16 February 2022
by Dominic Owens
It feels like a lifetime ago now. It was early March 2020 and, having just recently completed my DPhil viva in January, I was visiting Oxford for a two-week stint in the lab of my DPhil supervisor, Prof. Marella de Bruijn at the MRC WIMM. News reports vaguely impeded on my consciousness (something about a new virus having been identified somewhere in China?), but primarily, I was focusing on much more important things to me than news from the other side of the world – the final experiments I needed to complete before being able to publish my DPhil project as a paper. Like most of us then, I had no idea what was coming.
My DPhil had led me to investigate the three-dimensional structure of a gene called Runx1, which is critical for the normal development of blood cells during gestation and is frequently mutated in leukaemia. Not only is Runx1 a critically important gene, it is also particularly large and structurally, very complex. As such, and as is often the case with a DPhil, the timeline of the science and the timeline of the examination schools weren’t entirely aligned… So, there were quite a few experiments left to do after completing my doctoral work before I would finally be able to submit a paper.
Thankfully, two fantastic scientists had arrived in the lab prior to me leaving, and just in the nick of time. Giorgio Anselmi was an incoming postdoc and Alessandro Cavallo was a new DPhil student in Marella’s lab. Along with the other long-standing members of the lab, both would be critical to helping me finish the project. I would be relying on all their help if the paper I imagined would ever be published one day.
Maybe it was tempting fate to plan two weeks of critical experiments ending on a Friday 13th. Despite this, and to our great relief (we only had one shot at this), the experiments went exactly according to plan! We were using embryonic stem cells to make blood cells in a dish and mapping the three-dimensional structure of Runx1 throughout the differentiation process. To do this, we were utilising a technique called Tiled-C which was developed in the lab of Prof. Jim Hughes at the WIMM, who co-supervised my DPhil. Even though the laboratory experiments had gone well, it would take months of hard computational work analyzing the data before any sort of sense could be made from it. It was the last day of experiments, and I was leaving the lab, so how was that going to work? I tried not to think about it.
The next morning, it seemed like everything had changed. The night before, I remember celebrating the successful trip heartily with family and friends in Oxford, while preparing for the exciting next step in my career – a postdoc at the University of Toronto, Canada, which I was due to begin in a few months’ time. However, the trepidation I was feeling that morning wasn’t just down to the hangover.
I’m sure that what happened next will be all too vivid in the reader’s mind. The Prime Minister announced the first restrictions on 16th March 2020, and the global SARS-CoV2 pandemic we are all too familiar with ensued. There are so many examples of truly awful outcomes caused by the pandemic. Ironically from the point of view of this paper, the pandemic offered an opportunity.
Once the UK was fully ensconced in lockdown, it became clear there was no way I would be moving to Canada to start my postdoc any time soon. And so, finding myself with plenty of time on my hands, I set about delving into the fascinating world of the three-dimensional structure of Runx1. As I am sure many scientists can relate to, the statistics software RStudio became the backdrop to my days. Aside from my daily dose of outdoor exercise, dopamine hits were strictly synchronized to any new ggplot window popping up, offering a rare glimpse onto the indiscernible patterns buried in the mind-numbing matrices of numbers still visible behind my closed eyelids.
A diagram of the three-dimensional structure of the Runx1 gene in blood cells made using the Tiled-C technique. A darker colour indicates a more frequent interaction between DNA regions. Owens et al 2022; NatComms.
As the lockdown became lockdowns and the months dragged on, our hopes for a normal summer diminished. At the same time, I looked on as our paper began to emerge. We saw that initially Runx1 sits in a quiet corner of the genome, in a large but fairly unremarkable domain. At the earliest signs of blood cell formation, however, distant corners of the domain start contacting each other more and more frequently, and activity at Runx1 begins to stir. Next, as differentiation really gets underway, Runx1 activity is at its highest and the gene itself becomes sub-compartmentalized into even smaller regions – a remarkable phenomenon not seen at more typical genes. The appearance of these smaller regions partially depends on specific DNA elements neighbouring the gene, as well as the activation of the gene itself. The results fascinated me; I longed to see them published one day.
Happily, as I write this now, I am sitting in my office as a postdoc at the Structural Genomics Consortium, University of Toronto. It has been between -10 to -20oC outside for most of the last couple of weeks, and more snow fell in one evening recently than I ever saw in all my four years at Oxford combined (and I was there for 2018’s notorious Beast from the East!). Overall, it took until January 2022 for our paper to finally be published in Nature Communications (https://www.nature.com/articles/s41467-022-28376-8). But it would most likely not have been possible at all weren’t it for the SARS-CoV2 pandemic. It gave all of us the time needed to focus and work deeply on the interesting and complex question of how the three-dimensional structure of a large and complex gene like Runx1 changes over differentiation.
Despite all the obvious and as yet undiscovered costs the pandemic has wreaked on us all, I take some comfort in knowing that many papers like ours were born during this time—Pandemic papers.