Speaking of Science: From early detection to impact: improving outcomes of children with leukaemia

The team eventually went on to develop a highly accurate and sensitive technique known as minimal residual disease (MRD) testing which assists doctors tailor anti-cancer treatment for children with the most common type of leukaemia.

The use of MRD testing to guide treatment decisions for children with leukaemia has been the standard of care in Australia for over a decade, leading to many positive outcomes for the patient, their family and the national health system.

Watch and listen to our latest Speaking of Science with an integral research leader in this area, Professor Murray Norris AM, below.

Recorded on Friday 25 September 2026, from 10:00AM–11:00AM AEST.

Video transcript

0:07 Cadence Haynes 

Okay, welcome everybody. I hope everyone can hear me and we're ready to go. Thank you so much for joining me this morning for our September webinar in the Speaking of Science series. My name is Cadence Haynes and for those who don't know me, I'm acting in the role of Executive Director of NHMRC's Research Foundations Branch.

I'd like to start this morning by acknowledging the Traditional Custodians of the land on which each of us is meeting. I'd personally like to acknowledge the Kaurna people as the traditional custodians of the Adelaide region, where I'm joining you from today. I acknowledge and respect their continuing culture and the contributions they make to the life of this nation.

I pay my respects to their elders, past, present and emerging, and I extend this respect to all Aboriginal and Torres Strait Islander people joining us online today. I encourage you all to take a moment to reflect on the land on which you stand or sit today, and to recognise the deep connection Aboriginal and Torres Strait Islander peoples have with those lands.

I’ve got a little bit of housekeeping before we begin. There will be an opportunity to ask questions of our guest speaker, and we'll run through those questions and answers towards the end of the webinar. Please submit your questions through the Teams Q&A function.

If you're ever unable to attend a webinar or would like to go back and re-watch your favourite, all our recordings are made available afterwards on NHMRC's website, so track those down if you're interested.

Some of you may know that September is Childhood Cancer Awareness Month. Childhood Cancer Awareness Month is a global initiative held each September to raise awareness of paediatric cancer, honour children affected by the disease and rally community support for research and family services.

Each year, around 750 to 800 Australian children under the age of 15 are diagnosed with cancer. Acute lymphoblastic leukaemia, or ALL, is the most commonly diagnosed cancer in children and the second most common cause of cancer-related death among children in Australia.

Beginning in the 1990s, researchers at the Children's Cancer Institute received a succession of NHMRC grants to support research focused on childhood cancers. With important additional support by Cancer Council New South Wales, Anthony Ruth Memorial Trust and the Leukaemia Foundation, the team went on to develop
a highly accurate and sensitive technique known as minimal residual disease or MRD testing.
MRD testing helps doctors tailor anti-cancer treatments for children with the most common types of leukaemia. The use of MRD testing to guide treatment decisions for children with leukaemia has been the standard of care in Australia for over a decade for patients, their families, and the national health system.

An integral member of this NHMRC funded research team is our guest speaker today; Professor Murray Norris AM. Professor Norris is a group leader of the Experimental Therapeutics and Molecular Oncology Group at the Children's Cancer Institute and was one of the Institute's original scientists when it opened in 1984.

Professor Norris's research has focused on utilising new molecular technologies to improve the diagnosis, risk classification and treatment of childhood cancer. He's been responsible for developing and implementing unique technology enabling the molecular detection of MRD for the early prediction of relapse in children with ALL.

His research has been recognised by several awards, including the inaugural Sally Crossing AM Award for an outstanding outcome in cancer research in 2019, and he was appointed a Member of the Order of Australia in 2015 for significant service to medical research as a molecular biologist and through pioneering developments of treatments for cancer in children. It's incredible work.
Please join me in welcoming Professor Morris to Speaking of Science today as he discusses improving outcomes for children with leukaemia. Welcome, Murray.

4:21 Professor Murray Norris

Thank you very much for that introduction, and for everybody, I'd just like to say that I want to tell you a story that starts with a single idea back in the early 1990s and ends with a test that Medicare now pays for and that decides how every child in Australia with acute lymphoblastic leukemia is treated.

I think many of you working in research have heard the concept of the valley of death, and this describes that difficult gap between basic scientific discovery that's made in the laboratory and the actual application of that to the clinic. Moving a promising diagnostic test, device or drug to the clinic requires extensive testing and most of these ideas fail either during the preclinical testing phase or early clinical trials, human clinical trials, frequently because of ineffectiveness in the case of a test or in the case of the drug, toxicity or safety issues.

