Issue 7, February 2003
Yams of Fortune: The (Uncontrolled) Birth of Oral Contraceptives
Biochemistry, University of Arizona
Marker hated wasting time. Upon qualifying for a doctoral degree
in chemistry as a twenty-three-year-old student at the University
of Maryland in 1925, all that stood between him and his degree were
several required physical chemistry courses. But Marker didn't want
to take physical chemistry, as he already had a master's degree
in the subject. The university refused to modify its graduation
requirements and Marker's own advisor threatened him with the dead
end career of "urine analyst" if he didn't complete his coursework.
Marker refused and left the university without his degree, an independent
scientist in search of a job.
his advisor's lack of optimism, Marker did indeed go on to make
tremendous scientific contributions throughout his career. While
not the only scientist or social visionary involved, Marker's work
formed the scientific cornerstone for the development of oral contraceptives,
among the most socially significant scientific discoveries ever
made. Yet despite such professional achievements, Marker's story
remains marked by the combination of independence, good fortune,
and ingenuity that led him to walk away from a Ph.D. because of
a disagreement over coursework.
the words of Steven Weintraub, the Russell and Mildred Marker Professor
of Natural Products Chemistry at Pennsylvania State University,
"There are more stories told about Russell Marker than perhaps any
chemist. Although many of these stories are apocryphal, they are
so fascinating that most of us cannot bear to stop repeating them.
This is the oral history of our profession that we pass to our colleagues
and our students. They are the campfire stories that bind our profession
his less-than-glorious send-off from the University of Maryland,
Marker's interest in hydrocarbon research led him to Ethyl Corporation.
While at Ethyl, he developed an octane rating system for gasoline
that is still used today. However, after a few years Marker's chemical
interests changed, and he left Ethyl to work as an organic chemist
at the Rockefeller Institute. Here too he met with success; over
a six-year period he produced many publications focusing on molecular
configurations and their relationship to reaction chemistry. Eventually,
Marker's background in hydrocarbon chemistry and molecular orientation
led him to the developing field of steroid research. In 1938, he
accepted a funded position at Pennsylvania State University.
The power of hormones
1: An overview of the menstrual cycle. Progesterone is critically
important in controlling this progression of events and thus
the ability to medically manipulate progesterone led to the
development of birth control.
(Click on image to see larger version)
Courtesy of Holistic
particular interest at this time in chemical history were the recently
discovered sex hormones, or androgens, molecules such as testosterone,
estrogen, and progesterone (see Figure 1). Of these, progesterone
was perhaps the most interesting because it is the chemical precursor
for another class of steroids, the glucocorticoids. Glucocorticoids
and androgens are instrumental in controlling many of life processes.
Metabolic disposal of carbohydrates, proteins, and lipids, inflammatory
responses vital to a functioning immune system, maintenance of blood
hydration, pH and salt levels, as well as sexual development and
function all rely on the proper functioning of various steroids.
The vast power of such hormones was not lost on physicians, and
by the 1930s, progesterone was used to treat menstrual disorders,
problem pregnancies, and gynecological cancers. However, progesterone
was so expensive to purchase that both research and medical endeavors
were often stymied. The only known way to isolate the hormone involved
laborious and inefficient synthesis exploiting the byproducts of
cholesterol oxidation. In a price comparison, at today's market
value, gold sells for about $11 a gram; in the 1930s, progesterone
sold for $80 a gram. And so, despite the potential medical benefits
of steroid hormones, progress in the field remained frustratingly
may have been his unusual academic background or work experience
that contributed to Russell Marker's breakthrough in the field of
hormone synthesis. In 1938 he presented a chemical hypothesis that
contradicted prevailing chemical beliefs of the time. He proposed
that the side chain of sarsasapogenin, a plant steroid derived from
the sarsparilla plant, was not chemically inert but actually chemically
reactive. As a result, if chemical groups were removed from the
sarsasapogenin side chain, then what remained was no longer sarsasapogenin
but progesterone (see Figure 2). In a series of reactions now known
as Marker degradation, Marker had found a way to synthesize progesterone.
was only one problem - sarsasapogenin was also extremely expensive.
