Articles

Undermining the regulation of stem cell therapies in Italy: A warning for the future?

Stem cells are magical.

At least, if you listen to what docs and “practitioners” who run stem cell clinics in various parts of the world, usually where regulation is lax and money from First World clientele is much sought after, that’s what you could easily come to believe. Unfortunately, it’s not just Third World countries in which “stem cell clinics” have proliferated. For instance, they are not nearly uncommon enough in Europe. The example that is most troubling right now is Italy, and the reason is that there is currently a law being considered that would greatly weaken the regulation of stem cell therapies, so much so that on Friday I saw something that’s fairly rare: a major scientific journal published a pointed editorial about this new law. Specifically EMBO Journal published a commentary by an international group of scientists warning about the path that the government of Italy is considering entitled Regulation of stem cell therapies under attack in Europe: for whom the bell tolls.

Stem cell quackery is a very popular form of quackery these days because, well, stem cells are so magical-seeming. You can now find stem cell treatments offered for autism (one of which, offered at a clinic in Costa Rica, I’ve discussed before and involves injecting “stem cells” into the cerebrospinal fluid of autistic children for a cool $15,000). Kent Heckenlively, the man who took his daughter to the aforementioned Costa Rica clinic for this treatment, is not alone in subjecting his autistic child to such unproven uses of stem cells. Just a couple of months ago, a broadcast journalist in the Philippines named Karen Davila took her autistic son to the Villa Medica Clinic in Germany, which offers variants of stem cell therapy. One is known as “fresh cell therapy” and involves harvesting cells from lamb fetuses and injecting them into the patient. The other is called fat stem cell repair therapy, which is claimed to involve harvesting fat from the patient’s abdomen or thigh and then isolating “stem cells” from them to be injected back into the patient’s body.

There’s also a variation on this “stem cell” theme in China, discussed by Steve Novella a few years ago, in which Dr. Hongyun Huang runs a clinic in which he injects “stem cells” claimed to be derived from olfactory sheath cells taken from aborted fetuses into the cerebrospinal fluid of patients suffering from spinal cord injury or motor neuron disease like amyotropic lateral sclerosis (Lou Gehrig’s disease), claiming what can only be referred to as miraculous cures, sadly credulously reported by the press. He’s a little more expensive, in that he charges $20,000 (or at least he did back in 2008, when Steve wrote his post).

It’s not just neurological diseases and conditions for which stem cell treatments are offered, though. Dubious “stem cell” treatments can be easily found for virtually any disease that is currently incurable, chronic, or only treatable with great effort and not-so-great success. The list of diseases and conditions include, in addition to developmental disorders such as autism, neurological injury, and degenerative neurological diseases such as multiple sclerosis, diseases as diverse as heart disease, autoimmune diseases, respiratory disease, HIV/AIDS, diabetes, hypertension, cancer, and, of course, anti-aging. Truly, there is seemingly no disease for which some clinic, somewhere in the world (usually in Central America and China, but sometimes in Germany and the former Soviet Union) won’t be claiming miraculous cures with “stem cells.”

One example, a clinic in the Ukraine called EmCell, advertises its wares with slickly-produced infomercials, chock full of impressive-appearing graphics and animations:

It’s hard not to note that 1994, the year that this clinic came into existence, was long before legitimate stem cell therapy, other than bone marrow transplantation, had progressed to anywhere near being a viable therapy. Notice the claims of patents, mostly in Russia and the Ukraine, but a few European patents and a couple of US patents as well. I looked at one of the US patents. All it is, is a method to prepare a “cell suspension” from human embryos that, or so it is claimed, is suitable for treating HIV. You know what you don’t see on the website? Solid evidence from randomized clinical trials. There are, however, many testimonials. It doesn’t help that well-known antivaccinationist and autism quack (in my opinion) Jeff Bradstreet is apparently the US contact for EmCell.

Of course, EmCell is far from alone; it’s just one of the older and slicker “stem cell” clinics. There are many others, such as the Stem Cell Institute in Panama, the Bio-Cellular Research Organization in Ireland, the Regenerative Medicine Institute in Tijuana, among many others. Astute readers might have noticed that I use scare quotes when I discuss stem cells in the context of these clinics. That’s because it’s very much in doubt in most of these clinics whether what is being administered actually consists of stem cells. That’s where the need for regulation comes in most acutely. It’s also why what is going on in Italy right now is of great concern.

Attacking regulation of stem cell therapies in Italy

It’s been a bad year for Italian science thus far. Just last month, animal rights activists broke into the animal facility at the University of Milan and occupied it. During the occupation, they stole animals and rearranged all the cage cards so that scientists didn’t know which group of animals were which anymore, rendering their work uninterpretable and ruining years of research. Now this. If you think that the “health freedom” movement is limited just to the US and its more libertarian-leaning groups, think again. The EMBO article, by Bianco et al, starts out describing how this proposed law came to be. Noting that this is the first case in which unproven “stem cell” treatments are recognized as legitimate therapy without having been tested in rigorous clinical trials and based only upon flimsy preclinical evidence, “to be made part of a publicly funded, public health care system,” Bianco et al write (note that “MSC” = “mesenchymal stem cell”):

Patients with disparate, severe neurological diseases were and are being treated, and will continue to be treated in a major public hospital in Italy, by intravenous and intrathecal infusions of ‘MSCs’, purportedly prepared according to a unique, novel method of isolation in culture, and in vitro differentiation into neurons. This activity had previously been taking place in Trieste. In Brescia, an official agreement had been stipulated between the public hospital and a private foundation, whereby the foundation was granted permission to prepare cells with the purportedly proprietary method. Cells for infusion into patients were prepared within a GLP lab (not stringent enough for growing cells in culture before use in patients), intended for the handling of bone marrow and cord blood-derived haematopoietic cells. Patients were being treated in the hospital. Patient care in public hospitals in Italy is paid for by the Government.

