JOHN RASKO: For me, stem cell research is exciting because it offers a whole new dimension, an opportunity to deliver therapeutics. When you stand back and look at what modern medicine has to offer, the categories that we have at our disposal are familiar things like drugs, like surgery, like radiotherapy.
These are categories of deliverables for therapeutic intervention. The possibility that we can use cells as therapeutics is yet another level of therapeutic intervention that is practically untapped.
CAMILLE MERCEP: Welcome to Pomegranate—a CPD podcast from the Royal Australasian College of Physicians.
This month we're presenting a review of stem cell research and stem cell therapies from Professor and Fellow John Rasko, head of the Department of Cell and Molecular Therapies at the Royal Prince Alfred Hospital.
A self-confessed "stem cell tragic," Professor Rasko routinely separates the hope and the hype surrounding any new medical research. In this episode, he reviews the stem cell treatments currently available in Australia and New Zealand, and a few of the many clinical trials worth watching. He also discusses why some patients engage with unproven and riskier procedures, and what advice he offers them.
JOHN RASKO: My name is Professor John Rasko and I wear two main hats—the first is as Head and Director of the Department of Cell and Molecular Therapies at Royal Prince Alfred Hospital, within the Sydney Local Health District. And secondly, I am in charge of the program in Gene and Stem Cell Therapy at the Centenary Institute, which is affiliated with University of Sydney.
Stem-cell-based therapies have been demonstrated over many decades—from the Nobel-Prize-winning work of Don Thomas in Seattle in the 1960s, where he was seeking to provide a new therapeutic possibility for diseases like leukaemia and related haematological malignancies.
The last chapter that's been introduced into the firmament of stem cells are the induced pluripotent stem cells. These were cells that were potentially imagined even 50 years ago by John Gurdon, who anticipated the extraordinary Nobel-Prize-winning work of Shinya Yamanaka in discovering the idea that we can reprogram adult cells of any type back up the differentiation tree to become the most primitive precursor cells of all—which are these pluripotent, or embryonic-like, stem cells. Still to this day, ever since the discovery in 2006, and then subsequently shown in humans in 2008, it still sends shivers down my spine how important it is in terms of changing our perception of how stem cells work.
So what's here and now and routine is a standard of care for: many haematological malignancies, acute myeloid leukaemia, acute lymphoblastic leukaemia, some lymphomas, and also a few rare solid tumours such as germ cell tumours or testicular carcinoma. And then a whole host of other genetic diseases for which a bone marrow transplant from an allogeneically-matched or sibling donor may be appropriate. And these are diseases potentially like thalassemia, like immune deficiencies of which there are a large number of different rare types, and so on.
These are now standard of care in many centres, and are routinely made available in centres of excellence that provide for bone marrow transplantation and peripheral blood stem cell transplantation.
When we look back over the last 50 years we can confidently identify bone marrow transplantation and all those related technologies as offering a new dimension of therapeutics for some malignant haematological diseases, and a few others. But when we reflect on the possibilities of organ transplantation (and the current limitations by virtue of the fact that there simply aren't enough organs to go around), that one day stem cell research may offer us the capacity to be able to provide for new organs, new tissues, 3D-printing perhaps, even, for the possibilities in the future—frankly, it makes me skip to work every day.
There are some diseases for which some stem cell therapies are now becoming more likely to be showing evidence of efficacy. So for example, a controversy at the moment is multiple sclerosis and whether or not that disease would best be treated by some form of autologous stem cell transplantation. Some autoimmune diseases such as rheumatoid arthritis, scleroderma, and lupus—in their most severe cases—may also appropriately be tested under clinical trial conditions to see whether or not there is efficacy able to be shown in a properly controlled trial.
At this stage of the game, the evidence is equivocal. We all hope that the evidence will be forthcoming soon, but I can guarantee that the only way that will be forthcoming is if some individuals commit themselves to clinical trials, and ultimately then the statistics will show whether or not this is efficacious.