What I want to talk about though is a successful story, and that's the molecular diagnostic testing to improve survival rates in acute lymphoblastic leukemia. So just to give you an outline of the 5 areas that I'll look at. Firstly, it will be the disease. What is ALL and where does it come from? The problem that we had back in the 1990s, which was that one in 5 children were relapsing, and by and large we couldn't tell which of those children were going to be the children who relapsed, certainly not with any accuracy.

Then the idea, the idea being that ALL carries its own genetic barcode so that each leukaemia has its own genetic barcode or fingerprint. And then taking that idea, developing a new test and showing that the proof, testing in a national clinical trial had some usefulness in the clinic, and then finally ending up with the impact, beyond the frontline treatment, the increased survival in Medicare funding.

Okay, so let's start with the disease, and of course acute lymphoblastic is the most common cancer that children get. Like other blood cancers, it starts in the bone marrow, which does the body's blood cell factory. Bone marrow makes every blood cell we have, red cells that carry oxygen, platelets that clot, and white cells that fight infection and of those white cells, lymphocytes, one type.

And acute lymphoblastic leukaemia begins in an immature lymphocyte or stem cell. These stop maturing and start expanding and eventually crowd out everything else in the marrow, and so this is what makes the children sick, gives them the anaemia, bruising and infections.

So, what's the history been? Well, prior to the 1960s, ALL was uniformly fatal. No one was cured. And then by 2010, in quite a short time frame really, we ended up with an 80%
cure rate of ALL and this is despite the fact that 98% of children will actually achieve remission. Almost all children will go into remission. It's a very chemo sensitive disease. However, back at the time then, 20 to 25% of the children were relapsing and the relapse is due to small numbers of surviving cells that are undetected by morphological examination, which was the standard that was being used at the time.

As I said before, ALL is the most diagnosed cancer in children, and it used to be the most common cause of death from cancer or disease, but now it's been replaced by brain cancer. It's second only to brain cancer and the number of deaths it causes.

Around 410 Australians are diagnosed with ALL each year and more than half of them are children and adolescents under the age of 20. It's a rare disease at a national scale, particularly when you compare it to the big 4 cancers in adults, breast cancer, lung cancer, bowel cancer and prostate cancer, which essentially only occur in adults, not children. Yet, as I said, it is the single most common cancer that children can get.

If you look at the diagnosis and when it peaks, it peaks in the early preschool years, between the ages of 2 and 5, with a slight excess in boys. Most cases arise in B cell precursors, as shown in the graph there at the left in the orange, is the common, the most common type of ALL, which is called common B cell precursor ALL. But it also occurs in a smaller share of T cells and of course, B cells and T cells play a central role in the human adaptation the immune system by destroying infected cells and regulating immune responses.

This early peak between 2 and 5 also provides a clue about when the disease actually starts. So, the first hit actually occurs in the womb and we know this from studying blood spots taken in newborns, the so called Guthrie Test which is taken the also from identical twin studies. 
We've had cases where identical twins who share the same placenta and hence the same blood supply, if one child, one identical twin gets leukemia, you can actually find this pre-leukemic clone in the other child and they are at increased risk of developing leukaemia themselves.

Roughly speaking, out of every 100 newborns, one will carry one of these pre-leukemic clones and then there's this silent interval where the clone really sits harmlessly in the body and it's only really out of every 100 newborns that have a pre-leukemic clone, only one of those will actually go on to develop leukaemia. It's actually quite a rare event.

Then for it to develop leukaemia, a second hit has to occur after birth, and that is providing further mutations to then form full-blown leukaemia and in terms of the cause, it probably is multifactorial, but one particular hypothesis has been gaining a lot of traction over the decades because there's a lot of epidemiological evidence to support it, is the delayed infection hypothesis and this posits that high exposure to germs in infancy is actually protective.

In other words, priming the immune system very early on is actually protective to a child, whereas a child that's not exposed very early on to infections, when they do eventually come across new infections, they can have an abnormal response with the delayed infection supplying a second hit.

As I said, this has been, this hypothesis has been around for decades. It was proposed by Mel Greaves, a well known oncologist, and it's gaining a lot of evidence to support it.

Okay, so ALL has really been one of medicine's great success stories. We've seen it go from a death sentence. It actually, you know, in the 1940s, chemotherapy actually occurred in children with leukemia. Up until that particular point in time, no chemotherapy was being used to treat patients, but the first evidence of this came from Sydney Farber's work at the Boston's Children's Hospital, taking antifolates like aminopterin and trying these on children with leukemia, and showing that he could get remissions. Although these only lasted for a few months at most before the child relapsed again and survival was essentially zero.

