy Simpson died when
their search for one kind of speed brought them fatally to another.
Remarkably, though the testing of horses for performance enhancing drugs dates back to 1910,
the testing of humans for drug use in sports is a phenomenon of only the past quarter century.
It was as recent as 1965 that Arnold Beckett first applied sensitive gas chromatographic techniques
to monitor drug abuse at an athletic event, the Tour of Britain cycle races.
And it was only in 1968 that the IOC medical commission actually published a banned list of
drugs for the 1968 winter Olympics.
The introduction of the banned list was coincident with the development of new technologies in
the laboratory and this confluence set the stage for a 35-year contest between those determined to
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gain an unfair athletic advantage by using drugs and the forensic detectives of the laboratory.
It’s a struggle between the manipulators versus the investigators and each side’s armaments grow
more advanced each day.
Since the 1960s, an explosion of science and technology have brought countless new drugs to
market, black and otherwise.
In what seems to be a variation of newton’s third law, which states that “For every action there is
an equal and opposite reaction,” it appears as if for every new drug that is developed, some
athlete, determined to gain athletic advantage, will misuse or abuse that drug. This should come as
no surprise. We live in a culture where individuals seek to maximize performance by what ever
means available.
Let’s examine steroids as an example of newton’s third law meeting sports.
First isolated, structurally identified, and synthesized in the 1930s, anabolic steroids were used to
promote a positive nitrogen balance in starvation victims and as a means of hormone replacement
for those deficient in testosterone by means of disease or trauma.
New, positive applications of steroids continue to emerge. As recently as April 1999, two articles
were published in J.A.M.A. exploring the therapeutic uses of anabolic steroids in the management
of aids, and in dialysis patients.
Unfortunately, since its initial isolation in the 1930s, it didn’t take long for anabolic steroids to
become widely misused and abused by athletes - a problem that continues to plague sports to this
very day.
And as science marches on, abuse is not far behind.
Some twenty years have passed since the first recombinant DNA molecules were constructed at
Stanford University. Since then, the applications of genetic engineering, that is the artificial
manipulation of the genetic code, have been numerous.
The techniques of altering the DNA of cells in order to change or produce biologicals has given
rise to human growth hormone and to erythropoietin, to name but a few.
Recombinant human growth hormone means normal height for children otherwise destined to be
dwarfs, but for the drug abusing athlete it means bigger, albeit not stronger, muscles.
Erythropoietin means renewed vitality for those with anemia, but for the drug abusing athlete , it
means greater endurance.
The dramatic abuse of the latest biotechnology breakthroughs crystalizes the need for an accepted
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working definition of the word doping.
This definition sits at the heart of any doping control program. Doping, a term that derives from
the Dutch word “doop” referring to a viscous opium juice that was the drug of choice of the
ancient Greeks.
In 1963, the Council of Europe established a definition of doping which the IOC slightly modified
and adopted. It defined doping as “The administration of or use by a competing athlete of any
substance foreign to the body or any physiologic substance taken in abnormal quantity or taken
by an abnormal route of entry into the body with the sole intention of increasing in an artificial
and unfair manner his/her performance in competition. When necessity demands medical
treatment with any substance which, because of its nature, dosage, or application is able to boost
the athlete’s performance in competition in an artificial and unfair manner, this too is regarded as
doping.”
It is a definition that I happen to like, but a definition that has been abandoned.
According to the IOC Medical Code currently posted on the IOC web site, doping is presently
defined as “the use of certain substances and methods intended to enhance and/or having the
effect of enhancing athletic performance, such practices being contrary to medical ethics.”
However, like the banned drug list itself, the definition of doping is a moving target.
And speaking of lists, the banned drug list must be based on a generally recognized body of
science, and where one does not exist, it must be based on some clearly reasoned rationale,
including issues related to laboratory science. I am sure we would all agree that the current IOC
list falls short in this regard.
Most recently, the Olympic Movement Anti-doping Code, as articulated in February of this year in
The World Conference on Doping defined doping “as the use of an artifice, whether substance or
method, potentially dangerous to athletes’ health and/or capable of enhancing their performances,
or the presence in the athletes’ body of a substance, or the ascertainment of the use of a method
on the list annexed to the Olympic movement anti-doping code.”
It is a good thing we are holding this conference in a law school!
Although I personally prefer the first definition of doping that speaks of sole intent, it is still
problematic. The linchpin of that definition is the notion that we can actually assess one’s intent,
both qualitatively and quantitatively
About intent, Peter Marc Latham in the early 1800s wrote: “Poisons and medicines are the same
substance given with different intent.”