More information can be found in these news reports in Nature from March and April. Here’s what happened. Apparently, Italy’s health minister, Renato Balduzzi, has been impressed by the blandishments and claims regarding adult stem cell therapy and on March 21 decreed that that a controversial (actually, let’s be honest, a quack) stem cell therapy can continue in 32 terminally ill patients, mostly children, even though the stem cells were not isolated according to Italy’s safety standards. This decision followed a prolonged campaign and media pressure to authorize the compassionate use of the therapy. As noted in this Nature report, hundreds of people protested in Rome on March 23, including a naked woman with pro-stem cell slogans painted on her body.

This particular therapy is marketed by the Stamina Foundation and has been banned multiple times. However, this time the Stamina Foundation has found a winning public relations message, pushing for “compassionate use” of its unproven therapies:

Stamina Foundation president Davide Vannoni, a psychologist at the University of Udine, says that the publicity around the treatment has won him 9,000 new patients. He hopes that further modifications to the law will allow him to expand the therapy.

A month ago, an investigatory television programme, The Hyena, reported that children with incurable diseases such as spinal muscular atrophy were being denied supposedly important treatment, and Italian show-business personalities joined the call to relax rules on stem-cell treatment.

As is my wont, I wandered over to the Stamina Foundation website. Unfortunately, it’s in Italian, and I don’t speak Italian. However, a little Google Translate allowed me to get the gist of what the Stamina Foundation is selling. For instance, this page touts MSC for everything from heart disease, to Parkinson’s disease, to multiple sclerosis, to kidney damage, to type I diabetes, to Alzheimer’s disease, to Huntington’s chorea, to spinal injuries, and just about anything else you can think of. That, in and of itself, should be a massive red flag, of course, coupled with the fact that in the news reports Vannoni admits that he’s never published his outcomes. Moreover, the only published outcome, a small trial involving five babies with type I spinal muscular atrophy treated with Vannoni’s MSCs was published in October and was entirely negative, leading the authors to conclude:

More generally, our findings highlight the risk that the combination of newspaper ‘hype’ and parental ‘hope’, with the support of courts that are sympathetic to families with children with severe disorders, may produce shortcuts in the design of clinical studies that would need more rigorous preclinical information and more accurate safety and efficacy measures and may actually put patients at risk of potential side effects of therapy.

Vannoni’s response? He claimed that the therapy didn’t work because the clinicians did not use his exact cocktail of cells.

Indeed, I can’t help but compare Vannoni unfavorably to Stanislaw Burzynski, who at least has published a few papers and case reports. They might be crappy papers, case reports, and incomplete clinical trials that, when examined closely, don’t support his claims, but he has published. Vannoni, on the other hand, seems not to care about even the appearance of not being a quack.

One aspect that Vannoni does share with Burzynski, however, is his willingness to cynically use desperate patients to try to get approval for his unproven therapies. Indeed, public hospital Spedali Civili of Brescia has been permitting the Stamina Foundation to administer MSC treatment for various neurodegenerative treatments, despite it not being one of the 13 authorized Italian stem cell factories. After an inspection in 2012, the Italian version of the FDA ordered an immediate halt to these treatments, and that’s when the protests began:

But the halt sparked protests among patients’ families who believed the treatment was working. Some appealed to the courts, and as a result a few patients were allowed to go ahead with the therapy. On 15 March, a group of 13 Italian stem cell researchers published an open letter to the country’s Minister of Health, Renato Balduzzi, asking him to shut down all of the Stamina Foundation’s treatments at the hospital.

The open letter urged Balduzzi not to succumb to the wave of emotion and pointed out that there was no evidence that MSCs can do what Vannoni and his patients’ parents claim they can do. They also argued that “compassionate use” exemptions shouldn’t be used as a means of weakening regulation of completely unproven therapies. Indeed, it’s worth citing a couple of passages, conveniently translated into English here:

The decision seems to be dictated by emotions raised by public opinion rather than by scientifically based reasons. No scientific evidence whatsoever has been produced suggesting that mesenchymal cells may have any effect on those diseases for which it is claimed they could be employed. Moreover, no scientific description has been given of the method by which it is claimed these cells may be obtained. This seems a real subversion of the scientific and moral foundations of medicine, denying both the dignity and the traumatic experiences of patients and their relatives. We are aware of these issues and they profoundly motivate the scientific community to generate and guarantee accepted, visible and public data that will change any potential scientific hypothesis into an accepted curative procedure.

The scientists also addressed the health freedom issue head on:

The freedom of any citizen to adopt any personal health decision, including the wish to refuse any cure, does not imply that the Government is obliged to authorize all medical procedures that anyone may suggest as appropriate. In fact, although the individual choice to use an imaginary or inappropriate therapy complies with the rights of individual citizens, such therapies should not necessarily be approved by the Government and provided by public or private health structures. It is not the Government’s role to respond to pressure from patients to translate an individual choice into a therapeutic option for ready use in any health structure. Media campaigns should not become instrumental in adopting decisions on medical or health procedures. The right of single individuals to adopt snake oil as a freely chosen drug does not mean that snake oil has to be prepared in hospital pharmacies as a result of Government-authorized procedures.

