"This trial is not intended for pregnant women" is an almost universal clause in the conditions for acceptance to a clinical trial. In the past, clinical trials excluded any woman of childbearing age, for fear she would become pregnant during the trial and the drug being tested would affect the fetus adversely. As a result, for five decades now, no new drugs have been developed for pregnant women. But the problem is much broader; it is very difficult to study the female reproductive system, explains Dr. Ola Gutzeit, head of the Fertility Preservation Unit at Rambam Hospital.
This is a system that changes so much with the menstrual cycle and hormonal fluctuations that researchers become frustrated even before they start. Animal models don't represent it well, and cell cultures fall far short of reflecting its complexity. "Therefore, we know almost nothing about the female reproductive system, in comparison with, for example, what we know about cardiology or cancer," says Dr. Gutzeit.
To address some of these challenges, she has developed an organ-on-a-chip (OoC) model of the female reproductive system. This is a miniaturized biological model developed from stem cells - sometimes from a specific patient - that mimics the functioning of the vagina and cervix.
OoC technology has matured over the past decade. The chips are usually made of silicone or other polymers, on which are grown living cells that mimic the tissues of a particular organ. The chip contains microscopic channels through which fluids flow - artificial blood or nutrients - that simulate the physiological environment of the real organ. However, until now, such models of the female reproductive system have been lacking.
"When we connected between the cervix and the vagina, we discovered very significant tasks for communication between them," Gutzeit says. "Their microbiomes influence each other, and we discovered that the cervix is very important in treating recurrent infections."
These infections significantly impair quality of life for many women, and their recurrence is often impossible to prevent. "We discovered that the cervix responds to inflammation at the immune level and secretes proteins that play a part in the bacterial balance in the vagina, and when there is a disruption in this process, the chance of vaginitis is higher," she says. This discovery opens the door not only to diagnosing the problem, but also to developing a cure - the protein itself.
A new discovery: Sperm-killing bacteria
Beyond studying inflammation, Gutzeit is now applying her model to other areas. "A quarter of infertility cases are unexplained," she says. "You can do in vitro fertilization, but it's a very painful and dangerous process, full of side effects."
The chip she developed helps examine the link between bacteria and infertility. "My chips have a known and controlled hormonal environment, and I can ask questions about the interaction between bacteria at a certain stage of the cycle and sperm activity. This has been very difficult to test until now, because the entire female microbiome changes with menstruation," Gutzeit explains.
"And so, we identified that certain bacterial environments kill sperm or impair its activity. It binds less to the hyaluronic acid that helps it enter the egg, and on the other hand it undergoes more DNA fragmentation. And we saw that this is a completely reversible process. If we change the bacterial environment on the chip, the sperm can function successfully again."
And those proteins will be the treatment?
"That's one option, and another is to inseminate in a way that is protected from bacteria, bypassing them, or you can even prescribe antibiotics for that time."
Reimagining in-vitro fertilization
Another project Gutzeit is working on involves fertility preservation. Here, the hope is not just to research using the organelles she produces, but actually to implant them.
"When girls undergo treatments that damage fertility, especially chemotherapy, we preserve their ovarian tissue with the eggs. However, this achieves pregnancy in just 50% of women, and these girls will spend most of their lives having undergone menopause.
"I am currently working with a 3D tissue and organ engineering company to develop organelles that can be transplanted and these will serve as a replacement for the existing ovary, for hormone production and perhaps egg production as well."
The more far-reaching ideal, she says, is to make the in-vitro fertilization process easier. Today, women go through hormonal treatments to mature the eggs inside the ovary. After a few weeks of hormonal maturation, they undergo a surgical process to extract the eggs. "Shouldn’t it be possible to perform an ovarian biopsy and grow the eggs inside the tissue, outside the body?" asks Gutzeit. The process would still require a biopsy, but it would spare those women the difficult hormonal treatments.
From Harvard to Haifa during wartime
Gutzeit is in a unique position to translate research into a real solution. She is part of the Israeli Translational Research Network (ITRN) at Rambam Hospital, a program to train research physicians, in partnership with Yad Hanadiv (The Rothschild Foundation) and the 8400 Health Network. Gutzeit knows the problem, both from the laboratory and the chips she is developing, and from the patients she sees every day.
How she got to this point was anything but straightforward. After studying genetics at the University of Rochester, she wanted more, and went back to study medicine with a specialization in gynecology, while always continuing to conduct research. She specialized in fertility and IVF, and went on to a research internship at Harvard University. She says it was an eye-opening experience.
"At Harvard's Wyss Institute, I saw how to take scientific discoveries and make them really benefit the patient. The institute has startups in all sorts of areas, about 90 startups that they also support with business development. And they had many developments to do with all of the organs, but none to do with the female reproductive system."
You came back to Israel from Harvard towards the end of 2024. How was it to return?
"Harvard was great. They are rich in technologies and budgets. The feeling was that you could get a grant to make almost any dream come true. But in Israel - even though I went back to work as a fertility doctor and it's hard to find time for research, and the budgets are also lower - it's easier to create collaborations, and that compensates to some extent for the lack of funds. The feeling is that everyone's goal here is to really advance things.
"Even though I came back straight into a tough period of air raids in Haifa, I didn't feel worried for my personal safety. As for the more general concern about where this place is headed, it was no less strong when I was there than it is now that I’m here. It's easier being at home, even when the house is a mess."
Published by Globes, Israel business news - en.globes.co.il - on March 23, 2025.
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