27.9.2021From the world of research – Ovumia’s new laboratory director is solving the egg cell riddle

Marjut Otala, who has returned to Ovumia’s laboratory in Helsinki as the Laboratory Director, wants to be the link between science and practical medicine. An experienced researcher, she believes that her background will also benefit Ovumia’s patients.

The new Laboratory Director of Ovumia Helsinki, Marjut Otala, PhD, looks thoughtful. A clinical embryologist specialising in infertility treatments with a long research career behind her, she stops to consider which path may eventually lead to a breakthrough: growing egg cells from ovarian tissue or stem cells.

“That is actually a very difficult question,” she replies.

It is also a personal question, and here is the background as to why. Let’s return to the end of the last millennium when Otala was studying physiology, biochemistry and genetics at the University of Helsinki. The future researcher’s studies for her master’s thesis took her to the University of Minnesota where Alan Hunter, Professor of Veterinary Medicine, encouraged her to take his courses.

Otala took several courses on in vitro fertilisation (IVF) in veterinary medicine and worked in Hunter’s laboratory during the summer. They received a bucketful of bovine ovaries from the slaughterhouse, and Otala collected oocytes from them using a needle.

In Finland, Otala ended up writing her master’s thesis for Väestöliitto, the Family Federation of Finland, and participated in Professor Outi Hovatta’s research on ovarian tissue cultures. In her master’s thesis, she examined how ovarian tissue follicles could be cultured in a laboratory in vitro. In her work, Otala compared tissue culture substrata.

After completing her master’s thesis, she returned to the USA for further studies. She was offered a place in a team run by Barry Bavister, who was a student of the Nobel Prize winner Robert Edwards, but she also received an interesting offer for a place in Leo Dunkel’s team at the Children’s Hospital in Helsinki and decided to stay in Finland.

Dunkel specialised in the apoptosis, or programmed cell death, of gametes. Cancer treatments, for example, destroy gametes. A study had been published in Harvard on the successful manipulation of apoptosis pathways in mice, which resulted in mouse egg cells that did not die from radiation treatment.

Otala tested the same method on male mice, but their apoptosis pathways proved convertible. Preventing one pathway led to the creation of a new one, which resulted in cell death.

Acting as a link between two worlds

Otala has studied these two subjects, the preservation of egg cells and laboratory cultivation, almost throughout her career. She has performed demanding expert and managerial duties at Biomedicum, the Family Federation of Finland, Fimlab and most recently at the HUS Helsinki University Hospital.

In between these positions, she worked for just over a year at Ovumia too (known as Fertinova at the time). It is fairly rare for a researcher to return to a dayjob in the private sector.

“I think I’m a bit of an oddball in these circles. I consider myself a link between the academic world and an ordinary person seeking IVF treatment. They really shouldn’t be two separate worlds, although in Finland they tend to be.”

Otala carries out basic research. In half of her doctoral thesis, she examined ovarian tissue cultures and in the other half the preservation of male fertility through sphingosine-1-phosphate.

The ability to grow egg cells outside the ovary would revolutionise fertility treatments, but we are a long way from that, and when completed, the new technology would not be immediately available to ordinary patients.

“Understanding the pathways involved in egg cell maturation may also help ordinary fertility patients. This may be exactly where their problems lie. But we are still far from achieving personalised fertility care.”

Otala considers patient work highly valuable. The queues to public fertility care are long, and not everyone qualifies for them due to age limits and other criteria. Private customers who have tried to get pregnant for a long time deserve a chance.

“Being involved in the world of research brings a special interest to my work in an IVF laboratory. I can see the everyday life of fertility clinics and what they and their patients need; why research is carried out and what benefits it can bring and to whom.”

The same goes the other way round: everyday experiences benefit research.

“Knowledge about infertility and its treatments and the ability to handle follicles and eggs absolutely benefit research. At the same time, there should be a link between research and people so that the knowledge achieved can be utilised also outside researcher catacombs.”

The goal is an egg cell grown in a laboratory

The number of eggs is at its greatest when the female is still a foetus, at the midpoint of pregnancy. A female baby has between 1 and 2 million eggs at birth – or only hundreds of thousands. It varies greatly from one individual to another.

The majority of the eggs in the ovarian follicles are dormant and in their ‘primordial’ form. As a woman ages, her reserve of eggs decreases. Menopause begins on average around the age of 51 when there are only about a thousand eggs left.

As an egg ages, its chromosomal problems increase. Knowledge of processes that influence the quality of eggs would greatly benefit IVF treatments.

Some women also need treatment because their ovarian function becomes prematurely reduced. If a doctor knew that a woman is genetically predisposed to primary ovarian insufficiency (POI), then in theory, an ovarian biopsy could be performed when the ovaries are still functioning, and the resulting piece of ovary tissue could be frozen for later use.

However, growing an egg from ovarian tissue is easier said than done.

