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By Roger Highfield on

The baby who launched a test tube revolution

Louise Brown was conceived four decades ago this month, launching a revolution in reproductive medicine that has seen millions of test tube babies born worldwide.

At the Manchester Science Festival you will have the opportunity to hear about the latest chapter in an extraordinary story that began in earnest on 25 July 1978 with the birth in Oldham General Hospital of Louise Brown, the first person to be conceived by In Vitro (in glass) Fertilisation, or IVF.

The Science Museum, the sister museum of the Museum of Science and Industry, will celebrate Louise Brown’s 40th birthday next year in London because the research that led to her birth not only revolutionized reproductive science, through techniques such as embryo screening (preimplantation genetic diagnosis) but also raised many ethical issues and underpinned the derivation of human stem cells, which has been crucial for our understanding of how embryos develop, and is likely to become important in regenerative medicine to grow new tissues, organs and even artificial embryos.

Three leading figures in the reproductive science revolution that has come in the wake of the birth of Louise Brown will join me in Manchester on Thursday 19 October for a discussion about the latest work on ‘three parent’ babies, gene editing, and fundamental research on human embryos.

Fundamental insights

From left: Dr Norah Fogarty, Dr Marta Shahbazi and Prof Sir Doug Turnbull

Our first speaker is Prof Sir Doug Turnbull, Newcastle University, neurologist and expert on mitochondrial disorders who has been at the forefront of efforts to prevent these serious genetic diseases by the creation of ‘three parent babies,’ and will describe the years of effort that it takes to turn laboratory science into an approved clinical service.

Dr Marta Shahbazi works with Professor Magdalena Zernicka-Goetz in Cambridge University on fundamental embryo research and was first author of the paper that describes how the team doubled the time human embryos can be grown in the lab, without using any maternal tissues. “In other words they do it on their own,” said Dr Shahbazi. “And this is what in scientific terms we call ‘self-organisation’”.

Our third speaker is Dr Norah Fogarty, who works with Dr Kathy Niakan at The Francis Crick Institute (the Crick) in London on ‘genome editing’ techniques (CRISPR, or to give it its full name, CRISPR/Cas9) to make specific alterations to genetic code, in this case to understand the genes that ensure a healthy human embryo develops.

As well as giving fundamental insights into the earliest stages of human development this knowledge may, in the future, lead to improvements in IVF treatment, improve our understanding of pregnancy failure, and has tremendous potential for stem cell research, which will have benefits and advances in many different fields of medicine.

Dr Fogarty was the first author of a milestone paper published a few days ago that marked the first time that genome editing was used to study gene function in human embryos.

A risky idea

Before Louise Brown was conceived, human reproduction was regarded as being almost sacred. Dr Robert Edwards, who helped bring her into the world, said that procreation seemed to be a matter for theologians, rather than scientists.

Working with him was Patrick Steptoe, a gynaecologist and innovator in the field of laparoscopy (keyhole surgery), who had been interested in treating infertility since the late 1940s – he was truly a pioneer.  I was fortunate to have dealt with both, first while working for the magazine Pulse, and then for The Daily Telegraph.

Doctors of the day thought that IVF was a risky idea driven more by an appetite for headlines than scientific curiosity. Meanwhile, the public imagination had been “dramatically doom-lit and gaudily coloured by science-fiction fantasies,” said Edwards, along with “visions of white-coated, heartless men, breeding and rearing embryos in the laboratory to bring forth Frankenstein genetic monsters.”

Edwards was probably referring to Aldous Huxley’s Brave New World, which leaned heavily on the technologies that the geneticist J. B. S Haldane had forecast in his essay Daedalus, or Science and the Future (1924), notably ectogenesis — the gestation of embryos in artificial containers.

And yet knee-jerk revulsion would give way to acceptance when the public and the science funding bodies became aware of the benefits for infertile couples. Edwards went on to be awarded the Nobel Prize in 2010 (Steptoe died in 1988 and the prize is not awarded posthumously).

An unintentional start

Intriguingly, Dr Edwards’ development of IVF was not the initial aim of his research, remarked Dr Fogarty. “We have to note that in the 1950s and 60s infertility was not a major concern in medical fields. In fact, people were more concerned with contraception and overpopulation.”

Initially, Dr Edwards was interested in studying the basic science of genetic and chromosomal disorders and how the egg, sperm and embryo developed.

IVF began when Edwards, while working in Cambridge, was keen to extend research on animals to find ways to treat women with blocked Fallopian tubes, which prevent eggs from travelling from the ovaries to the womb, where they can be fertilised.

While some doctors, such as Robert Winston, were investigating tubal surgery, Edwards was struck by the thought that “what we should be trying to do was pluck the egg from the ovary and fertilise it in the laboratory.”

Edwards had prepared eggs for fertilisation in several animal species and by 1965, thanks to work with Howard and Georgeanna Jones, Baltimore gynaecologists, he had transferred these techniques to humans.

Molly Rose, a gynaecologist, had agreed to supply Edwards with ovarian tissue. Another key figure in the story of IVF was Jean Purdy, who was recruited by Edwards at the Physiological Laboratory in Cambridge in 1968. Decades later, at a plenary lecture celebrating the anniversary of IVF in Marrakesh, Dr Edwards remarked: “There were three original pioneers in IVF and not just two.”