In other words, the Italian government is on the brink of giving free rein to stem cell quacks, but it’s worse than that. This order, as the scientists point out, in essence allows government-funded facilities to collaborate with stem cell quacks and facilitate their treating patients.

One point that the scientists didn’t really nail, and that’s the issue of informed consent. One notes that Vannoni’s stem cell quackery has no evidence for it published in the peer-reviewed biomedical literature nor any compelling clinical trial results. Consequently, if claims are being made for this treatment it is impossible to give informed consent because there is no evidence upon which to base even a rough estimate of the chances for success weighed against the risks of the treatment. Even worse, we don’t even know that these are really stem cells. Seriously. As the scientists point out, there is no transparency, and if there’s an area of clinical research where transparency is essential, it’s stem cell research.

Sadly, the scientists’ words fell on deaf ears. In fact, Balduzzi had called a scientific review committee to examine the cases and make recommendations. It recommended against authorizing further use of the Stamina Foundation’s stem cells in a public hospital, but Balduzzi ignored the recommendations of his own panel and permitted use of the Foundation’s procedure in a terminally ill three year-old. Indeed, Balduzzi signed the order allowing the bogus MSC therapy to continue at a public hospital. On April 10, the Italian Senate amended Balduzzi’s ministerial decree with a clause that would redefine stem cell therapy as tissue transplantation, thereby releasing it from any regulatory oversight by the government. If this decree is passed by the other parliamentary chamber in Italy, the Camera dei Deputati, then dubious stem cell therapies will be out of reach of Italian drug regulators. One notes that this will be in marked contrast to European Union and US standards, which treat cells removed, treated, and reinfused as drugs, although sadly one also has to note that the attempt to redefine cell therapies as not being drugs but surgical procedures or “tissue transplantation” is not unique to Italy. Regulations for stem cell therapies are in a perpetual state of catch-up.

It’s also hard not to note that the Catholic Church apparently played a role in this scientific debacle. As noted in Nature, Vannoni’s stem cell treatments are not embryonic stem cells; they are claimed to be MSCs; i.e., “adult stem cells.” Because of its opposition to the use of embryonic stem cells, the “scientifically naïve” Vatican is enamored of the sorts of treatments offered by the Stamina Foundation, and indeed even held its Second International Vatican Adult Stem Cell meeting from April 11 to 13, described as “a shamelessly choreographed performance” in which “sick children were paraded for television, sharing the stage with stem-cell companies and scientists desperate to hawk a message that their therapies must be speeded to clinical use” and was framed as a “fight for reason and fairness against an uncaring and intransigent scientific community.”

If you go to the Stem For Life website, you’ll find a lot of anecdotes, some preclinical science described, but not a whole lot of actual compelling evidence. One anecdote in particular is as manipulative as any I’ve ever seen anywhere else. Don’t get me wrong. I do believe that eventually that stem cells, be they adult or embryonic, will be used for more and more therapies and that they will eventually allow the treatment of diseases that we currently cannot treat, but we have to be realistic and understand what is and is not known about adult and embryonic stem cells before they are used as therapies.

Why the Stamina Foundation’s stem cell treatment is highly dubious

All of this brings us back to the EMBO article. I really do have to give the authors credit for a well-written, clear explanation of why MSCs are not ready for prime time yet and therefore why deregulating them, as the Italian government appears to be on the verge of doing, is madness. They pull no punches. First, they argue in a manner that I approve of heartily (and paraphrasing Tim Minchin) that “regenerative medicine must be medicine.” In other words:

Stem cells are not a homogeneous class of cells; ‘stem cells’ are not one-size-fits-all cures. There are different kinds of stem cells in different tissues, and even when the appropriate stem cell is selected for an indication it takes years of research to learn how to administer the stem cell safely and effectively, as demonstrated by the decades of research that was required to transplant bone marrow safely and effectively. The use of stem cells in medicine must remain cognizant not only of the true biological nature of the type of cells considered for use, but also of the biology of the diseases being targeted. Treating patients with disparate neurological diseases with intravenous or intrathecal infusion of MSCs, which is being done in Italy, has no medical rationale.

You can tell a lot about a purported stem cell therapy by how the “stem cells” are isolated and administered. If the physician doing the therapy can’t tell you what specific kind of stem cells he’s using, give a good technical description of how they are isolated and purified, show preclinical evidence demonstrating that they are, in fact, stem cells, and describe how he is going to target them to the correct area, then chances are good that the therapy is dubious. As Bianco et al point out:

In the case of systemic administration of mesenchymal stem cells (MSCs), cells are introduced into the bloodstream, which is not their natural environment. They are infused in the hope that they will reach target organs that do not normally contain MSCs. There is a wealth of knowledge about their function in their natural site (the bone marrow) and a wealth of knowledge on the properties they exhibit in a tissue culture dish. But it is not clear how exogenous MSCs will behave in the brain, kidney, or the lung. As inherently osteogenic and adipogenic cells, MSCs could generate bone or fat in the wrong organs if transplanted in sufficient numbers (Breitbach et al, 2007). MSCs can also embolize in the lungs and damage the local microcirculation. Allogeneic MSCs can trigger an adverse reaction (instant blood mediated inflammatory reaction, IBMIR; Moll et al, 2012), which leads to activation of the coagulation and complement cascades, and to the death of the infused cells. IBMIR can result occasionally in thromboembolism, but we were unaware until recently that IBMIR could be triggered by MSCs. This exemplifies why infusion of MSCs must necessarily be studied in rigorously controlled and monitored clinical trials before such therapies can be considered safe in patients.