However, following that in the 50s and 60s, they had the breakthrough insight that
durable cures from combination chemotherapy plus treatment aimed at the central nervous system could actually increase the survival rates. Then in the 1970s up to the 1990s, successive cooperative trials have refined the treatment on the same backbone and cure rates climbed past 70%. Today, of course, over 90%, you know, 9 in 10 children with ALL are completely cured of their disease.

So, what was the problem? The problem was that relapses were occurring in one in 5 children, and by and large it was difficult to determine which child the disease would recur in.

If we look at that, at diagnosis, as I said, ALL responds to chemotherapy really well. It's a chemo-sensitive disease and the vast majority of patients, over 98%, will enter remission.
But one in 5 are relapsing with treatment failing to fully eliminate cancer cells and of course, when a child does relapse, the chance of getting a cure is substantially lower.

Salvage treatment is very harsh. Re-induction chemotherapy, often a bone marrow transplant, all can have lifelong consequences, and they can have lifelong effects from the treatment they had as a child.

On the other hand, under treatment, of a high risk child and they relapse, the chance of cure falls sharply. So, if we just look at the development of leukaemia shown in a graph here on the left, we can see down the bottom the horizontal axis is showing time from diagnosis throughout to 3 years. Then on the vertical axis is the ratio of ALL cells to normal cells in the bone marrow. So, like the vast majority of cancers, ALL begins with a single cell that turns into the leukaemia and that multiplies quite quickly.

Acute lymphoblastic leukaemia up to the point of diagnosis shown here, and an average child at that point can have in the order of 10 to the 12th leukaemia cells. Ten to the 12th trillion leukaemia cells equate to about a kilogram of cancer cells. So they can have quite a high load.

Following diagnosis, the children are very quickly put on to induction therapy, which lasts about a month and that's defined here at day 35, this month of therapy. And as I said, virtually all children will go into remission. But remission here has a really specific but modest definition as shown by the dotted line at the very top here.

Under the microscope, they're using microscopy to look for the evidence of leukaemia. This has a sensitivity of only about one leukaemia cell in 20. So, remission is really not the same as cure. The disease is just invisible, not gone and obviously it was known that you couldn't stop induction therapy there.

So, therapy, actually consolidation and maintenance therapy goes out to 2 years, and one of 2 things happen. In the majority of cases shown by the green line, the cells will keep on being eliminated till you get long term survival.

However, either on treatment, a small proportion of cancer cells will become resistant to the therapy and then grow back and cause an early relapse, or following those same resistant cells, following the incompletion of therapy, come back to force a later relapse. Of course, you're now back to where you were at the beginning with this high load of leukaemia cells that have already become resistant to the initial treatment and therefore very difficult to cure.

Which child was the one in 5? And before MRD testing, we really only had indirect markers to help. And this is age, so the children, older children have a worse outcome and very young infants also have a worse outcome because of particular genetic rearrangement that occurs in them. High white cell counts, chromosomal changes, response to steroid and bone marrow examination. These are all important, but really greater precision was needed and if you undertreat a child, as I said in a relapse, their chance of cure falls sharply. But if you ever treat a low risk child with harsher treatments, there's a long term cost as well and that can include infections, infertility, heart damage, second cancers, and even effects on learning and cognition.

Both errors harm children, and so what is needed is a better test. And of course, if you define what you needed in that test, it had to be one that was sensitive, far below the level of doing microscopy, of finding one in 20 cancer cells, obviously needed to be specific. Detection of a patient's leukaemia specifically and not the healthy cells that look similar.

Quantification was critical because you just didn't want to have a black and white. There are residual cells here. How many of those cells was important in terms of grading a response? Timely, that was a big issue when we started out. It was taking us inordinate amounts of time to determine the level of residual disease. You needed something where a result could be returned within weeks of starting treatment, while therapy can still be changed. And of course, accuracy, you needed to standardise and have quality assured testing, so you know enough about the accuracy of the test to bet a child's treatment on.

The answer to all of that turned out to be minimum residual disease or MRD testing. And so, this was based on the idea, of course, that every leukaemia carries its own genetic barcode. Antibody, so leukemia, obviously acute lymphoblastic leukemia arise in either B cells, mostly B cells, but also T cells. And antibodies and T cells are part of our adaptive immune system with a role in identifying germs and neutralising or destroying them.

And B cells shown here on the left carry B cell receptors on the surface and when they're in the bloodstream, they're the antibodies. The antibody is made up of 4 proteins. Two of them are immunoglobulin heavy chains shown in the middle and then there are 2 immunoglobulin light chains on the outside, and these antibodies are floating around in your system to recognise germs that we've never met. And how does it do that? Well, it solves it with randomness, making unique antibodies for each cell and of course, ALL arises when a single immature lymphocyte or stem cell becomes cancerous.

