As is well known, in addition to the National Laboratory of Virology, the National Laboratory for Human Reproduction was opened at the University of Pécs last September to find answers to a significant global problem such as reproductive disorders through collaboration of national professional workshops. In Hungary, the number of married couples struggling with infertility problems reaches 15 percent, which means 150,000 couples. Innovative, integrated clinical research and development in human reproduction are essential to increase the effectiveness of successful infertility and assisted reproductive treatments and create demographic stability. We interviewed the head of the National Laboratory for Human Reproduction, Professor Emeritus Kovács, L. Gábor, about the achievements and further goals of the centre, which opened nearly a year ago.
Written by Rita Schweier
- Cooperation on the topic of infertility began almost ten years ago by bringing together several disciplines. What did your research focus on at the time?
- We have had a professional and friendly relationship with Professor József Bódis for many years. During a conversation, it emerged that research laboratory methods now allow much deeper examinations than those used by the clinic. It would be useful to benefit from them in the field of human reproduction. Initially, we won tenders for in vitro fertilization, namely the artificial insemination program, which is a narrower field and asked the simple question of whether modern molecular medicine, biology, endocrinology, and immunology testing methods could improve this rather frustrating success rate, which is artificial insemination, and which, even in a good lab, is only 30 to 32 percent. This rate may not seem scary because it is not very different from the possibilities of natural reproduction, but here the couples have many years of struggle in the background, which is important to consider. Any extracted change that positively modifies this percentage can already be encouraging, especially given the data that there are between 7 and 8 million people born in the world today by artificial insemination.
We have that many fellow human beings who were conceived outside of their mother’s womb, and this could not have happened if this method had not been developed forty years ago. In Europe, about 600,000 interventions are planned each year, thirty percent of which mean 200,000 new babies. These were the initial facts while we confronted the ethical implications of the issue. Biology and experimental medicine are technically more ahead today than what modern society ethically allows. To illustrate it with an example, boys and girls could be selected with one hundred percent certainty during in vitro fertilization, but this is prohibited.
Similarly, any intervention on embryos that would change anything on them is unacceptable. There are now state-of-the-art genetic methods that would allow us to take a single cell from the embryo consisting of a few hundred cells and draw conclusions from it, but Hungarian law only allows this if the suspicion of genetic diseases is very serious. Therefore, our examinations were performed without touching the embryo, and we analysed only the fluid environment around it. The embryo sits in a drop of fluid - about forty microliters - while it is being cultivated and when the obstetrician decides to select one of the available embryos and then implants it in the womb, this fluid is no longer needed because it does not carry life, so it is practically discarded. We asked for ethical permission to perform tests on this fluid regarding protein composition, genetic material, nucleic acids, and microRNAs. We have built a line of research for this, knowing that we are on a difficult path because we can only scrutinize the bathwater of the embryo.
In our previous tenders, we addressed the question of whether we can provide additional information beyond what the international protocol contains to the biologist who manages embryos in an in vitro fertilization laboratory. The point of the protocol is to look at the embryos under a microscope and have 6-8 properties - from size, shape to internal arrangement - to judge which embryo is the most promising, the most developed of them. However, only the 30-32 percent success mentioned earlier can be guaranteed with this procedure. So, it is far from certain that life will develop from embryos that seem to be good under the microscope and show signs of healthy reproduction. The main goal of our research was to find protein and genetic markers through which we can give another biochemical help to the obstetrician. Fortunately, we have discovered protein particles, the concentration of which is proportionate to the chance of survival. We hope that this will increase the success rate to 40-50 percent. We have published and patented our results and have European, American, and Australian patents.
However, we had to face great difficulty because of the inability to apply these methods in routine obstetric practice. Our measurements are made with a hypermodern, sensitive measurement procedure, mass spectrometry, but this equipment worth HUF 200 million cannot be placed in an obstetric flask laboratory. So, we had to find a solution that makes the work of the biologist easy. In this phase, which is very difficult, but at the same time a rich source of experience spiritually, we started cooperating with 77 Elektronika Kft., a double Hungarian Innovation Grand Prix-winner Budapest company, which currently employs 400-500 people, and its performance is world-class in certain diagnostic areas. Semmelweis University, the Institute of Materials Science of the Hungarian Academy of Sciences, and the Budapest University of Technology and Economics also joined the work, and we jointly developed a miniature chip diagnostic device, by which we can apply our methods in obstetric practice as well. Unfortunately, this process stopped due to the pandemic, the device has only now arrived, and currently, we are very far from its routine use. In the world of innovation, the process of the development and introduction of technology is characterized by a measure, the so-called TRL number (Technology Readiness Level). It contains a system of nine scales in which the basic tests give the first three scales, the 4-5-6 phases are experimental development, and we have now reached the sixth. It will take several more years before the device can be tested in various centres.
