When he was five, Mark Shackleton’s grandmother asked him what he wanted to do when he grew up. “I am going to cure cancer,” came the confident reply amid raucous family laughter.
Although he’s not there yet, the winner of the 2012 Science Minister’s Prize for Life Scientist of the Year, Dr Mark Shackleton, is already changing the way researchers view, approach and treat cancer.
In his PhD studies on breast cancer at the Walter and Eliza Hall Institute of Medical Research (WEHI) in Melbourne, Mark demonstrated for the first time that an entire solid organ—a functioning breast—could be grown from a single cell, a stem cell. He thus proved that, although rare, stem cells exist in solid organs and contribute importantly to normal organ function.
Along with other research at the time, this strengthened a prevailing view that cancers were organised like normal organs, maintained by cancerous stem cells that drove tumour growth. Mark then proceeded, however, to destroy that view and in the process turned the field of cancer research on its head.
In post-doctoral studies at the University of Michigan on the deadly skin cancer known as melanoma, Mark showed that a high proportion of the cells in these tumours—at least one in four—is capable of producing cancerous offspring. This meant that instead of trying to seek out and destroy rare cancer stem cells, effective treatments for melanoma needed a scorched earth policy, attempting to kill as many tumour cells as possible.
Mark is now at the Peter MacCallum Cancer Centre in Melbourne undertaking further work on melanomas that suggests these tumours are intrinsically dynamic, changing their behaviour—sometimes dramatically and quickly—over time. That has huge implications if we are to develop new cancer treatments that provide lasting benefit to patients.
Mark Shackleton’s full citation
“Cancer is a disease of enormous complexity. Our latest research is revealing quite starkly that it is a living entity, that can evolve remarkably quickly,” Mark says. “To paraphrase some words from the film Jurassic Park: cancer finds a way to break free.”
Ask him why he went into cancer research and Mark looks somewhat perplexed because, he says, all he ever really wanted to be was a doctor—and to cure cancer. And therein lies the answer. After years of specialty training as a cancer doctor, or medical oncologist, he was ultimately disappointed by the state of his chosen profession.
“I have a problem with a culture that spends millions of dollars on advances that provide only two or three months of extra survival to patients. A 22-year-old with cancer wants 50 more years, not just a few months. So I really wanted to do something brand new, to contribute in a way that was more fundamental than prescribing drugs too often of limited efficacy. What impresses me about basic science is its power to change history. Its potential impact is quite staggering.”
And the lesson he has learned from his time in research is not to trust pre-conceived ideas—to go back to the beginning and figure things out for yourself.
Cancer occurs when normal cells begin to proliferate uncontrollably. There are two phases to this, Mark says. First, something has to trigger the change that makes a normal cell malignant and, second, cancers have to maintain and propagate themselves.
So he started at WEHI investigating the trigger mechanisms that cause breast cancer. The first step was finding the normal cell equivalent of a breast cancer cell. The idea was that if you could identify the normal counterpart to a breast cancer cell, you could figure out what changed in that cell to make it cancerous.
Because he needed to compare like cell with like, Mark had to develop a way of sorting out and isolating all the different subtypes of cells that make up a breast— the surrounding and supporting cells and the specialised cells that make milk and line the milk ducts. He wanted to find out how these cells developed, and what their relationships to each other were.
For many years, scientists have isolated different cells in blood, using such techniques as flow cytometry, where cells are separated based on how they emit and scatter light. Mark and his colleagues discovered they could do the same with cells in solid organs, if they first broke up the organs and suspended the cells in liquid.
In this way, they found different subtypes of normal breast cells that were all related to each other by being derived from a single type of cell—the breast stem cell. “The day I looked down the microscope and saw that we had grown an entire milk-producing breast from a single mammary stem cell—that day changed my life. From that moment on, I was bitten by the research bug, and I wasn’t going back.”
To study how tumours grow and maintain themselves, he moved to the University of Michigan, where Professor Sean Morrison was looking for someone to help establish a new program of melanoma research. Mark saw this as an opportunity to test out the theory that tumour growth was driven by cancer stem cells. “The idea that tumours could be maintained by rare cancer stem cells is incredibly important. If true, it changes the way you do cancer research and treat patients.”
And Mark already had the tools and skills with which to do the work—particularly his ability to identify different cell types in tumours. What he needed was a means of testing which human melanoma cells harboured malignant potential, and which did not. Once again he went back to first principles.
