I could not have guessed just how much I would love working in a laboratory.
My passion for science was nurtured by my parents. Particularly by my Mum (Mrs. Belinda Scott) who fostered curiosity and innovation. My mother trained as a surgeon at a time when women were actively discouraged from doing so and I have listened in on many conversations around the dinner table about the difficulties she faced breaking through glass ceilings. My sister and I would accompany her on hospital visits and so, early in life I had an understanding of the difficulties cancer patients face.
I knew I didn’t want to be a medical professional, but I still wanted to do something to benefit cancer patients and so when the opportunity presented itself in 2012, I applied to do an honours degree (and later a PhD) at the Centre for Translation Cancer Research at the University of Otago New Zealand, under the supervision of Professor Parry Guilford. Although I had the drive to contribute in some way, I could not have guessed just how much I would love working in a laboratory. I enjoyed the excitement of discovering and learning new things; the honing of techniques and the creativity of designing new experiments. And then there was the stimulation and inspiration gained from sharing and discussing findings.
I have a particular interest in the use of CRISPR technology (‘molecular scissors’ enabling the editing of DNA by deleting or adding genes into the genome). Probably the largest audience I’ve ever presented to was during my PhD at the Biochemistry Department Journal Club. The talk entitled “The end of CRISPR?” attracted so many people they were standing in the hallway to listen in. There was immense excitement around CRISPR as it was considerably easier to use and highly customisable compared to its predecessors. Of course, the title was ‘click bait’ but I wanted to highlight the biggest problem I saw then, that even now is still an issue– off-target genome editing. The main problem being that we can’t always predict where an off-target edit will occur or its impact on, for example, a human embryo. This issue raises a myriad of the ethical issues, including who makes the judgement call on its use.
I think everyone is aware that eventually this technology would lead to heritable human genome editing. But we also thought it would be a long way down the track, when we better understood the risks of editing embryos and hopefully had created new CRISPR constructs that drastically decreased the chance of off-targets occurring in the first place (some foreboding here).
At the time, I was very keen to use CRISPR as a tool to enable genome editing of laboratory-grown cancer cell lines to enable better models of human diseases. My research interest focused on loss of the protein E-cadherin, which can be inherited and comes with a 70% lifetime risk of developing diffuse gastric cancer and a 40% risk for lobular breast cancer. I had just started to create some TALENs (a cumbersome precursor to CRISPR) to delete E-cadherin in breast cancer cells and so CRISPR was going to save me a lot of time and hassle. Using these cell lines, I then went on to undertake a compound screen, where I treated the cells with 114,000 novel drug-like compounds at the Walter and Eliza Hall Institute of Medical Research to identify compounds that could work in synergy with E-cadherin loss (1).
After my PhD, I wanted to go all in on breast cancer research and started working with Professor Valerie Brunton at the University of Edinburgh. There I used CRISPR to perform a whole-genome screen – essentially, all 18,053 genes in the genome were deleted one-by-one in a breast cancer cell line model. This approach was used in combination with our drug of interest – a SRC inhibitor called bosutinib. We discovered a synergistic gene-drug interaction between integrin-linked kinase (ILK) loss and the SRC inhibitors bosutinib and eCF506 (which has now been picked up by Nuvectis Pharmaceuticals!) (2).
I have always been interested in all things high-throughput and when thinking about my next move, my partner and I were keen to relocate to Melbourne again. I am now a Research Officer at the Victorian Centre for Function Genomics (VCFG) here at the Peter MacCallum Cancer Centre. My current project is on developing novel high-throughput methodologies to screen patient derived stem cell lines.
In 2018 my interest in off-targets was again piqued when I heard about a research scientist who had edited human embryos in an attempt to prevent the resulting babies from contracting HIV. This was quickly condemned by the research community and the three scientists involved were sentenced to up to three years in jail.
So, the next click bait title I want to go with is: “How long until CRISPR embryo editing is commercialised?” Perhaps first in pets – do you want to have the cutest pet? There are of course much more efficient ways to prevent passing on genetic disorders – for example screening embryos for unwanted mutations and then undergoing in vitro fertilisation. However the ability of CRISPR technologies to enable relatively simple gene editing is why it is here to stay. Of course, informed debate on the ethics and safe use of this technology needs to be progressed before the commercialisation of CRISPR is on our doorstep. I think my mother would be pleased to think the curiosity and innovation is tempted with some ethical reflection.
Figure Legend: Images taken over time using my favourite equipment – the IncuCyte. The top right image shows the breast cancer cell line MDA-MB-231 one hour after drug addition. If you compare this with the bottom right image where integrin-linked kinase (ILK) has been knocked out after one hour of bosutinib treatment, you can see the cells have begun to ‘round up’, which means they have stopped proliferating.
References:
1. Beetham, H. et al. A high-throughput screen to identify novel synthetic lethal compounds for the treatment of E-cadherin-deficient cells. Scientific Reports 9, 12511 (2019).
2. Beetham, H. et al. Loss of Integrin-Linked Kinase Sensitizes Breast Cancer to SRC Inhibitors. Cancer Research 82, 632-647 (2022).
Dr Henry Beetham is a postdoctoral Research Officer at the Victorian Centre for Functional Genomics, headed by Associate Professor Kaylene Simpson at the Peter MacCallum Cancer Centre. His postdoctoral work was recently published in the top cancer journal Cancer Research. Henry has a background in cancer genomics and his expertise include high-content imaging and a host of high-throughput screening technologies including the associated bioinformatics analysis.
Dr Henry Beetham can be contacted by:
Email: [email protected]
Research Gate: https://www.researchgate.net/profile/Henry-Beetham
LinkedIn: https://www.linkedin.com/in/henry-beetham-666a991aa/
