?We must bet on people?: interview with Prof. Andrzej Dziembowski, 2018 Foundation for Polish Science Prize laureate

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?We must bet on people and their ideas,? says Prof. Andrzej Dziembowski, laureate of the 2018 Foundation for Polish Science Prize in the life and earth sciences. ?When we start new projects, I always seek out people with diverse research experience. In today?s times, research cannot be conducted at a high level without some type of interdisciplinary element.? Dziembowski was interviewed by Patrycja Dołowy, journalist and popularizer of science.

PATRYCJA DOŁOWY: We are here in the basement of the Institute of Biochemistry and Biophysics of the Polish Academy of Sciences in Warsaw, where the Laboratory of RNA Biology and Functional Genomics is located. It is here you conduct research projects of great importance not only for science, but also for medicine.

ANDRZEJ DZIEMBOWSKI: First I would like to stress that everything we have achieved in recent years we developed together as a team. Cooperation is vital. It?s never the case that a single person is responsible for a discovery. In the lab that I direct, I don?t just sit down, dream up issues, and assign tasks. My colleagues and I discuss the results we have found and decide together what is most interesting at the moment and what questions we want to pursue.

We succeeded in describing the molecular mechanism for operation of the exosome, an important protein complex constituting the ?command centre? for RNA metabolism. Mutations in one of the subunits of the exosome lead to the development of multiple myeloma, a cancer of the bone marrow. Thanks to this research, we could propose a new therapeutic approach to treatment of myeloma. But the medical application of the results of our experiments was not the aim, but rather a side effect. Here, as in several other instances, it simply turned out that the protein we were studying, the genes we were analyzing, have a connection with medicine?mutations in them cause disease. We were always interested in the fundamental questions concerning the molecular processes occurring in living organisms: how our genome is regulated, how gene expression occurs, how the stability of mRNA molecules where proteins are created is regulated, why some proteins are created and others not, how aberrant molecules are degraded. We are a team researching RNA metabolism. The exosome complex is the fundamental enzyme that degrades RNA in cells. It has been splendidly maintained through evolution, occurring in yeasts, in plants, and in humans.

Is RNA key to regulation of cells?

Cellular processes are regulated primarily by proteins. Proteins build our cells, create enzymes, regulate the shape of cells and their growth, and take part in practically every process. Proteins are coded in DNA, but the process of their expression is complicated. First we have DNA, where our genes coding for proteins are found. In the nucleus of the cell, DNA must be transcripted onto RNA, which in turn undergoes complicated processing and then is retransported to cytoplasm. In the cytoplasm, proteins form in ribosomes. Thus the level of molecules of mRNA?the matrix RNA in whose matrix proteins are created?is very strictly regulated. The level of mRNA determines how much of a given protein is created. Therefore the stability of mRNA molecules is key. For 17 years we have been trying to understand how the degradation of mRNA molecules is regulated, as well as other types of RNA being created. In recent years, thanks to a technological revolution, a breakthrough occurred in experimental biology. It turned out that in addition to proteins, our genome codes many RNA molecules that perform regulatory functions. Now we now that a process occurs in the cell known as ?pervasive transcription.? As a result of this, over half of our genome is transcripted onto RNA. In most cases these RNA molecules do not code proteins. Pervasive transcription means that a great deal of RNA is formed in the cell and must be quickly degraded. Our research issues concerned enzymes degrading RNA. The analysis led us to an understanding of how degradation occurs, what enzymes take part in it, and how they function. This brings us closer to an understanding of the mechanisms of cellular homeostasis?how it happens that many different processes are regulated in the cell simultaneously.

FNP Prize awarded to Prof. Andrzej Dziembowski by Prof. Maciej Żylicz and Prof. Lech Gradoń at the gala

What is the path from basic research to cancer therapy?

We were particularly interested in subunits of the exosome complex degrading RNA. In 2012, when great strides were made in the methodology for sequencing and all the possible mutations occurring in cancers began to be studied, it turned out that the gene coding the DIS3 protein, which is a nucleic subunit of the exosome complex, is mutated in about 10% of all cases of multiple myeloma. And these are very specific mutations. Such a protein containing mutations is partially dysfunctional. DIS3 is a big protein, with several different domains, and activity of both exonuclease and endonuclease, which means that it digests RNA internally. Mutations always halt exoribonucleasic activity but do not affect endonucleasic activity. We have various hypotheses concerning the role of these mutations in the development of multiple myeloma, and we conduct wide-ranging research, mainly on mouse models. Multiple myeloma is a very specific cancer, arising in mature B lymphocytes, the so-called plasma cells, which produce huge quantities of antibodies. The generation of antibodies specific to concrete antigens requires special processes. First there is a shuffling of the chunks of antibodies, followed by the process of maturation of B lymphocytes, hypermutation, and change in the classes of antibodies. This is a process during which mutations occur in the genome. In the case of myeloma cells, it appears that mutations don?t occur only in the location where they should for the antibodies to become more specific, but also in other places. This leads to rearrangement in the genome and over-expression of oncogenes, which in turn launches the pathogenic process. Mutations of DIS3 halt the exoribonucleasic activity. We showed that if we can halt the endonucleasic activity at the same time, all of the cancer cells will die. And because similar mutations occur only in myeloma cells (the exosome complex in healthy cells has both activities, exo- and endonucleasic), halting the endonucleolytic domain will be deadly only for cancer cells. In other cells, the enzyme will remain functional despite shutting off one of its activities. We have developed mice with a mutation halting the endonucleolytic activity of DIS3, for which we sought inhibitors. These mice are healthy. Thus it is an ideal therapeutic concept?a process called synthetic lethality: we kill cancer cells in targeted therapy which has no negative effect on normally functioning cells.