At this stage, we had the opportunity to establish a national laboratory, and thus we were able to place our research on an even broader basis. We are taking the issue of in vitro fertilization further, some of which are closer to the clinic and much more extensive. One issue, for example, is how hormonal imbalance affects fertility. Many people are unaware that correcting minimal abnormalities in thyroid function sometimes results in immediate pregnancy. We launched new studies on immunological abnormalities, led by Professors Júlia Szekeres and Tímea Berki, in which a working group of the University of Vienna joined. Together with them, we submitted an Austro-Hungarian OTKA application for the same field in both countries, complementing each other. The application is about the relationship between mothers suffering from immune system disorders and pregnancy. The Viennese also have a large, immunocompromised ambulance with which they are happy to join our national laboratory.
We have also included the male factor in our research, as half of the cases are due to men’s infertility. The Department of Urology, cooperating with basic researchers, is conducting research in entirely new areas in connection with this.
One of our very ambitious ideas is ovarian and, in the long run, uterine transplantation, which we are working on in collaboration with the Department of Obstetrics and Gynaecology. The program will start with the ovaries because it is easier to implement technically. With this, we would like to help young ladies who are diagnosed with a malignant tumour. They receive a radiation dose during their treatment that would never allow them to have a child, but their dream could come true with a restored ovary.
We also have an Erasmus+ application, which we submitted together with the University of Tîrgu Mureș and the University of Vienna. The application aims to provide human reproduction education at two levels, for medical students and obstetrician-gynaecologist candidates, in four languages, Hungarian, English, German and Romanian. We would do this along the lines of the idea of ‘new social challenges and reproduction,’ referring to minorities, those living in poverty, those with AIDS, or post-Covid mothers. For the time being, the application’s fate is still in question, but we hope it will succeed.
- The national laboratory operates only partially at the Szentágothai Research Center; how is it structured?
- The Szentágothai Research Center and the Department of Obstetrics and Gynaecology operate as intellectual centres; most research groups work on their premises. We have a core with whom we discuss problems and tasks every week, and we also hold online seminars every two weeks. Sixty-seventy of us participate in these on Fridays, which I consider a success. However, the impersonality of indirect information carriers is also a challenge for us. As for the future, we will continue in a mixed seminar system; we will have personal and online meetings as well.
- The HUF two and a half billion support received from the Hungarian state sounds like a huge amount for an outsider. What is behind the money?
- This is indeed a considerable amount, but it is important to consider the fact that 95 professionals are involved in the project, and we also need to fund the instruments from it. We need very well-conceived management, and there is also a lot of control over us. We must report quarterly to the High Authority on the status of the project. There is a professional jury with professor members and an application administration jury, the latter chaired by the Deputy Director-General of the National Research Office. An important aspect is how we manage to involve Ph.D. students in the work, how many dissertations will be written about this topic, and whether the topics we represent will also appear in a sufficient number in our doctoral schools. We are also expected to participate successfully in international applications, but we have not excelled sufficiently in them so far. Although we have won international applications, we have not achieved real breakthroughs in these; we will have to make progress in this area.
The novelty of the national laboratory system is that it is important to communicate our innovations towards the economic sphere as well, to generate collaborations, and although it is not easy to achieve it from Pécs, it is not impossible either. Currently, a very promising negotiation with an Israeli investment company is ahead of us, involving not only us but the entire university. This company is showing great interest in the field of medical diagnostics in our activities, and in the long run, it also includes the fact that we can put the diagnosis of sexually transmitted diseases on a new footing with them.
- How many faculties do the 95 professionals working on the project come from, and who are they?
- We work with the staff of the Medical School, the Clinical Center, the Faculty of Pharmacy, and the Faculty of Health Sciences, the former two giving 90 percent of the professionals. From the Faculty of Pharmacy, dr. Katalin Sipos and her team try to shed light on the susceptibility of the uterus; she performs measurements in connection with this; from the Faculty of Health Sciences, Professor Imre Boncz’s group assesses the social and economic burdens of fertility-related diseases. Our long-term plans include the establishment of a disease registry as well.
There is a core of young people - Ph.D. students, young researchers - who we employ for a fixed period in the project, and older colleagues who work part-time.
Dr. Kinga Hadzsiev and her team from the Department of Medical Genetics recently applied to join the 14th working group who have been using methods for decades that complement our areas perfectly, so we welcomed their initiative.
