(Vienna, 07.09.2020) Prof. Heinrich Kovar PhD, heads the Molecular Biology of Solid Tumors group at St. Anna Children's Cancer Research Institute. He was one of the Institute’s founders and its scientific director for 17 years. The molecular biologist provided essential knowledge for a better understanding of Ewing sarcoma, an aggressive bone tumor in adolescents. On the occasion of the Childhood Cancer Awareness Month, Kovar talks about how his life as a researcher was shaped by jumping in at the deep end, but also by coincidence, and what motivates him to face the challenges of Ewing sarcoma research again and again.
What are your current research questions?
In everything we do, we always focus on the following questions: Why does Ewing sarcoma develop? How does metastasis occur and why does resistance to therapy develop? Foremost: Can we use our research findings to develop new therapies?
Above all, we want to develop therapies that prevent metastasis. Once the tumor has metastasized, the chance of survival is 20 to 30 percent at most.
Which approaches are you pursuing to solve these problems?
We must succeed in preventing the cells from migrating out of the primary tumor and spreading through the blood all over the body. We are currently working on a study with a drug that could prevent migration. However, many questions remain unanswered.
We are also investigating how the tumor cell responds to stress. As soon as it leaves the primary tumor and migrates into the blood vessel, it is exposed to different forms of stress. Stress responses are acutely activated as a reaction to the environment, and this cannot be explained by mutations. We are investigating the acute stress responses at protein level, which have received far too little attention so far.
What makes it so difficult to investigate and treat cancer?
Cancer cells originate from normal cells in which then certain mechanisms are activated and different mutations start to interact. We are particularly interested in their plasticity, i.e. their mutability. For example, the cancer cell changes from a state in which it multiplies strongly to a state of migration in which it journeys to settle in other tissues. If one pathway in the development of the cancer cell does not work, another one is taken. This is why resistance to therapies emerges.
Another open question is the origin of Ewing sarcoma. Many of the tumor's peculiarities do not come from mutations, but are characteristics of the original tissue. There is probably a connection between tumor pathogenesis and hormonal development or growth. Most Ewing sarcoma develop in adolescence and usually remain undetected for the first one to two years.
Why did you choose to become a scientist?
In my family there were several natural scientists, physicians and philosophers. I was also extremely curious and very interested in nature and animals. One of the people who were particularly formative for my development was a professor at university, with whom I had to do an oral examination. He had examined me for two hours. I was well prepared, was able to answer almost everything, until at some point the sweat stood on my forehead and I couldn´t answer his question anymore. His intention was to show me: You might know a lot, but you will never know everything.
Another professor had impressed me very much with his lecture on molecular biology of protein biosynthesis. I understood very little of what he was saying, not least because he was always snuffy. But he presented his topic with a fascination and enthusiasm that was absolutely thrilling. Later I learned that he had a chronic cold because he was working with rhinoviruses in the lab and was therefore repeatedly infected.
And that's when you became fascinated by molecular biology?
Yes, I wanted to do that. So I completely left my original field of study, zoology/chemistry, and started my dissertation at the Institute of Molecular Biology. However, that was not an easy time. I was left on my own and today's technical possibilities were not available back then. When I was working as an assistant professor at the Institute of Molecular Biology at the Medical University of Vienna and had already completed training in medical biochemistry, I started to ask myself the question of meaning. I had studied something intellectually challenging, but it was not so easy to apply. Then I learned by chance that a research laboratory was to be built at St. Anna Children's Cancer Hospital. In general, my scientific career was very much determined by coincidence.
How did it go on?
I asked myself whether I should give up the secure assistant job. On my father's advice, I went to a pediatrician in Vienna who was very well known at the time and who held Prof. Gadner, the former director of St. Anna Children's Hospital, in high esteem and advised me to jump in at the deep end.
Sabine Strehl, Peter Ambros and his later wife Inge Ambros worked at the institute at that time. They were all cytogeneticists who thought it would be wise to bring in molecular biology. Prof. Gadner agreed.
You spoke of coincidences...