That sounds like a perfect therapy!

Also because the crystal structure of the exosome is known. If we want to seek new inhibitors in a deliberate manner, knowledge of this structure is vital. We know what the active centre of the enzyme is like and thus we can design new inhibitors. We conducted a research project in cooperation with a Polish firm that handles medical chemistry. Unfortunately we didn?t manage to locate good enough inhibitors. The ones we found were not specific enough. So we can?t say that our therapeutic concept has ?reached the clinic.? Nonetheless, it has huge potential.

So this is a path from basic research on yeast to work on possible applications in cancer therapy?

In our case it?s a fairly natural path. In the beginning we wanted to understand how fundamental processes connected with RNA metabolism occur, and yeasts offer an excellent, simple model. Then we began to study human cells in culture, and finally to work on myeloma. Now we often use genetically modified mice as a model. We use the CRISPR/Cas9 technology to develop mice with specific mutations. We have entered into cooperation with research teams involved in the search for new mutations in heritable diseases. We continue first and foremost to ask questions at the level of basic research, which sometimes can lead to discoveries from which new therapeutic approaches can be proposed.

How do you select your research objectives?

That is an excellent question. Certainly that is a lot of chance involved. Particularly at the beginning of your career, you don?t have too much influence over what you study. Later, the main reason for choosing certain research objectives or topics and not others is simply curiosity. The main driving force is what interests us, and newly acquired knowledge raises further questions. But there are many technical limitations that have to be taken into consideration when planning experiments. Certain things can?t be studied under our conditions. I should add, however, that it is getting easier and easier to do research in Poland. The percentage of GDP earmarked for science is still small, but on the other hand, funding can be raised through a very transparent grant system. In other countries is also not as easy as it might seem.

So how should good science be pursued under Polish conditions?

We must bet on people and their ideas. When we start new projects, I always seek out people with diverse research experience. In today?s times, research cannot be conducted at a high level without some type of interdisciplinary element. In my team cooperation with molecular biologists, bioinformatic specialists, and biochemists is essential. Moreover, in science there are lots of interesting questions, including those that everyone is asking. We try to avoid obvious questions, because quite frankly we could easily be overtaken. We also have to be rational. Among the questions that interest us, we must select those that we are actually in a position to answer at this time. I think that we can still ask lots of interesting questions that others are not asking, but I don?t think our discoveries so far are fundamental for molecular biology.

The Foundation for Polish Science disagrees with you on that.

I?ve discovered a few important things, but they are not discoveries altering the path of science, as was the case in last year?s prize for Prof. Andrzej Trautman for the first theoretical demonstration of gravitational waves, or the earlier prize for Prof. Andrzej Tarkowski, who was the first to develop mouse chimeras. Those experiments changed the course of biology and physics. We operate within quite narrow fields, asking quite specific questions. I remember the beginnings of modern molecular biology, what could be discovered in the 1980s and 1990s. That was a wonderful time. If you picked up Nature there was something important and interesting in every issue.

But can you still do groundbreaking things in science?

You can. There are several breakthroughs, such as the revolution in electron microscopy or CRISPR/Cas9. There are discoveries that will take science to the next level. In my case what?s probably most important is reaching an understanding of the mechanisms for the operation of the exosome complex, which we originally isolated for an entirely different purpose. This complex is the most important enzyme degrading RNA. That was the start of my research team after returning to Poland. We managed to publish a work on this topic in Nature. Later we became interested in catalytic subunits of the exosome in human cells. When the multiple myeloma genome was sequenced, apart from well-known oncogenes mutations were also identified in the gene coding a subunit of the exosome of DIS3. There were also frequent mutations in the FAM46C gene coding another protein with an entirely unknown function. We examined this family of proteins and it turned out that they are poly(A) polymerases, i.e. enzymes attaching chains of adenosines to one end of the RNA thread, the so-called poly(A) tail. MRNA molecules have regulated stability, and contain certain specific structures on the ends protecting them against degradation. A ?cap? is attached to one end and on the other end the poly(A) tail. FAM46C stabilizes mRNA coding proteins excreted from the cell, such as antibodies, huge quantities of which are produced by myeloma cells. In vertebrates, the FAM46 family has four genes, and not much is known about their function. Thank to the CRISPR/Cas9 technology we obtained mice lacking these genes (known as ?knockout mice?). It?s fascinating that we obtained a large number of interesting phenotypes (sets of characteristics that can be measured or observed), which demonstrates that in cells the activity of these proteins regulates such diverse processes as the release of hormones in the pituitary gland, changes in the mice?s behaviour, and gametogenesis. But the road from identification of a phenotype to understanding ?how it works? will take years. Certainly it?s important.

