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“We have underestimated the complexity of cancer.”

Anton Berns doesn’t sound like someone who is about to stop working. The 74 years old professor in Molecular Genetics talks with great enthusiasm about new technologies which, according to him, will drive the progress in cancer research the coming years.

Hidde Boersma

Anton Berns makes you feel that he will jump up and get back to work to implement those new techniques right away. Nonetheless, his retirement is looming: The synergy ERC grant that supported his research at the Netherlands Cancer Institute (NKI) the last 6 years ended in April, and he felt that this was the right moment to close his lab after stepping down as director of the institute 7 years earlier. Berns was involved in the setting up of Oncode as a founding scientist right from the start.

New people, with fresh ideas, have to step in. But, it is not easy to stop, there is always more to do. - Anton Berns

Are you nostalgic about retiring?

“Closing your lab is somewhat painful. I can still think of a couple of experiments to do, but there has to be a time where one should say: it’s enough. Getting a grant is harder nowadays then it used to be, and it also just doesn’t feel quite right that an old man with a long career continues to compete with young researchers for the small number of grants that are available. New people, with fresh ideas, have to step in. But, it is not easy to stop, there is always more to do.”

So, what are your plans?

“I will still be around at the NKI. At the moment I am working on setting up new European structures to channel more grants to cancer research, with the hope to improve chances for young researchers. I will also continue to work as a reviewer, both for Oncode proposals as for scientific journals. I am in the editorial board of PNAS and that alone takes quite a bit of time. But this is a way to remain connected.”

Anton Berns, Founding Scientist, Oncode Institute

One of my highlights was during my time as postdoc and young group leader where I contributed to the discovery of how retroviruses that integrate into the genomes of their hosts as part of their life cycle, can lead to cancer. - Anton Berns

Do you feel satisfied if you look back at your career?

“I’ve been lucky in my career, transitioning smoothly from PhD student, via postdoc to group leader, director of the NKI and subsequently the position I am in now. One of my highlights was during my time as postdoc and young group leader where I contributed to the discovery of how retroviruses that integrate into the genomes of their hosts as part of their life cycle, can lead to cancer. They do this by accidentally activating and thereby also “tagging” genes that upon overexpression cause cancer. Cells carrying the insertions that promote tumour growth are selected and these “tags” then often mark cancer causing genes.”

“This led to the identification of various new oncogenes. We then found out that specific combinations of oncogenes can have enormous synergistic effects. Often, the activation of one oncogene is hardly noticeable, but combined their effect turned out to be disastrous. Nowadays this is common knowledge, but back then it was quite revolutionary.”

A lot of your work consisted of developing new tools for research.

“Technology has always been driving cancer research. New technologies permit us to ask questions that could not be addressed before. Obviously, everybody jumps on the bandwagon of new technologies, and science progresses. Take single cell sequencing, which makes it possible for the first time to sequence the DNA or RNA of a specific cancer cell, instead of “the average” of a pool of cells. This is teaching us a great deal about tumour heterogeneity and how this influences the development of resistance to treatment, which would be impossible if the technology hadn’t been there.”

“Another example; in the eighties, a researcher in my lab found how to better exploit homologous recombination, then the technique of choice to introduce changes in the genome of animals, in our case in mice, for research purposes. At the time, it was really hard to generate so called knock-out mice in which a specific gene in the genome is inactivated in the germ line, this with the goal to assess its role in tumour formation. We discovered the importance of nearly complete homology of the DNA-sequence you use to introduce the sequence change with the target DNA. This has facilitated the experimental work of many of scientist in the field.”

Technology has always been driving cancer research. New technologies permit us to ask questions that could not be addressed before. - Anton Berns

Improving laboratory animals was also one of the focus points in your work. Why was this important?

“Laboratory animals are important to elucidate the mechanism of tumours formation, but making new strains was really hard and it would take more than a year before you could do any experimental work on those mice. Especially studying the effects of combinations of oncogenic lesions appeared difficult. With the advance of so called “conditional alleles” that permitted the generation of mouse strains without any phenotype until one would switch the conditional alleles on or off, permitted much more precise studies. We also succeeded in creating viruses which were able to activate oncogenes in specific cell types of the body, and only there, so to study the cell-of-origin of specific cancers.”

What did you find with this?

