Swapping stethoscopes for sequencing – a doctor’s journey

During my medical degree at the University of Cambridge, I found I liked working in the lab. After I graduated I pursued clinical medicine, specialising in paediatrics, and then was an academic clinical fellow for three years, which involved blocks of nine months of research in different lab environments. So applying for the Wellcome Clinical PhD Fellowship was a natural next step. I knew I wanted to study immunology, and had seen this amazing stream of papers coming from Sarah Teichmann’s lab. When I emailed Sarah she replied within 10 minutes, and incredibly positively! This really was a good sign, and foretold her great mentorship to come.

The thymus is an organ in your chest that makes T cells, which are absolutely critical for your adaptive immune response. A previous postdoc, Jong-Eun Park, had led the project that mapped the human thymus across the lifespan, defining all the different cell types and how they arose during development. My task when I started was to test some of the hypotheses that came out of this ‘thymus cell atlas’. For instance, how are different types of T cells made, and how does the tissue microenvironment influence cell fate choices? To address these questions, we use a special method in the lab: we start with stem cells, and culture them to become 3D structures known as organoids. With the right signals and conditions, these organoids make T cells for us. And by altering these signals, we can deduce which ones are important for T cell development.

Indeed: I was just getting started when COVID-19 hit. I had to stop all my experiments and was sent to work from home. It was particularly painful as I had to throw away lots of batches of organoids I had just established.

At that time, the demand in the NHS was for doctors with experience working on adults, and I had only done paediatrics so wasn’t much use to them. I found I was stuck (like millions of others!).

So when Qianxin Wu from the Human Genome Editing R&D Team asked if I wanted to help with a COVID-19 test she was developing, I jumped at the chance. At the end of March 2020 we got permission to start doing experiments on site, and aside from COVID-19 sequencing work happening at the Sanger Institute we were pretty much working alone – a whole floor to ourselves, which was totally surreal. I worked some very weird hours, being at home with my son in the morning and then coming to the lab in the afternoon until 10pm. You’ll remember that at that time everyone was highly stressed, everyone wanted a solution but couldn’t see a way out. To be able to come to work in the lab and work on something that could help the pandemic - just to be doing something, it was really a relief.

We were aiming for a way of testing for COVID-19 reliably. We developed an ‘isothermal’ test that amplifies viral RNA at 41ºC, so could be used in a wide variety of places that don’t have access to a PCR machine for immediate results, and also allowed us to sequence samples later on as a pool for centralised data collection.

It’s actually a very clever bit of tech. While antigen tests of course became the standard, at that time these hadn’t come out yet - everyone was scrabbling around for anything that might help. So I’m very proud of that work.

When I came back to my project, I was carrying on the organoid work - creating systems in the laboratory that can help us understand how T cells develop. But I also wanted to extend the cell atlasing work to look at all of the different immune cell lineages, across the body, not just the thymus. Basically, take a holistic approach and understand the whole immune system. We had a lot of data from the lab’s previous developmental atlasing work, and went on to generate a lot more ourselves in a highly comprehensive manner. This led us to make the first whole body atlas of the developing immune system, which was published last year.

My favourite discovery was expanding the sites of haematopoiesis [immune cell production]. Before our paper, the conventional narrative was that immune cell development begins in a restricted set of organs in the embryo. But what we saw was progenitors of different lineages across all the organs we sampled. B cell progenitors in particular were almost everywhere.

We then assessed which other cell types these progenitors co-localised with across different organs. Rather than the usual suspects (like stromal cells, endothelial cells or fibroblasts), we actually discovered that these progenitors co-localised with other types of immune cells (natural killer cells and macrophages). So the initial immune cells migrate very early on to colonise various tissues, and in turn create the niche for the other immune progenitors. It’s a fascinating process that has great implications for making B cells in the lab (which has been very difficult to do).

I had very little bioinformatics experience before coming here, but found I liked it compared to laboratory work. I have quite a mathematical mind and it suited that side of me. I’m really happy with the two tools we developed. One of them, Dandelion, offers a neat way of using the sequences of special kinds of receptors expressed on immune cell surfaces to understand their developmental origins.

The second tool was Genes2Genes, and is a method to compare any two cell trajectories. Both computational tools have shed new biological insights on immune cell development, and are guiding us to further optimise our organoid protocols. The ultimate aim is to learn from development to design different ‘flavours’ of immune cells, which could in the future be used for therapies in an ‘off-the-shelf’ way.

One thing I was really struck by was the different mindsets of academic research and of clinical medicine. Here, I’m confronted with a basic problem, day in day out – like how to diagnose a serious disease early, which might have the same presentation to other less serious problems. I need to find the best solution to these problems, fast – the initiative and mindset is just very different because there is such an acute need. This contrasts to refining an organoid protocol over months, for instance. But the contrast has given me new ideas of how to do some more translational research, perhaps by utilising the new technologies I was exposed to during my PhD. It’s an exciting challenge.

Sanger was a fantastic place to do a PhD. I was exposed to so many kinds of science: sequencing, genetic engineering, organoids, computation, everything! There was always something new I could learn. Plus the support from the laboratory and informatics teams is truly phenomenal. I’m incredibly grateful for that.

“Sanger was a fantastic place to do a PhD. I was exposed to so many kinds of science: sequencing, genetic engineering, organoids, computation, everything!”

Chenqu Suo,
Former PhD student at the Wellcome Sanger Institute

Sarah Teichmann’s lab was a wonderful niche within this larger environment. Sarah was always so supportive of whatever I wanted to try – if an idea was not quite solid, she wouldn’t shut it down, rather guide me to interrogate these ideas, talk to the right people in the Institute, and help me come up with my own practical solutions. I found an environment where intellectual curiosity can come to fruition.

• Chenqu Suo's profile at the Sanger Institute
• Qianxin Wu interview: A passion for problem solving
• Teichmann research group at the Sanger Institute
• Cellular Genetics research programme at the Sanger Institute
• Sanger News: Immune cell characteristics mapped across multiple tissues, from early life to adulthood
• INSIGHT
• Dandelion
• Genes2Genes