“This idea has been talked about for as long as I have been in the business. Yet, so far a safe and efficient way to do it has not been found. I think Evelyn Telfer’s team of researchers in Edinburgh has made the greatest progress. They were the first to grow an egg that is suitable for fertilisation to maturity outside the ovary from a primordial, dormant ovarian follicle.”

However, fertilisation cannot be attempted without thorough further research because human tissue and cells are protected by law.

“We can’t just experiment and find that, oops, it turned out almost human,” Otala sums up.

For example, epigenetic factors, the environment and nutrition affect the way the cells of an egg are interpreted. It is important to make sure that the genes are as normal as possible before even considering using the cell.

Freezing protects eggs from cancer treatments

If we ever succeed in growing small dormant eggs directly from ovarian tissue in a laboratory, it might first be used, for example, to help cancer patients. Over the last few years, Otala has studied the ovarian tissue of girls with cancer at the HUS Helsinki University Hospital.

The aim is to protect girls’ fertility from cancer treatments. The purpose of freezing tissue obtained from a child is to transplant it back in their body years later. Tissue obtained from adults and frozen has already resulted in hundreds of children being born all over the world using this method.

“If tissue is taken from someone with leukaemia, it may contain cancer cells. When the tissue is transplanted back in the person’s body, the cancer may be transplanted at the same time. That’s why it would be extremely useful to also be able to mature follicles in vitro, that is, by cultivating ovarian tissue and growing ovarian follicles in an incubator.”

Children with cancer are often treated with small doses of cytotoxin even before freezing. It is important to study how the treatment has affected their ovaries and ovarian follicles. Variations in children are not well known as it is.

Mice have follicle populations that specialise in different tasks. During the foetal period, the purpose of the population that is formed first is not to produce eggs that are suitable for fertilisation but to achieve fertility. The second population produces mature eggs for fertilisation.

“Is it possible that humans have a similar mechanism? We are studying the kinds of cells and follicles ovaries contain, what kind of dialogue takes place between them and what RNA follicles produce. We need to know more about children’s ovaries and what they can do in the future.”

Freezing in anticipation, i.e. social freezing, also for healthy people

Even tissue from babies has been frozen, but we do not know yet whether it will be able to initiate hormonal action. As far as we know, a 9-year-old is the youngest person whose frozen ovarian tissue has been successfully transplanted at a later age and who has given birth to a child as a result.

“But a 9-year-old is not necessarily a child anymore. The age that adolescence begins varies greatly, especially in girls. If a girl’s ovarian tissue is destroyed, it also destroys the hormonal regulation of her body.”

The method is also suitable for people suffering from blood diseases – such as sickle-cell anaemia or any other serious illnesses – who are given total body irradiation or bone marrow transplants.

Of course, eggs grown in the ovaries of healthy women can already be frozen today. This type of freezing of eggs in anticipation, also known as social freezing, is performed, for example, at Ovumia. It is a fairly common employee benefit in Sweden, while in Finland only Ovumia offers it to its staff, as far as we know.

Few women at the peak of their fertility are able to anticipate problems with fertility and even fewer have the opportunity. That is why we must also find methods to help women in their forties.

“In the end, we know very little about the physiology behind the maturation of an egg. What causes it to activate, how it moves from one stage to the next and what is involved in all the different stages,” Otala says.

An oocyte is only about 25 micrometres in diameter. Activation causes the flat granulosa cells around it to bulge, and a primary follicle is created. When the granulosa cells divide into layers around the egg, a secondary follicle is formed.

Before ovulation, granulosa cells increase, and vesicles are formed in between which then merge to form an antrum. In the end, the egg is an eighth of a millimetre and the entire structure a couple of centimetres in diameter.

“At this clinic, we deal with egg cells that are in the final phase. Nevertheless, we are able to recognise immature eggs among them. Perhaps at some stage we will be able to analyse what has caused a particular large problem.”

Looking at stem cells

Ovarian research has a new challenger: stem-cell research. Skin stem cells, for example, can be reprogrammed to produce other cells, such as eggs. Eggs have already successfully been made from the stem cells of mice.

Professor Sherman Silber, renowned developer of fertility treatments, now considers stem cells an easier source of in vitro egg cells than the ovaries.

“I recently listened to a lecture where Silber expressed his opinion that stem cells were definitely the way forward. He thought there is no point in trying to mature dormant primordial follicles because some pathways are locked so that manipulation is not possible. On the other hand, a British team says they have been able to create eggs from primordial follicles.”

Otala believes that neither route has yet been able to achieve suitable human egg cells, even if they look right. There is still a lot of work to do.

And so, we return to the question, which is the more probable route to achieve success?

“That’s a very tricky question. I want to believe that it is possible to create healthy mature eggs outside the ovaries from the primordial follicles of a woman’s, or even a child’s, own ovarian tissue. This would allow us to make use of all the samples collected from patients.”

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