Playing chess against an invisible enemy - Joining forces against neuroblastoma

As an Einstein BIH Visiting Fellow, Prof. Versteeg regularly travels to Berlin from his lab in Amsterdam to work together with Prof. Eggert and her team at the Charité Clinic for Pediatric Oncology and Hematology. Joining forces in this special bilateral collaboration, they are taking the fight against neuroblastoma, the third most-common cancer in children, to the next level. We had the pleasure to meet them during Prof. Versteeg’s first stay in Berlin talking about the beginning of a 20-year friendship, their dedication for neuroblastoma cure, and personal motivation.

 

Prof. Versteeg, you and Prof. Eggert [she will join us shortly] have been working on neuroblastoma for many years. Now the two of you are working together in Berlin. When and how did you actually meet?

Versteeg: We met more than 20 years ago at a big international meeting of neuroblastoma researchers in Philadelphia, USA. I did not know Angelika back then. I heard her giving fantastic presentations but it was not until later after the conference that we actually talked to each other. I was sitting on the plane back home to Amsterdam from this exact conference. We were about to take off and I was very happy about the fact, that the only free seat left on the plane was the one next to me, and that I would have a little more space for myself. He smiles. Suddenly, on the very last minute, the door opened again and a woman came in. It was Angelika and – she was taking the place next to me. We started to talk, she was extremely nice, and we immediately became good friends. In the end, even with less space for myself than I hoped, I enjoyed that 12-hour flight very much. He laughs.

Angelika Eggert enters the room.

Versteeg: Angelika, I just told how we met on that plane.

Both laugh.

Versteeg: We have been collaborating very intensively for many many years.

Eggert: Almost 20 years.

Versteeg: 20 years ago, it was extremely difficult to understand this tumor. We were not studying a mouse model of a disease or a simple selected issue like the cell cycle or some other molecular principle. No, we simply did not understand the disease. Since we could get no grip on neuroblastoma, we were forced to do the most advanced research. The Human Genome project started at the end of the 90s, many new technologies became available, and we were one of the first to learn them, to use them, and to apply them on our patient material. We were one of the first to sequence the entire genome of a huge series of neuroblastomas and comparing the primary tumors and the relapses. Each time we were bringing these new technologies to this terrible disease. However, each time it was also extremely disappointing, because you had billions of data, fantastic bioinformatics, and still we could not understand neuroblastoma.

Playing chess against an invisible enemy - Joining forces against neuroblastoma
Prof. Dr. Rogier Versteeg

Funding program

Einstein BIH Visiting Fellows

Funding period

2020 – 2022

Project title

Targeting plasticity in neuroblastoma: Prevention of lethal relapses in cancer by pattern analysis of cancer cell heterogeneity and application of combination therapy

Research area

Hematology, oncology

Institution

Charité – Universitätsmedizin Berlin

 

Since 2004

Professor in Genetics at the University of Amsterdam, The Netherlands

Since 2003

Head of the Department of Oncogenomics at Amsterdam University Medical Center (AMC), The Netherlands

2001 – 2002

Visiting Scholar at Max Planck Institute for Molecular Genetics, Berlin, Germany

1990 - 2002

Research Group Leader at the Department of Human Genetics, Academic Medical Center (AMC), Amsterdam, The Netherlands

Where do you stand today in understanding neuroblastoma?

Eggert: Rogier was the first in the neuroblastoma field to discover cancer cell plasticity as an interesting feature and he started to study it in neuroblastoma. I realized that this really is a fascinating field, which has the potential to contribute a lot to our understanding of neuroblastoma. Berlin is lacking this expertise in both pediatric and adult oncology. With Rogier coming to Berlin as an Einstein BIH Visiting Fellow, we can learn from his expertise, exchange our ideas on how to proceed with the research, and how to transfer the findings into the clinical arena as fast as possible. It is always beneficial when expertise on the experimental side and clinical expertise are teaming up. This is the most interesting field right now in neuroblastoma research - we have to address it together.

