The dark suit and a tie the hue of lime sherbet offered little in the way of disguise. Ditto for the salt-and-pepper beard and the rimless reading glasses perched on the bridge of his nose. No, one glimpse at the jacket stretched thin in a futile struggle to contain his grapefruit-sized biceps, and you could tell one thing about this man: He did not spend his days in an office.
Or, for that matter, testifying to a panel of legislators on Capitol Hill. Dr. Charles Kochakian never imagined that his research would transform baseball players like former St. Louis Cardinals slugger Mark McGwire into steroid-pumped home run machines. Yet here he was, Mark McGwire, all six-foot-five of him, folded into a chair and tucked in behind a microphone. The year was 2005, and the former Major League Baseball slugger was struggling to answer questions from members of a U.S. House committee about the use of anabolic steroids and other performance-enhancing drugs in America’s pastime. Inquiries about how, exactly, a once-lanky rookie grew into a muscle-bound Hercules who, on 586 separate occasions, managed to drive a cork wrapped in yarn and covered in horsehide over outfield walls in places like Wrigley Field and Yankee Stadium.
“My lawyers have advised me that I cannot answer these questions without jeopardizing my friends, my family or myself,” he told the committee, choking up and appearing close to tears.
Later, he refused a Congressman’s request to give a clear answer about whether he’d used steroids.
“Are you taking the Fifth?” the Congressman demanded.
“I’m not here to discuss the past,” responded the slugger who’d once clubbed a record-breaking 70 home runs in a single season. “I’m here to be positive.”
And so it went through the proceeding, with McGwire neither admitting nor denying what many suspected. But five years later, he would confess that he’d cheated. That like so many others who had played in baseball’s so-called “Steroid Era,” his prodigious power had come, at least in part, from a syringe.
Of course, baseball is hardly the only sport in which competitors have resorted to chemicals to gain an edge over their peers. Athletes in a variety of other sports (weight-lifting, body-building, wrestling, football, track and field, cycling, bobsledding, volleyball, basketball, swimming) have also been caught with their hands in the steroid jar.
Mark McGwire may be the most famous person to admit to using anabolic steroids, but he certainly didn’t invent them. That happened long before he ever laced up his first pair of spikes.
As is so often the case in medicine, the tale of steroids stretches back many thousands of years. The story offers lessons in unintended consequences, about how beneficial research can come with an Achilles heel. And, oddly enough, it’s a narrative that runs smack-dab through the laboratories of the Oklahoma Medical Research Foundation.
Before the period we call “history,” which academics generally agree began with the Sumerians’ invention of writing around 3500 B.C., ancient farmers developed methods for domesticating animals. As they experimented with how to transform feral beasts into obedient creatures they could use for food and to assist them in chores like farming and transportation, they hit upon a medical procedure that made the process significantly easier: castration.
The removal of testicles and penises made animals more docile, leading the Egyptians and Romans to believe that male reproductive organs held special powers. Later, the Greeks built upon this notion, using extracts from the testes in attempts to enhance athletic performance.
This idea endured for millennia. Then, in the 19th century, scientists found the first concrete evidence of a substance in the bloodstream produced by the testicles that, when eliminated, caused roosters’ combs to shrink and the animals to lose both their interest in hens and aggressive behavior. A prominent physiologist and Harvard professor subsequently conducted a string of experiments where he injected himself with substances extracted from the testicles of guinea pigs and dogs. He reported not only that he enjoyed increased strength, mental ability and appetite, but also that the injections relieved his constipation and increased the arc of his urine stream. In no time, scientists and physicians began injecting patients with a wide variety of testicular extracts in attempts to find cures for ailments ranging from paralysis to migraine headaches.
The studies yielded mixed results. But they did suggest that the testes produced something that played a major role in stimulating the development of both muscle and male sexual characteristics. Researchers coined the term hormone for it, which in Greek means “to urge on.”
After World War I, pharmaceutical companies ramped up efforts to isolate this hormone. In 1935, a team from the Dutch drug manufacturer Organon succeeded. It dubbed the hormone, which required 220 pounds of bull testicles to generate less than a thimbleful of the compound, testosterone. Later that same year, scientists from a pair of other companies showed that they could obtain testosterone without requiring staggering quantities of animal testicles; they’d found a way to synthesize it from cholesterol.
