With ambitions to become a surgeon, he eventually became a neuroendocrinologist, Dr István Merchenthaler, whose career took him from the Medical University of Pécs to the United States of America. We spoke to the University of Maryland professor about his time at POTE and his eventful career, as well as his research that could revolutionise the treatment of menopausal symptoms.
Written by Viktor Harta
- You attended the Medical University of Pécs between 1968 and 1974. How do you remember the POTE times of about half a century ago?
- They were amazing years, I loved being a medical student in Pécs. I attended almost every lecture, no matter when it started. Every moment you learned something new, the world opened up to you more and more. I had teachers of great influence and stature, who were a pleasure to listen to and encouraged you. They gave me a love of teaching as well as professional knowledge: in addition to research, I myself teach anatomy, histology and developmental biology to medical students, and I also teach a course on the ‘Biology of Aging’.
- Are there any teachers you particularly remember with fond memories?
- If I think of someone as the “number one” teacher during my years at the Medical University of Pécs, it is Professor György Romhányi. His personality, his lectures were amazingly good and exciting, we had first-rate classes with him. I would also like to mention, among many others, Professors Béla Flerkó, anatomist, and Szilárd Donhoffer, pathologist, who gave extremely good lectures. I attended their classes without exception.
- You had ambitions to become a surgeon, but then you specialised in neuroendocrinology.
- Yes, I originally wanted to be a surgeon. But as a medical student I was attracted to the Institute of Anatomy at POTE, where an excellent neuroendocrinology group operated. After the sophomore year, we had a year of quasi-technical work ahead of us, after which we could get into someone’s group to delve more seriously into science. I remember Professor Béla Flerkó choosing me along with another candidate to support the work of Professor István Rozsos. After learning the necessary microsurgical procedures, we operated on animals for almost two years in connection with Professor Rozsos’ research.
This work brought me together with neuroendocrinologists, and I kept telling myself that I would switch to a surgical career. I was transferred to another group led by Professor György Sétáló, who had just returned from Denver at the time. He dealt with immunocytochemistry in the USA, which was a very mystical and new thing at the time. I also delved into it, and together we focused on researching the neurons that play a role in regulating the pituitary gland. This is where my neuroendocrinological career began.
- Soon your career continued seven thousand kilometres away, in the United States of America. How did the change come about?
- In my life, the combination of the right time and the right place has been very decisive. I was invited to the Department of Cell Biology and Anatomy at the University of North Carolina at Chapel Hill, where I arrived in 1981. It was during this period that the corticotropin-releasing hormone and the so-called growth hormone-releasing hormone (GHRH) were discovered, and the developments had an impact on my work.
After the one year passed (the practice at the time was to spend that much time abroad), I asked for an extension and was given a second year. This allowed me to bring my family out. The second year went well, thanks in part to the discoveries mentioned above. In the meantime, I was invited to Tulane University in New Orleans, so I got a third year. We came home in the summer of 1984. I spent the period 1984-88 at the Institute of Anatomy at POTE, but I was allowed to go to the USA every summer for two or three months when I had no teaching duties.
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But in 1988 I was back in the USA, where I had the opportunity to do research at the National Institute of Environmental Health Sciences (NIEHS) in North Carolina. By then, my work was less descriptive. One of the main questions we were concerned with was the role of colocalization (when different neurotransmitters, neuropeptides, occur in the same neuron). This was a new thing at the time, with many people focusing on colocalization and its mechanism. I spent a lot of time on the colocalization and oestrogen dependence of luteinizing hormone-releasing hormone (LHRH) and galanin.
In the meantime, I invited a colleague of mine from Pécs, Zsolt Liposits from the Institute of Anatomy at POTE. Zsolt spent twice six months at the NIEHS. Our work together was so successful that the idea of setting up a small “Hungarian lab”, which Zsolt and I would run on a six-month rotation, came up.
The NIEHS was such a partner in this that they offered to donate their freshly replaced instruments to the Institute of Anatomy at the Medical University of Pécs in exchange for the cost of transport. But the response I got from home was more than surprising: they said “no, and you’re coming home”. I didn’t sleep for days, wondering what to do: stay or go home. After a few sleepless nights I decided to stay in the US, although I had never thought about it before.
- Such a decision could not have been easy to live with.
- It was not at all. All this happened in 1990, but even now there are many days when I say I regret it, and other days when I see it as the right decision.