So if we just look at the immunoglobulin heavy chain and the rearrangements using PCR, lymphocyte DNA carries libraries of these interchangeable gene segments. They're called V variable segments, D diversity segments, J joining segments, and constant regions and during the development of a lymphocyte maturing, VDJ segments are cut and spliced. And during that cutting and splicing, random nucleotides are both inserted and deleted so you end up with a specific gene sequence which is unique to that particular lymphocyte.

Then using primers and PCR, forward and reverse primer, you can actually amplify up that sequence and find out the genetic makeup of that sequence and shown here is precisely what that's been done. Here are 5 patients, and this is the IGH rearrangement in those patients. Shown in the box is the diversity region that I just pointed out in that last slide and you can see even that diversity region that has been retained is completely different in all 5 patients. But the true randomness comes from the red nucleotides shown here, which have all been inserted into the sequences. It's very easy to just look at any one patient and you can see that that whole genetic sequence there is completely unique to that particular leukemia.

I should also say the dot point down bottom that real time quantitative PCR was introduced in 1996, which was a big boom to our work. We were one of the first labs to get real time PCR, because although we could detect these sequences, what we nearly needed was being able to quantitate it at the same time and do it in a timely fashion. And that's precisely what happened. So, technology finally caught up with what we needed.

So, it's important to realise then that, you know, leukaemia is clonal in origin. So, every leukaemia cell in a child descends from one ancestor and they all carry that ancestor's rearranged receptor gene. Now healthy marrow, if you look at it, has billions of lymphocytes, each carrying a different sequence, marking that particular cell. But a leukemic marrow at the point of diagnosis has billions of copies, shown in the diagram on the right, of 1 sequence. And that unique sequence is a marker of that child's cancer in that child, and I should have just one little caveat there. Although we have a unique barcode, most leukaemias have more than one unique rearrangement. They not only rearrange IGH and IGL, but also TCR genes as well.

And so, it's important that you follow more than one rearrangement because although they're present in the cells, leukemia cells are inherently, like other cancers, inherently unstable and they can cause further random mutations as they go along. And so you can see clonal evolution where there was a very nice barcode for that leukemia that may actually be degraded. So following more than one rearrangement gets around that problem.

Okay, and the other important thing to realise is this is not an off-the-shelf kit that can be used. It's not like, say, a PSA test, a prostate specific antigen test, of which there is just a single test that can be given to a male where you're worried about the risk of prostate cancer. This test actually had to be designed and validated for every single child. And so, this is sequence if we look at it at diagnosis, we sequence the leukaemia’s antigen receptor gene rearrangements and then design and develop and optimise a highly sensitive assay for each leukemia. This test is then used to monitor at set points and amplify and quantitate the cells carrying that barcode and then getting the results back to the treating clinician in time to change treatment.

So, each assay is designed, validated and reported fast enough to change the treatment plan. So, um... If we look at this in a schematic way, at the top we're showing microscopy, which is actually used to define remission. And as I said before, this is pretty insensitive. It can only get down to about one leukemia cell amongst the 20 normal cells. Flow cytometry is routinely used to measure MRD, minimal residual disease. This routinely gets down to one in 10,000, can be even more sensitive in this.

Patient specific PCR or MRD testing has a routine level of one in 100,000 cells and the most sensitive assays can get down to one in a million normal cells. And so, this is a test, the MRD test, which is 10,000 to 50,000 times more sensitive than microscopy. Okay, so that sounds great. Sounds like it'll help a lot. But, you know, a good idea and a working assay are still not evidence that children live longer. We had to have the proof that this could do something.

And 2 different questions needed answering. First one, an easier one, I guess, is does MRD testing predict what happens? And for this, this could be answered retrospectively. And that's precisely what we did. We had samples stored from previous trials that had gone on. And by taking those and assessing them completely blindly, taking the samples, and here again, this is a Kaplan-Meier, where you can see months from diagnosis on the horizontal axis and survival on the vertical axis from 100 down to zero. And this test was being done right back here near the beginning at day 35. Just a single test was these children were all in remission. But can we determine the level of residual disease and how did they do? And those children that had less than 10 to the minus 3 cells, one in 1000, their survival was 81%, and this was at a time when survival was way, way back, 81%, whereas those that had high levels of residual disease greater than 10 to the -3, the survival rate was only 23% so that was great, but of course that says, yes, we can detect it and they do poorly.

