2001 Albert Lasker Clinical Medical Research Award

In vitro fertilization for treating 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 UK, and Steptoe, of the Oldham and District General Hospital in the UK, 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 PhD 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 maturation — outside 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 visible — one of the key steps in maturation — after 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 ovary — not 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 women — why 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 time — even 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 United States. In 1990, the number rose to 4000 in the United States, 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

Key publications of Robert Edwards

Fowler, R.E. and Edwards, R.G. (1957). Induction of superovulation and pregnancy in mature mice by gonadotrophions. J. Endocrin. 15, 374–384.

Edwards, R.G. (1965). Maturation in vitro of mouse, sheep, cow, pig, rhesus monkey and human ovarian oocytes. Nature. 208, 349–351.

Cole, R.J., Edwards, R.J., and Paul, J. (1966). Cytodifferentiation and embryogenesis in cell colonies and tissue cultures derived from ova and blastocysts of the rabbit. Dev. Biol. 13, 385–407.

Gardner, R.L. and Edward, R.J. (1968). Control of the sex ratio at full term in the rabbit by transferring sexed blastocysts. Nature 218, 346–349.

Edwards, R.G., Bavister, B.D., and Steptoe, P.C. (1969). Early stages of fertilization in vitro of human oocytes matured in vitro. Nature. 221, 632–635.

Steptoe, P.C. and Edwards, R.G. (1978). Birth after the reimplantation of a human embryo. Lancet. 2, 366.

Edwards, R. G., Steptoe, P.C., and Purdy, J. M. (1980). Establishing full-term human pregancies using cleaving embryos grown in vitro. Br. J. Obstet. Gynaecol. 87, 737–756.

Steptoe, P.C., Edwards, R.G., and Purdy, J. M. (1980). Clinical aspects of pregnancies established with cleaving embryos grown in vitro. Br. J. Obstet. Gynaecol. 87, 757–768.

Edwards, R.G. (1981). Test-tube babies, 1981. Nature. 29, 253–256.

Edwards, R.G. (1997). Recent scientific and medical advances in assisted human conception. Int. J. Dev. Biol. 41, 255–262.

Award presentation by Joseph Goldstein

The publication of The Origin of Species in 1858 and the birth of the first test-tube baby in 1978 are defining events in the history of human society. These events are defining because they forced us to confront some of the most fundamental ideas about being human. The instigators of these revolutionary events, Charles Darwin and Robert Edwards, share several attributes. Both owe their intellectual origins to Cambridge University in England. Darwin, the father of evolution theory, was a student at Cambridge where he was introduced to biology, geology, and natural history. Edwards, the father of in vitro fertilization, was a professor of physiology at Cambridge from 1963–1989. At Cambridge, he performed the experiments with human eggs that we honor today. His experiments were truly seminal — literally as well as figuratively.

As one might expect, when we challenge our conception of humanity, we arouse controversy. Indeed, The Origin of Species and the first test-tube baby ignited two of the most violent controversies in the history of biology and medicine. If the human species evolved by natural selection instead of by Divine creation, then the Bible cannot be literally true. If human beings can be conceived in test tubes by scientists, then the act of conception has lost much of its mystery. As instigators of revolutionary science, Darwin and Edwards were subjected to vitriolic personal criticisms. But both of them, befitting their British gentlemanliness, conducted themselves with dignity and forthrightness, much to the admiration of their scientific comrades.

Most of you are familiar with Darwin's story, but many of you may not be so familiar with the Edwards's story. Who is Robert Edwards and what led him to develop in vitro fertilization, known to the world as IVF? Edwards was born in a small Yorkshire town, grew up in Manchester, served four years in the British army during World War II, and then entered universities in Wales and Edinburgh, where he took courses in agriculture and zoology and became fascinated with reproduction and embryology. He obtained a PhD in 1957 from the Institute of Animal Genetics in Edinburgh. Here, he worked out a method for treating female mice with hormones so that scientists could precisely control the time of ovulation and the number of eggs produced. This classic study was done in collaboration with his future wife, Ruth Fowler. The Fowler-Edwards method for controlled superovulation made the mouse the animal of choice for studying early events in reproduction. Edwards no longer had to come into the lab in the middle of the night to harvest immature eggs. He could now decide exactly the time the eggs would be produced. His next goal, like that of many reproductive biologists in the 1950s, was to learn how to mix eggs with sperm so that fertilization would occur in vitro outside the womb of the mother.

