Do you know that moment? When you are meeting your new boyfriends’ parents, or are at this neighbourhood party. They all know you’re a scientist, but now they would like to know what you actually DO. You may start to sweat a little, because how do you explain all the intricacies of – enter your field here – in the minute or two you can hold their attention?
I tried during my PhD defence. To write this post, I actually opened the ppt of my defence talk, which still lives in a dark corner of my laptop. It’s called PhD_presentation_edit_final.ppt and seeing it stirs up some good memories. My viva lasted a whole 30 minutes……
I started by explaining to my audience, which included my grandparents, neighbours, friends and many non-scientists, what enzymes are. They can make reactions go faster, without being consumed themselves. They can do this over and over again, provided the circumstances are right.
No matter how hard I try, I can’t remember which enzyme I talked about. Perhaps a lipase that can help degrade stains in clothes? Or alcohol dehydrogenase – seeing how much we were enjoying student life, which included regular TGIF drinks!
I then continued to explain that cells in the human body exist of many components: lipids, DNA, proteins… Which can all be altered when conditions change. Certain enzymes can attach something to proteins – call it a flag – which can influence this proteins’ behaviour. These flags, known in scientific jargon as posttranslational modifications, exist in many colours and shapes.
And then you think “yeah alright, we have proteins in our body which have some function which can be regulated – so what?”. After all: tax payers paid for my playing around in the lab, so there should be some benefit for society in it. What can we do with this knowledge? This is where the concept of synthetic lethality comes in – I loved and still love it! Let me explain it in easier terms…
The eggs in this image are very much simplified cells, the double lines inside DNA. DNA can get damaged – indicated by the lightning. The proteins BRCA1 and ARTD1 (much better known as PARP1) work to repair this damage, partially by PARP1 creating lots of flags at the site of damage as indicated by red beads. No probs in healthy cells – BRCA1 and PARP1 to the rescue! Some people however have a mutation in the BRCA1 protein, leaving PARP1 to do the dirty job all alone. Having lost functional BRCA1 can lead to cancer formation in those cells which lost this protein. If we now in addition block PARP1 from repairing the broken DNA (using drugs such as olaparib): ka-ching! The tumour cells die as a consequence of the unprepared DNA, leaving healthy cells relatively unscathed as they still have BRCA1 to repair the mess.
Since this was already known at the time I was doing my PhD, I picked one of the lesser gods to study: PARP10, also known as ARTD10. To my audience, which was still awake or at least pretending, I next explained exactly what my research goals had been.
I’m proud to say – these research goals are pretty clear, right? Not much explaining I need to do there. I’ll skip through the experimental data I presented next, as I fear it was inevitable I’d lose the grandparents at some point, but had to explain my work to my examiners. Scoot over to our research if you’d like to read up on it… Or get in touch! Skipping to the conclusions then.
And with the knowledge we have now: the first hypothesis – wrong! Although it turns out I was partially right – this particular enzyme has a role to play in immunity. Just not through secreted proteins but instead by modifying targets inside the cell with this little flag. Second – still hard to answer, due to various technical reasons which I won’t explain here and now. Third – we’re working on understanding the function of the proteins reversing those little flags – when are they active, why, how?
Which makes me painfully aware how slow scientific progress can be. It’s been 7 years since we’ve published our work identifying proteins modified by PARP10, and also concerning the enzymes which reverse this reaction, but we’re not that much closer to understanding their function in the human body… We’ll crawl a little closer day by day!
What I did learn over the years: practise makes perfect! The more people I try to explain what I do, the more understandable it gets… Although some times, I admit, “cancer research” is still the only thing I say in reply to that one question.