But if treatment has changed based on MRD level, do more children actually survive? And for that, you can only answer that prospectively. So, you know, showing that MRD predicts relapse was the easy part, showing that it actually saves life, actually took a decade. And that's because you had to run a trial and this was the ANSTOB 38 trial. The Australian New Zealand Children's Haematology Oncology Group Study 38 enrolled over 600 children across Australia and New Zealand from 2002 to 2011.

There were also another 500 patients from the Netherlands being done in the Netherlands on the same study as well. It was a prospective national trial across Australia and New Zealand where the results were used to determine treatment.

MRD was measured by quantitative PCR at day 33 and day 79. Results were combined with clinical and genetic features to define risk groups and those children with high MRD were escalated to more intensive therapy with intervention before relapse rather than treatment after it. The study was run as a companion study to a large European trial, 2000 trial, so anchoring it into an international evidence base and what did the results show after this 10-year clinic trial? Here again is another Kaplan-Meier survival curve with
again, months from diagnosis on the x-axis and survival on the y-axis and I've shown the last one down the bottom, the black line is the entire group, the survival of the entire group, and that sits up here with the blue line showing that it's around 90% survival, just under 90% survival for children overall.

And most importantly, I guess, is the red line. The red line here is the group defined as high risk. These are the children based on a test being done in the very early stages of treatment. These were the high risk children. The survival rate for these children was 70% and yet when this trial began back in 2002, the survival rate for the high risk children was around 35%. We're doubling in survival rate, which is very good.

Since then, we know that we could even do it earlier than day 35 or day 79, going back to day 15. About one in 5 relapses were happening in children who were classified as intermediate risk. So MRD testing was looked at day 15.

This separated children even more accurately into those that had other very high levels, high levels of MRD, moderate, and their outcomes followed that accordingly. And you can see that the MRD negative, you would expect there to be 100% survival, but there was one patient who had a negative MRD who still relapsed. And it turned out that that patient did indeed have a negative MRD, but they'd had an isolated CNS relapse. Quite a rare event to occur, but they had a relapse in the brain and spinal cord, which is not that uncommon, and treatment is usually given to the spinal cord CNS prophylactically, but this one patient had an isolated relapse there.

MRD is now the strongest single predictor of outcome for patients with ALL. This testing has been applied in many trials run by groups in Australia and internationally, and I should say that the international studies, they independently had developed MRD, PCR-based MRD detection as well and together, these trials established values for patients of different ages and at different stages of treatment.

There's really, for ALL, there's really no other single measurement that tells you as much about what will happen to an individual tile. Okay, and what about the impact? MRD testing had other benefits apart from identifying patients at high risk of relapse. If you measure MRD before and after transplant, it actually has a very high predictive value. There's a Kaplan-Meier curve shown there doing MRD before transplant where the negative patients had 100% survival.

From 2014, MRD testing prior to transplant was shown to predict relapse. Persistent MRD before and after treatment identifies children at highest risk, and pre-emptive treatment has been designed to try and prevent that relapse. And it's the same logic as before. Intervene while the disease is still small.

It's now the same framework now has been used for teenagers, young adults and adults as well. As part of the Australasian leukemia and lymphoma groups ALL 06 study, adolescents and young adults were treated on a paediatric style regimen with MRD risk stratification and that was extending what had occurred in the study 8 approach, the ANSTOC study 8 approach to patients from their mid-teens to late 30s.

MRD is also used as an entry criteria and response measure in trials for relapse and high risk disease. And it's also a research tool because, you know, if there's a new drug that's being introduced, you can actually measure how completely that drug is clearing disease, far more sensitively than just counting the number of remissions and things. It can also decide who can get access to new targeted therapies and that's because MRD identifies a group at genuinely high levels of risk. It therefore defines who qualifies for newer targeted treatments. Medicare listing of MRD testing allowed patients who test MRD positive to access drugs like immunotherapy, blinatumomab, through the pharmaceutical benefits scheme.

So blinatumomab shown on the diagram on the left, it's a bispecific T-cell engager, a BITE, that combines 2 binding sites, a CD3 site, that binds to the CD3 receptor on the T cell and a CD19 site for the tumour B cells binding to CD19. This drug works by linking these 2 cell types together and activating the T cell to exert a cytotoxic effect on the target cell. This shows that, you know, a diagnostic test and a therapy funded together. Without the test, the drug cannot be directed to the patients who need it.

So in 2000, I think I mentioned before, children with high risk ALL, the survival rate was 35%. But following the clinical trial and in 2013, that MRD guided treatment led to a 70% survival in these high risk children, so a doubling in survival rate. Another, what was an unanticipated outcome, you know, when we first started, all we were after was trying to find residual cancer cells showing that these patients were high risk. But although the test was originally aimed to do that, it could also identify children who could safely be given less treatment.