Mark and his colleagues tested the different strains of mice with which they were working—to see which were more efficient in allowing injected human melanoma cells to grow into tumours. Unexpectedly, they found a new mouse strain that was more than 100 times as efficient at detecting malignant cells as the strain traditionally used. And the difference had nothing to do with the cancer cells themselves. Whereas the immune system of the traditional mouse strain tended to reject human cells outright, that of the new mouse strain did not.
With his new mouse model, Mark found that instead of one in a million melanoma cells being able to form a tumour—as was thought at the time—that one in four cells was potentially malignant. This completely overturned the idea that cancer growth is fuelled by rare cancer stem cells. In at least some cancers, pretty much every cell is as bad as another. For these cancers, doctors will effectively need to eliminate all cells in order to offer the hope of a cure.
At the Peter MacCallum Cancer Centre in Melbourne, Mark is now studying the organisation of tumours and tracing their development in patients. In doing this, he is testing another theory, clonal evolution—the idea that tumours evolve and change by natural selection of the cells in them. What he is finding is that melanoma cells can mutate surprisingly quickly and easily—perhaps explaining the rapid spread of this disease in patients and why melanoma notoriously becomes resistant to drugs. This evolutionary nature of cancer makes the job of finding cures much more complex—possibly requiring different approaches altogether.
Mark says he came back to Australia and the Peter Mac for several reasons. He is from Melbourne, as is his wife, Kylie, who also works in cancer research. So, being at the Peter Mac brings him closer to his extended family—and Melbourne is a good place to raise his two daughters, who are seven and ten. But none of these reasons were as influential as the work environment.
“Of all the opportunities we had to consider, the package offered by the Peter Mac was the best. There was a great melanoma unit already established, run by outstanding health professionals, a fantastic clinical trials program treating people with the latest and greatest drugs, and cutting edge basic research technologies—everything I needed. They said to me, ‘Just keep doing what you are doing.’ So I am.”
The clincher was that Mark wanted to get back into clinical practice—“After all, I always wanted to be a doctor”—and that would have been more difficult overseas. “It was important for me to get back into clinical work as an oncologist. It keeps me grounded, and leaves me with no doubt as to why I’m upstairs working in the laboratory on the other days of the week.”
A former competitive rower, Mark remains interested in keeping fit, and in playing and watching sports—although he is still getting over the 2012 AFL Grand Final. He also enjoys reading great literature, both the classics and more modern works. But mostly he spends his time away from work as a keen supporter of his girls’ obsession with callisthenics.
Mark’s work on mammary stem cells was recognised by the 2006 Victorian Premier’s Award for Medical Research. More recently, he received an NHMRC Achievement Award and a Victorian Endowment for Science, Knowledge and Innovation (VESKI) Fellowship. So the 2012 Prize for Life Scientist of the Year really caps off a remarkable period for this doctor-turned-scientist.
2006 PhD, WEHI/The University of Melbourne
1999 Fellow of the Royal Australasian College of Physicians (FRACP)
1992 Bachelor of Medicine, Bachelor of Surgery, The University of Melbourne
2011-2015 Pfizer Australia Senior Research Fellowship
2010 Achievement Award, National Health and Medical Research Council
2010-present Group Leader Research Division, Peter MacCallum Cancer Centre, Melbourne
2010-present Medical Oncologist, Peter MacCallum Cancer Centre, Melbourne
2010 Publication in the New England Journal of Medicine (first author): Moving targets that drive cancer progression
2010-2012 VESKI Innovation Fellowship, Victorian Government
2009 Publication in Cell (first author): Heterogeneity in cancer: cancer stem cells vs clonal evolution
2008 Publication in Nature (first author): Efficient tumor formation by single human melanoma cells
2006-2009 Post-doctoral Scientist, The University of Michigan, Ann Arbor, USA
2006 Finalist and People’s Choice Award Prizes (for work on mammary stem cells), Australian Museum Eureka Prizes
2006 Premier’s Award for Medical Research (excellence of PhD studies), Victorian Government
2006 Publication in Nature (first author): Purification and unique properties of mammary epithelial stem cells
2006 Publication in Nature (first author): Generation of a functional mammary gland from a single stem cell
2005 Cleveland Young Investigator Award, Royal Melbourne Hospital
Image: Mark Shackleton (credit: Prime Minister’s Science Prizes/Bearcage)