Dr Oliver Hickman is the research area scientific lead for Immuno-oncology at Abcam. He completed his PhD research at King’s College London and subsequently undertook an extensive postdoctoral fellowship at the Institute of Cancer Research. During his postdoc, Oliver made a cutting-edge discovery that senescent cells, previously thought to be dormant, can actually resume growth. Additionally, he identified a novel method to target and eliminate these cells.

Could you provide an overview of the current state of research in senolytics, aging, and oncology?

I became obsessed with senescence because relatively few people studied it or seemed to care about it. It wasn’t really taught when I did my undergraduate (or maybe I missed that day!), and yet I think it’s probably one of the most important areas of translational cancer research. When you give patients anti-cancer drugs, say chemotherapies or even targeted therapies such as CDK4/6 inhibitors or EGFR inhibitors, the targeted cells either die - which is what you hope will happen - or they don’t die.
Because these therapies are almost never curative in advanced cancer, it means a lot of the cells didn’t die. So, what happened to them? Well, they probably became transiently senescent, then started growing again. The thing is the biology of senescent cells is completely different from that of dividing cancer cells. They aren’t dividing for a start, so they are completely resistant to therapies that target cell division, and they are epigenetically radically altered, which means there are other areas of regulation and biology that we could be targeting, induced by the original treatment.
It’s a huge, missed opportunity.

How did working with complex multi-stage assays and 3D cell models influence your research approach? Any key learnings?

In all my work, I tried to use 3D culture - spheroids or organoids if I could. Most of my functional assays and drug/genetic screens were done in 3D to try and make the insights as physiologically relevant as possible, especially as I was studying responses to drugs. 3D models are much more difficult to work with. For a start, you can’t tell whether a spheroid is alive or dead if it’s not growing - and senescent cells don’t divide. But I found that if I just made all my cells express GFP, I knew if they were alive. I then also had an effective way of measuring if and when I’d killed them – and this became one of my main screening tools.

What are the biggest challenges your research field faces today?

One of the reasons we know so little about senescence in animal models of treatment or patients is that there are no good markers for senescent cells. This is why most people don’t really think about it or study it – because you can’t visualize/detect it in vivo, so most of the work done in senescence, especially  regarding senescence in cancer cells, has been done in vitro using cell lines models.  As such, trying to convince people that it is relevant is difficult.

What do you think the future holds for the field? Are there any exciting upcoming developments or breakthroughs? Are there any promising treatment approaches out there?

There are some promising senolytic drugs, and I think there are some great labs and biotech companies focusing on this now, so hopefully, the future is bright. One really cool area of research is uncovering the epigenetic regulators that allow cells to re-enter the cell cycle. Chromatin methylation patterns completely change in senescence, and cells gain these “senescence-associated heterochromatic foci.” But people are starting to pin down the specific histone demethylases that allow senescent cells to “escape” senescence, which opens avenues for treatments to prevent this happening.

Very recently, there was breaking news about researchers from Osaka University who discovered that the protein subunit AP2A1 may play a role in the unique structural organization of senescent cells. Could you comment on that finding and how it could affect this field?

One main reason to study senescence in cancer cells is that, functionally,  cancer cells are using senescence as a mechanism of surviving cancer therapy. If AP2A1 is helping replicative senescent cells survive, then maybe it is doing the same to cancer cells that are entering senescence following damage induced by anti-cancer drugs. If that is the case, targeting AP2A1 may prevent these treatment-induced senescent cells from entering senescence, and this may force them towards cell death instead – which should increase the efficacy of cancer treatments. Certainly, there are some really cool experiments to be done!

What changed in the research during your time in academia?

Technology has changed fast. When I started, people were using microarrays, but these days, running thousands of cells through scRNA-seq is not uncommon. Now, all life scientists need to be happy handling, wrangling, and thinking about big data.

Transition to Industry

What motivated you to transition from academia to a role at Abcam?

My time at the ICR drew to a natural close. There is no senescence research there besides my own, and in addition, having a young family motivated me to move out of London. I decided I wanted a role away from the bench that was still science-based and utilized my experience in Immunology and Oncology. Furthermore, Abcam was a company I’d used for many years – so all the pieces fit!

How has your work at Abcam differed from your previous academic research?

It’s very different from what I was doing before, but regarding analyzing data, it draws on the core skills you learn as a research scientist. In addition, my background in research, especially working across several areas and techniques, is crucial to understanding researchers’ antibody needs at the bench – and it is by meeting these needs that Abcam is going to succeed.

What skills or knowledge from your academic career have been most valuable in your current role?

Ironically, the most useful thing was that my research career covered a lot of different areas. I never focused on one assay type or method; I never focused on one disease area, so learning a little bit of everything gives me a broad understanding of what tools scientists need and how to make them.

What are some of the biggest challenges you face in your current role, and how do you address them?

My role covers many different areas, from collaborating with academia to reviewing our pipeline products to being the go-to scientist for several different teams, amongst other responsibilities – so it’s not that there is one challenging part, so much as it’s hard to know how best to contribute to several spaces at once. Having great colleagues to learn from helps.

Personal Insights

What advice would you give young scientists interested in pursuing a career in drug discovery and/or senolytics or new product development?

To a young career researcher, I would advise them to learn to network and learn how to sell their work to other people. I didn’t, and I should have. In addition, a surprising number of established scientists are quite conservative - they have found their niche and don’t want anyone to come and rock the boat. So, when someone tells you not to bother, it won’t work – you should trust your instincts and try it.

I don’t feel ready yet to offer advice in NPD; ask again in a few years

How did you stay motivated and inspired in your research?

When I needed motivation or inspiration, I’d print out a bunch of papers, sit in a cafe, and read a lot. Every time you read a new paper, you’re reminded of an experiment you could have done or come across an idea you would never have otherwise. And regarding motivation, remember that progress is non-linear; weeks can go by when nothing works and time is ticking away, and then bang. You get a result that moves the project to a whole new level!

Can you share a memorable moment, learning, or breakthrough from your career that significantly impacted you?

I had worked on my novel senolytic in cell lines for several years – but had not tested it in mice. Several people had looked at its structure and told me not to bother; it won’t work, or even worse... it’s too toxic. But we did a trial experiment, and not only was the compound very well tolerated, but when combined with the chemotherapy treatment, there was no sign of tumors remaining in the treated mice; it has worked way better than expected. It was a really profound feeling of vindication and relief that I had stuck with it despite several people telling me to stop.

Picture credit: Vivien Gilles