In other words, you can’t just inject the cells either into the bloodstream or the cerebrospinal fluid, and hope like hell that they “home in” to the right place and know what to do. It’s not that simple, unfortunately. Adult stem cell therapy works for bone marrow transplantation because progenitor cells are made in the bone marrow and they tend naturally to stay there when the circulation takes them through the marrow. We also have 30 years of experience using adult stem cell therapy for bone marrow transplantation. Bianco et al recount a little history about this pointing out that the first trial using bone marrow transplant between unrelated patients resulted in the deaths of all the recipients in the trial. Indeed, Donnell Thomas, we are told, spent 14 additional years in the laboratory figuring out why donors had to be matched to recipients before transplant, observing that “This illustrates how even the simplest and most promising cell therapies must be studied in depth to be delivered safely and effectively to patients.” He also notes that the situation becomes much more complex for cell therapies in which the scientific rationale for whom they might work is not known, unclear, or unproven.

Basically, it turns out that to date there are very few examples of proven stem cell therapies. There is bone marrow transplantation, of course. There are also corneal resurfacing procedures with limbal stem cells and skin regeneration with epidermal stem cells. There is also decent preclinical evidence and a few case reports for bone regeneration, and it is not unreasonable to hypothesize the use of specific types of stem cells for cardiovascular disease, although progress in this area has been disappointing.

Then, as I’ve pointed out, there’s the whole issue of exactly what kind of cell is being used. Just because someone says they are isolating and using “stem cells” does not mean that what is being isolated and used are, in fact, stem cells. Indeed, Bianco et al get almost downright sarcastic (at least as sarcastic as I’ve seen in a scientific review article) and refer to mesenchymal stem cells as “most suspicious cells,” stating:

Cells that have become known as ‘MSCs’ are locally transplantable, system-specific and self-renewing perivascular progenitors of skeletal tissues, including the haematopoietic microenvironment (Sacchetti et al, 2007). They are found in the bone marrow and have significant potential in medicine and unique biological appeal. It is therefore perhaps not surprising that multiple cases of unauthorized stem cell treatments being offered directly to the public before any approval or evidence of efficacy are centred on the use of the so-called MSCs. Lack of scientific rigour, although not unique to the MSC subfield, has flourished therein. Loose definitions and poor assays have disseminated across the scientific community as ‘gold standards’ (Dominici et al, 2006), creating huge confusion and opening the way to the completely erroneous belief that any culture of cells from any kind of connective tissue is a culture of stem cells. The apparent ease of isolation and culture, and the conceptual confusion between a stem cell as a physical and functional entity, and a culture of cells originating from stem cells ex vivo (Caplan and Correa, 2011), have contributed to the widespread use of such cells worldwide. Their nature as ‘adult’ stem cells has granted license and exemption from unwanted ethical controversy. Pressure towards development of therapies from all funding bodies around the world, a general climate dominated by the need to develop treatments (‘translational medicine’, Zerhouni (2005)) and the very existence of multiple companies ready to commercialize ‘MSCs’ have contributed, in turn, to making this particular biological object prone to misuse in the clinic and user-friendly for ill-intentioned salesmen.

This cannot be repeated often enough. Whenever a stem cell clinic claims to be using “stem cells,” are they really? What is their scientific rationale? What are their preclinical data? Do they really support the use of these cells? In the vast majority of cases, including that of the Stamina Foundation, the answer is no.

Finally, we should think of these cells in the same way we think of any “complementary and alternative therapy”—or any therapy, for that matter—and I have yet to find a better paragraph, even one of mine, arguing for the importance of there being at least a plausible mechanism:

Complementary to empirical clinical trials, a number of studies have been conducted, claiming ‘beneficial effects’ of systemically infused MSCs in animal models. The conceptual design of these studies as ‘clinical trials in a mouse’ is often flawed, detracting from the power of such studies to highlight a robust rationale for subsequent clinical use. Typically, a pharmacological effect is measured, without measuring the dose, kinetics and dynamics of the active principle, unknown at the outset. A putative active principle is often identified ex post through ex vivo reductionistic experiments. These arbitrarily single out a putative ad hoc molecular mechanism out of a maze of possible, pleiotropic, interlocking mechanisms. An arbitrary hypothesis that fits the results is pursued and alternative hypotheses are ignored. In vivo effects are often interpreted in a biased way (e.g., in studies on ischaemic heart disease, size of post-infarct scars is equated to extent of necrosis; effects of cardiac remodelling are ignored). Even though these studies sometimes specifically record the vanishing of infused cells, they fail to relate any claimed effect to kinetics of cell survival. ‘Clinical data in the mouse’ are descriptive and insufficient to offer mechanistic insight. Mechanistic insight is not a dispensable intellectual luxury. It is specifically required to develop effective therapies. It is to this end that we need mechanisms and rationale. MSCs are thought to have a role in treating GvHD and arthritis alike (Keating, 2012), owing to their generic ‘known immune modulatory effects’. The specific immune modulatory effects are not known. We have no way to model and measure them effectively in vitro or in vivo. We have, therefore, no way to distinguish those operating in GvHD from those operating in arthritis, or to tell whether they are the same or different. We have no way to tell whether these effects are unique to MSCs or shared with other kinds of cells, and which ones. While potentially crucial to advance therapies that harness immune modulation, these issues are mostly neglected. Meanwhile repetitive, expensive, small, uncontrolled phase I–II trials with i.v. infusions of MSCs continue to be pursued as useful.

