Thomas Carell talks to Kathleen Too about epigenetics, DNA lesions, repair and crystallisation
| Thomas Carell is a professor for organic chemistry at the Ludwig-Maximilians-University (LMU) in Munich, Germany. His research covers the synthesis of DNA hybrid materials and the study of DNA damage and repair. In 2008, he became an elected member of the Deutsche Akademie der Naturforscher Leopoldina which is the world's oldest continuously existing academy for medicine and natural sciences. |
Who or what inspired you to become a scientist?
In both biology and chemistry, I had superb teachers. Then during my studies I always had the privilege to work with very inspiring people, for example Heinz Staab, former head of the Max-Planck Society, and Burchard Franck, a very important natural products researcher at Münster University, Germany. Both were very fine personalities and inspirational to me.
What motivated you to work in the area of nucleic acids?
I started my independent career studying motor compounds for electron transfer studies. We connected electron donors and acceptors to nucleobases to study electron injections and electron abstractions and then we put these building blocks into DNA to study electron transfers through DNA. We decided that we were creating so many lesions that we should look at the lesion repair and lesion tolerance process. So it was a gradual move from physical organic chemistry into nucleic acid research.
How do you think nucleic acid chemistry will be able to solve the biggest challenges in biology?
I really believe that nucleic acid research is fundamentally important, simply because DNA is one of the most important molecules on earth. One can think about some kind of life without proteins but you can't think about life without DNA or RNA. Cancer and all these fundamental diseases have to do with DNA and failures in the information storage and transport system. So I think that with DNA and nucleic acids you work at the most fundamental level of chemistry.
So what sort of areas do you think nucleic acids will be able to help in?
First nucleic acid chemistry will help us to better understand life. How did it evolve and from where did we come? I also think it can contribute to finding treatments for diseases. I'm sure that nucleic chemistry will allow us to produce better drugs to fight cancer. Also, if we want to tackle the ageing problem we have to study nucleic acids. I also believe that if you look at the whole new field of RNA interference (RNAi), you will see that a lot of regulations in our cells, at the very fundamental level, are done by small RNAs. Also, if you look into epigenetics then you will discover that there is an information level beyond this sequence information, methylation information, which is very important for the functioning of cells. At the moment, I can see two very hot areas of research: RNAi is one (micro RNAs and small RNAs). The other one is epigenetics. Both areas are linked to nucleic acid chemistry.
Could you explain what you are working on at the moment?
We are working on the degradation processes of DNA. We know that the DNA double strand is a molecule which is not 100 per cent stable. It is degrading and strand breaks can occur causing the loss of nucleic acids and subsequently the loss of genetic information. Looking at the lengths of the molecules needed to encode the genetic information of a human being, it is very clear that we have to deal with 50-80000 lesions per day per cell. We are investigating what causes these lesions and how they can be repaired. The genetic information system is based on two things - one is the DNA molecule itself and the other one is the DNA repair system that keeps it working. The third question we ask is if these DNA lesions cause mutations, what type of mutations are formed in response to each lesion. I believe these are very fundamental problems.
So how are you doing this, how are you going to achieve it?
The strategy is very simple: we synthesise the lesion, put it into a small piece of DNA, add the DNA to a repair protein or polymerase to see how the lesion induces mutation and how it is repaired. We have a strategic advantage as our DNA synthesiser is heavily modified in order to do chemistry that is not possible with a normal DNA synthesiser.
How, in general, has crystallisation helped to speed up the understanding of biological processes?
I think that crystallisation itself is always complicated because it takes time in order to get the full story depending on how well the system crystallises. Very often you need years to obtain the results but new robotic systems have vastly speeded up the crystallisation process making life much easier. This automated high throughput crystallisation technique allows you to get crystals from each step.
How has the advent of new techniques in crystallisation helped?
We have seen a radical change. Today you don't make a single crystal structure as in the past, but a whole series of crystal structures showing the entire process at different stages and then at the end you get movies of the complete process of repair. You can now obtain intermediates of the repair process and see how the repaired DNA is released and so you can really make a movie of the cellular process that is going on. I think the ability to make this movie has changed the crystallographic world.
Which scientists do you most admire and why?
During my time at ETH Zurich, I had the privilege to meet Vladimir Prelog, winner of the 1975 Nobel Prize in Chemistry. Vladimir really impressed me as he had a sharp mind, a very good sense of humour and extremely high analytical skills. He always told me 'Thomas, don't fiddle along with small things, go with the most important question.' I must say that I am also impressed by my former advisor François Diederich. He is always so energetic, it is very difficult to stop him and I always feel that in comparison to him I am a lazy scientist. He is truly outstanding in his achievements; it is unbelievable.
What is the most rewarding thing about your career in chemistry?
For a German scientist, the most rewarding thing is to get the Gottfried Wilhem Leibniz Award, which we call the "German Nobel Prize". It is the most prestigious award you can get in Germany and it is extremely competitive. Each year about ten scientists will get this award, which includes all disciplines such as history, language, science, law and business. I received this award very early in my career, when I was 35, so I was one of the youngest Leibniz winners in Germany.
What is the trickiest problem you have had to overcome in your research and how did you solve it or get around it?
In my research there are problems at all stages. The synthesis of these fragile lesions is already tricky and then their incorporation into DNA using non-standard solid phase chemistry conditions is also very challenging. Another problem is that the proteins we are working with are very difficult to handle. These are repair proteins and some exist in only low copy numbers and so they are very difficult to express, particularly if you look at human repair proteins. There are almost no structural studies because of the difficulties in over-expressing the proteins. Therefore, at each step of the research, you have to overcome a challenge. But there is not one thing that is particularly difficult, it is difficult at every stage.
If you weren't a scientist what would you be?
I think I would like to be a medical doctor, a surgeon, because I could help people - that would be my motivation behind it.http://www.rsc.org/Publishing/Journals/cb/Volume/2009/3/Making_DNA_movies.asp
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