ORIGINS OF IVF
The quest to develop In Vitro (‘in glass’) Fertilisation or IVF as a treatment for infertility rests on research that dates back more than a century.
British zoologist Walter Heape (1855 – 1929) showed in 1890 that it was possible to transfer embryos when he put Angora-fertilized eggs into a Belgian Hare doe rabbit, which gave birth to Angora offspring.
The first IVF births in a mammal resulted in 1959, when Min Chueh Chang at the Worcester Foundation for Experimental Biology in the United States showed that rabbit eggs could be fertilized in the lab and give rise to viable offspring.
Robert Edwards, working at that time in the National Institute for Medical Research in London, was committed to develop a method that would alleviate human infertility, which affects more than 10% of all couples worldwide, often due to damage to the Fallopian tubes in women, or impaired sperm quantity and quality in men.
In 1965, by now working in Cambridge University, Edwards discovered how to mature human eggs suitable for IVF and in 1969 succeeded in fertilising them.
Jean Purdy – whose important contribution to human embryology has been neglected in traditional accounts – had by then started to work with him to develop IVF, along with surgeon Patrick Steptoe at the Oldham and District General Hospital, where he had developed the use of laparoscopy, and they showed in 1970 that eggs could be retrieved this way from infertile women.
The first IVF pregnancy was reported in Australia in 1973 by a Monash research team but resulted in early miscarriage. Three years later, the Cambridge team reported an ectopic pregnancy.
Despite the hostility and unease of their peers, Steptoe, Purdy and Edwards eventually succeeded with the first human IVF birth, Louise Joy Brown on 25 July 1978, in Oldham General Hospital, Greater Manchester. Behind the success was another unsung figure, Muriel Harris, who led the nursing staff.
ETHICS OF IVF
Once the euphoria surrounding the birth of Louise Brown in 1978 had abated, concerns about growing human embryos in the laboratory for experiments grew.
There was a perception that scientists could not be certain of the outcome of implanting artificially-conceived embryos, indeed many were appalled by the thought that scientists could discard living embryos that were deemed imperfect.
In June of 1982 Norman Fowler, the Government’s Secretary of State for Health and Social Services, wrote to Mary Warnock, then a University of Oxford philosopher and educationalist, to invite her to advise ministers on whether IVF should be banned and, if it did go ahead, how it should be regulated.
In recognition of how the early embryo is not the same as a person, or a child, 14 days was adopted as the limit for embryo research. Remarkably, the UK still abides by their recommendations, which were enshrined in the UK in the Human Fertilisation and Embryology Act in 1990, making Warnock arguably the most influential proponent of applied bioethics in recent decades.
Today, new research has reopened the debate about how long to grow human embryos in the laboratory.
SECRETS OF HUMAN DEVELOPMENT
The ability to fertilise human embryos outside the body gave us, for the first time, the opportunity to study these embryos in a controlled way and created the field of human embryology. Today this research is constantly challenging ethical boundaries.
A new technique that doubles the time that human embryos can be grown in the laboratory has been developed in the Cambridge laboratory where Robert Edwards did the basic research which paved the way to the birth Louise Brown and his Nobel prize.
Using their new methods developed by Prof Magda Zernicka-Goetz and colleagues they could reveal processes during the all-important stage of implantation, around day six. Around 30 to 70 per cent of pregnancies fail at implantation and, until this work, it had been called the ‘black box of human development’ because it was so difficult to study.
However, their feat has also triggered intense debate because international guidelines and UK legislation forbid human embryos being grown beyond 14 days, since only at this point in development does the embryo have a glimmer of a body axis. This is also the latest stage at which the embryo can split to form twins.
Professor Magdalena Zernicka-Goetz reflects on how human embryos appear to have an ‘intrinsic capability’ for self-organisation, at least until day 13, without the help of the mother.
EDITING HUMAN EMBRYOS
The ability to grow human embryos in the laboratory now means they can be screened for disease and manipulated more easily too.
Pioneering gene editing research has been performed at the Francis Crick Institute in London.
Kathy Niaken and her colleagues used genetic surgery (genome editing, with the formal title CRISPR/Cas9) to turn off genes in human development to study molecular mechanisms of development before implantation. Genes are the recipes to make the body’s building blocks, proteins, and her lab focused on one particular protein, OCT4, which they revealed was at work in the embryo’s cells by using a chemical label that glowed green.