I love two of the sentences in that paragraph; so I will repeat them again: Mechanistic insight is not a dispensable intellectual luxury. It is specifically required to develop effective therapies. Live them. Learn them. Love them. I do, and I try to live by them in my research.

The same admonition could be directed at, say, acupuncture, except that at least MSCs have more plausible mechanisms. However, as Bianco et al point out, preclinical data and understanding are critical to designing clinical trials that can actually give the answer that is being sought. Just taking a bunch of ill-defined cells and willy-nilly injecting them into small groups of patients with wildly disparate conditions with wildly differing mechanisms of disease is likely to be no more informative than taking some needles and sticking them willy-nilly into patients with wildly disparate conditions with wildly differing mechanisms of disease and hoping we’ll gain therapeutic insight.

There can be no compassion without safety and efficacy

One of the most potent arguments for Balduzzi’s decision in Italy is an emotional one: Look at the suffering children! They are dying! How can we possibly deny them this therapy? My response would be to rephrase that a bit by adding specific therapies other than stem cell therapies.

For example: Look at the suffering children! They are dying! How can we possibly deny them MMS enema (bleach enema) therapy?

Or: Look at the suffering children! They are dying! How can we possibly deny them homeopathy?

Or: Look at the suffering children! They are dying! How can we possibly deny them bloodletting?

Sounds ridiculous when put in those terms, doesn’t it? But, even though some day they might turn out to be wonderful treatments, right now stem cells are in the same boat. We do not know if they are effective and safe, and there is an incredible paucity of preclinical evidence to show that they do anything for the deadly diseases for which they are being used in Italy. The argument is that these severely ill children have nothing else going for them, no other therapeutic alternatives; so safety concerns can be thrown out the window. However, terminally ill patients need more safety and protection, and exposing them to unknown risks in a therapy with no evidence of efficacy is, as Bianco et al, put it, ethically unacceptable. Most people would accept the contention that someone who is severely or terminally ill has the right to take risks in search of treatment, but their willingness to take such risks because “they have nothing to lose” makes them vulnerable to any number of unproven treatments or even outright quackery. Without some sound evidence that a treatment might be effective, they are in essence taking all risk with at best an unknown and likely very small chance of benefit and at worst no benefit at all for all the risk. While personal freedom might give them the right to “roll the dice” and take large risks for minimal chance of benefit, neither physicians nor the government are obligated to facilitate their taking such risks. In fact, quite the contrary for physicians, who are ethically bound to give proper informed consent and obligated not to provide treatments without evidence of efficacy. As Bianco et al put it, “There can be no compassion without safety and efficacy.”

One can only hope that the Italian government figures that out before the Camera dei Deputati takes up the minister’s decree.

Posted in: Basic Science, Clinical Trials, Legal, Medical Ethics, Politics and Regulation

Leave a Comment (41) ↓

41 thoughts on “Undermining the regulation of stem cell therapies in Italy: A warning for the future?

  1. So whats the Gorski solution to Spinal Muscular Atrophy?

    Criticism is cheap.

    Stem cell research is still work in progress, but there are promising results, in particular in field of SMA:
    http://www.ncbi.nlm.nih.gov/pubmed/19098894

  2. WilliamLawrenceUtridge says:

    So we only get to criticize research for being unethical when we have a perfect solution? You don’t seem to really “get” science. Valid criticism is required if a treatment, particularly one so complicated as stem cell treatments, is to be come reliable, replicable and safe.

    Now your criticism, devoid of anything resembling substance, is cheap.

    Did you notice the article you linked was about “a” patient, as in singular? And what does that have to do with the substantive criticisms ventured here? That’s the kind of ex vivo work that Bianco et al. are talking about that forms the basis for an actual treatment, or even cure. Note that the researchers didn’t just take some skin cells, put them in a centrifuge, then re-inject them hoping they would reach the spine – the approach taken by the Stamina Foundation.

    Dr. Gorski also noted quite explicitly that stem cells hold tremendous promise:

    I do believe that eventually that stem cells, be they adult or embryonic, will be used for more and more therapies and that they will eventually allow the treatment of diseases that we currently cannot treat, but we have to be realistic and understand what is and is not known about adult and embryonic stem cells before they are used as therapies.

    We could also apply your own solution to your own comments – until you have a perfect solution for whatever problem or issue is being discussed here, perhapsy you might not bother posting them.

  3. goodnightirene says:

    @FBA

    The abstract at your link appears to my layperson’s eye to be a step in appropriate research–not a touted “cure” hawked via website complete with testimonials and lack of evidence.

    So, what’s your point?

  4. @WilliamLawrenceUtridge: So we only get to criticize research for being unethical when we have a perfect solution?

    And what imperfect solution do you have? We are talking about children born with a genetic disorder that turns them into a floppy cripple, completely disabled by age 2, until they have no muscle to breath with, and die a gruesome death.

    Stem cell therapy is in early days of development, and is a potential treatment. It will take 10-15 years for that research to yield something that can become an FDA-approved product (maybe), but sick people today dont have that much time to wait.

