Human Egg Farming

We called the ambitious program, ‘Egg Farming,’ over 30 years ago when I worked at Edinburgh University. That goal drew a step closer today as my graduate student from so many years ago published results of growing human eggs in vitro, to a blaze of publicity.

We started by growing mouse and rat eggs in Petri dishes. They were tiny cells nested in follicles that nurse their development, and some reached full size in a week and even ovulated a fertile egg into the culture medium. Our sole competitor in this new science was in the USA where John Eppig developed a more efficient method, and he called the first pup conceived from an egg grown in vitro, ‘Egbert.’ He was a strange and obese animal, and we worried if egg farming was too risky to apply in veterinary or human medicine, but many healthy mice were born later.

Human egg (oocyte). Courtesy: Lucinda Veeck Gosden

It seemed a huge leap from mouse to clinic. Human eggs grow more slowly in the ovary, and we expected the cultures would take weeks or even months and be risky. Progress was agonizingly slow because human ovarian tissue is rarely available for research, especially at the premenopausal ages required. Instead of relying on rodents, we needed intermediate species to forge better methods, and turned to sheep and cow ovaries. Visits to the local slaughterhouse for discarded tissue from butchered carcasses were some of the most unpleasant experiences ever, and almost turned me vegetarian from hearing the crack of the bolt-gun followed by a heavy slump. But they helped us to gain new knowledge when human tissue was unavailable.

A view of Edinburgh and its castle

Professor Telfer’s team in Edinburgh has succeeded with human eggs through careful work with clinical colleagues who asked consent from women to donate tiny slivers of ovarian tissue during C-section. The biopsy doesn’t harm them.

They watched eggs growing in dishes from the earliest stages to full size when a nuclear division occurred and signaled they were ready for fertilization. It is puzzling why the growth is much faster in vitro than in the body, though it is welcome if the eggs are no less competent for making babies. They look normal, but we know from experience how deceptive appearances can be. The only sure test is to fertilize eggs to see if they create healthy embryos, and that will require a special license under UK law.

Why is farming eggs worth the trouble and long struggle?

Progress will continue at a dawdling pace because a mature egg is the rarest cell in the body. For every egg ovulated each month, a man makes 3 billion sperm cells which offer researchers enough material for galloping discoveries in testes. Animals that fertilize eggs outside the body, like frogs and most other species, release as many eggs as they can make because the cost to them is small while superovulation maximizes the chance of making babies. But ovulation in mammals with internal fertilization and pregnancy is restrained by the limited accommodation of the uterus. Nature has arranged a bottle-neck in the egg production line to ensure that few eggs, or only one or at most two in humans, ripen at a time. The rest are consigned to the trash, which egg farming aims to rescue.

If more eggs can be ripened in vitro there will be benefits for animal breeding technology and young patients will have a better chance of preserving their fertility after freezing ovarian tissue during sterilizing treatment for cancer and other diseases. Egg farming will work better for child patients with their larger stores of eggs than in adults. Nearly a quarter-century ago, our first patient at an infant age had ovarian tissue stored while she was treated for Wilm’s tumor. The news from Edinburgh today was welcome for her and others with investments in the frozen ovary bank.

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Fertility owes Preservation to a Sheep

The journal Human Reproduction reported a 27-year old woman in Belgium has delivered a healthy baby boy. That would not be newsworthy if she had not been rendered sterile at 13 years old by a life-saving bone marrow transplant for sickle cell anemia.

This was neither conception with a donor egg, nor from a mature egg retrieved and frozen from her ovaries before chemotherapy. But it did involve one of her eggs, so she could become the birth mother and genetic mother. So how did it happen?

Shortly before curative treatment for sickle cell, her gynecologist harvested strips of tissue from her right ovary for frozen storage. In excellent health a decade later, her tissue was thawed and transplanted to the now sterile left ovary, as well as elsewhere. After 5 months, she had her first period, which confirmed that eggs had survived inside their follicles, and she continued having regular periods until conceiving naturally within two years. Yes, it gave her periods and fertility without any further medical help—naturally!

It’s a newsworthy case because she is first to deliver after transplanting an ovary stored from childhood. Girls undergoing sterilizing treatment are rarely offered fertility preservation, and this can be their only option. The first case of its kind was 20 years ago for a two-year-old Yorkshire infant called Harriet. We would never have suggested it except she had to undergo an operation to remove a kidney tumor, which gave us the chance to safeguard some of her ovaries “just in case.” I don’t know if she has requested the hospital to have her tissue back, but it is wise to wait until ready to start a family because we can’t predict how long a transplant will function before it fails and then plunges her back to a menopausal condition.

There have been about 40 births to women worldwide after a frozen ovary transplant, all of them healthy to my knowledge. And there is a further series of 11 women who received a fresh transplant donated by a sister at the Infertility Center of St. Louis led by my colleague, Sherman Silber, M.D. He recently reported in Reproductive BioMedicine Online that menstrual cycles have returned in every case. Two women are still cycling after 8 years, with 11 births in all. It has turned into a rather robust procedure.

While ovary transplants have been in the news for over a decade, there is no full account in public space of how they originated. The story depended on a sheep, but the idea was really a brainstorm in a blind alley. Science doesn’t always proceed linearly, and sometimes backs out of a cul-de-sac to find the main highway.

Around 25 years ago at Edinburgh University, I naively mentioned on a BBC TV science documentary that I was testing if fetal ovarian tissue can restore fertility in adult animals. This was before the era of egg donation and at a time when egg freezing was considered unsafe. Since there are more eggs in fetal ovaries than after birth, the prospects of a long functioning graft seemed high—provided the eggs were healthy for making babies. When the experiments were successful, women with premature menopause or Turner’s syndrome urged me forward, but it was an idea stillborn.

I was the target of huge opposition and not a little opprobrium from bioethicists, churches, politicians, and just about everyone else. A senior American scientist even warned me not to travel to the USA because people were saying the procedure would encourage abortion for donating tissue. Nothing was further from my mind than that horrific idea, because my research agenda was entirely pro-fertility! I had simply believed it is better to do some good with discarded tissue than no good at all, although I acknowledged there were issues about safety and consent.

The bumpy ride did, however, take me back to a new and much less controversial agenda. It was a time when cancer survival rates were starting to climb, especially for children, but sooner or later the highly toxic and aggressive treatment could make them sterile. Men had the option of semen freezing, but there was no equivalent chance of preserving fertility for children. I started to wonder if ovary banking for girls and testis banking for boys was the answer.

Roslin Institute
Frosty conceived after ovary freezing and transplantation in Scotland

We had modest hopes because freezing whole tissue is harder than single cells, but if it worked with sheep ovaries we were hopeful of the same for patients. I remember working with my colleague David Baird in a cold operating room at the experimental farm outside Edinburgh where Dolly the cloned sheep was born a few years later. We returned frozen ovarian tissue to the same ewes a month after a harvesting operation. Four to five months later the animals showed signs of graft activity, the same delay we have observed in patients. Not long afterwards, there was a pregnancy, and a little “Frosty” was born.

The Daily Telegraph September 23, 1999
The Daily Telegraph September 23, 1999

A research fellow who returned to the USA from my lab was first to transplant frozen tissue to a patient. It happened to be on my birthday in 1999 and the eve of emigration to a job at McGill University that the patient came to the UK and visited my lab. There was a huge splash in the media, perhaps because there was no other news that day!

Unfortunately for her, the graft was not successful. It had been frozen as minute fragments at an unknown center, but the attention she received encouraged others, and there was happier news for them. By 2004, the first birth was reported, and this too in Belgium.

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