Meanwhile, across the Atlantic, scientists in the United States were furiously trying to fertilize human eggs in the test tube. Although several claimed reproductive success, their results could not be reproduced. The first major breakthrough came not with human eggs, but with rabbit eggs. In the early 1960s, Min Chang, a scientist at the Worcester Foundation in Shrewsbury, Massachusetts, took eggs from a black rabbit, fertilized them with sperm from a black rabbit, transferred the embryo to the uterus of a white rabbit, and produced a litter of black pups. This was the first unequivocal demonstration of in vitro fertilization.

Spurred by Chang's success in the rabbit, Edwards began to fertilize the eggs of many different species of mammals, and in 1965 he first attempted the fertilization of human eggs. In developing IVF for humans, Edwards had to overcome formidable technical problems — problems that were orders of magnitude more difficult in humans than in animals confined to a cage. Edwards's story is one of courage — technical and moral. He had to learn how to induce ovulation in women, how to harvest their eggs from the ovary at the perfect moment, how to incubate them in a test tube with sperm so that normal fertilization would occur, and how to implant the embryos into the mother's uterus so that a normal baby would be born. All of this had to be carried out without doing harm to the woman or her baby. The most technically demanding step was finding a way to obtain eggs from the ovaries of women without having to subject them to open abdominal surgery. This problem was especially challenging to Edwards because he was a PhD with no experience in clinical research.

As luck would have it, in 1967 Edwards read a paper in The Lancet that described a new procedure called laparoscopy. The author was a gynecologic surgeon named Patrick Steptoe who was affiliated with a small hospital in Oldham near Manchester. Steptoe reported that he could visualize the organs of the female reproductive tract by making a tiny keyhole-sized incision near the navel through which he inserted a long thin telescope equipped with a fiber-optic light. This newfangled instrument was called a laparoscope. Although Steptoe did not invent the laparoscope, he was the first English-speaking surgeon to learn the procedure firsthand from its inventors in France and Germany. In 1967, Steptoe published the first book in English to describe laparoscopy. The book became an instant surgical classic on both sides of the Atlantic.

Edwards was immediately struck by the potential of laparoscopy for retrieving eggs directly from the ovaries of women at just the right time in the ovulation cycle. He rang up Steptoe and proposed a collaboration. Edwards's colleagues in Cambridge raised their academic eyebrows, thinking he was mad to hook up with a non-academic surgeon in private practice in a backwater hospital who was fiddling around with a dangerous foreign device that should never have been allowed into England in the first place. But, the irrepressible Edwards had the vision to realize that he needed the technology that Steptoe could provide. Like many discoveries in medicine, the discovery of in vitro fertilization itself required fertilization — the cross-fertilization between a scientist and a physician.

For the next 10 years, from 1968 to 1978, Edwards traveled back and forth by car over bumpy country roads from Cambridge to Oldham and back to Cambridge, an arduous eight-hour journey. Edwards calculated that he traveled the world four times over in his decade of near-weekly commutes. Commuting may have been tiresome, but that was nothing to equal the scientific frustrations and disappointments that Edwards and Steptoe experienced during the first decade of their collaboration. Within 18 months, they had successfully harvested eggs from infertile women, fertilized them, and developed living human embryos. But, success was short-lived. In their first 40 patients the embryos failed to implant in the uterus of the mother. Then, in 1975 the 41st patient became pregnant. Steptoe and Edwards were exhilarated, but their jubilation was again short-lived: the pregnancy had to be terminated because the embryo implanted in the fallopian tubes rather than the uterus.

Edwards and Steptoe persevered despite overwhelming odds. To make a 10-year story short, 102 patients received embryo transfers without a single successful pregnancy. In the end, success turned out to be a matter of getting the hormones right so that the transferred embryos would implant properly in the uterus and normal pregnancy would ensue. The first test-tube baby was born on July 25, 1978 — her name, Louise Joy Brown. July 25, 1978, also marked the beginning of joy for many, many infertile couples.