That discovery would earn a Nobel Prize. The researchers had invented an efficient method of creating a chemical that offered the tantalizing promise of both strength and fertility. This opened a new frontier in medical research, one that could be accessed through a substance—cholesterol—found in everyone’s blood.
But though scientists possessed a method of producing testosterone, they now had to figure out what this mythical hormone could actually do.
As a boy growing up in northern Massachusetts, Charles Kochakian couldn’t wait for winter to come. With the falling mercury came days filled with sledding and skiing, two of his favorite pursuits. It also offered the chance to skate on the Merrimack River, which sliced his hometown, Haverhill, in two.
The waterway, though, would not freeze with the snap of Jack Frost’s fingers. Rather, around Thanksgiving, the ice would begin to form like Bermuda grass, advancing in tendrils that poked farther upriver each day. It was this annual winter occurrence that gave rise to one of Kochakian’s first experiments.
On moonlit nights, he and his friends would strap on their skates and race atop the frozen waters to see how far they could get. But because rivers turn from liquid to solid from the top down, a hard, silvery face didn’t necessarily guarantee a thick block of ice beneath.
The boys knew this well enough. Still, their curiosity and derring-do would inevitably get the better of them. They’d abandon the relative safety of long-frozen spots to explore new territory, the ice growing thinner with each push of the skate. The experiment would inevitably come to an end with the sharp crack of cleaving ice and, too often, at least one boy tumbling into the black, bone-chilling waters.
“At such times,” wrote Kochakian, “we would build a fire on shore and dry out as best we could.” Of course, “no mention was made of such an incident to our parents.”
When not pitching himself headlong into the Merrimack, Kochakian proved an adept student. In the classroom, his curious nature also drew him to experiments of an altogether different sort: At Boston University, he earned his undergraduate degree in chemistry and, in 1931, a masters in organic chemistry.
Still, with the Depression in full swing, professional employment was nowhere to be found. For the next two years, he searched fruitlessly for jobs in chemistry while earning a meager income delivering newspapers and helping out at his hometown grocery store. Living with his parents, both of whom had emigrated from Armenia just after the turn of the century, he helped out around the house. He did his best to keep his scientific skills honed by conducting experiments in a makeshift lab he’d set up in a vacant bedroom.
In 1933, a professor at the University of Rochester responded to an ad Kochakian had placed seeking employment. Unfortunately, wrote the professor, the university could offer no position. Nevertheless, if Kochakian was interested, the university could waive his tuition and provide him with a small fellowship of $500 for living expenses and food that would enable him to pursue a Ph.D. in biochemistry. The young chemist accepted.
Although he had taken but a single biology course in college, Kochakian proved so adept at the classwork that his advisor soon excused him from attendance. This freed him up to spend the balance of his graduate school career at work in the laboratory.
Kochakian’s mentor had a particular interest in how the body transforms food into energy. Researchers had already shown that males’ base metabolism rates were greater than those of females. But, the advisor asked his protégé, why is this the case? So Kochakian set to work in the lab to solve this metabolic mystery.
Preliminary data gathered from previous experiments suggested that the mythical male hormone (it would still be two years before scientists isolated and definitively identified testosterone) might be responsible for this differential. But who wanted to gather hundreds, or even thousands, of pounds of bull testicles to perform experiments?
Instead, Kochakian found a more readily accessible, but no less distasteful, source of male hormone: human urine.
He didn’t know how much he’d need, so the eager graduate student erred on the side of excess. Using jugs that he placed in men’s restrooms around the university campus, he managed to gather more than 1,000 gallons in the space of a half-year. Then, employing a multi-step process that involved both boiling the liquid and treating the distillate with various chemical agents, he was able to extract the hormone necessary to perform his experiments. “Needless to say,” Kochakian wrote years later about the process, “the atmosphere in the laboratory and corridor was aromatic.”