And so MRD guided treatment for patients who didn't need the same level of treatment as high risk, and that leads to shorter hospital stays, reducing the risk of infections, heart damage, secondary cancers, infertility, fewer nights in hospital means that parents can get back to work more quickly. Siblings can be at home with the family. Families outside the cities are spending less time away from them.

Since 2018, MRD testing has become the national standard of care for ALL. Treatment decisions for every child diagnosed with ALL in Australia are now based on MRD testing. Testing has been carried out on more than 3,000 patients in the Children's Cancer Institute where I work and have provided the service to hospitals throughout the country and oncologists worldwide. As I said, the test was independently developed overseas, now rely on MRD to guide treatment decisions.

And here's an example of actually using MRD testing to follow an individual child with very high risk ALLs and an infant with a rearranged MIL gene where their prognosis is very grim. You can see at the time of diagnosis, the child's given treatment. It starts out as being a very sensitive disease and the level of residual degrees drops quite sharply, all the way down to 10 to the minus 6 here, but still detectable.

Transplant was given to this child, but unfortunately within months they'd become resistant and relapsed. A new drug was introduced which caused a small decrease in the level of residual disease. Patient relapsed again. Another drug was tried that caused an even greater drop, but it eventually came back again until finally this drug there, and I can't remember which one it was in red, actually brought the patient down to having no measurable residual disease left at all, and a second transplant was performed at that particular point in time.

On the 1st of November 2023, new Medicare benefits schedule listed 2 items, and that was whole genome sequencing and flow cytometry. Whole genome sequencing has now replaced doing the PCR-based detection of antigen receptor gene rearrangements, and it covers the detection of measurable residual disease in patients with ALL. I've highlighted measurable there because although it was for many decades just called minimum residual disease, Medicare decided that measurable residual disease is far more intuitively appropriate for its own measurable residual disease.

Whole genome sequencing has been a real boon. It would have been something great back in the 1990s to have had that, but it was a pipe dream. You know, the first human genome was sequenced and reported, I think, by President Bill Clinton in about 2002. And that cost roughly $3 billion to produce the very first human genome sequence. Fortunately, today, with the improvements in technology, a human genome can now be sequenced for under $1,000. That's been a great boon to have.

But what this shows is that sustainable funding, instead of a dependence on grants and philanthropy, is important. It's providing equal access regardless of postcode or hospital, and it's also the gateway to PBS subsidised access to new therapies.

So, here's a sort of a path of 30 years that turned one idea into a funded national service. Beginning in 1994, showing that residual leukaemia cells could predict outcome through to
optimising and improving it until the 10-year clinical trial starting in 2022, and then completion of that in 2011, and then seeing this doubling in the survival rate of high risk ALL. 2014 MRD after transplant, before transplant, predicts relapse.

By 2018, it had become a national standard of care for ALL in Australia. 2023, as I just said, listed on the Medicare benefits schedule. And then in 2024, our institute of Dunno had
tested over 3,000 Australian patients with this particular test. So, it's been a long journey, 29 years from a laboratory idea to a Medicare item. It required a series of NHMRC Project Grants. This never would have happened without NHMRC funding, the Postgraduate Scholarship, Cancer Council New South Wales Grants are also extremely important, as well as the Anthony Rota Memorial Trust and the Leukaemia Foundation and philanthropy. It's been a durable collaboration between a research institute, a national trials group, children's hospitals across 2 countries, and international partners. And no single grant could have achieved this.

What's the future hold? Well, whole genome sequencing, of course, can give you deep sequencing based detection, reaching towards one in a million cells and beyond, and possibly with less need for a customised assay per patient. Gently working towards monitoring residual disease, measurable residual disease in the blood rather than bone marrow. So, children face fewer invasive procedures. Broader, you can start monitoring now for cellular and immune therapies such as T cell treatment and probably another big one there is wider. Applying the same logic which happened in leukemia because of the unique barcodes that leukemia cells had, but now having whole genome sequencing, being able to apply this to other childhood cancers particularly solid tumours.

And so just to acknowledge the, you know, particularly Michelle Hayter at the Children's Cancer Institute and Glen Marshall at the Kids Cancer Centre. The 3 of us were, you know, we all met very early on in the 1990s and really picked Glen's brain about you know, what was needed for childhood cancer as we were starting out. And, you know, we came up with this MRD testing.

