Meet the first authors: Lisa Martina and Michal Malszycki

In our interview series we take a look behind the scenes of science. 

Lisa and Michal, you’re recent paper centered around nuclear speckles. What do you find captivating about them—was there even a specific moment, image, or idea that made you think “I have to understand this”?

Lisa: Since I was in university, I have been fascinated by molecular biology, and one of the things that captured me most was the scale of the entities we were studying: so small one can’t see them, but so intricate, complex, and vital. Once I shifted from the theory to the practice, this fascination with microscopic (and nanoscopic) entities also became a challenge: I initially found it hard to interpret my data without the visual aid. I think speckles are very cool because they merge these two aspects: you can easily see them in the microscope, but then inside there’s a universe of proteins and RNA that you can’t see, but can play with.

Michał: When I joined the lab, Tugce and Ibrahim were investigating two unusual proteins, SON and SRRM2, which they’d just identified as the structural core of nuclear speckles. As a side project (initially), they asked me to explore their evolutionary history. What I found out was extraordinary: both proteins were enormous, composed mostly from unstructured repeats, which they accumulated by expansion of a single exon. I don’t know of any other human gene like that. Obviously, it made me want to understand what is going on.

If you had to explain “nuclear speckles” to a non-expert in 30 seconds, what are they—and what do people often get wrong about them?

Lisa: Nuclear Speckles are membraneless organelles that occupy around 20-25% of the nuclear volume of Amniotes cells. Before our paper, researchers mainly referred to them as storage units for transcription and splicing factors, while we show that they have a more active role in splicing, which is coordinating the binding of splicing factors that determine which splice sites will be used.

What was the original question or observation that kicked off this project—and did the focus change as the data came in?

Lisa: The path to this paper was quite unconventional. It started with other lab members trying to characterize a previously mis-labeled antibody, which turned out to target SRRM2. Following up on this unexpected discovery, the lab was able to finally identify the core proteins of speckles, SON and SRRM2. This was an important discovery, as it allowed the investigation of the roles of speckles, which was hindered by the absence of knowledge about their composition.

Michał: After our lab identified the core members of nuclear speckles, the next steps were obvious: to finally answer the questions that piled up over the past century since speckles were discovered. We initially focused on their molecular function, but noticing that they evolved recently shifted our attention. While speckles were assumed universal in eukaryotes, we found speckles and the gene architecture they coordinate emerged only in land vertebrates. This means much of what we learn from yeast or fruit flies about RNA processing doesn’t fully apply to humans.

Nuclear speckles can be studied from very different angles. What was your guiding strategy for finding their functions?

Lisa: Once their core proteins have been identified, it was possible to create a cell line model where either or both these proteins could be acutely depleted. This gave us a tool to perturb and dissolve speckles and study the consequences of this perturbation. Since their scale is quite wide we got to apply a wide range of techniques, both imaging- and sequencing-based.

Michał: To be honest, we did it all. We wanted to paint the full picture, so we started by checking what happens when we remove the proteins which keep speckles together. We then moved to genome organisation, transcription and RNA processing. Ibrahim then did an astonishing computational analysis of all eukaryotic genomes to test the connection between genome evolution and the emergence of speckles. I cloned the speckle core protein and expressed them in human and speckle-less fish cells to test whether it could form speckles. Lisa designed and executed an ingenious experiment, where she microscopically traced the mobility of chromatin in living cells with or without nuclear speckles. And there’s much more in the paper.

You two collaborated closely— among each other but also with several collaborators outside the institute. What did you do to stay aligned day-to-day and what would you do differently next time?

Lisa: Michal and I are very different people when it comes to work. I am a morning person, while he is more active in the afternoon. I organize my work weeks in advance, while he is more flexible. The game changer was not making these differences come in the way, but using them at our advantage. For example, I had no problem arriving early in the lab to start an experiment and Michal had no problem staying late to conclude it. During the revision process he added the adaptability in case something didn’t work as expected without panicking.

Zooming out from this project—what part of doing science feels most meaningful to you personally? 

Lisa: I honestly think it is fun: it is like a treasure hunt, and at the end you solve a little mystery.

Michał: True. It’s never boring and rarely repetitive. But what I’d really like is for it to be not just interesting, but genuinely useful for others. I hope that with our work we laid a foundation to better understand not only RNA processing, but also its role in disease. There are already papers functionally linking nuclear speckles with cancers and developmental disorders. 

Looking forward: what is the most important open question about nuclear speckles that your study raises? 

Michał: With this paper we essentially described what speckles are, their main function, and how they evolved. But many questions remain unanswered. We only scratched the surface regarding the material properties of nuclear speckles. If we understood better how they are kept together and what is their internal structure, we could potentially learn to modulate them and in turn modulate the cellular functions. 

Lisa: In my opinion, the most interesting path our paper opens is the study of speckles in cell lines of other animals. We started looking into the evolution of speckles in primates, fish, fruit fly and turtle, but a more detailed analysis of speckles functions in these and more organisms will be of great interest and importance.