Clinical Medical Research Award
For the development of in vitro fertilization, a technological advance that has revolutionized the treatment of human infertility.
This year's Lasker Clinical Medical Research Award honors the scientist who developed in vitro fertilization (IVF), a technology that has revolutionized the treatment of infertility. When Robert Edwards began his work in 1955, physicians could do little more for their infertile patients than squeeze a shoulder and cast a sympathetic look. Edwards pioneered a field that has touched millions of lives, as infertility afflicts more than 3.5 percent of people. He and his colleague Patrick Steptoe, who died in 1988, marched staunchly forward against tremendous opposition from churches, governments, and the press, as well as intense skepticism from scientific colleagues. As a result of their efforts, almost one million babies have gazed and giggled at parents who otherwise would have failed to conceive children.The birth of the first "test tube baby" in 1978 heralded the beginning of a new field of medicine. The technology that Edwards, of Cambridge University in the U.K, and Steptoe, of the Oldham and District General Hospital in the U.K., developed has given rise to numerous refinements. Now, for example, clinicians can treat male as well as female infertility. Even post-menopausal women and those with blocked fallopian tubes or non-functioning ovaries can become pregnant. And Edwards's discoveries lay the groundwork for additional innovations in reproductive health, such as pre-implantation diagnosis of genetic disorders. His work has opened up areas further from reproductive health, such as human embryonic stem cell research, which has raised the possibility of potential treatments for neurodegenerative diseases, type I diabetes, and other debilitating disorders. Since the beginning of his career, Edwards realized the wide-ranging potential for therapeutic applications of embryos created outside a woman's body.
As a Ph.D. student and young independent investigator, Edwards tackled a wide variety of questions in mouse reproductive biology. His studies involved fertilizing eggs in a test tube that he had collected from female mice. Mice tend to ovulate in the middle of the night. Because the eggs were available for harvest only then, this aspect of mouse physiology drew Edwards to the lab at inconvenient times.
After three years of midnight visits, he got fed up. Building on the work of others, he worked with his wife-to-be, Ruth Fowler, to develop a scheme by which he coaxed the animals to ovulate during the day. By administering particular combinations and doses of hormones, he could control the number of eggs female mice would produce as well as the timing of ovulation. Furthermore, he extended earlier work to figure out how to prod dormant eggs removed from an ovary toward maturationoutside the female's body. These experiments and others established the timing of many key steps in fertilization and subsequent events required for reproduction, such as implantation of the embryo in the uterus.
The successes foreshadowed his later work in humans and lay the groundwork for it. Indeed, much of his accrued insight into the mouse reproductive system and his growing ability to manipulate events crucial for fertilization and embryonic growth gave him a jump start on challenges he faced later, when he confronted the task of overcoming human infertility. Very early, he realized that if he could translate his work from mice to humans, he could perhaps address problems of human infertility and diagnose genetic disorders before an embryo even implanted.
He persuaded several gynecologists to give him slices of human ovaries from women who had to undergo surgery for medical reasons. From these tissue samples, he extracted eggs that had not yet taken a committed step toward ovulation. Although researchers had succeeded in this feat using some types of animals, attempts with human eggs had failed. Conventional wisdom held that the process would take 12 hours, but after this amount of time, the eggs continued to lay idle, with no indication that they had even inched toward ripeness. He started questioning whether 12 hours was long enough, and began waiting longer and longer before giving up on the apparently inert eggs. Finally, the chromosomes became visibleone of the key steps in maturationafter 25 hours. He documented the sequence of events during human egg maturation in a test tube, and figured out that eggs took approximately 37 hours to ripen.
Soon he discovered that other popular ideas also held flaws. Scientists thought that sperm needed to be exposed to secretions in the woman's reproductive tract before it was competent for fertilization. But Edwards showed that sperm fresh from a man's ejaculate would work. In so doing, he had achieved fertilization completely outside the woman's body, and published this advance in 1969.
Even while he celebrated this success, he realized that a major roadblock remained. Other researchers had shown that fertilized animal eggs that had matured in culture dishes would develop for a while and then the embryos would die. Edwards needed eggs that had matured in the ovarynot in a test tube.
Foraging for solutions, he dove into the literature. He learned about the surgical work of Patrick Steptoe. At the time, an operation called a laparotomy provided the standard means to explore a woman's reproductive tract. Surgeons would open up the abdominal cavity so they could view and feel the tissues and organs. In this way, they would try to pinpoint diagnoses that could not be nailed by less invasive tests such as X-rays and hormone measurements.
