Back in 1997, my unthinking 17-year old younger self was obsessed with the ocean, fish and fishing, and I vehemently wanted my future career to reflect this passion.
A favourite author of mine once wrote, “We spend most of our walking lives at work – in occupations often chosen by our unthinking younger selves”. Back in 1997, my unthinking 17-year old younger self was obsessed with the ocean, fish and fishing, and I vehemently wanted my future career to reflect this passion. Two years later, with high school complete, I left my childhood home in suburban Melbourne and journeyed off to Warrnambool on the south-west coast of Victoria to undertake a Bachelor of Science degree in Fisheries Management and Aquaculture at Deakin University.
Even though undergraduate coursework was largely uninspiring, it was my Honours year that gave me my first real taste of the scientific process, and I revelled in it! My mission that year was to investigate sea sweep – a poorly studied saltwater fish common along the southern Australian coastline and I spent a lot of time with a mask, snorkel and spear collecting specimens while being repeatedly battered by the rolling Southern Ocean swells. Although the ocean diving was hard and not sustainable long-term, I relished the scientific process and took great joy and pride in piecing together the data and creating a coherent whole. And when I was offered a scholarship to undertake a PhD the following year, I jumped at the opportunity.
This time I chose to stay on dry land for my doctoral studies. My PhD research would investigate the reproductive biology and breeding of Murray cod (Australia’s largest freshwater fish species) within controlled indoor aquaculture systems. Data from my experiments resulted in the publication of four primary research papers and perhaps most importantly, my love of scientific research continued to grow. The science world had me hooked (excuse the pun), and with my PhD now accepted, I eagerly wanted to pursue this career path into the future.
But by now you must be wondering, ‘How the hell does a glorified fish farmer end up in cancer research?’. The answer is largely serendipitous.
The journey started only four months after my PhD graduation, when my life was completely upended. A routine blood test revealed a white blood cell count that was abnormally high. A bone marrow biopsy a week later confirmed a diagnosis of primary myelofibrosis – a chronic blood cancer that progressively scars the bone marrow ultimately leading to severe anaemia and a life expectancy of around 3-11 years. My only hope of a cure was a bone marrow transplant, but given my disease was still in its early stages, the transplant procedure carried too much risk to justify as a first line of treatment. I was told by my doctor that I would need to ‘earn’ my right to receive a transplant – that is, my body would need to deteriorate to a point where the risks of a transplant where no longer overshadowed by the immediate risks of the disease.
The poet Jason Shinder wrote that “Cancer is a tremendous opportunity to have your face pressed right up against the glass of your mortality.” At only 29 years of age, I suddenly found myself pinned up against that glass with no way of escape. Those first few months following the diagnosis were brutal and traumatic and any lingering thoughts about a professional career in science seemed no longer important, even trivial. Fortunately, I had my partner and future wife-to-be beside me and she was (and continues to be) an incredible source of support and comfort. My medical journey also meant that I was back living in Melbourne and as time passed and the initial shock slowly dissipated, I started to find my feet again and began to look for work.
Unsurprisingly, there wasn’t a great deal of opportunities available for a newly graduated fish researcher in the big city, but I made the best of a bad situation. And after several months of submitting job applications, endless emails, phone calls, and door knocking, I was lucky enough to secure a short-term contract as a research assistant in Professor Graham Lieschke’s lab within the Cancer and Haematology Division at the Walter and Eliza Hall Institute (WEHI). A lot could be said about securing a post in a blood cancer research lab immediately after being diagnosed with blood cancer, but I can assure you that it was nothing but a coincidence - I certainly wasn’t harbouring any grand ambitions to find a cure for my own disease. I was hired because Prof. Lieschke’s speciality was zebrafish – a small ornamental fish species that is also an important biomedical animal model - and I was brought onboard to help create a library of cryopreserved zebrafish sperm that would act as a tissue bank for rare genetic mutants. The project was still a long way off conventional medical research, but the zebrafish job meant that I had my ‘foot in the door’ of the biomedical research community.
My time in the Lieschke lab only lasted 9 months before the research funds dried up and I found myself hunting for a job again. However, my ability to garner interest from potential employers felt a little easier this time around, no doubt supported by a sparkling reference from Prof. Lieschke and a modicum of new ‘biomedical experience’ listed on my CV. And soon enough I was offered a research assistant position within the Molecular Immunology Division at WEHI with Dr Erika Cretney and Prof. Gabrielle Belz. This time, there wasn’t a fish tank in sight and I would now have to become accustomed to working with mice. Looks like I would now be staying on dry land for the foreseeable future!
The Belz lab focussed on a group of immune cells called ‘T’ cells. T cells are one of the body’s best defences against infection and cancer and they represent a wonderfully fine-tuned killing machine. When T cells respond to an infection, they must orchestrate a difficult balance between efficiently killing infected/mutated cells, while at the same time minimising collateral damage to healthy tissues (and thereby avoiding autoimmune disease). A primary focus of the Belz lab was to identify the molecular machinery that would allow T cells to navigate this narrow bridge between health and disease. Although I found the subject deeply fascinating, my life in the Belz lab began with virtually no experience in cellular, molecular, or immune research, so my first couple of years were like learning a foreign language. Gratefully, I had some wonderful mentors in Dr Cretney and Dr Rhys Allan and over time, I gradually started to speak the language and find my groove.