However, rather than give up on his idea, Marker began studying
botany, trying to find a less-expensive chemical relative of sarsasapogenin
with which to further his studies. His search led him south, to
the Mexican-American border in the Southwest, and finally into Mexico
A trip to Verzcruz, Mexico
November 1941, he found his steroid source in the most unlikely
of plants, the wild yam Dioscorea that grows near the city of Oriziba
in the state of Veracruz (see Figure 3). Marker went on a field
trip, collecting two large sacks of the tuber in the mountains of
Veracruz. With this precious luggage he headed back to Oriziba to
return to his position at Penn State.
Unfortunately, when he went to claim his yams, he discovered that
they had disappeared from the top of the bus; luckily he was able
to bribe a police officer for their release. He later smuggled the
yams across the border. Once back in Pennsylvania, Marker demonstrated
that diosgenin, the compound extracted from the yams, could be efficiently
synthesized into progesterone. Yet despite this achievement, not
a single American pharmaceutical company wanted to commercialize
Marker's process. In a 1979 interview, Marker recounted his tale
I was convinced that Parke-Davis would not go into it, I tried other
companies to get support. For instance, I tried Merck and they said
that since Parke-Davis turned me down they would not go into it.
… Then I decided that I was going to have to go into it myself."
so, with the determination that had once led him to walk out on
a Ph.D., Marker resigned his position at Penn State, withdrew all
of his savings, and moved to Veracruz. He soon became an expert
on yams, harvesting 10 tons of them from the Mexican jungle. The
yams were dried and reduced to a syrup that was easily transported
back to the United States. Marker borrowed a friend's lab to convert
his yam syrup into three kilograms of progesterone, at that time
the largest batch ever produced, with a 1943 market value of about
$240,000. Convinced that his idea was commercially viable, Marker
decided to return to Mexico in search of partners in industry.
Arriving in Mexico City, he turned to the phonebook. In 1944 a small
company called Syntex was formed as a result of a partnership between
Marker, Emerik Somolo, a Hungarian immigrant to Mexico, and Dr.
Federico Lehmann, a German-trained scientist. Unfortunately, this
relationship was not to last. Following disputes over profits, Marker
pulled out of Syntex by the end of 1945 and established his own
company. For personal reasons he retired from this position, and
from chemical research itself, in 1949 at the age of 47.
Continuing on Marker's foundation
Syntex as well as other companies were able to continue on the foundation
Marker had pioneered. Back in the early 1920s when Marker was still
a graduate student, experimental manipulation in rats proved that
an unknown compound secreted from the ovaries of a pregnant mammal
prevented ovulation, in a process called
1950 two additional discoveries had been made. First, the "magic
substance" first described in 1921 was properly identified as progesterone.
Second, following the achievements of Russell Marker and succeeding
chemists, progesterone had become one of the cheapest and most readily
available of all hormones. Thanks to Syntex, the price of progesterone
had plummeted from $80 to $1 per gram.
development of the first oral contraceptives was a cumulative
event following the work and visions of many people
on an international scale - men and women as well as
scientists and social activists. This timeline is an
attempt to place Russell Marker, credited with inventing
"the pill," in historical and scientific perspective.
Sanger opens the first birth control clinic in the United
endocrinologist Ludwig Haberlandt begins experiments
on the role of progesterone.
Marker leaves his doctoral work and begins a career
proposes the Marker degradation for the synthesis of
progesterone from plant products.
demonstrates that diosgenin, extracted from wild yams,
can be used to synthesize progesterone.
a joint venture between Marker, Emerik Somlo, and Federico
Lehmann, is launched.
recruits Dr. George Rosenkranz, a Hungarian émigré
in Cuba, as research director.
retires from chemical research.
Djerassi, a chemist at Ciba Pharmeceutical Company in
New Jersey, is recruited by Rosenkranz to go to Mexico
as director of steroid research at Syntex
an orally active variant of progesterone, is discovered
in a Syntex lab under the direction of Rosenkranz and
challenges her friend Dr. Gregory Pincus to find an
oral contraceptive. Katherine McCormick, a friend of
Sanger, donates research funds.
Djerassi leaves Mexico but retains a research connection
Gregory Pincus begins testing oral contraceptives using
G.D. Searle's norethynodrel.