In the late 1960s, a safer and less intrusive means to peer into the abdomen was being developed. This method was called laparoscopy, and involved only a small incision. With the technique, surgeons inserted a telescope-like device to view the internal organs and tissues. Steptoe had collected fluids from the reproductive tracts of womenwhy not eggs?
Edwards and Steptoe hooked up in 1968, and decided that Steptoe would obtain the ripened eggs directly from women by laparoscopy. He would have to withdraw eggs directly from the ovary without damaging them. In order to know when to perform the procedure, they would use hormones to control the menstrual cycle and spur ovulation. At a critical time near the end of the ripening program, Steptoe would collect the eggs and then Edwards would try to fertilize these eggs in a culture dish with the ejaculated sperm of the potential father. If Edwards's time estimates were right, the eggs would be at a perfect stage to welcome the sperm.
This process worked, and fertilized eggs doubled several times, developing to the point where the embryos were composed of eight and sixteen cells. By 1971, the team had prodded the embryo to develop past these first few cell divisions to the point where one could distinguish between the cells that would become the fetus and cells that would become the placenta. Creating and growing embryos in the lab had become routine. The team decided it was time to try transferring them to their mothers via the cervical canal.
Replacing embryos into infertile mothers began in 1972. Several short-lived pregnancies developed in the early 1970s, and Edwards wondered why these embryos spontaneously aborted. He realized that the hormone treatments were flawed. Although the hormones spurred multiple eggs to form and boosted the chances of success by increasing the likelihood of fertilization and subsequent implantation, they also caused the uterus to shed its lining exactly when the embryo needed to implant. Edwards and Steptoe altered the hormone regimen and generated a pregnancy. Unfortunately, the embryo lodged itself in a fallopian tube, and Steptoe had to terminate this ectopic pregnancy at 13 weeks. They decided to stop manipulating the menstrual cycle altogether. But if they didn't give fertility drugs, the woman's body would produce only one egg per cycle.
Nevertheless, they decided to take this leap. If they knew exactly when the egg would ripen, they reasoned, Steptoe could nab it at exactly that time. They predicted when the woman was going to ovulate by measuring the concentration of a particular hormone in her urine, called luteinizing hormone (LH). A set amount of time later, Steptoe performed the laparoscopy and retrieved the single egg. His technique had advanced to the point where he succeeded most of the timeeven though he now had only a single target.
In the fall of 1976, Edwards and Steptoe met the Browns, and agreed to try their procedure on Lesley Brown, who had no fallopian tubes. On Nov 9, 1977, the telltale LH surged and the next day they took the egg and fertilized it. On July 25, Louise Brown was born. The first "test tube baby" had arrived.
During the decade that preceded this monumental success, ethical battles raged around Edwards and Steptoe's work. Many people believed that conception was sacred and that embryos had full rights from the moment of fertilization. Some scientists worried that abnormal children would result from embryos created in a test tube, and accused Edwards and Steptoe of misleading their patients with false hopes. Edwards engaged in these discussions about his work, and published the first paper on the ethics of IVF in 1971 with the lawyer David Sharpe. In that article, they discussed the possibility of alleviating infertility, using pre-implantation genetic diagnosis to avoid sex-linked medical disorders, the possibility of modifying embryos, and other issues that persist even now, 30 years later.
Edwards co-founded one of the first IVF clinics in the world at Bourn Hall, Cambridge in 1980. That same year, one "test tube baby" was born in the U.S. In 1990, the number rose to 4000 in the U.S., and in 1998, it reached 28,500. The IVF baby boom is exploding similarly around the globe.
Edwards and Steptoe's work has spawned a variety of new techniques that have reached deep into the world of reproductive science. Now, infertility rarely stumps the medical establishment. Because medical practitioners can now inject a single sperm into an egg, infertile men as well as infertile women can have children. With this advance, called Intracytoplasmic Sperm Injection (ICSI), even men who harbor small numbers of sperm can father babies. Edwards's work lay the groundwork for pre-implantation genetic diagnosis. Scientists can test whether an embryo carries an inherited disease before they deposit it in the mother.
Robert Edwards faced many scientific, cultural, and ethical obstacles in the course of his career. He met the moral dilemmas with considered thought, and the scientific ones with creative spirit and dedication. Each time he hit a roadblock, he scratched his head and devised possible ways to circumvent it. Through careful observation and clinical exploration, he and Steptoe persevered and succeeded in transforming an entire field and millions of people's lives.
by Evelyn Strauss, Ph.D.