JRF Dr Henry Lee-Six talks about his research into cancer and working on the NHS frontline during the pandemic.
Why did you choose to study Medicine and how did you end up doing research?
I came up in 2011 to study Medicine, which I chose because I loved Biology and wanted to be useful. I had always been keen on research, and in the summer of my second year I worked in the labs of Rebecca Fitzgerald and Paul Edwards. It was exciting because for the first time we were sequencing large numbers of whole genomes of oesophageal cancers, and I got to scrutinise them as they came off the machines. I was fascinated by how the DNA of these cancers had become so chaotic, and I was thrilled by the idea that I was the first person in the world to see and reconstruct events in the histories of these cancers.
I continued to work on the same project during my Part II, and spent the next summer in the lab of Patrick Maxwell trying my hand at a different kind of research, to check that I really liked being a scientist (I did!) I met current and former MB/PhD students through the lab (Jamie Weaver and Anna Paterson) and through my Supervisors at Trinity (Catherine Aiken and Gary Docherty). I was impressed by the way they approached problems, so I applied for the MB/PhD programme, and was lucky enough to be accepted. That allowed me to take three years out in the middle of the medicine course to do a PhD, which I spent at the Wellcome Sanger Institute, just outside Cambridge, under the supervision of Peter Campbell and Mike Stratton. I had an amazing time. I lapped up the intellectual freedom of the thesis and the fact that at the Sanger we had the ambition and resources to tackle big questions – on which more later.
How was it working and training during the pandemic?
On 12 March 2020, as I was revising for my medicine finals, an email popped up that the exams had been cancelled and that we had all passed. A few weeks later, we received another email to tell us that we were now doctors, and then another inviting us to join the front line if we wanted to. There was an odd feeling of going to war. I signed up, and was sent to work in the Intensive Care Unit (ICU) in Harlow, which was particularly badly affected. At its worst (which was just before I started), the normally 10-bed unit had 39 patients, spilling out of ICU into theatres and endoscopy suites.
As a first-year doctor who couldn’t intubate and was frightened of pressing the wrong button on the ventilator I wasn’t much use on the shop floor, but I would go in for proning shifts (proning is when you roll patients onto their front to help their breathing). There were too many patients to keep track of, and you’d go around a corner to find another one, and another, and another… Sweating in full body suits, unable to hear over the hum of our hoods and the beeps of the ventilators, going around these white and metal rooms full of unconscious people, it was completely surreal. My main job was keeping track of who was where and had had which treatments, prescribing drugs, requesting investigations, talking to families, and verifying deaths. I had it much easier than the nurses and the consultants and registrars, but the sheer number who died, and whose faces and stories I can remember, does take a toll. The situation got better over the summer, bad again in the winter (when, with more experience and working on the normal wards I could do more and was busier), and now, at last, things are looking up. But we are all tired.
Why is it important to study the genomics of normal tissues?
All cancers were once normal cells. For a normal cell to become a cancer, it has to acquire certain mutations, or typos, in the DNA code. Those typos make the cell behave in a selfish way that means that it outcompetes its healthy neighbours. So the first mutation, that sets a cell on the road to cancer, occurs by definition in a normal cell. But what causes these mutations in normal cells? Some processes we know about, like smoking and UV radiation, but we found that, if you sequence a normal cell, lots of the mutations can’t be explained. You can investigate this by looking at the pattern of mutations in normal cells, as different mutational processes cause mutations in a specific pattern.
A large part of my thesis described the patterns of mutations in normal human gut cells. This showed a remarkable diversity in mutagenic processes between different people, and, even within one person’s gut, different cells may have been mutated by a very different set of processes. By describing these patterns, we hope to find ways of preventing the mutations from ever happening, and so to stop cancers from developing. For example, I found one pattern that was responsible for thousands of mutations in the colons of certain children. The Clevers lab, in the Netherlands, then showed that they could produce exactly the same pattern by growing gut cells with a certain strain of E. coli bacteria. Presumably, then, if we can stop children from being exposed to these bacteria we can reduce the number of mutations in their normal cells and significantly reduce their risk of cancer later in life.
There are many exciting directions to explore now. I want to keep on trying to understand where cancers come from, but move towards paediatric cancers as that is where my clinical interests lie. I want to try to develop a more probabilistic model of how a mutation leads to a cancer: once a cell has acquired a mutation, what is the probability that it will displace its neighbour? And then what is the probability that its descendants will acquire the next cancer-causing mutation? And so on until we have a full-blown cancer. I also want to try to understand the process mechanistically, looking beyond DNA: once that normal cell has acquired its first mutation, what changes in the cell actually allow it to outcompete its neighbours, and are there places that we can interfere? I’m really looking forward to coming back to Trinity to investigate these questions further and to be a part of the exchange of ideas that made it such a fantastic place to be a student.