  5. rork says:

    The solution is to do real science about it.
    I don’t follow it closely, but hear about EL Feldman doing it here, perhaps mostly about ALS.
    Trying pubmed gets hits of trials in animal models and a phase I in human already completed:
    http://www.ncbi.nlm.nih.gov/pubmed/?term=Feldman%20Stem%20cell%20therapy%20for%20ALS

    And as I almost always point out, my larger hope is not about using stem cells in patients directly – it is about learning what we need to know from doing research with the cells in the lab. That can be cells from folks with genetic issues leading to disease, or it can be just studying genes found to be interesting – knowing more about POU5F1 and EZH2 (to pick just 2) is good, very likely useful.

  6. @irene

    Svendsen’s work was to develop new tools in understanding the disease.
    More recent work has suggested potential stem cell treatments, from an Italian lab (not a coincidence):
    http://brain.oxfordjournals.org/content/133/2/465.short

    following their intrathecal transplantation into spinal muscular atrophy mice, the neural stem cells, like those derived from spinal cord, survived and migrated to appropriate areas, ameliorated behavioural endpoints and lifespan, and exhibited neuroprotective capability. Neural stem cells obtained using a drug-selectable embryonic stem cell line yielded the greatest improvements.

  7. WilliamLawrenceUtridge says:

    And what imperfect solution do you have? We are talking about children born with a genetic disorder that turns them into a floppy cripple, completely disabled by age 2, until they have no muscle to breath with, and die a gruesome death.

    You really don’t understand science, nor apparently ethics.

    Good research results in effective, safe treatments for all sufferers of a disease. The shoddy non-research of Burzynski and these guys use up the money and time of the patients, and slow down the science. Burzynski and the Stamina people muddy the waters, so even if by some miracle they are onto something, it’s harder to convince other scientists to study it and validate the approach such that it becomes standard care. Those children dying a gruesome death may die sooner because of this approach, without proper control groups you have no way of knowing and their deaths stand for absolutely nothing.

    If everyone used your “sick people don’t have time to wait” approach, the result would be all scientific progress halting since we would never know which treatments were effective and which weren’t.

    But hey, it makes Burzynski and the Stamina Foundation richer, so it’s good for them (and a whole lot more profitable than running actual clinical trials).

  8. David Gorski says:

    The solution is to do real science about it.

    Exactly. And to use the knowledge that comes from that real science to design real clinical trials to test treatments developed from that knowledge.

    It is not to inject poorly characterized cells that might or might not really be stem cells (probably not) using protocols that might or might not allow these cells to home where they are needed (almost certainly not) into patients because the emotion of the moment is screaming at doctors to “DO SOMETHING!” That is the course not only to harming the most vulnerable of patients but failing to figure out whether stem cell treatments can do what we think they might be able to do and, if they can, how best to utilize their power for good.

  9. WilliamLawrenceUtridge says:

    I’m also not sure why FBA keeps putting up real scientific articles about glass and mouse studies as if they had any relevance to this. Those studies rather strongly support the idea that human trials are far too preliminary. Or, at best, that human trials should be trials with stringent record keeping, ethical oversight, and above all – free to the patient since they are assuming all risk with no reason to suspect benefits. Not to mention, you can’t just say “stem cells” and assume findings in one area cover all stem cells. Biology is all about specifics – specific cells, specific genomes, specific locations, specific tissues, specific interactions, specific therapies. It’s pretty rare that you can blanket-apply one solution or protocol to a variety of conditions. And it takes a lot of research to nail down those specifics.

    This seems to be rather transparent profiting on the desperation of the parents of sick children. Or, at best, clueless science by well-intentioned doctors who, again, will end up hurting patients overall. If their therapy doesn’t work, it’s all risk for zero benefit. If it does work, they are preventing it from being adopted by more doctors.

  10. windriven says:

    “It will take 10-15 years for that research to yield something that can become an FDA-approved product”

    Yes, science takes time.

    “[B]ut sick people today dont have that much time to wait.”

    And that is sad, isn’t it? This has been the story throughout history. Think of how many died of the plague long before the germ theory of medicine was even understood, much less that fleas carried by rats were a vector of transmission. Look at how many died of AIDS before HART was developed.

    But coffee enemas and eye of newt didn’t stop the plague and it didn’t abate AIDS. What you are advocating is a thousand monkeys clacking away at keyboards in the hope of writing the great American novel. It doesn’t happen that way.

    We all empathize with the plight of those afflicted with various incurable conditions. But jacking them around with shots in the dark is horsesh!t. If you want to help, donate to a charity funding research into a condition that interests you.

  11. windriven says:

    “It will take 10-15 years for that research to yield something that can become an FDA-approved product”

    Yes, science takes time.

    “[B]ut sick people today dont have that much time to wait.”

    And that is sad, isn’t it? This has been the story throughout history. Think of how many died of the plague long before the germ theory of medicine was even understood, much less that fleas carried by rats were a vector of transmission. Look at how many died of AIDS before HART was developed.

    But coffee enemas and eye of newt didn’t stop the plague and it didn’t abate AIDS. What you are advocating is a thousand monkeys clacking away at keyboards in the hope of writing the great American novel. It doesn’t happen that way.

    We all empathize with the plight of those afflicted with various incurable conditions. But jacking them around with shots in the dark is horsesh!t. If you want to help, donate to a charity funding research into a condition that interests you.

  12. windriven says:

    ??
    Sorry for the double post.

  13. DugganSC says:

    It is a shame to see the Church getting rooked on this, but it is also nice to get confirmation that the only successful stem cell therapy so far has been with adult stem cells. The fact that people use stem cell without distinction leads to some very bizarre situations. When I lived in New Jersey, two political ads ran back to back decrying how the other candidate supported “stem cell therapy”, but they didn’t. Turns out, one supported adult stem cell therapy and the other supported fetal stem cell therapy.