Kochakian regularly administered the hormone (which scientists would soon identify as androstenedione, a less potent cousin of testosterone) to a trio of dogs in the laboratory. His mentor had hypothesized that the hormonal “goosing” would amp up the animals’ metabolism. But Kochakian found no such effect.
When repeated attempts yielded the same result, the graduate student worried that something had gone awry. So he decided to redo the experiment yet again. Only this time, to ensure that the hormones extracted from urine hadn’t somehow confused the outcome, he’d gather his hormone from a different source.
With the help of a local slaughterhouse, he collected 100 or so bull testicles, then proceeded with the long and arduous process of extracting enough hormone to perform the experiments. Yet when he gave this new batch of hormone to the dogs, he got the same outcome.
Kochakian now felt confident that the hormone wasn’t causing males to burn calories faster than females. This finding, though, wasn’t the sort of ah-hah! moment he had hoped for.
Science takes its biggest steps forward by demonstrating a positive correlation—by establishing that x causes y. All Kochakian had shown was that x (male hormone) didn’t cause y (revved up metabolic rates).
At best, the experiments were the scientific equivalent of solid but unspectacular police work. They’d eliminated a suspect. Perhaps that knowledge would help narrow the field of inquiry so that scientists might one day identify the “culprit” responsible for men’s speedier metabolisms. In the meantime, though, that culprit was still out there.
As for Kochakian, he’d devoted two years of his life to trying to prove something he’d now demonstrated wasn’t true. That wasn’t the sort of research scientific journals would be eager to publish. And without a publication, his prospects for earning his doctorate looked bleak.
Desperate to rescue something meaningful from the experiments, he decided to pore back over his experimental data. Surely, he thought, there must be something of value in there.
As it turns out, there was. Buried in the results was a finding that would change Kochakian’s life. It would also forever change the field of endocrinology.
When Kochakian scoured his lab notebooks, he discovered that each time he’d administered the urine extract to the dogs, their bodies produced a strongly positive nitrogen balance. This had happened almost immediately, and, Kochakian confirmed, it had also occurred when he’d given them the testicular extract.
Nitrogen serves as a fundamental component of amino acids, the molecular building blocks of protein. Usually, we get it through food sources such as meat, dairy, eggs and legumes. Our bodies constantly need to replenish our nitrogen stores, as we regularly deplete supplies through sweating, going to the bathroom, and the ongoing replacement of skin and hair.
A positive nitrogen balance means the body is taking in more nitrogen than it is losing. This state, Kochakian knew, was usually linked to periods of growth, times when the body is adding substantial amounts of muscle.
Here, Kochakian had simply induced the same condition by giving hormones to the dogs. When published in 1935, his studies were the first to prove the connection between male hormones and muscle-building.
This research would earn Kochakian his Ph.D. in biochemistry. It would also earn him a full-time academic appointment at the university.
Not long after Kochakian’s watershed research, the pharmaceutical companies showed that the hormones he’d worked with (now dubbed testosterone and androstenedione) could be easily synthesized. So Kochakian repeated the experiments with the synthesized hormones, and he got the same results. That work cemented the idea that those compounds—members of a family of similarly structured compounds called steroids—promoted anabolism, the metabolic process of constructing larger molecules from smaller ones.
Anabolic steroids had been born. And the young researcher who’d figured out how they worked? Some would later call him “the father of anabolic steroids.”
For the balance of his career, Kochakian would continue to study testosterone and other sex hormones. But he was never interested in building super men and women. Instead, his research centered on understanding how, exactly, they worked and how they might be harnessed to improve human health.
In 1951, Kochakian moved his laboratory from Rochester to the Oklahoma Medical Research Foundation, which had opened its doors only the year before. OMRF’s new director of research offered Kochakian the chance to lead a program in biochemistry and endocrinology.
At OMRF, Kochakian received a grant from the National Arthritis and Metabolic Institute to study whether testosterone could help control diabetes. He led a National Cancer Institute project examining how the hormone might be used to combat cancer. In yet another initiative, this one underwritten by the American Heart Association, he looked at how testosterone regulated the biochemistry of the heart.
