Catching the killers


Rebecca Pool

Thursday, March 21, 2019 - 14:00
Dr Misty Jenkins, Laboratory Head at the Walter and Eliza Hall Institute, Australia, uses live cell imaging to understand how immune cells attack cancer cells.
Three years ago, Dr Misty Jenkins' neurosurgeon friend said to her, 'Misty, I'm sick of telling my patients they're going to die from brain cancer, what are you going to do?'
At the time, Jenkins, Laboratory Head at the Walter and Eliza Hall Institute of Medical Research, Australia, was using live cell imaging and other cutting-edge techniques to understand how immune cells, known as killer lymphocytes, attack cancerous cells.
Jenkins and her team had been harnessing results to develop a new immunotherapy, CAR T-cell therapy, in which they would genetically modify a patient's immune cells to kill his or her own cancer cells. But while the researchers had already achieved huge success in leukaemia, brain tumours remained untouched.
"I looked into this and came to realise that for decades there had been a dearth of medical research into brain cancer, so I thought I am going to do something about this, " she says. "The average age kids are diagnosed with a brain-stem tumour is age six or seven, and most are dead within the year, so I saw this huge opportunity to make a real difference."
A glimpse of T cells as efficient killers. [Misty Jenkins/WEHI]
Within eighteen months, Jenkins had secured hundreds of thousands of Australian dollars to translate her research to brain tumours. And today, her immune system research continues apace.
"We're focusing on the most aggressive brain tumours in adults and children, and I'd like to use two-photon microscopy to image the immune system within tumours in the brain, as that's never been done before," she says.
"We're already moving into preclinical models of brain cancer, and are starting to grow tumours in the brains of mice," she adds. "We've kept moving, and always had an eye on what can be learnt about the cell's behaviour to design these better therapies."
Passion for progress
Jenkins always wanted to make a difference. At aged 8, her blue-collar parents encouraged her to join a St John Ambulance first aid training programme, where she was taught the basics of the human body by paramedics.
As a teenager she was helping out at a local motorbike park at weekends, dealing with any medical emergencies. And by the time she was finishing high school, her interest in the biological sciences and health was sealed.
"I'd started looking down microscopes and was fascinated by the wayward invaders and germs that attack our bodies every day," she says. "I'd always loved asking questions but had much to learn about the world, so decided to immerse myself in a general science degree at university, and learn more about the world and my place in it."
Come 1997, and at the University of Melbourne, Jenkins soon discovered biotechnology, microbiology and immunology. "I loved learning about cancer and our immune system and felt like there was so much more to understand and explore," she says.
"I'd learnt about T-cell biology and was using light microscopes to study T cell responses to viruses infected cells," she adds. "This was pretty cool and that's when I knew I wanted to do a PhD."
Fortuitously, a colleague had told Jenkins to carefully choose her PhD supervisor, as he or she would 'be writing your references for the rest of your academic career'.
So with this in mind, together with her love of T cell biology, she emailed Nobel Prize winner and immunologist, Peter Doherty, also at the University of Melbourne.
He phoned back within hours, and Jenkins started her doctorate in Microbiology and Immunology with Doherty and viral immunologist, Stephen Turner, in 2003.
Killer T cells: Super-resolution image of a group of killer T cells (green and red) surrounding a cancer cell (blue, centre). [National Institutes of Health]
"I was so very brazen at the time," laughs Jenkins. "But I now tell my students that even the most senior researchers will be very generous with their time, if approached by young, enthusiastic scientists."
Doherty had won his Nobel Prize in Physiology or Medicine in 1996 for describing how the body's immune cells - T-cells - protect against viruses, and Jenkins was now investigating how these cells killed virus-infected and cancer cells. However, during her time with the Nobel Laureate and Professor Turner, she learned much more than how to carry out world-class research.
"Doherty didn't just teach me how to do experiments, he taught me how to read a paper, write, give a presentation and why these things are important," recalls Jenkins.
"He also taught me about the power of communication, and how the general public is really interested in what scientists do and how we have an obligation to talk to people and increase scientific literacy, " she says. "Imagine today if the public was more informed on climate change or vaccination; people could make more informed choices on their lives and impact on the planet."
Two years into her PhD, Jenkins saw Professor Nigel Waterhouse, then at the Cancer Cell Death Laboratory at the Peter MacCallum Cancer Institute, presenting his research on natural killer cells.
"Using live cell imaging he had produced these beautiful movies of natural killer cells killing cancer, and at the time I thought, 'Wow I could apply that technology to look at my T-cells killing my targets'," she says. "The images were simple, but I was hooked, and that was when I really fell in love with microscopy."