After 5 years in WEHI’s Molecular Immunology Division, I had published a few immunology papers and I was offered my first postdoc position at the Peter Doherty Institute in the lab of Dr Laura Mackay and Prof. Frank Carbone. The focus in the Mackay/Carbone lab was on a specialised form of T cell called a ‘Tissue-Resident Memory T Cell’ or ‘TRM’ and I was there to help understand the unique molecular program that allows TRM to adapt and maintain permanent residence in non-lymphoid tissues such as the skin and gut. These investigations continued to expand my knowledge and insight into the immense plasticity and environmental adaption that T cells can exhibit both during and after infection.
During the latter part of my postdoc, 7 years after my initial diagnosis, my disease had started to catch up with me. A series of sub-standard liver function tests meant that the time had come to run the gauntlet and undergo a bone marrow transplant. Given my young age and relatively low number of co-morbidities, the odds of a successful transplant were in my favour. However, the risks of serious complications and death were still very real. One of the ways I dealt with the fear and uncertainty in the lead up to the procedure was to write about it. You can read about my transplant journey here: https://dnewman80.wixsite.com/mfandme/home.
My bone marrow transplant process began with a week-long intensive chemotherapy regime that destroyed my existing diseased bone marrow. Stem cells from a compatible donor (an anonymous gentleman from Queensland) were then infused into my bloodstream from which they migrated into the recently emptied cavities of my bone marrow. A couple of weeks later, the stem cells had regenerated into a brand new and healthy haematopoietic system. Pretty amazing hey! Of course, this description is a pretty overt simplification of a very complex procedure, a process that carries many life-threatening risks and certainly no guarantees of success. One of the major risk factors is graft versus host disease (GVHD), a situation whereby the newly developed immune system from the donor begin to recognise the host (e.g. me) as foreign and begins to attack healthy tissues. About 10% of all transplant patients receiving stem cells from a donor will die from severe GVHD. The harmful effects of this disease are primarily orchestrated by killer T cells that have been let off the leash. Weak or imbalanced molecular signals that ordinarily instruct these cells to calm down, switch off, or die, mean that these cells are unable to curb their destructive enthusiasm and suddenly, the skin, liver and gut are no longer spared from immune attack.
In addition to GVHD, two other major risk factors following bone marrow transplantation are infection and relapse (i.e. the original cancer returns). These situations often occur as a result of weak or suppressed immunity – essentially, the inverse of what occurs with GVHD. Here, the molecular machinery that enables T cells to activate, switch on and survive are imbalanced or malfunctioning, thus enabling a situation where opportunistic pathogens and malignant cells are allowed to grow and thrive. Therefore, for a bone marrow transplant to be successful and to avoid GVHD, infection and relapse, the newly established immune system must find and maintain a tightly regulated balance between hypo- and hyper-activation – the Goldilocks zone.
I owe my life to my donor’s perfectly balanced immune system. In the months after my transplant, I experienced a mild form of GVHD on my skin and liver, but it was never enough to cause any serious damage and it soon resolved. However, rather than being viewed as a burden, this mild and treatable form of GVHD was regarded by my doctors as an ‘encouraging sign’ and that my donor’s T cells appeared to be happy in their new home and functioning well. Not only would they protect me from infection, but any residual disease left in my system would be recognised and destroyed. Ultimately, the T cells from a complete stranger gave me a second chance at life and I’ll be forever indebted to him, as well as the medical community at Royal Melbourne Hospital and PeterMac for giving me this extraordinary gift.
And while my T cells managed to destroy my disease, I also realise that a small molecular aberration here or there could have upset this delicate balance and left me in grave danger. It really is a fine line between cure and death when transplanting a new immune system.
These days, I work as a postdoc in the lab of Professor Ricky Johnstone at PeterMac where we are investigating the use of small molecule inhibitors for reinvigorating a patient’s T cell response against tumours. We rarely notice when someone’s immune system is working effectively against cancer, it is only in circumstances where tumours are able to escape immune control that we begin to understand the shortcomings of human immunity. In many cancer patients, the T cell response against the tumour has (over time) become hypo-activated as a protective mechanism to minimise collateral damage to healthy tissue. Problem is that the patient will die if the T cell response is not restored to a level where tumours can be cleared. My current research is trying to understand the molecular machinery that causes the T cells to suppress their activity and identify small pharmacological inhibitors that might help subvert these processes and re-establish the life-saving function of anti-tumour T cells. The balance must be restored!
Figure legend: Time-lapse photography of anti-tumour T cells (small transparent cells) targeting and killing cancer. Live cancer cells are shown in green and turn red when destroyed by their killer. In contrast, another group of cancer cells (shown in blue) are unrecognisable to the T cells and largely escape death. Photo Credit: Kelly Ramsbottom.
Dr Dane Newman is a Postdoctoral Researcher in the Gene Regulation Laboratory headed by Professor Ricky Johnstone. His expertise includes T cell immunology and preclinical models of malignant and infectious disease.
Dr Dane Newman can be contacted by:
Email: [email protected]