... yes, through a series of coincidences we were able to intensively investigate Ewing sarcoma at a very early stage. Peter Ambros had confirmed that all Ewing sarcomas have a certain chromosomal rearrangement in common that is relevant for diagnostics. At the same time, an orthopedic surgeon isolated an antibody against Ewing sarcoma at the Institute of Experimental Pathology at Vienna General Hospital. The pathologist Inge Ambros discovered that the antibody is specific for Ewing sarcoma and must have something to do with the chromosomal rearrangement. We did intensive research and found that the antigens matching the antibody were also present on healthy cells. However, a particularly high expression of the antigen is found in Ewing sarcoma and is still considered an important immunological marker.
In order to find out which antigen, i.e. signal on the tumor cells, the antibody recognizes, I developed the first complementary (c)DNA library at that time and thus recognized the antigen. At about the same time, a colleague from France isolated the fusion point where two genes of Ewing sarcoma fuse. However, he did not know which genes fused. With the help of my cDNA library, he could screen the DNA fragments and use them to characterize the two genes. On this basis, we were able to do early functional studies and see what this fusion gene does. This is what we are still working on today.
What motivates you to investigate this tumor so intensively and since such a long period of time?
My brother fell ill with Ewing sarcoma as an adult and eventually died of it. This experience motivates me every day. In the metastatic stage, it is difficult to stop the tumor. My goal is therefore to find new forms of therapy. This is why I am a great advocate of basic research. It is, what enables true innovation.
Where do you see particular challenges in childhood cancer research?
Our times are very fast-moving, we are under great pressure to achieve demonstrable results quickly. As a result, complex problems, the solution of which would require more effort, time and money, may fall by the wayside.
Another challenge is that you can't just revolve around yourself, you have to be strongly connected. It has always been very important to me to raise people´s interest in questions of childhood cancer research who come from a completely different field and can contribute their way of thinking. Our group provides valuable pieces of the mosaic. However, one piece of the mosaic does not heal patients. Only in the context of many other mosaic pieces, often coming from researchers of different disciplines and nations, real breakthroughs become possible.
What does it take to be successful in science?
I see science very closely related to art: creative people are needed. If you tell scientists too much what to do, creativity might be lost. This is certainly controversial to discuss, but in my view, too much bureaucracy also poses a danger.
Are there times when you switch off and don’t think about your research at all?
Switching off is difficult. Sometimes it would be pleasant, but I am occupied with my projects all the time.
All further researcher portraits will be published online during the childhood cancer awareness month of September on our websites:
Professor Heinrich Kovar, PhD
Prof. Dr. Heinrich Kovar has been head of the Molecular Biology of Solid Tumors group of St. Anna Children's Cancer Research since 1988. From 2001 to 2017 he was the scientific director of the research institute. The molecular biologist was previously an assistant professor at the Institute of Molecular Biology at the Medical University of Vienna.
Kovar has received numerous awards for his research, including the Grand Middle European Prize for Interdisciplinary Cancer Research, the Science Award of the Austrian Pediatric Society and the Nöllenburg Prize for bone tumor research. In order to present his work, Kovar has been invited to speak at numerous international scientific symposia, including the Bone Cancer Research Trust, the International Academy of Pathology and the American Association for Cancer Research. Furthermore, the researcher has received a number of highly endowed research grants and is a scientific advisor to renowned international research institutions and programs, including the Interdisciplinary Cancer Research Institute in Lille, the Children's Cancer Research Center in Hamburg, and the Ewing Sarcoma Research Program at UTSW in Houston. In addition, Kovar is a reviewer for renowned scientific journals such as Nature, Cancer Cell and Cancer Research.
Ewing sarcoma is a very aggressive bone tumor that occurs mainly in children and adolescents. The long-term survival rate is only 50 to 80 percent. The goal of the scientists at St. Anna Children's Cancer Research is to cure significantly more patients affected in the long term. Current chemotherapies have considerable side effects that impair the quality of life in the long term. Nevertheless, they unfortunately do not help all patients by a long way.
Various approaches are being pursued to better understand the development of this tumor and to develop new therapies based on this knowledge.