“My work over the last 15 years mainly dealt with lung cancer. There are several types. We discovered that certain cancer types are able to arise from almost every cell in the lung, but others can only originate from distinct cells. It really is the combination of mutation and tissue or cell type which defines which tumour is formed. This combination determines its aggressiveness, and also what might be the most promising treatment. The viruses we created to test this in lung cancer became very popular and are being used all over the world.”

Which technology do you think will have the biggest impact the coming years?

CRISPR/cas9 is such recent game-changer. This is a technique to alter DNA in a fast, easy and cheap manner. The opportunities it offers are astounding. Where before it took ages to make a new mouse strain with potential cancer inducing mutations, now they are ready in weeks. Even multiple mutations in one strain are a piece of cake. This makes it so much easier to generate new models and test new treatment paradigms. Other advances that will move the field are more analytical: following individual cells in vivo and defining gene mutations and RNA expression at the single cell level, with knowledge of the position of the cell and its neighbours.

In fact, we are fighting evolution, and through the years we’ve learned that evolution is a formidable enemy by the treatment of cancer. - Anton Berns

Does this mean we will finally be able to beat cancer?

“Time will tell. In the past we have repeatedly underestimated the complexity of cancer. Take the example of a specific mutation often found in melanoma that serves as a driver in tumour formation, and for which investigators have developed an excellent small molecule inhibitor. We had high expectations, and indeed the patients carrying this mutation in their melanoma responded remarkably. But the tumour came back in a matter of months and was now resistant to the drug. Quite disappointing.”

“In fact, we are fighting evolution, and through the years we’ve learned that evolution is a formidable enemy by the treatment of cancer. A lot of work now goes into combining several existing medicines, to beat evolution in its track, but this also turns out more difficult than we thought. There are so many variations to test: which doses do you prescribe, in which order do you give the different medicines, and how do you prevent severe side effects in the patients? It is a hard puzzle.”

Are you becoming pessimistic?

“No, we are making steady progress. Take for instance immunotherapy, a new treatment technology where we harness the body’s own immune system to combat a tumour. We see remarkable results in often a substantial fraction of the patients. Clearly, evolution has a harder time countering it, at least harder than when you give a patient chemotherapy. We want to know why and how we can exploit this. This might well be due to the so-called bystander effect, meaning that our immune cells kill tumour cells so effectively, that the few resistant cells cannot survive because their environment is killed off, before they form a new tumour. However, there are and likely will remain tumours that are simply hard to treat.”

You’ve never been someone who overestimates the power of science.

“I understand that, as a scientist, you are enthusiastic about your latest “breakthrough” and that you hope this might lead to the cure of some specific cancer and also that you want to communicate that to the general public. But one has to be cautious. Inflating results or doing wild predictions will diminish the trust in what we do. It also makes the work of doctors more difficult. They have to manage patient expectations every time a scientist publicly claims that his or her new finding will lead to a new spectacular cure. We ought to be nuanced, honest, and preferentially also modest.”

As you said, starting a science career is harder than it used to be. What would be your tip for starting PhDs or postdocs?

“Science has changed and how you approach it is also a matter of taste. I prefer hypothesis driven research: proving or falsifying a predefined biological concept. However, with the advent of new techniques which can spew enough data in one day to keep you busy for years, it is tempting to let data speak for themselves using intelligent algorithms to generate new hypothesis. Probably, a sound mixture of both makes sense. Still, I would advise students to keep generating their own “hypotheses” that they subsequently prove or falsify. That’s so much more fun.”

As a surprise, we asked two successful researchers that used to work in Anton’s lab about their experiences.

There are many things that come to mind when I think about Anton. To me he has been an inspiring mentor who has fostered and supported my career, and continues to do so. - Kate Sutherland, Laboratory Head

Peter W. Laird, Professor, Van Andel Research Institute, United States: “Ton’s fearless pursuit of big ideas using creative approaches and cutting-edge technologies were a major inspiration at a critical point in my career.”

Kate Sutherland, Laboratory Head - The Walter and Eliza Hall Institute, Australia: “There are many things that come to mind when I think about Anton. To me he has been an inspiring mentor who has fostered and supported my career, and continues to do so. In this fast evolving scientific world we find ourselves in, he has many refreshing attributes that I value and have tried to adopt in my research and scientific collaborations. The biggest one is that he is generous with his time and reagents. Most importantly, his knowledge is not surpassed by many others. He is a true visionary! My time in his lab (and Amsterdam) was life changing for me, and I cherish the opportunity I had to work together with him.”

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