  14. qetzal says:

    Actually, adult stem cells are not the only ones with proven efficacy. Stem cells from umbilical cord & placental blood have proven value in place of bone marrow transplants from adult donors. We could argue whether such cord blood products are fetal or infant, but they’re certainly not adult, and their more fetal-like immature properties apparently offer some advantages when no matched adult donor is available. In fact, cord blood products are FDA approved (e.g. Hemacord.

  15. @windriven

    So what are you suggesting for existing sufferers to do?
    The Gorski Solution to incurable disease patients – “Bag them and Tag them”?

    No experimental treatments for you, here is a body bag, jump in and zip it.

    The treatments Vannoni offers may prove ineffective, but the service is raising public interest in the treatment, and the research funding will follow. At least we will learn which treatment doesnt work, and thats valuable info in itself.

  16. mho says:

    slightly off topic,

    one of my favorite not-a-doctors posted a “study” wherein.

    “Subjects: Ten (10) healthy adult subjects were recruited by word-of-mouth”

    the world would be a better place if those 10 people spent an afternoon playing frisbee.

  17. elburto says:

    @FBA –

    sick people today dont have that much time to wait

    and

    The Gorski Solution to incurable disease patients – “Bag them and Tag them”?

    No experimental treatments for you, here is a body bag, jump in and zip it.

    Wow. You’re so profoundly ignorant that I have this awful, creeping fremdschämen from reading your comments.

    Seriously. What’s your solution for things like SMA? Time travel, DNA transplant,
    cryogenic storage until a solution is found, screaming “OH THE HUMANITY!”?

    When scientists say “We just don’t know why X happens” that isn’t an admission of failure. I’d rather hear that sort of truth than the lies peddled by the likes of Burzynski et al.

    Some people never get the chance to benefit from new advances in science. Children died of VPDs (like polio) prior to mass immunisation protocols. People died from end-stage HIV/AIDS before HAART was developed, and one of the conditions I have led to many slow and painful deaths before effective treatment was devised.

    People die. Some people die earlier than others, and that’s sad, but those of us who may never live to see a cure cannot do anything about that but but hope that study of our lives and deaths can improve current scientific knowledge.

    Scam artists prey on ignorance like yours. An infant who’s going to die, from a terminal and currently incurable disease, deserves dignity, respect, and relief from pain. Schlepping the poor kid to every quack above the Equator, so that they can perform a walletectomy on his parents and run bizarre experiments on him, is neither dignified nor likely to extend his life.

    Proper replicable, ethically sound, scientifically rigorous research, that has a distinct hypothesis and endpoint, is the only way to come up with sound and effective treatment protocols. Doing otherwise, capitulating to emotional pleas and public pressure, gets you abominations like AZT, and a pile of corpses.

    So what is your solution Stan? What would you substitute for ethical, logical. research?

    I was a guinea pig for a particular surgery to implant a new conceptual device. I was seriously ill, the traditional surgery would have killed me, so I had nothing to lose. My specialist was an established and respected researcher in his field. He showed me the design blueprints, the data he’d collected thus far, and the proposed mechanism of action. So I agreed to join the tiny pool of subjects from across the country.

    My surgery was a success, the device functioned perfectly in me, but NICE could not approve it as the results were mixed. That made me happy, because it means the system works in all the right ways:

    Transparency.- I could google the publicly funded dev team and device, and follow the rulings in the application procedure, and the final report stating the reasons for the device not being approved.

    Accountability- The final judgement admitted that the concept was brilliant, but that results were inconsistent, so approval for general use could not be granted, given the nature of the conditions it was designed to ameliorate.

    Progress – Even an apparent failure is a success, because rejected but promising designs/hypotheses mean that ultimately patients end up with the best possible treatments/refined and more efficient device designs, rather than “good enough” prototypes.

    That all takes time, money, and sacrifices on behalf of researchers and participants alike, as Dr Gorski knows only too well.
    What would you say to patients (or their parents/advocates) who say “Listen, I know that a cure isn’t coming in my lifetime, but that’s ok because my contribution, by way of my stats and disease progression history, can be used to help others in the future” Would you advise us to chase ephemeral and dubious “cures” that defy the laws of science instead of slowly developing and testing consistently efficient procedures, devices and drugs?

    Why is it apparently so difficult for you to understand that science-based medicine has to be rooted in scientific (and ethical)principles? Anecdotes and bizarre experiments are not scientific, unless you mean it in a homeopathic sense, where less is more?

  18. WilliamLawrenceUtridge says:

    So what are you suggesting for existing sufferers to do?

    My sarcastic solution is “anything but charging them large amounts of money for injecting them with a random collection of cells that could cause them to stroke out”.

    My real solution is “well-designed and controlled research that permits the accumulation of knowledge that helps people in the future”.

    This is compassion the same way it is compassionate to give water to a thirsty person with extremely low blood volume. Sure, it helps you both feel better. It just makes them die sooner.

  19. @elburrito

    Seriously. What’s your solution for things like SMA? Time travel, DNA transplant,
    cryogenic storage until a solution is found, screaming “OH THE HUMANITY!”?

    You hit close to the mark with DNA transplant (by accident I am sure)
    Pluripotent stem cells of the patient can be genetically corrected to produce injectable motor neurons to be delivered into the spine. It has been done in animals.