Versteeg: It was about six years ago, that we discovered, that there are in fact two different cell types in neuroblastoma. Previously only one cell type was recognized, and all the drugs were tested only on that one cell type, and not on the other one. Then we discovered that both tumor cell types could simply switch into one another phenotypically. We had to find drugs for that other cell type. In Amsterdam, we know a lot about the fundamental biology of these cells and we are working with new drugs that do indeed kill these other cells. Now, we have to bring this completely new insight - which really is a game changer in oncology - to the clinic. To develop a new treatment and translate it to the clinic is a very complicated thing to do. This is where Angelika and I meet again. Angelika has a fantastic infrastructure in the lab, and we have been discussing a very complex translational program to bring this new approach, that could help to cure neuroblastoma patients, to the clinic within the next four years.

What was your first touch point with the disease and what made you decide to focus your research on that specific disease?

Versteeg: I started as a molecular researcher. As a young researcher, I was bringing neuroblastoma tumor cells into culture and first, all you see are nasty aggressive cells that had just killed a patient, and you hate these cells. Then, in the days after, they start to grow in the culture, and a sort of metamorphosis is happening. These cells start to look beautiful through the microscope. It is a world by itself, very quiet, and you start to love these cells. It takes a week to make that switch and it is typical for what is going on when you work in a laboratory. These analyses of DNA and RNA, the billions of data points – you are playing chess against an enemy that is invisible and is beautiful at the same time. For me, it is very important to be in the clinic very often and to see the patients. They inspire me. I just made a tour here in the clinic and it was so good to see the faces of the little children. Then I know why I have been doing this chess game for so long – 25 years of total abstraction – and it helps me to keep going towards this end game of a new drug treatment.

Eggert: The story how I came to neuroblastoma was a little different. I have always wanted to become a pediatrician. With my experience from the MD thesis in molecular biology, though, I wanted to continue some experimental work. My clinical mentor at the University of Essen invited me to join an international neuroblastoma meeting in Heidelberg. This was the first time I heard Rogier speaking. He gave an exciting lecture and the whole meeting was very inspiring. Later, in the coffee break my mentor suggested to a famous neuroblastoma researcher from Philadelphia that I would like to do a post-doc in his lab for two years. We had never discussed it before. This was literally coming up in the coffee break, while I was standing there. The American, Garrett Brodeur1, said: “Oh yes, we have a new lab building and a lot of space. If you bring your own scholarship, you're very welcome and we will fund the projects”. This sounded way too easy. I really got a scholarship from the German Cancer Aid (Deutsche Krebshilfe). However, I was still heavily hesitating, because I never really thought that this was my career way. I was not sure if this was not too much research for me personally. Finally, I chose to go to Philadelphia. From the first day on, Philadelphia was a fantastic research environment and I enjoyed it so much that after three years, I wasn't sure if I wanted to return to Germany. But staying there would have meant leaving clinical work. This was difficult for me to imagine, and I decided to come back to combine clinical work and research.

Prof. Versteeg, you are now visiting Berlin regularly as an Einstein BIH Visiting Fellow to collaborate with Prof. Eggert. How usual or unusual is this kind of collaboration in your field?

Eggert: Such a strong bilateral cooperation is unique, but in general, I would say, the pediatric oncology community really likes to collaborate.

Versteeg: Research has become highly technology-driven. If you study one tumor, as we do with neuroblastoma, you have to tackle it with every new technology. For this, you need large collaborative groups. Bringing together all this knowledge and technology of two large groups is very challenging, also socially. Not only the group leader is coming to Berlin, but there are 20 people in Amsterdam doing a lot of research, whom you also want to integrate. In Amsterdam and in Berlin, you have the bioinformatics as an integrating parapluie. However, we are not working completely integrated yet, especially when it comes to data.

Eggert: We are planning to build a molecular database that is hosting not only all the data obtained by this consortium but also other published data to be able to do metaanalysis and to compare it. Rogier's group has an amazing database established in Amsterdam. We might either use this database or connect to it to make it usable and available to the European research community as an Open Access tool.