We have a massive potential, an enormous amount of hope that’s been invested in stem cell technologies for the future—whether that be regenerative medicine, whether that be anti-cancer therapies, or therapies for a whole vast number of genetic diseases. But until such time as those proofs are made available, we can't slide down the slippery slope of confusing hope with the hype of false salespeople who might be seeking to take a financial advantage. Or seeking to proffer benefit when it's never been proven—or indeed, when there may be risks that aren't being discussed.
The example that I like to remind listeners about is in the mid-1980s and early 90s, there was an extremely strong push to use stem cell therapy in the context of high-dose chemotherapy for women suffering from metastatic breast cancer. And it became a massive cause in the United States, because there was increasing evidence that high-dose chemotherapy would be able to cure, or at least improve, the outcome of women suffering from horrible metastatic cancer. There were tens of thousands of women who received transplants because of the demand.
However, it turns out that the evidence was extremely scant at the start of that process. And it took 10 to 15 years for the clinical trials to be actually done. In the end, after 15 years, there was an overwhelming and unambiguous conclusion: autologous bone marrow transplantation and high-dose chemotherapy had absolutely no benefit whatsoever for women suffering from metastatic breast cancer.
The worst part is, of course, that these individual women had to suffer high-dose chemotherapy with all of the complications associated with that—and proven had more complications and increased toxicity, because of course they were receiving bone marrow transplant and chemotherapy.
How could this have happened? The books are still being written, the stories are still being told. And indeed, there was medical fraud involved, where one of the South African investigators was shamed eventually and showed no evidence, but was publishing papers showing efficacy when none was actually forthcoming—when it was ultimately reviewed later on by properly constituted committees.
So the purpose of this story is really to highlight that even though something sounds like a great idea, the fact of the matter was that once clinical trials empirically performed, critically, are reviewed and undertaken in the end it wasn't efficacious.
I think it's always hard for anybody suffering from any disease to understand why it is that physicians like myself say, “Hold on a minute, you may be placing yourself at risk.” And at financial risk, because often times individuals will seek to travel internationally to go to so-called "stem cell clinics" in Russia, perhaps in Southeast Asia, perhaps in the United States. And perhaps, I should also say, in Australia. Because really, "stem cell tourism" is here and now in Australia as it is in other areas of the world. And it does reflect, strongly I think, on the disconnect between what our patients would like modern medicine to be offering, and what it is currently offering.
I do think there are some areas that might raise eyebrows in terms of clinical stem cell therapy trials. One in particular that springs to mind is the very experimental use of cord blood stem cells in trying to alleviate the symptoms of autism. There are babies between the ages of 2-5 being enrolled in an extremely ambitious and large scale trial costing some forty million U.S. dollars at Duke University, by one of the most respected cord blood stem cell clinicians in the world, Joanne Kurtzberg—who is seeking to infuse cord blood stem cells in babies suffering from autism to see if there may be a benefit. The idea, perhaps, to make neural connections with these cells to facilitate improvements. It builds on previous studies at the same institution in cerebral palsy.
But many people who have reviewed the underlying science for this clinical trial regard it as somewhat of Hail Mary approach. By which they mean that it's really not supported by thorough basic science, it really is “Well, let's just see if there's a benefit that might be able to be accrued, in the context of exciting cord blood stem cells.”
And so because there are so few potential therapies available, many families who seek any possible hope are signing up to this clinical trial—which is very well designed and extremely well funded—to see whether or not potentially a benefit may be obtained.
So that is a surprising trial that has come out of nowhere, in some ways, to see whether or not this in a sense one-off study might actually lead to a benefit. And if it does, of course that would be a game changer, that would be an amazing discovery. Quite an eyebrow-raising clinical trial in the United States, which is ongoing at the moment.
