labor&more in interview with prize-winning scientist Dr. Ben Lehner

‘Luckily, Individuals Turn out to Be Different.’

Why are individuals different? Why do the same mutations in the genome have different effects on different individuals? Why does one twin get sick when another does not? How do sicknesses come about through the combination of different mutations? These are the questions which British scientist Dr Ben Lehner – ICREA Research Professor, EMBL-CRG ­Systems Biology Unit, at the Centre de Regulació Genòmica (CRG) in Barcelona – investigates in his research. In recognition­ of his trailblazing discoveries he received the Eppendorf Award for Young European Investigators 2013. The prize has ­been presented by Eppendorf since 1995 in partnership with the scientific journal Nature, and is awarded for outstanding research work in the biomedical sector.

C. elegans – with its deceptively simple struc- ture, the nematode shows surprisingly wide phenotypic variability.
Photo: A. Klosin / B. Lehner Lab, CRG, Spain

l&m: We know that cancer is associated with a series of mutations. In your highly regarded Nature article (doi:10.1038/nature11273) you were able to show the part played in the process by epigenetics. What exactly did you discover?

Dr Ben Lehner: We were interested in the basic question of whether mutations are equally likely to occur in different regions of the genome. What we (and others) realised is that we could use the data coming from cancer genome projects to address this problem. Most of the mutations that happen in cancer cells have nothing to do with causing cancer – they are simply mutations that have accumulated during the history of the tumour cells. Therefore you can use these ‘passenger’ mutations to look at where mutations are most likely to occur in the genome. The human genome is 3 billion bases long and yet is compacted into a tiny space inside the nucleus of each cell. What we (and others) found was that not all regions of the genome (and so not all genes) are equally likely to mutate. Some­how – and we still don’t understand what molecularly causes this – these differences relate to how the genome is packaged in the nucleus.

Can you give us an overview of the mechanisms of genetic interaction that have been known to date?

Normally when people are talking about genetic interactions they mean an interaction that occurs between two or more different mutations in a genome. When you combine two mutations together in the same individual there is often a much stronger (or much weaker) outcome than expected – each mutation alone may not cause disease, but the combination does. This is a fascinating problem because it’s something that we don’t understand very well at a molecular level – why does this happen for particular combinations of mutations and genes? It’s also a very important problem because we each inherit mutations in thousands of different genes and so there are a huge number of potential interactions that could be going on in each of us.

More recently we have been interested in the problem of why there is still variation in the outcome of mutations even without any additional mutations. What we thought was that the same thing could be going on with one mutation as when you combine two different mutations. For example, if when you mutate gene A and gene B at the same time something bad happens, the same­ bad thing would happen if you only mutate gene A but, for some chance or environmental reason, gene B is not switched on enough at a critical time in an individual. Using the simple worm C. elegans we showed that this is what happens – that variation in the extent to which particular genes are switched on and off during the very early development of embryos determines to some extent whether an inherited mutation has an effect or not.

You studied in Cambridge, where Crick and Watson worked on the decoding of DNA and revolutionised biology 60 years ago with their description of the DNA structure. Watson was one of the initiators of the Human Genome Project, which made history at the start of the millennium with the complete sequencing of the human genome. To what extent have you been influenced by these milestones?

It’s true that Cambridge has a unique history when it comes to science and molecular biology in particular – it’s not just the structure of DNA and the sequencing of the genome, but also the isolation of embryonic stem cells, protein crystallography, DNA sequencing, monoclonal antibodies, in vitro fertilisation, and more than 80 Nobel prizes in total. There are two things I appreciated about this: first, that it helps you put your own work and achievements (and those of others) in perspective – compared to what has already been achieved we are only making small steps; second, that even the ‘famous’ people at Cambridge were normally very down to earth and only had small labs. So it creates this culture that as long as you work on important problems there is a chance that you might progress towards something important.

Angelina Jolie’s drastic prophylactic decision has stimulated a lot of discussion worldwide, after a test for BRCA mutations apparently showed that she had an 87% risk of contracting breast cancer. Will your research make it easier in future to predict accurately whether and when a disease will be contracted and whether it can be avoided?

We hope so. Actually examples like the hereditary BRCA mutations where most individuals carrying the mutations will eventually be affected are quite rare. For most common diseases, we already know from studying identical twins that we’ll never be able to predict accurately what happens to individuals from their genome sequences alone. So I think that a really important challenge that should receive much more attention is how to combine the genetic information with other measurements that are made on the individuals. Just as in C. elegans we could make much more accurate predictions if we combine the genetic information with measurements made in each individual, so this should also be possible in humans. It will be the combination of genetics and clinical measurements that will be most effective in predicting what will happen to individuals.

What tips, Dr Lehner, would you give to young scientists who are just at the start of their career?

Inspired by your question above, one tip would be to read something about the history of your field. I think this helps you to distinguish questions that are important from techniques or approaches that are just popular or fashionable at the moment. Also, one of the frustrating things about science is that you have to be able to cope with almost continuous disappointment and rejection – both in the lab and when trying to publish papers. So it’s important not to be too affected by that!

Dr Lehner, many thanks for the interview – we wish you every continuing success.

(Interview: Claudia Schiller)