Since there is no way to measure an athlete’s intent, a surrogate measure, the testing of bodily
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fluids, especially urine, has become a marker for assessing intent.
However, the neuro-chemical-biological pathways from what is on an athlete’s mind, call it intent
or call it artifice, to what comes out in his or her urine is tortuous and replete with physiologic
treachery.
It has led to expensive and explosive litigation centered around the concept of strict liability, a
subject I am sure we will hear much more about at this conference.
Creatine underscores a second problem when defining doping.
All would agree, that in recent years, the physiologic substance creatine has been taken in large
amounts by an extraordinary large number of athletes, a process called creatine loading.
All would agree that at least in certain high intensity, short duration exercises, it enhances
performance.
But, to date, there is no practical way to ban the practice and many would argue that beyond
pragmatism, there is no definitional basis to ban it. Not only is creatine naturally produced by the
body, it is widely found in a variety of food stuffs, such as meat and fish, thus raising the question:
when is a physiologic substance considered to have been taken in abnormal quantity with the
intent of gaining an unfair athletic advantage?
Employing urinary cut-off levels to eliminate its abuse remains a possibility. However, because
creatine is so ubiquitous, the use of urinary cut-off levels probably would devolve into little more
than an attorney’s field day.
Inherent in any definition of doping is the notion that the technology exists that permits the
definitive detection of substances foreign to the body or physiologic substances taken in abnormal
quantity. Good luck!
Because advances in biotechnology have outpaced advances in laboratory science, the detection of
certain drugs or biologicals is today either impractical or impossible. To wit, human growth
hormone, erythropoietin and most recently, IGF-1.
IGF-1 is a polypeptide that is indirectly responsible for most of the growth-promoting effects of
hGH. It is associated with a plethora of physiologic functions many of which are shared with hGH.
These include increased protein synthesis, decreased protein breakdown and increased fat
metabolism - all attractive to athletes.
Its approved uses in the united states are for a certain form of dwarfism and a rare form of insulin
resistant diabetes. Like hGH, IGF-1 is not detectable with current screening methods and like
hGH it needs to be administered intramuscularly.
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One of the newer performance enhancing drugs, relatively little is known about its abuse patterns,
cost, availability and long term side effects. The cost of IGF-1 is about $3 thousand per month and
counterfeit products are problematic.
It is noteworthy that phase ii trials are currently underway utilizing a novel complex of
IGF-1 and its major binding protein BP-3 to treat the degradation of muscles in a variety of
medical conditions.
Those are some of the drugs we know but what about those we don’t know? New drugs that are
not listed. Hein Verbruggen, head of International Cycling Federation has suggested that
“undetectable drugs are 90 percent of estimated doping cases.”
We were told that in Atlanta, performance enhancing drugs would meet their match in high
resolution mass spectrometry. And yes, it is an effective technique - but when investigators
introduce something so new, it often takes a number of years for the technology to withstand legal
challenges. To wit, O. J. And DNA. That’s why the Atlanta games were clouded by the presence
in the urine of the “new” stimulant drug, bromantan, and why political machinations resulted in
five athletes being cleared of a doping offense by the on-site court of arbitration in sport.
Too often, it seems, we define international sports competitions and events, not by the city or
country in which they were held, but by the drug that made the headlines - the Clenbuterol
Olympics, the Bromantan Olympics, the Growth Hormone Games, the Steroid Pan Am Games, or
the EPO Tour de France, or as some have suggested the Tour des Drugs.
There is good reason for this. If we look at the number and kind of new drugs that have come to
market since the introduction of doping control in the Olympic movement in 1960s, the number is
staggering.
This complicates life for every athlete who is faced with taking a drug or a biological substance for
any reason whatsoever. He or she must first ask a series of questions: is it banned? Will it
adversely affect my performance and is it safe?
Those determined to gain an unfair advantage will ask the additional questions: does it work?
How does it work? Can it be detected during competition or out of competition, and perhaps, he
or she might even be concerned about its long and short term safety?
That’s today. But what about tomorrow? What is around the corner - brake drugs, blood
substitutes, genetic manipulation? It is not a matter of a brave new world, but of brave new
worlds.
Cyproterone acetate, also known as a Cyprostat and Androcur, is a synthetic steroidal anti-
androgen and contraceptive hormone used in the treatment of prostate cancer in men, hair loss in
women and precocious puberty in children.