Rosemary Sutton, who's led the MRD team, who led it for many years, and then Michelle Henderson, who took over the entire MRD lab team. We’ve had too many people to name over that, over that 30 year process. The funding organisations that I mentioned previously particularly like to acknowledge the families who consented to the clinical trials and the clinical trials groups, ANCHOG, the Australian, Australasia Leukemia and Lymphoma Group, and every participating hospital, and thank you.

47:49 Cadence Haynes 

Thank you so much, Murray. That was a wonderful journey across the decades. We have some time now for questions and if anyone has any burning queries, don't be shy in posting them into the group chat. I'll be sure to read them out while people have a think.

I've actually got a question for you. So, your research has got a really clear pathway from that bench to bedside, you know, across the valley and your connection, I can hear as you speak with the people and children at that bedside has been beautifully demonstrated.

You mentioned earlier when we were chatting about the origins of your institute sort of coming from this chance encounter with some families. But connecting with patients, parents, what we now sort of call consumers and community members, for molecular and cell biologists, that's not always a natural connection to make.

I would love to hear some of your experiences in making those connections with consumers and communities and whether you've got any special tips you could offer for those of us whose research is in the realm of basic or discovery science.

48:56 Professor Norris

That's a very good question and you're right. You know, when I first started out, I arrived at the Institute when it just opened its doors. So that was 42 years ago. I really knew nothing about childhood cancer. I just thought this would be an interesting place to do a PhD in really and that's when back in 1984 is when I started that.

But it didn't take me long meeting the parents and the children who were suffering cancer to know that this was something that I really wanted to continue doing. And I think it was a very important part of my education. I didn't realise it at the time because you were helping in the fundraising in those days, holding fate's chocolate wheels to raise money for what would become the Institute. It was just a small centre at that time and so, you were working with the parents who were highly motivated to see, they wanted to see more being done for children with cancer and the children themselves.

And I don't know, it was like a drug, I guess. It was something that you just wanted to, they really are the salt of the earth kind of people. And, you know, and as we're seeing now, organisations like the Cancer Council of New South Wales now involve consumers in how they decide how funding is going to be given out and I think that's a very important thing to have happen and particularly parents who are highly motivated, who have done some training, so they're not just your everyday lay people, they know about the disease that they're interested in and they are quite happy to give their ideas and call out things that they don't know and contribute. I think that's a great part of everything that we do. So for me, it's been very important. Very important.

50:52 Cadence Haynes

That's wonderful. I will also speak, NHMRC is building involvement of people with lived experience into many of our schemes these days, including in the assessment of the applications we get. It's so important. I'm curious about what you went through with getting things listed on Medicare.

50:57 Professor Norris 

No. Absolutely.

51:11 Cadence Haynes

What would you say was the thing that made the biggest difference for your team in getting over that particular hurdle?

51:18 Professor Norris

Yeah, I think it took a lot longer than it would if somebody had developed a new drug, for instance, because it's such a well, a drug is so well defined. You use it, you do it in a phase one trial, and if it works, it goes on to phase 2 and eventually phase 3, and it's all very clear the outcome.

The problem with MRD testing, as I was saying during the talk, it's not an off-the-shelf kit that you can use. It's not the one kit that is used for every child. It had to be designed specifically for that child, and it was using PCR detection of gene rearrangements and developing specific primers for that particular child.

And I think this was something very difficult for Medicare to grasp of how you would sort of handle that. And also, probably because, you know, I think if once you did that for one PCR test, it might open the way for a huge number of other Medicare.

So, I think that's one of the reasons it took so long. In the end, I think this the way that the evidence was such that this really was something that is a game changer and that with the advent of whole genome sequencing, that made it a bit more easier to put it as an item and things like that as well.

52:29 Cadence Haynes

Yeah.

Yeah. Wonderful. We're getting some questions coming from the audience, so I'll read them out. The first is from Rachelle. Thank you, Rachelle.

Currently, the test is conducted by the Children's Cancer Institute. Do you imagine a time where the tests will be available to be performed in other like pathology labs in states and territories across the country?

53:03 Professor Norris 

Yeah, it's already happening and that's the thing. Once it becomes a Medicare benefit, then, you know, any pathology lab that wants to, you know, scale up to be able to do the test and things, and a little bit easier now with whole, you know, sequencing, as I said or flow cytometry. Yes, it's already happening already and that's the future.

53:25 Cadence Haynes

That's happening, yeah.

How does the Australian MRD test compare to the MRD tests that were developed overseas? Interesting to hear about that sort of parallel development that was happening across the globe. Is ours the best? It's a question from Jane.

53:42 Professor Norris

Yeah, it was. It was completely parallel, which was really interesting. I guess that, you know, a number of groups around the world could see that lymphocytes or leukaemias have this barcode if you like, or fingerprint that was there. It just, we just had to work out a way of how to, you know, harness that and use it.