Using gene editing, they turned off OCT4 and compared the consequences with an unedited control embryo in time-lapse videos. Both embryos cleaved as they developed but when it came to the formation of a cavity, when the embryo is at the stage of implantation and called a blastocyst, the edited embryos were unstable and collapsed. They concluded that OCT4 is fundamental to the proper development of human blastocysts, a small but important step in beginning to understand what genes are necessary for embryo development.
Recently the influential Nuffield Council on Bioethics concluded that editing the DNA of a human embryo to influence the characteristics of a future person (‘heritable genome editing’) could be morally permissible.
MITOCHONDRIAL DONATION AND DISEASE
Professor Doug Turnbull has worked in Newcastle for more than a decade to offer a treatment to families who are blighted by disorders in mitochondria – the cell’s power packs (around one in 5000 of the population).
His team has developed a way to have unaffected children by the creation of what are called ‘three parent babies’, with a second ‘mother’ providing normal mitochondria. Their proposal was radical because scientists have agonised for decades over what is called ‘germ-line’ gene therapy – genetic changes passed down in eggs and sperm.
However, what the Newcastle team proposed was not like conventional germ-line therapy, since it would only affect future generations if used to free a baby girl of the disease (mitochondria are only passed from mother to child.)
After a long and exhaustive period of consultation, the Newcastle Fertility Centre was granted the first UK licence– in fact first of its kind anywhere – to offer mitochondrial donation by pronuclear transfer, a way to take the parent’s DNA and combine it with mitochondria from an egg donor.
When a child is eventually born with another woman’s mitochondria, which is likely in the next year or two, their long-term development will be monitored in what is not an IVF technique but ‘a pathway of care’.
NEXT GENERATION IVF
By the end of this century, 400 million babies – 3% of the global population – could by one estimate exist as a direct and indirect result of in vitro fertilisation, according to Sally Cheshire, CBE, Chair of the UK’s independent regulator of fertility treatment, the Human Fertilisation and Embryology Authority, at the launch of IVF: Six Million Babies Later.
The research that led to the birth of Louise Brown not only revolutionized reproductive science, through techniques such as embryo screening (preimplantation genetic diagnosis) but has also underpinned the derivation of human stem cells, which has been crucial for our understanding of how embryos develop, helped preserve species such as the rhino, and is likely to become important in regenerative medicine to grow new tissues, organs and even create artificial embryos.
Success rates have doubled over the last 25-30 years to around 30% but we still have a long way to go, says Cheshire. The treatment remains an ordeal, also for the men who undergo IVF. And it is expensive, so the quest is under way to develop cheap and efficient methods.
The ability to grow embryos in the laboratory has given new insights into development that have raised an extraordinary possibility: building embryos from three kinds of stem cells, parent cells of other types, rather than by fertilising eggs with sperm.
When an egg is fertilised by a sperm, it divides to generate a small, free-floating ball of cells comprising three kinds of stem cells, which go on to develop into hundreds of other types in the body: embryonic stem cells, which develop into the fetus, and other two types which form the placenta, and yolk sac, ensuring that the foetus is nourished and develops properly.
A little over a year ago a University of Cambridge team, based in the building where Robert Edwards did his pioneering IVF research, assembled two types of stem cells on a jelly-like scaffold into an embryo-like structure which, surprisingly, grew a little like the real thing.
Now, in a study published in Nature Cell Biology, Prof Zernicka-Goetz and her colleagues have used all three types of stem cells to create an embryo-like structure that can undergo a critical process in development known as gastrulation, in which the embryonic cells self-organise into three layers of cells which go on to form tissues or organs.
‘By replacing the scaffold that we used in earlier experiments with this third type of stem cell, we were able to generate structures whose development was astonishingly successful,’ says Zernicka-Goetz. ‘Our artificial embryo-like structures underwent one of the most important events in life in the culture dish.’
However, to develop further, they would have to implant into the body of the mother, or an artificial placenta.
‘The early stages of embryo development are when a large proportion of pregnancies are lost and yet it is a stage that we know very little about,’ adds Zernicka-Goetz. ‘Now we have a way of simulating embryonic development in the culture dish, so it will open a way to understand what is going on during this remarkable period in an embryo’s life, and why sometimes this process fails.’
With colleague Marta Shahbazi, she has published an overview of progress in the creation of artificial embryos, also in the journal Nature Cell Biology.
Explore the remarkable story of in vitro fertilisation from the opposition and immense challenges faced by early pioneers to the latest research today in IVF: 6 Million Babies Later in our Who Am I? gallery. Find out more.