The working group of 15-20 people led by dr. Attila Gyenesei operates at the Szentágothai Research Center as the best-equipped genetic workshop in Hungary, where 2-3 people perform the mass spectrometric examinations for the obstetric project, and Professor Tamás Kőszegi and his team work here as well.
The focus is on genetic testing; there is no clinical issue that would not raise the importance of genetic background analyses. Unfortunately, there were cases when the obstetrician implanted the embryos they considered most beautiful, and then some of them aborted. It would be important for us to know which embryos have a higher chance of abortion before the implantation, whether certain genetic constellations suggest this.
In parallel, Dr. Kálmán Kovács and his obstetric colleagues are examining the capacity of the uterus. Today, genetic tests try to create mathematical regularities from the combined analysis of hundreds of genes to determine in which constellation there is a better or worse chance for embryos to survive.
- Does the research concentrate on three themes and periods? On the time interval before conception, on the conception itself, and the period after fertilization?
- Yes, because each has its own rules and problems. We can also call it pre-conceptual, conceptual, and post-conceptual topics and the same researchers are often involved in all three. Perhaps few people think of the third stage, the post-conception period many years after the conception. One working group, with paediatrician and obstetrician members, is looking at the long-term effects of artificial insemination. Do those conceived in vitro have the same life and disease chances? Studies have shown so far that, unfortunately, there are diseases that can cumulatively occur in them. These include male urinary tract obstruction or hip problems. This does not mean that they will indeed have such problems, just that certain rare diseases are more common in them. This working group wants to follow up on those born this way to the age of 18. Paediatricians are also taking on the big project that examines the relationship between nutrition and genes in terms of development.
- What could be the reason that certain diseases can occur cumulatively in those born with the help of artificial insemination?
- It is hard to say. The most trivial reason that may come to mind is that these mothers are no longer in their twenties. It is a known biological law that as women age, after the age of 30, the quality of ova deteriorates drastically, and after the age of 40, they are often unfit for reproduction. It may also play a role that there is a race between semen and the most viable one reaches the ovum during natural reproduction. In the artificial form, the obstetrician or urologist takes the semen they find beautiful and implants it in the ovum. There remain many questions, but the child is certainly a huge gift, even if in some cases, developmental disorders occur.
- We hear a lot about the drastic increase in the number of people who cannot have children naturally. Is this trend truly scary?
- The situation is no worse here than in any of the neighbouring countries, but if we look at it in historical time, it is depressing for men. In their twenties, the sperm count of men suitable for reproduction is drastically less than fifty or a hundred years ago. This includes many lifestyle factors: smoking, alcohol, drugs, wearing jeans, using the sauna every other day, and similar “sperm-frying” procedures.
Moreover, young married people today have a different way of life than earlier because they must create financial security before having a child. When they are willing to do so, the potential mother is usually past the age of thirty, and the potential father has a quarter as much semen as his own father had, which is an alarming sign. Although medicine is developing rapidly, our project is only a tiny link in the chain of the survival of the Hungarian people. To reverse the trend, young people need to feel the security that existential guarantee elements provide. So, we are facing a very complex social issue. In any case, it is encouraging that the number of live births is currently a bit more than a couple of years ago, and the tendency has reversed in the capital city.
- When can this very promising ovarian and uterine transplantation become a reality in Hungary?
- It will take many more years. Uterine transplantation has been performed in only 20-25 cases in the world so far. In Europe, there are experts at the Karolinska University in Sweden, and we plan to send a young colleague there. Organ transplantation is also a highly complex task when it comes to people’s own organs - say, the ovaries are removed before irradiation and then implanted elsewhere - and it is not merely a surgical task. A well-trained team of immunologists, a good clinic, and last but not least, the conditions for funding are needed. In the case of the uterus, the interventions performed so far are also promising, performed from relatives and deceased people. This may seem unthinkable for now, but liver or lung transplantations were also considered like that forty years ago, and kidney transplantation has become a routine that does not surprise anyone anymore.
- The HUF 2.5 billion state aid is provided until 2023. How do you see your longer-term operation?
- It also depends on how successful we are. I believe that innovation tenders will be published specifically for national laboratories as well.
Last year, 17 national laboratories were launched nationwide, four of them in the medical field: two in Pécs, one in Szeged, and one in Budapest. The others are already being prepared, and we will be involved in two or three of them: there will be a large national laboratory for pharmaceutical research in the capital, and a national laboratory for neuroscience research will be established in Pécs led by Professor Tamás Dóczi. This new kind of financing idea has stimulated us and accelerated the processes; I am confident that many of our ideas can come true.