And I should say some of the early work in Australia was done by Alec Morley's group down in South Australia and we've done some collaborative work with him as well. And, you know, I just evolved both groups overseas and our group as well found that you could use PCR, particularly quantitative.

I think we published the first paper on the simultaneous detection and quantification of minimum residual disease using quantitative PCR. But what was important, of course, from our point of view, is that we were one lab doing this test and providing results and of course, you always have that thought: where's the quality control here?

You know, we can do this as a group, but how do we know that the test that we're doing is giving the right result? And that's where the Europeans in particular really came to the fore because they had established their own quality control group amongst hospitals around Europe.

And we were the first non-European country to be involved in that quality control testing. And so, we'd send samples. What they would do is send out unknown samples and you have to do your own tests on them and provide the result back and then it would all be uncovered and you look at them.

We became, we had to be the sort of the lab that at one stage was providing samples to the other European labs as well and then come back and do it. And that was a way of giving the assurance and the quality control that what we were delivering was accurate, which is an important thing to do.

55:51 Cadence Haynes

Yeah.

That is international collaborations is so important, especially when because you've got small patient groups as well and you need to pull resources like that.

55:57 Professor Norris

Absolutely critical. Yeah, yeah. And you've got such a big group, you know, in Europe across there with all their millions of people.

56:07 Cadence Haynes

Yeah, yeah.

So, you mentioned in your talk that you were one of the first groups to get your hands on RT-PCR setup. What was it like realising what that revolutionary piece of infrastructure could mean for your investigations and the translation of your discoveries?

56:10 Professor Norris

It was fantastic. You know, I was doing everything. I remember when we first started out, somebody once sent to me, not sure why you're doing this, because you know you're never going to be able to return results in real time to make a difference in things.

I guess we always had the belief that technology would change and technology would catch up, and that's precisely what happened. Up until that point, we were really struggling with the quantitation, being able to tell what the level and things and you was had crude ways of doing it, but it wasn't great.

And then we saw this machine coming out, went, that's what we need. That's really what we need. And so, yeah, we got one of the first ones and it was such a great sort of, you know, it's exciting times, sort of saying, okay, now, let's develop that test now, so that it can be done with this machine, and yeah, great feeling.

57:17 Cadence Haynes

This will kind of segue to my final question.

What sort of future opportunities do you see opening up as new equipment and tech driven tools are appearing on the scene? Is there anything on the horizon that you are especially excited to explore?

57:35 Professor Norris

There are many things going around. Liquid biopsy now is really exciting. And, you know, being able to take a blood sample and being, you know, determining so much about any cancer, really, not just blood cancers, but you know, cancers when they metastasise, solid tumours, when they metastasise, they release cells and DNA into the bloodstream, and being able to determine so much using liquid biopsy is a real moon. There's, you know, whole genome sequencing is just providing untold insights into cancers and the genes that are actually driving particular malignancies and being able to use that in treatment.

So, we've got in the Institute the Zero Childhood Cancer Program. And so, this is a program that's received a significant amount of government funding. It's available to every child in Australia who has cancer, every child who has cancer. Their genome is sequenced along with some of their normal cells and these started out with children who only had a 30% chance of survival. But as I said, now it's been rolled out to every child in Australia that has that potential to be on it. Sequencing their genome, finding the driver genes and seeing if there are drugs available that will actually hit that driver gene or the pathway and things.

And there's been some amazing successes there too. You know, I had on one of my header slides, so that boy jumping in the air, he was a boy who was wheelchair bound with a brain cancer and was on the Zero program. And...

59:30 Cadence Haynes

Really?

59:34 Professor Norris

He managed to get access to a drug in America, an experimental drug that targeted his particular brain cancer and he's now a healthy young adult and things.

59:45 Cadence Haynes

That is incredible. Put that on a footnote on the slide because that is remarkable.

This has been a fantastic presentation. Thank you so much for sharing the story of your discoveries and how they were translated into impact.

I think it's a powerful reminder of how funding from NHMRC and elsewhere can bring teams together, support the sharing of knowledge and generate research that benefits people in Australia and around the world.

I'd also like to thank everyone who joined us online this morning. For anyone you know who might have missed out or if you want to re-watch, it'll be available to stream on our website in the coming week. Thank you again, everyone, and another very special thank you to Professor Norris.

We'll see you all at the next Speaking of Science. Enjoy the rest of your Friday. Bye-bye.

1:00:32 Professor Norris

Thank you, Cadence.

End of transcript.