I had a good position at the NIEHS, my boss liked me a lot and wanted to promote me to a permanent position. This happened in 1993-94. But during the application process, it turned out that there was a problem with my visa. I was on an H-1 visa, which did not qualify me for a permanent job in the US. Changing that is not easy, and one of the requirements was that I had to return home to Hungary for two years. Will I still have the job I applied for?
A few uncomfortable weeks followed, not knowing what to do. Then the ‘right place at the right time’ factor came to my rescue again: my boss was asked to set up a new institute in a pharmaceutical research institute. He asked me to go with him and I said yes. I was given the job of “Director” at the Women’s Health Research Institute (then part of Wyeth) and within months I had my green card, so my residency in the States was resolved.
The institute itself was fantastic, beautiful, ultra-modern, with amazing facilities. It was there that Premarin was developed to alleviate the symptoms of menopause, with huge benefits, but also the need to develop a hormone therapy that did not have the side effects of the oestrogens like in Premarin. Once again, a scientific breakthrough came at the right time: the beta-type oestrogenic receptor (ERβ) was discovered, and we immediately embarked on a very successful research project that would last for years. The central nervous system localisation of ERβ suggested that an ERβ-specific molecule could help avoid the side effects of oestrogen.
Things were going very well at the Institute - until 2002. That’s when a study of tens of thousands of women showed that oestrogen has many dangers, including an increased risk of uterine cancer, breast cancer and thrombosis. This has made doctors reluctant to prescribe Premarin and women reluctant to take it, even though they need it to treat menopausal symptoms such as hot flushes, mood swings and sleep problems.
It became a huge mess, with Wyeth suffering the consequences. It was clear to me that I had no future at Wyeth. After ten years there, I could retire. But during the retirement process, I contacted the University of Maryland, where I was offered a professorship. I accepted, and I am still here, as a professor in the Department of Epidemiology and Public Health and the Department of Anatomy and Neurobiology.
Perhaps a year ago, I was in my new position when, at a seminar, a colleague from Texas talked about so-called “non-feminizing” oestrogens: oestrogens that do not damage the uterus or the breast. During his presentation, he dropped the sentence that a Hungarian chemist had come to his lab and discovered a brain-specific oestrogen. This was huge news for me. When I was working at Wyeth, I kept saying that I wanted to find brain-specific oestrogen and I was convinced that this breakthrough could be made by chemists. Dream on, they said, it was simply impossible to do. Understandably, I was extremely excited by what I heard. I asked the name of the Hungarian chemist: László Prókai.
I went up to my office and immediately called my compatriot. When he answered the phone, I said, “Laci, I’m István Merchenthaler, I’m Hungarian too. And you won”. His discovery was extremely important: while studying the metabolism of oestrogen, he found a compound that is converted into oestrogen by a certain enzyme. Essentially, he found a pro-oestrogen molecule that the body (but only the brain) converts into oestrogen. The idea is that the female sex hormone can be delivered to the brain in such a way that it crosses the brain-blood barrier and is converted into oestrogen without damaging the periphery, where the conversion does not take place.
László and I started working together, with great enthusiasm, lots of experiments and valuable publications. For the last decade we have been working mainly on this molecule. The aim of our research is to use animal models to demonstrate that this pro-oestrogen can be used as a drug (oestrogen therapy) that is effective in treating menopausal depression, sleep disturbance, hot flushes, can slow or stop memory loss, and does not carry potential adverse side effects on the breast and uterus.
It seems to me that we, as fundamental researchers, are almost at the top. The remaining work is now drug development. If that happens, I really can retire (laughs.)
- You had a great career, one that spans continents. Are there any contacts left from your old student days in Pécs?
- When I first returned home from America, András Büki became one of my students (Prof. András Büki, currently Director of the Department of Neurosurgery at the University of Pécs Medical School). He is a very dear friend of mine and I am still in contact with him to this day. We stayed in touch for a long time with Zsolt Liposits, who was with me in the USA. With other old colleagues from Pécs we mostly exchange e-mails from time to time.
- How do you value the knowledge you acquired at the Medical University of Pécs?
- I think it’s very positive, the whole neuroendocrinological way of thinking was born at POTE, where I was influenced in such a way that I became a researcher rather than a practitioner. Also, the Institute of Anatomy in Pécs was a fantastic institution. It was family-like, we supported each other, we enjoyed being there, we got a lot of positive reinforcement. I will never forget Professor Flerkó, who would take time out of his busy schedule to come to me at seven in the evening and ask me, “well, Pistám, what have you been doing?”. He would literally look into my microscope and, seeing the slide, the staining, he would just say, “beautiful, fantastic”. What more does a young person need than encouragement?