Although we now typically refer to these compounds (and their synthetic twins) as anabolic steroids, they’re actually more accurately described as anabolic-androgenic steroids, says OMRF President Dr. Stephen Prescott, a physician and medical researcher. “In addition to their muscle and tissue-building anabolic properties, the hormones are also androgens. That means they’re responsible for giving men many of their male characteristics, things like deepening of the voice, body hair, fertility and maturation of the genitals.”
Women also produce these androgens, though in much smaller amounts than men.
“In women, like in men, they’re essential for kick-starting the process of puberty,” says Prescott.
Although Kochakian’s research failed to show that the hormones could treat diabetes or cancer, it did reveal their important role in growing heart muscle. “He also helped scientists understand how testosterone helps regulate other organs such as the kidneys and liver,” says Prescott.
His work on the muscle-building properties of testosterone and other steroids helped illuminate their importance in the development of muscle and bones. “He discovered that administering testosterone could help control incontinence in older men by strengthening their bladder muscles,” says Prescott.
While Kochakian was working at OMRF to understand how physicians might use steroids to help patients, West Coast bodybuilders had discovered that the compounds’ anabolic properties could provide a significant competitive edge. At the 1952 Olympics, Russian weightlifters are believed to have won the first of what would prove to be many steroid-tinted Olympic medals.
These unintended consequences of his discovery, though, did not deter the OMRF researcher, who in 1953 added the title of coordinator of research to his duties at OMRF. “Dr. Kochakian had his program and knew what he was going to do,” said Dr. Paul McCay, who joined OMRF as a metabolic researcher in 1954. “He wanted to understand the beneficial effects of male sex hormones.”
But while Kochakian “was a hard worker who did a lot of good research” while at OMRF, says McCay, “he was a little bit aloof.” He eschewed collaborations with foundation colleagues, preferring instead to work on his own projects. Over time, this created tension within the foundation’s scientific faculty and led OMRF to create a second, separate biochemistry research program.
“We have to go inside and look around. Because if we don’t, we’ll never know where a new idea might have led.”
In 1957, the University of Alabama at Birmingham offered Kochakian a position as a professor in its biochemistry department. Kochakian took the job, and he ended up spending the remainder of his career there.
Kochakian’s biochemistry program at OMRF would represent the foundation’s first and only foray into steroid research. When he left, that program ended.
OMRF’s “other” biochemistry program, though, grew and thrived. Increasingly, it focused on metabolic processes and how they suffered damage as the body aged. McCay eventually led the program, which has since undergone several changes in name and research focus. More than 60 years after it began, the program—now known as the Aging and Metabolism Research Program—continues to search for new insights and therapies for diseases of aging.
While at OMRF, in addition to his lab work, Kochakian also started a summer research program for select high school and college students. That initiative would lay the groundwork for OMRF’s Fleming Scholar Program, which since 1956 has provided more than 500 of Oklahoma’s most promising science students with a one-of-a-kind summer laboratory experience. More than 100 of the program’s graduates have gone on to careers in medicine and research.
Medical history is chock full of examples of unintended consequences. Sir Alexander Fleming never dreamed that failing to clean his Petri dishes would spawn the discovery of penicillin. When Pfizer scientists created the experimental drug known as UK92480 to alleviate chest pain, little did they know it would become Viagra, the best-selling treatment for erectile dysfunction.
Likewise, Charles Kochakian surely never imagined Mark McGwire, Lance Armstrong, Brian Bosworth nor Alex Rodriguez when he first observed the anabolic effects of male hormones. But his tale reminds us that the law of unintended consequences can cut both ways. Even seemingly beneficial medical research can have a weak spot.
Still, Kochakian’s legacy does not end there. Today, physicians prescribe the hormones for burn victims and bedridden patients. They also use anabolic steroids to treat people suffering from muscle atrophy caused by HIV, anemia and certain types of breast cancer.
In the end, says Prescott, “A scientific discovery is neither good nor evil.” It simply opens the door to knowledge.
“We might be inclined to shut the door for fear of what it might reveal,” he says. “But that’s the wrong approach. We have to go inside and look around. Because if we don’t, we’ll never know where a new idea might have led.”