Infertility is a frequent medical problem. Throughout the world, infertility affects 1 in 6 couples. In the US right now, more than six million infertile couples desperately want to have children. Many infertile women produce normal eggs, but these eggs are unable to reach the uterus because of blockage in the fallopian tubes. That was the problem in the mother of Louise Brown. Since the birth of Louise Brown 23 years ago, nearly a million healthy babies have been born to infertile parents through IVF. Last year alone, more than 100,000 IVF babies were born, accounting for 1 in 200 births in the United States and more than 1 in 50 births in the United Kingdom, France, Scandinavia, and Israel.

Edwards and Steptoe's breakthrough in IVF spawned five new fields of clinical investigation. The first spin-off is the preimplantation diagnosis of genetic diseases, which makes it possible to prevent the birth of embryos that are destined to develop serious inherited disorders like cystic fibrosis and Down's syndrome. The second spin-off is the freezing of human embryos (cryopreservation), which makes it possible for patients undergoing cancer chemotherapy to preserve their fertility. A third spin-off is a new treatment for male infertility, called ICSI, in which a single sperm from a man with a low sperm count is injected into the cytoplasm of the egg. The fourth spin-off is the new field of human embryonic stem-cell research, which holds great potential for treating many common disorders such as Parkinson's disease and juvenile diabetes. Without Edwards's technique of mixing eggs with sperm in the test tube, there would be no blastocysts to produce the stem cells. And finally, the birth of Louise Brown led to a new field of reproductive bioethics and law, which is especially timely in view of the current controversy surrounding stem-cell research.

Patrick Steptoe, Edwards's long-term clinical collaborator, died in 1988 at age 75, one week before he was to be knighted at Buckingham Palace by Queen Elizabeth II. Had Steptoe been alive today, he would have undoubtedly shared in this Lasker Award with Robert Edwards. Without cross-fertilization, there would be no in vitro fertilization.

Most advances in medicine proceed in small steps. A precious few are great leaps. We know that IVF was a great leap because Edwards and Steptoe were immediately attacked by an unlikely Trinity — the Press, the Pope, and Prominent Nobel Laureates! The passage of time — plus a million smiling babies full of joy — have vindicated Edwards. This millennial year, the United Kingdom issued four stamps to celebrate the most noteworthy British advances in clinical medicine over the last 1000 years. Those honored were: Edward Jenner for vaccination against smallpox (1796); Florence Nightingale for founding the field of nursing (1890); Alexander Fleming for penicillin (1928); and Robert Edwards for developing IVF (1978). If one picture is worth 1000 words, then one's picture on a millennial stamp should be worth 1000 Laskers!

Robert G. Edwards

Acceptance remarks, 2001 Lasker Awards Ceremony

Nature Medicine Essay

Madame President, distinguished guests, and colleagues,

I am deeply honored to receive the Albert Lasker Clinical Medical Research Award, 2001. I wish to record my grateful thanks to so many people, family, teachers, collaborators, students, and friends who in their own way have helped at every stage. First, my wife has been there through triumphs, disasters, long absences from home at work or conferences, and always ready with love and advice. It is nice to thank Dean, my nephew, for coming at the last moment to represent all my wonderful family and relations. I regret Patrick Steptoe cannot be here. It is an honour to share this platform with my fellow prizewinners, whose work has long stimulated my own interest in my field of study.

As I grow older, I remember with increasing affection and admiration how my teachers in school led me gently into science. They stimulated my interest in genetics, which remained firm throughout four years of service in the British Army, and even as my University career began so disastrously, reading Agriculture. Two professors, Rogers-Brambell and Conrad Waddington, rescued my careers, and Alan Beatty was a superb PhD supervisor into the complex world of mammalian embryological genetics. They set me firmly on my career, where I have been lucky to meet so many admirable men and women scientists and clinicians, all working for their patients. Entering medicine in a most unconforming manner added immensely to my understanding and appreciation of patient care, achieved by the constant kindness of so many medical specialists. My colleagues and students, assistants and fellow publishers, have given unstinting help over more years than I care to remember. Without such support, research would have been immensely more difficult or impossible.