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Not available in the united sates, this so-called “brake drug” which has been associated with the
development of liver tumors has allegedly become popular amongst female gymnasts because it
puts the brakes on sexual development keeping the hips narrow and the breasts small.
And just as researchers are closing in on a method to detect the abuse of EPO, a potentially
dangerous new EPO replacement, which is likely to increase endurance, has surfaced.
The substance is perfluorocarbon, or PFC, a substance with enormous oxygen-carrying capacity.
It has been suggested that the abuse of this synthetic blood - like substance first surfaced in
Nagano where it had been allegedly abused by cross-country skiers and speed skaters.
The International Cycling Federation has issued warnings about PFC to its national federations.
Although not officially on the market in the united states, there is active research into PFCs for
legitimate medical use. PFC can significantly increase endurance by delivering more oxygen to
working muscles.
With the global market for blood substitutes probably exceeding $2 billion, the number of new
products will undoubtedly continue to grow. For example, active research is continuing using
purified bovine hemoglobin rather than products of human origin or the use of PFCs to carry
oxygen, and work continues on genetically engineered blood substitutes.
As we move into the next millennium, we are at the cusp of gene therapy for the correction of
defective human genes that cause or promote certain genetic diseases, and designer genes cannot
be far behind. Human skin has already been genetically engineered.
Combining cloning with genetic engineering, so called germ line therapy, will make possible the
passage of genetic changes from one generation to the next.
It was only six months ago that scientists achieved one of the most coveted goals in biology,
isolating from human embryos, a primitive cell, called a pluripotent stem cell, that can grow into
every kind of human tissue, including muscle, bone and even brain.
Already stem cells have been used to grow human heart muscle cells which beat in unison in a
petri dish, as well as nerve cells, bone, cartilage and skeletal muscle. To insure that stem cell
research is conducted in an ethically sound manner, just last month, an NIH special working
group was formed by the director of the NIH to develop research guidelines.
If this sounds like the twilight zone, think twice. Only five months ago, researchers at the
University of Pennsylvania discovered a form of gene therapy to counter muscle degeneration
associated with aging.
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The injection of this gene limits the effect of IGF-1 to the skeletal muscles into which the gene is
directly injected obviating any adverse effects of IGF-1 on the rest of the body.
With this technique young mice experienced a 15% increase in muscle strength, and old mice a
27% increase. Accordingly, the gene has been dubbed the “fountain of youth” for skeletal
muscles.
But in the world of doping, milestones become millstones.
The author of the original study has already expressed concern that this technology may be
sought out by athletes who are seeking a competitive edge. Interestingly, muscle strength
increased without any exercise and there was no way to detect the use of gene therapy from
analyzing the blood.
Trials are to begin in monkeys and, in the not too distant future, the first human study may be
done in people with a form of muscular dystrophy.
And in another study, IGF-1 producing genes have been successfully introduced into mouse
embryos. Is it a stretch that with the new technologies of genetic engineering that we are arming
parents with the tools to create designer offspring whether inside the uterus or out of it?
Of course, the ethical, moral and biological debate transcends sports. Indeed, it touches on the
transcendent as George Wald, the Nobel Prize-winning biologist and Harvard professor, opined:
“Recombinant DNA technology (genetic engineering) faces our society with problems
unprecedented not only in the history of science, but of life on earth. It places in human hands the
capacity to redesign living organisms, the products of some three billion years of evolution”.
We stand at the brink of an uncertain future. But I personally believe that the unpredictability and
the velocity of change are not an excuse for reserving judgment about some profound distinctions
that should fundamentally govern our perspective on the role of sports in our social fabric.
With that in mind, I would like to conclude by quoting the columnist George Will who reminds
us: “A society’s recreation is charged with moral significance. Sport - and a society that takes it
seriously - would be debased if it did not strictly forbid things that blur the distinction between the
triumph of character and the triumph of the chemistry.”
And finally, in order that we not blur the distinctions George Will speaks of, what we must do in
this complex and challenging environment, is confront the issues related to doping from the
broadest possible perspective.
Tempting as it is to get consumed by the intricacies of anabolic steroids, EPO or hGH, I urge you
to think expansively and inclusively, to keep the big picture in mind, and to maintain an aerial
view, for these drugs are only specific examples that stretch along the continuum from strychnine
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to genetic engineering.
Only in that way can we hope to forge a consensus, a unified, expert-wide point of view that will
help us put the details and the subtleties in proportion.
Stay tuned.