It is true to say that embryonic stem cells and their partners—the induced pluripotent stem cells—have only been tested in a few dozen individuals on the planet for clinical diseases. And in particular the trials have been in spinal cord injury and degenerative vision disorders such as Stargardt's disease and macular degeneration. This is a vanishingly small number of individuals when you consider that the first clinical trials were initiated over a decade ago now. But there has been a dramatic impact using human embryonic cells, and induced pluripotent stem cells, in the pharmaceutical industry in two particular areas. The first area is in disease modelling, and in the second area it is potentially drug toxicity screening.
We all know that there are some four thousand diseases that afflict humans—genetic diseases. Some of these diseases only affect a few dozen people on the planet, and yet they have a name, and sometimes we even know the gene that causes this vanishingly rare disease. The possibility of performing a properly controlled clinical trial in all the individuals on the planet suffering from that disease is impossible: they're distributed throughout the world, and there's no pharmaceutical company that's going to spend the many many millions of dollars developing a drug just so that they have a market of a handful of people.
But any individual now suffering from any genetic disease can provide their own cells to model a disease in a dish. I can now take peripheral blood cells from any individual person suffering from any rare genetic disease, reprogram them up the differentiation tree to become pluripotent-like stem cells, and then differentiate those cells to become cardiomyocytes. Or I can make them into blood cells, or into liver cells. And then I can use industrial might to screen hundreds of thousands of different compounds that are available in industrial libraries, to see whether or not they may have a benefit on a particular tissue type, derived from an incredibly rare individual's genetic predisposition.
So now we have the real possibility of doing, if you like, tens of thousands of clinical trials—yes, albeit in a dish—possibly then throwing away tens of thousands of wasteful or purposeless drugs that would never be useful, but focusing then on classes of drugs that may show efficacy.
The second one is in toxicity screening. Now what we can do is we can take libraries of genetic variation in induced pluripotent cells and create liver in a dish, or create beating cardiomyocytes in a dish. And then screen drugs to see whether or not there are people who may have toxicities based on their genetic variation. This is a game changer because it means that drug companies now can screen using the industrial might of high-throughput screening in a laboratory, versus the massive cost and expense of doing it in a large scale clinical trial with individual patients, and the complexity and lack of information that that sometimes provides.
I'm very well aware that many patients are approaching their physicians with questions regarding what's available for stem cell therapies here and now. And as I've said, stem cell therapies here and now are available for predominantly haematological malignancies, and some rare genetic disorders, as well as immunodeficiencies and a couple of solid tumours.
But for any other category of so-called stem cell therapies I would suggest that physicians avail themselves of the most reputable online resources—which in fact they are mostly familiar with. Resources such as clinicaltrials.gov, which provides for a summary of all approved clinical trials internationally, and is a requirement for publication in many journals these days—but also more specifically in the stem cell arena, the International Society for Stem Cell Research and the International Society for Cellular Therapies. And indeed some of the Australian stem cell society websites all have resources that physicians can routinely go to and take advantage of.
And of course then there are the long-standing bone marrow transplant and transplant related resources within Australia and Australasia that can be referenced online, Australia and New Zealand stem cell transplant reference centres, as well online resources that often are affiliated with government or government regulatory agencies. These would be the sources of information that I would regard as reliable, and that I would recommend to patients.
CAMILLE MERCEP: With guidance from Professor Rasko, the RACP has put together a comprehensive list of stem cell resources, including information on ongoing trials for type 1 diabetes and macular degeneration. You can find all this, plus past episodes, on our website: racp.edu.au/pomcast.
Many thanks to John Rasko for providing this clinical update. The views expressed on the program are his own, and may not represent those of the Royal Australasian College of Physicians. We'd love to read your views, as well as any CPD requests for future episodes, in our inbox: firstname.lastname@example.org.
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Pomegranate comes to you from the Learning Support Unit at the RACP. The program is presented by Camille Mercep and produced by Anne Fredrickson. Next month we're exploring preventive health...for physicians.
JILL GORDON: The old saying that “the doctor who cares for himself has a fool for a physician” is actually very true. Because you never know what another person is going to pick up until you present and actually place in front of a trusted colleague your own medical history, and see what kind of advice comes from that.
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