Food and Drug Administration approves the first oral
birth control pill using the norethynodrel produced
by G.D. Searle.
FDA approves a birth control pill containing norethindrone,
the Syntex compound.
hearings held on the safety of oral contraceptives.
discoveries became reality just as social consciousness was beginning
to explore the concept of contraception; hormonal manipulation of
the female reproductive system seemed an ideal possibility for birth
control. However, progesterone itself wasn't the best candidate
because it required injection; an orally-active mimic of progesterone
was a better alternative.
1951, Carl Djeressi, the scientist who succeeded Marker at Syntex,
filed for a patent on a compound he called norethindrone, a modification
of progesterone. In 1953, the pharmaceutical company G.D. Searle
obtained a patent on the work of Frank Colton, a chemical variant
they dubbed norethynodrel. The irony of this dual discovery is that
neither scientist had a birth control pill in mind when developing
the compounds. There was greater interest in using progesterone
mimics to synthesize cortisol, a compound already in use as a treatment
for inflammatory disease.
However, eventually the connection was made between orally active
"progesterone" and birth control. After several years of testing,
G.D. Searle obtained the first FDA patent for an oral contraceptive
in 1960. This was followed in 1962 by a Syntex patent now marketed
as part of Johnson & Johnson. Norethindrone, the chemical that got
its start in a small lab in Mexico, is the active ingredient in
nearly half of all oral contraceptives used today.
The birth control pill today
work that began with the study of sex hormones in the early 20th century
involved many research scientists, physicians, and social visionaries.
Indeed, there is a dialogue that continues today concerning the long-term
effects of hormonal manipulation (see a timeline of the history of
oral contraceptives). However, it cannot be denied that the science
begun by Russell Marker has had tremendous repercussions in many different
fields. With more than 10 million users in the United States alone,
"the pill," as it is commonly known, is the most common form of non-surgical
birth control. Also used in the developing world, the ability to control
pregnancy and family development has had an undeniable affect on women's
health and social opportunities. Says Susan Scrimshaw, dean of the
University of Illinois public health school:
the U.S., I believe, this led to more certainty in women's careers
and was part of women's really growing in stature and influence
in the professions.Internationally,
I think, it also helped women with the sense of control over their
lives and is still part of transformations in women's independence
and growth in education and leadership."
addition, beyond social influences, the scientific relationships
formed in Mexico have led to beneficial growth in that country's
research endeavors and scientific community. In 1951, following
the patent on norethindrone, Fortune magazine headlined an
article: "Syntex makes the biggest technological boom ever heard
south of the border." Further developments needed to sustain scientific
growth led to the establishment of what is now Mexico's leading
research institute, the Instituto de Quimica of the National University.
Noriega Bernechea, the president of the Mexican Sociedad de Quimica,
says, "the debt of gratitude that Mexican research and education
owe Syntex cannot be overshadowed by anything."
It would be impossible to tally the lives affected by Russell Marker's
contribution to chemistry. It would also be impossible to estimate
the odds that his discovery and the steps it entailed - walking
out on a Ph.D., conducting three completely different kinds of chemical
research before age 40, resigning a prestigious faculty position,
and spending life savings in pursuit of Mexican yams - would be
made at all. And that is what makes science fun. Great discoveries
are often made by those willing to see things in a slightly different
way. Even a remote, inedible wild tuber has value for those willing
to search for it.
Lisa. Mexico Celebrates Local Discovery that Led to the Pill.
[Link current as of February 1, 2003]
comparison between gold and progesterone:
Linda. "International Historic Chemical Landmark acclaims success
of Mexican steroid industry and a U.S. chemist who made it possible."
American Chemical Society 77 (43): 78-80, 1999.
Roberts, Royston. Serendipity: Accidental Discoveries in Science.
Wiley and Sons: New York, 1989.
Snider, Sharon. The Pill: Thirty Years of Health Concerns. FDA online
current as of February 1, 2003]
Voet, Donald and Judith Voet. Biochemistry. Wiley and Sons: New
Journal of Young
Investigators. 2003. Volume Six.
Copyright © 2003 by Mandy Redig and JYI. All rights reserved.