Jenkins collaborated with Waterhouse for the next year and soon published research on using influenza-specific T-cells to kill target cells in the Journal of Cell Biology.
Come 2006, and with PhD in tow, she moved to the University of Oxford, UK, to work with Professor Gillian Griffiths on synapse formation between killer T cells and their targets. 
"We've come a long way and we actually have cures for some cancers, but with these really tricky cancers we are behind the ball."  Misty Jenkins
Griffiths soon moved to the Cambridge Institute of Medical Research, Jenkins was appointed a Fellow of the University of Cambridge, and in her words, 'loved it'.
"I grew up in the country in Australia, and this was so different," she says. "I loved the cultural aspect of going to a formal hall every Friday, wearing an academic gown, and meeting the most extraordinary people from all over the world and from different disciplines."
"One minute I would be chatting to someone who studied Medieval coins and the next, it would be global warming, and the Archbishop of Canterbury would come to dinner" she adds. "The diversity was incredible."
Crucially, for the world of immunotherapy, Jenkins was now carrying out a lot more live cell imaging, using an Andor spinning disk confocal microscope, and learning how to label fixed cells with fluorophores and antibodies to get great immunofluorescence results.
"Gillian was very thorough," she says. "For example, she instilled in me to really test your antibodies, do your own quality control, and I gained such a deep understanding of many different tools."
During her time here, Jenkins uncovered key cell signalling mechanisms, and come 2011 she moved back to Melbourne to take up the position of Senior Research Officer, at the Peter MacCallum Cancer Centre. Building on her synapse and cell signalling breakthroughs, she was leading a small team of researchers that was focusing on using T-cells to defeat disease.
As she points out, she devoted the next several years to pinning down how T-cells delivered their 'lethal hit', and also working out what happened when this chain of events went awry. 
The killer T cell (blue) is engaging a target cell; signalling molecules (pink) gather at the site of cell-cell contact and indicate that the T cell identified a target [National Institutes of Health]
She heavily relied on confocal microscopy and key publications from this time include 'CAR-T-cells inflict sequential killing of multiple tumor target cells’ and ‘Failed CTL/NK cell killing and cytokine hypersecretion are directly linked through prolonged synapse time’, published in The Journal of Experimental Medicine. 
Beating brain cancer
Jenkins took up her current position of Laboratory Head at the Walter and Eliza Hall Institute in 2016. As she says: "I had a wonderful and productive time at the Peter MacCallum Centre, but it was time to develop my independent research group and head in a different direction."
Indeed, since joining WEHI, Jenkins continues to work on T-cell killers and is applying CAR T-cell therapy to brain tumours, specifically adult and children high-grade and lethal gliomas.
To date, CAR T-cell therapy has had mixed results in solid cancers, often causing 'cytokine storms'; a potentially fatal inflammatory response that can lead to organ failure. But Jenkins is now working on making CAR-T-cells more efficient, without the toxic side effects.
Currently establishing workflows, she also intends to use two-photon and lattice light sheet microscopy for live cell imaging, including studies on tumours in mouse models. "You can't operate surgically on these tumours so in the past they were never removed, but we're now also getting samples from rapid autopsy programmes," she says.
"The dogma has been that the brain is an immune-privileged site and with its blood-brain barrier, nothing could get across," she adds. "But now we know this just isn't true... and we're really trying to design therapies for brain cancer."
One questions that Jenkins is asked, repeatedly, is 'when will we have a cure for cancer?' As she points out, cancer is not a single disease, but is in fact, thousands of diseases. "Even adult and kids' brain cancers are different diseases with completely different molecular switches and a different pathogenesis," she says.
Still, Jenkins is confident amazing progress is being made. Highlighting how a generation ago, 90% of children with leukaemia died but today 90% survive, and that the five-year survival rate for breast cancer has risen from 50% to more than 75% in recent years, she believes the time is right to be looking at the rarer, low-prognosis cancers.
"We've come a long way and we actually have cures for some cancers, but with these really tricky cancers we are behind the ball as there just hasn't been the investment in medical research here," she says. "But in the last twelve months, at least in Australia, we've seen a little bit of groundswell and government is finally beginning to invest."
Clearly Jenkins' endless enthusiasm for immunology coupled with a relentless determination to make a difference has, and will continue, to quickly propel her research forward. But what advice does she have for today's up and coming researchers?
"Take your work seriously but not yourself too seriously, and have fun," she says. "Decide how you want to spend your days, have a plan and break down your goals into really small chunks, knowing that achieving each one is a win."
"And be resilient," she adds. "Know how to have a thick skin because as scientists we're constantly putting our ideas out there to be challenged, so take the feedback, learn and grow from it, and know that it isn't personal."
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