“That fabulous night”

Early attempts to fertilise eggs from ovarian tissue using Edward’s own sperm proved fruitless. Then, one afternoon in 1969 he tested a culture medium used to grow hamster embryos supplied by a student, Barry D. Bavister, who was working along the corridor.

After dinner, they inspected nine eggs in Bavister’s medium. “I focused up and down and bang, a sperm tail,” said Bavister. “It was a stunning moment.”

“In that fabulous night we saw all of the most beautiful stages of human fertilisation, from about six hours to 12 hours after fertilisation,” recalled Edwards.

“Is it human?”

Here Patrick Steptoe entered the story. Steptoe, who was routinely encountering ripe eggs in his work on laparoscopy met Edwards at the Royal Society of Medicine, where they made a historic decision to collaborate.

They gave patients small doses of hormones to produce more than one ripe egg, working out the best time to harvest eggs for fertilisation.

The embryos “grew beautifully” for up to three days. However, Edwards was keen to reach the five-day stage, when the embryo is a so-called blastocyst and is ready to implant in the womb.

One night, after returning from Oldham in Manchester where Steptoe worked, Edwards was confronted with a remarkable sight. He invited a colleague doing similar work on mice to look, who then asked, “Is it human?” And he said, “Yes, this is our first blastocyst”. “We just looked at each other and were extraordinarily silent,” he remembers.

Steptoe began to recruit infertile couples to a cottage hospital outside Oldham. One of the nurses recalled the mood of excited anticipation when an egg was removed. Even though half the eggs would develop into embryos, the attempt would fail after implantation.

Five years of failure

By 1977, Edwards and Steptoe had endured five years of failure. They decided to abandon the cocktail of drugs used to stimulate egg production and put their faith in the less productive natural cycle.

At that time, Lesley and John Brown were desperate but, inspired by the first heart transplant, they felt sure there must be an operation to fix a blocked Fallopian tube. She was referred to Steptoe, who met them in his shabby consulting rooms in Oldham.

He declared them ideal for IVF. “He told us that until then it hadn’t worked,” said Lesley, “but I didn’t want to hear that.” She reluctantly signed papers agreeing to an abortion if IVF caused abnormalities in the foetus.

The glass incubator now on display in the Making the Modern World gallery at the Science Museum, London. Image: The Churchill Archives

Steptoe and his team made a renewed attempt on Lesley and two other women in November 1977. “They found one solitary egg and that was Louise,” she recalled. Her husband, John, was invited to make his contribution to fertilise the egg: “I went into a quiet room, did my little bit.”

By this time, Steptoe and Edwards had decided to halve the period that the embryo was grown in the laboratory. Louise consisted of just eight cells when Steptoe transferred her to Lesley Brown. “I was just so positive it was going to work,” she said. “I’ve never been surer of anything in my life.”

She wept when she was given the ‘very encouraging’ results of blood tests before Christmas. Then came the confirmation, when the doctors listened to her stomach and there, loud and clear, was a heartbeat. The pregnancy caused a media sensation. “We didn’t realise we were the first, not until it actually came out in the papers,” said John Brown.

The moment of truth

In July 1978, Lesley Brown’s blood pressure spiralled, due to blood poisoning (toxaemia), and Steptoe decided to wait no longer. He left the hospital early to wrongfoot the press, telling his theatre sister to ready for a Caesarean just before midnight. Lesley Brown was prepared for the operation under torchlight, so journalists outside the building would not see her room light up.

“I was very apprehensive,” said Dr John Webster, who was assisting with the operation. “If she had any abnormality, that would have been put down to the technique and it would have been very difficult to defend.”  He crossed his fingers as Steptoe made the first incision.

Five seconds after she was removed from her mother, Louise Brown “let out the biggest yell you’ve heard a baby make,” said Edwards. “Patrick shouted, ‘That’s what I like to hear, good lung development’.”

Steptoe recalled that Lesley Brown was speechless when she first held Louise. “The expression on her face was extraordinary.” John Brown was shaking too much to hold her initially, on what he would call the most beautiful day of his life. “Her little face, her eyes and her squawking. From the day she was born, she’s never stopped squawking. She’s a credit to us. A real credit.”

Within hours, the story of Louise became worldwide news. Steptoe and Edwards, after two failures, managed to produce the second child, Alastair Montgomery. And the Browns would go on to have another IVF child, Natalie, who is thought to be the first IVF girl to conceive naturally.

IVF paved the way for reproductive science. In 1990 the Human Fertilisation and Embryology Act in the UK established the Authority to regulate the creation of embryos through IVF and the research involving them. The UK remains a world leader in human embryo research due to its strict legal framework.

When Dr. Edwards was awarded the Nobel prize the Nobel committee noted that his achievements made it possible to treat infertility, which affects more than 10% of couples. Today, IVF is established worldwide and has undergone several important refinements. For example, single sperm can be microinjected directly into the egg cell in the culture dish (intracytoplamsic sperm injection; ICSI).

Even though more than four million individuals have been born from IVF, only about 20-30% of fertilised eggs leading to a healthy birth. All three speakers in Reproduction 2.0 believe that more research into early human development will help further improve success rates.

 

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