Imagine working with a puzzle where you don’t know the number of pieces and not always where you should look to find them. Furthermore – the pieces are proteins living inside the cells of human brains and are only visible through a microscope. This has been the work life of 30-year-old Ph.D. Line Marie Christiansen throughout the last three years: finding answers to how the healthy brain works and as a result, what happens when it doesn’t:

“Science to me is playful, it is extremely complicated and challenging but it is that giant puzzle where so many pieces are missing and where we get the opportunity to find maybe one maybe two puzzle pieces to add to the whole picture,” says Line Marie.

Growing up Line Marie always thought she would become a medical doctor. Until she discovered a whole new perspective:

“In high school, I had a biology teacher who just finished her Ph.D. and she introduced me to the mysteries of science with the unpredictable and long processes and puzzles, which are the basis of research. That really got a hold of me and fascinated me”.

Lipid flippases meet Cryo-EM
And just like that, the science of molecular biology became her new career path. Just recently she defended her Ph.D. in Molecular Biology working on solving the function and malfunction of a small subgroup of proteins called “lipid flippases”.

Lipid flippases are a specialized group of membrane proteins that regulate the composition of lipids in the inner and outer membrane layers.

“We know from recent articles that if this protein does not perform its intended function in humans, you end up with quite severe phenotypes of neurological disorders. We just don’t know why and how yet”, Line Marie points.

Line Marie explains that in those patient cases where the lipid flippases do not function correctly, the risk of developing neurodevelopmental disorders like microcephaly is increased. Postnatal microcephaly describes babies where brain development stalls to varying degrees after birth. This can cause a variety of phenotypes from developmental delays, and epilepsy to severe intellectual disabilities. 

The scope of her Ph.D. was to capture a 3D model of this specific protein group using a method called Cryogenic Electron Microscopy, or Cryo-EM, to define the structure and follow the behavior of the protein and its function in the brain. The Cryo-EM method has been under development since the 1980s and has revolutionized the field of biochemistry by making it possible to visualize biomolecules such as proteins in a detail, which is decisive for both the basic understanding of life’s chemistry and for the development of pharmaceuticals.

Starting over again – and again
While this may sound like an easy method, working with biological material is unpredictable. It is both frustrating and fascinating at the same time, and she encountered numerous failures, obstacles, and setbacks in the process:

“Every time I thought the project was moving forward, I would hit a wall – many times. When I thought the protein was stable, I tried to purify it and suddenly it was not. Or I lost protein samples, or a machine malfunctioned. I have a lot of negative results from experiments that didn’t give the expected read out, but they also really add to the story of what we know”, she explains.

She is fully aware that basic research may not be a front-page seller and that the final endpoint might not always be clear when you are exploring new territory. But for Line Marie it is motivating to know that she and her protein research may change the future treatments of this specific group of patients:

“I don’t get to the large easily describable answers, I get those small puzzle pieces that someone else after me will continue to build on. Hopefully, in ten years we understand this group of proteins much better, which ideally may help people who are suffering from different diseases caused by it,” she explains.

On the verge…
Standing today with a Ph.D.-title on her resume, she is still not sure where her path will go. However, if it is the scientific path, she knows it requires strong will, motivation, and dedication: 

“After these three years, I feel mentally exhausted. I look forward to getting a break and a chance to reevaluate what really motivates me. It could be going all the way, but, if you don’t really want it with all your heart and it is everything you ever dreamed of, then I believe you must evaluate if it is really what you want,” she states.

Looking back, though, she does not doubt that working as a scientist has developed her in a way, she never imagined four years ago, and she feels proud knowing that the work she has done - including the failures - is adding important pieces to a larger picture:  

“We are on the verge of finding some really big answers. Hopefully in a year or so you will see a paper out with at least a big part of the answer to it – but we are still missing the final puzzle pieces”.

What's next?
Line Marie did her Ph.D. in Poul Nissens Lab and the Department of Molecular Biology and Genetics at AU.  
She will continue her research in a 1-year postdoc position in the group of Joseph Lyons at the Interdisciplinary Nanoscience Center, iNANO continuing the work in collaboration with Poul Nissen.
For now, she has no regrets about not becoming a medical doctor.