You both work in the highly challenging field of pediatric oncology. What is your personal day-to-day motivation?

Eggert: The origin of my motivation is the clinical work – seeing the patients suffer from this disease and not being able to help them all, just half of them. This carries my motivation to go to the lab and look for new solutions to the problem. It also helps me to balance, because you have times in the clinic, where nothing works and patients you know for a long time and feel attached to are not doing well or even die. At the same time, some hypotheses might work in the lab. This way, you can balance the frustration on the clinical side with success in the lab, and vice versa.

Versteeg: I am wondering whether I shall give you my little secret motivation. It’s referring to my interest in the relationship between individual freedom and societal control. Cancer is coming from a few cells in a huge body where billions of cells are exactly controlled and do exactly what they have to do, even to a level that cells commit suicide when they have to do it. There are also human societies where people commit suicide when they are told to. I want to understand, how cancer cells escape from the control of their surrounding body. They become somehow anarchist. Cancer is often viewed as a chaotic disease, as a disease where something is wrong with the DNA. You treat a tumor with a drug, e.g. chemotherapy, but while you are doing it, the tumor cells mutate further and can find the mutation that gives resistance to the drug. Whatever you do as clinician, the tumor cell always runs ahead of you, and you might lose. What we found in Amsterdam, is that it is probably not chaotic cancer, but, on the contrary, very much controlled. The cell does not mutate further and further. There are only these two tumor cells mentioned earlier. Maybe there are only a few tumor cell possibilities for the cancer – which is great news, if it’s true. We would only have to kill the few possibilities and not this enormous potential of chaos, which you will lose by definition. Now you have my philosophy in a nutshell. He smiles.

The dedication for neuroblastoma is what both of your professional paths have in common. What has been the best career advice given to you?

Eggert: The best career advice was given to me by my clinical mentor who always told me to take the luxury of an own opinion and to stick to it no matter what the consequences are. Sometimes that's difficult, but I try to follow it.

Versteeg: I have always been very stubborn. I got many problems because of that, but it also gave me fantastic research. Both laugh.

What advice would you give younger people?

Versteeg: Follow your fascination. Go for a dream.

Eggert: Yes, follow your interest. If you don’t know where your interests lie, expose yourself to different research environments and different interdisciplinary settings to find out. We put so much of our free time into what we do professionally. If you don't like it, if you are not fascinated by it...

Versteeg: ...it makes no sense.

Eggert: If you do it just as a career opportunity or for money, or because you think you have to do it…

Versteeg: … it's boring. The only way to feel the excitement, to do really groundbreaking research is to do it 24h a day. It's killing, but...

Both smile.

 

We closed the interview with a final question game and asked them to choose one to three persons, alive or dead, to have an imaginary dinner with. Here is what they answered:

Eggert:

  • - Rudolph Virchow
  • - Audrey Evans, the grande dame of neuroblastoma. Check out this video for her 90th birthday.
  • - Leonardo da Vinci, because he was a an exceptional creative mind thinking so much out of the box, that for some of his inventions, the world wasn't even ready

 

Versteeg:

  • - Rita Levi-Montalcini, Nobel Prize winner and one of the first to recognize very important events in neuronal development. In her memoirs, she describes looking through the microscope and all of sudden, she sees in embryos that thousands of cells die in a programmed way.
  • - Giacomo Casanova, because he is a very interesting person, knowing the underside of society while trying to climb the ladder at the courts. He travels through Europe in the 18th century and through his memoirs, you learn about the culture of Europe from a unique perspective.

 

1 Garrett M. Brodeur, MD, is the Director of the Cancer Predisposition Program at Children’s Hospital of Philadelphia CHOP and Associate Director of the Abramson Cancer Center at University of Pennsylvania. He is one of the most renowned experts in the field of molecular biology, genetics, and targeted therapy of neuroblastoma.

November 2019 / Marie Hoffmann