Prof. Andrzej Dziembowski with his colleagues

You said that technology pushed biology ahead strongly in 2012. I also have the impression that a lot changed. Today you can answer questions that you could raise before but didn?t have the tools to analyze.

Certainly we are at a stage of absolute, unheard-of technological capabilities. Molecular biology is one of the fastest-growing fields. We are still studying RNA metabolism, but we are modifying the research models because we are interested in new things. In our team we often use expensive, specialized apparatus, but typically the experiments consist of transferring small quantities from one test tube to another. Today, for example, thanks to technology we can examine all the RNA molecules in a cell. We are creating a library of RNA and sequencing the total RNA in a cell where we have manipulated something, e.g. creating mice with a specific mutation, isolating tissues or cells and checking what has changed in them. Often we launch projects because for example we see that there?s an interesting protein. When we observe a phenotype, we try to understand its connection with the function of the mutated gene. In a certain sense there?s a lot of chance in this instance, because it?s an experimental field. There have been times when something seemed unusually promising, and we created a mutation in the cells, but nothing happened. The opposite has also happened.

What?s your recipe for good science?

I believe that ideas come from knowledge, and more precisely from looking for gaps in knowledge. To find a gap, you have to know a lot. Contemporary biology in particular is such a field. If someone tells me that biology should be studied only using sources, I completely disagree with that. Without knowledge and an analytical approach, there is no basis for thinking up new projects in our field, with its degree of advancement. Of course, some discoveries are accidental, but if you want to begin a project based on an idea, such ideas aren?t born in a vacuum. To notice something in the results, you have to understand many diverse things. On the other hand, the more you know, the more reasons you can find not to study something?that is inhibiting. When you enter a new field, sometimes you have wild ideas that contribute a lot. But even such wild ideas require foundations.

I always loved learning. I became interested in molecular biology at the beginning of secondary school. One of the most important books I ever read was Molecular Biology of the Cell. In the third year of high school, without knowing English well, I sat down with a dictionary and read. That was absolutely fascinating for me. First I became interested in fruit flies, and more specifically the genes that regulate their development. My first professor, Piotr Stępień, had a great influence on me, as did, later, the adviser for my postdoctoral fellowship, Prof. Bertrand Séraphin.

I should point out a few things. In the experimental sciences we generate results, and you have to puzzle over what they might mean. Biology is a field full of artefacts, spurious elements in the research results. You can?t just accept knowledge as it is served up.

Is that a problem with our educational system? 

I?m very critical of the system. In Poland education is mainly made up of delivering knowledge, not showing the path to finding it. We must understand where knowledge has come from. In our education, even at the university level, we are not taught the path to knowledge. But we must master not only how something is constructed, but also how we arrived at that. Only then can we be certain that we haven?t overlooked something, or to the contrary, that there?s something else to examine. According to the Polish educational system, knowledge is given. But that is false. That way we begin to treat knowledge dogmatically. In science you really need to do a lot of work, and you have to like doing experiments. If someone doesn?t like to spend time for example on pipetting, they will not succeed, because it is an experimental field. You have to have a talent for it. This doesn?t just mean a manual talent, but the skill of long-term concentration. Most failures in experiments can be traced to small errors, which occur when we lose our concentration. On top of that, planning and appropriate selection of controls is essential, as without that the experiment will not be informative. It is also necessary to consider potential artefacts because one of them could set you back a couple of years. And you need luck. Sometimes wonderful ideas don?t work out. Someone spends five years on a project that leads to nothing. Then it?s hard to turn back. It?s unfortunate, but in science, time counts. If something is not published at the right time, career paths may be foreclosed.

Science isn?t easy. It requires determination. You can?t get depressed or discouraged. Personally I was lucky not to have any spectacular failures. That?s probably why I managed to establish my own research team fairly early.

So you have to have enthusiasm but also humility, because what you discover may be an artefact. How to find the golden mean?

You must remember that a great many results we obtain are not proof but correlations. You have to design further experiments, pose questions. We live in a time when they say, ?A lot of data, not so many ideas.? That is a question of intuition. But we have numerous possibilities.

When I talk to older scientists, they always say how they had to deal with difficult times, for example in the communist era. They ordered test tubes which had to cross the seas. Sometimes they were lost. To read an original article you also had to wait months for someone to deliver it.

I didn?t have such difficulties. Today the boundaries are set more by intellectual possibilities. It?s important that we have expertise, that we know how to do something. It?s a good time for science. And we can finally appreciate the difficulty of experimental work itself. It seems to me that what we are doing has some purpose. That people working in science can discover something?sometimes smaller, sometimes bigger. For me the wonderful thing is that a team of people can do something interesting together.

Why did you want to pursue research in Poland?

Doing good science here is truly important. What we do affects our reality, and thus the impulse is patriotic. I enjoy seeing the success of my colleagues who leave to form their own research teams. That is so important. The very aspect of creating science is more important to me than what we discover.

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Photo of Prof. Andrzej Dziembowski by OneHD / Photos from award ceremony by Paweł Kula