Dr Ström, basic researchers often get accused of “using up resources” while not providing new solutions to global problems such as diseases. Is there a truth in that?
Knowledge about almost everything can be used at some point in the future. Historically, many discoveries of new treatment methods were a coincidence: a lot of them are based on research that initially was not planned to solve this question. We need the results from basic research to have a general, non-directive understanding of a topic. Then we are free to follow our new results in the direction they take us and create new hypotheses. This is important to try to understand the bigger picture.
Being a researcher can be a tough job with lots of drawbacks, disappointments and long hours of hard work. Many scientists take their motivation from the aim to help patients or create new technologies. What drives you as a basic researcher?
I am mainly driven by the urge to learn more or to understand what is going on. I don't go around all day and think of tumours or cancer. My focus is not on creating a new drug or a new treatment. But I want to know more about the mechanisms that underlie everything. On the first look that sounds egoistic. But if one thinks again, basic research is as important as drug development and everything else because we need to understand the bigger picture to develop new drugs and make them safe.
When you look at the small details, don't you sometimes lose track of the bigger picture?
That is possible, of course. Yet, there are researchers and scientists that do nothing else but looking at the bigger picture. They use results like the ones that we gathered, put them into big models and get new results. These results can then be put into even bigger models and allow us to look at the topic from above or with a little more distance. An example: Some scientists model cells and try to estimate what effect a new drug will have and what could go wrong. To do that they need data from basic research projects such as ours.
Do you do that, too?
No - this is a completely different field of research and very complex. You need to have specific competence for that. Usually, it's modellers, programmers, bioinformaticians and computer scientists that are doing these types of analysis. But we as basic researchers provide the data for these models with our research. Looking at it this way, even a small dedicated research group such as ours contributes to the common knowledge that is essential for scientific progress.
What is your field of basic research?
We focus on the cellular responses to DNA damage, with a bigger perspective on genome integrity as a whole. This means that we for example look at the biology of chromosomes. Chromosomes are basically the structures which DNA is being packed into. In preparation for each cell division it is then copied, in order for a new cell generation to keep the identical genetic set up as its predecessors. The structure of the chromosomes is also what makes it possible to segregate the genetic material properly during cell division. We want to know how chromosomes are separated and how they are repaired if damage occurred. Thereby, our focus lies on the intactness of the chromosomes and their inheritance to the next generation of cells.
What exactly is it that you are investigating in this field?
We in my group are, among other things, interested in the type of damage that causes double-strand breaks in DNA and how they get repaired. Double-strand breaks are very toxic lesions. They are difficult for the cell to repair correctly because there is no template left for the repair. In other cases of DNA damage the cell would just use the other (intact) strand to repair the damage. Sometimes, in the course of the repair process, pieces of DNA end up in a place where they don't belong.
Which toxic effects could a badly mended double-strand break have?
If, for example, a region that codes for a certain protein is moved from a region where it is expressed at low levels to a genetic environment where it is suddenly regulated differently, we might end up with high levels of this protein or vice versa. If specific genes called tumour suppressors are affected, this could be very dangerous and lead to the development of cancer. It can also be that you just lose parts a gene or bigger pieces of DNA and the cell becomes dysfunctional as a result. Hopefully, this cell will then die. If it goes on and divides, however, it could lead to tumour growth or the development of various diseases. If this happens in an egg or a sperm cell (or sometime during the embryonic development of an unborn baby), the baby could then be born with a genetic disease.
There surely must be something the cell does to prevent that from happening?
This is what we look at in particular: the function of the so-called SMC protein complexes - the “structural maintenance of chromosomes complexes” - and in particular one of them, called “cohesin”. Cohesin holds the the sister chromatids, the two identical parts a chromosome consists of, together. It also gets recruited to the area where a double-strand break occurred. There it helps in DNA repair. But it doesn't do this spontaneously. It needs yet another complex, a loading complex, which recruits cohesin and facilitates its binding to the chromatin. Exactly how that happens is not known in detail. Not yet!
How do you study the role of cohesion in DNA repair?
We usually compare cells where cohesin is functional and where it's not to tease out the consequences on DNA repair. We also look at the importance of chemical modifications of the protein, such as its regulation through addition of certain chemical groups like phosphor groups or acetylations. These modifications can affect the interaction of the protein with other proteins and maybe result in conformational changes. By inhibiting components of the DNA damage response system, we can also analyse whether those factors are important in recruitment of cohesin to the damaged region or not.
Are mutations in cohesion or its recruiting complex a strictly artificial thing?
Mutations in both, the protein loader and cohesin itself, do exist naturally. Such mutations have been found for example in patients with the Cornelia de Lange Syndrome.
Cornelia de Lange Syndrome?
It's a developmental syndrome with very distinct features and a large range of severity. Affected children are often smaller than usual and have developmental limitations. Many of their organs are affected by the disease and the patients can become really, really sick. One of the main problems is Gastro-oesophageal reflux. On top of that cells from these patients are DNA-damage sensitive, which is frequently connected to cancer development. However, for some reason the patients with Cornelia de Lange Syndrome are not more likely to get cancer than others – it is not known why. If we manage to understand why they aren't, we might be able to use this knowledge in cancer treatment.
That doesn't sound so much like basic research any more.
That's the beauty of it: At some point, basic research more or less always becomes applicable. Maybe one day medicine will be able to use this information to create new drugs that help target cancer cells, maybe something completely different will come out of it. Knowledge will always have a purpose.
Thank you for the interesting interview, Dr Ström.
This interview was conducted by Sonja Klein for AcademiaNet.