Today, we witness a biomedical revolution. Advances thought virtually impossible have become commonplace. Beginning in 1962, assisted human conception passed through ethical objections, through a series of stages of oocyte maturation and fertilization in vitro, and giving mild forms of gonadotrophin stimulation to patients to stimulate the growth of several follicles. Patrick's superb laparoscopy enabled mature human oocytes to be aspirated, fertilised, and grown to blastocysts in vitro. Embryo transfers began in 1972, rewarded by a first clinical pregnancy in 1976, unfortunately ectopic, and the birth of Louise Brown in 1978. We could not have wished for a finer family than the Browns, who maintained their dignity and common sense throughout very trying times before and after Louise's birth. I am deeply sorry they could not come today, in view of John Brown's illness, which caused the family withdrawal.

IVF has now exploded worldwide. One million babies have been born. Advances along the way have formalised ethics and legislation in innumerable countries. Embryo research and cryopreservation, gamete and embryo donation, and surrogate pregnancies have become very well known, even on endless soap operas. ICSI now enables men with virtually no spermatozoa to conceive their own children. Preimplantation genetic diagnosis and the therapeutic use of embryo stem cells, also started in Cambridge and with immense contributions from my fellow prizewinners, attract novel ethics in such affairs as designer babies or the preimplantation diagnosis of late age-onset diseases, perhaps the greatest fear of middle age. The breadth and scope of the field constantly widens, as it imposes on conditions heretofore untreatable.

And the world of molecular genetics has now arrived. Scarcely believable opportunities for identifying, transferring, switching on, and switching off single genes begin to revolutionise our outlook on what is possible. Modern genetic technology tells us that 10,000 or more genes are active in embryos between fertilization and the blastocyst. How do we cope in interpreting the additive effects of such a huge number of complex genes! Comparative studies show how we humans utilize the same genetic systems as flies, nematodes and amphibians, placing us in our evolutionary place and opening innumerable studies on homologies between these widely spaced species. Young scientists and clinicians now have an armory for diagnosis and intervention undreamt of by their teachers, as advances speed up every day. The new world of proteonomics has already arrived, promising even more novelties.

Madame President, I repeat my deep fortune in receiving this honor. And this is reinforced by the knowledge of how much the Lasker Foundation has done to honor knowledge and medicine. This day will long remain in my memory. The award has made this one of my finest.

Key publications of Robert Edwards

Fowler, R.E. and Edwards, R.G. (1957). Induction of superovulation and pregnancy in mature mice by gonadotrophions. J. Endocrin. 15, 374–384.
Edwards, R.G. (1965). Maturation in vitro of mouse, sheep, cow, pig, rhesus monkey and human ovarian oocytes. Nature. 208, 349–351.
Cole, R.J., Edwards, R.J., and Paul, J. (1966). Cytodifferentiation and embryogenesis in cell colonies and tissue cultures derived from ova and blastocysts of the rabbit. Dev. Biol. 13, 385–407.
Gardner, R.L. and Edward, R.J. (1968). Control of the sex ratio at full term in the rabbit by transferring sexed blastocysts. Nature. 218, 346–349.
Edwards, R.G., Bavister, B.D., and Steptoe, P.C. (1969). Early stages of fertilization in vitro of human oocytes matured in vitro. Nature. 221, 632–635.
Steptoe, P.C. and Edwards, R.G. (1978). Birth after the reimplantation of a human embryo. Lancet 2, 366.
Edwards, R. G., Steptoe, P.C., and Purdy, J. M. (1980). Establishing full-term human pregancies using cleaving embryos grown in vitro. Br. J. Obstet. Gynaecol. 87, 737–756.
Steptoe, P.C., Edwards, R.G., and Purdy, J. M. (1980). Clinical aspects of pregnancies established with cleaving embryos grown in vitro. Br. J. Obstet. Gynaecol. 87, 757–768.
Edwards, R.G. (1981). Test-tube babies, 1981. Nature. 293, 253–256.
Edwards, R.G. (1997). Recent scientific and medical advances in assisted human conception. Int. J. Dev. Biol. 41, 255–262.