    Here is a recent work that just came out a few months ago: http://stm.sciencemag.org/content/4/165/165ra162.short

    The transplantation of corrected motor neurons derived from SMA-iPSCs into an SMA mouse model extended the life span of the animals and improved the disease phenotype. These results suggest that generating genetically corrected SMA-iPSCs and differentiating them into motor neurons may provide a source of motor neurons for therapeutic transplantation for SMA.

  20. windriven says:

    @FBA

    “No experimental treatments for you,”

    I would never suggest that. I have fewer ethical concerns than many in these pages regarding ‘hail mary passes’ for terminal patients. But my ethics stiffen up when it comes to informed consent and full disclosure.

    If a researcher is working on a treatment for, say, pancreatic cancer and an adult patient is dying of pancreatic cancer and has exhausted the existing therapeutic armamentarium and the researcher discloses that the treatment is entirely experimental and that the promise of any benefit is entirely speculative and the treatment will be offered at no cost as a part of the research, then I would have no objection.

    But when quacks promise miracles and charge big money for unproven therapies I bellow for the gallows.

  21. @windriven

    But when quacks promise miracles and charge big money for unproven therapies I bellow for the gallows.

    Where did you get the idea that Vannoni charges big money or promises miracles? Not from Gorski I hope. Stamina supplies the cells free for the patient: http://www.staminafoundation.org/article/alcune-considerazioni

    3. Stamina fornisce il proprio operato, ovvero la lavorazione delle cellule staminali, in modo completamente GRATUITO per i pazienti, rifiutando donazioni non solo dai pazienti stessi, ma anche da loro congiunti o amici, tutto ciò per evitare ulteriori polemiche e dubbi.

    3. Stamina supplies its service, the production of stem cells, completely free for the patients, and refuses donations not only from the patients themselves, but also from their friends and family, to remove any doubt or controversy.

  22. weing says:

    “Stamina supplies its service, the production of stem cells, completely free for the patients, and refuses donations not only from the patients themselves, but also from their friends and family, to remove any doubt or controversy.”

    Holy Loss Leader, Batman.

  23. WilliamLawrenceUtridge says:

    You hit close to the mark with DNA transplant (by accident I am sure)
    Pluripotent stem cells of the patient can be genetically corrected to produce injectable motor neurons to be delivered into the spine. It has been done in animals.

    Has it been done in people? What kinds of animals? How close are they to people? Has it been done in primates? For what conditions? People aren’t mice, and SMA mice are a very specific strain of genetically identical mice that are used to provide a simplified model for specific conditions. Success in mice is a starting point for a new round of research, not a time to implement wholescale treatment of the condition. Did you read Dr. Gorski’s article? Did you notice how the first rounds of experimental bone marrow transplantation killed all the patients?

    Biology is about specifics. Each species has its unique evolutionary history, causing it to respond differently to different inputs. Each individual within each species has its unique genetic inheritence. It would be lovely to simply inject DNA into a person and have a protein expressed or a genetic flaw fixed, but it’s not that easy.

    You appear to think that science, in particular, biology, is easy. It’s not. It’s far harder than physics because there are far more specifics to worry about. It would be akin to trying to get to the moon when gravity changed unpredictably and powerfully at random intervals, and you were only allowed to use equipment scavenged from a factory that made model-T fords, while several other alien species were trying to get there first and were willing to sacrifice millions of themselves in the process. There’s a reason the space race was won in a decade, but the War on Cancer failed.

    Stamina supplies its service, the production of stem cells, completely free for the patients, and refuses donations not only from the patients themselves, but also from their friends and family, to remove any doubt or controversy.

    Oh, great, so they’re getting precious research dollars, then squandering it on scientifically useless pragmatic trials. Excellent. That’s “better”. Still doesn’t change the fact that they’re conducting irresponsible, scientifically useless clinical trials that will have long-term detrimental consequences.

    By the FSM, it would be great if the science of medicine were as easy as you apparently think it is. it’s a real shame it’s not. But hey, the day you invent a mouse model that perfectly mimics how humans react to any and all biological agents is the day we can all look forward to science becoming simple.

    Are you aware of something known as the Dunning-Kruger effect perchance?

  24. @WLU

    Has it been done in people?

    No successful human trials yet for SMA, mice only so far. A transgenic mouse model breed.
    Its promising, we have now the ability to create pluripotent stem cells from a sample of patients mature cells. Last nobel medicine prize was awarded for this procedure: http://bit.ly/VPHIzv

    For other conditions, we already have some human trials – rork posted about the ALS trial earlier, there is a japanese group organising a trial for eye retina degeneration treatment with stem cells: http://bit.ly/11IWeif
    and there is a group in US running a human trial for stem cell treatment of spinal cord injuries.

    Yes, I am aware mice are not humans. There was a project I invested in for a candidate Alzheimer treatment, it was a drug that prevented buildup of beta-amyloid peptide plaque in the brain. In the brain of mice it did just that, very convincingly. In the brain of humans it did nothing measurable. Disappointing. Oh well, at least now we know what doesnt work. Cold comfort to the millions suffering from this horrible disease though.

  25. windriven says:

    @FBA

    “Where did you get the idea that Vannoni charges big money or promises miracles?”

    I didn’t. I never mentioned Vannoni. I was actually thinking more along the lines of Burzynski.

  26. SteveJ says:

    @FastBuckArtist
    “There was a project I invested in for a candidate Alzheimer treatment, it was a drug that prevented buildup of beta-amyloid peptide plaque in the brain. In the brain of mice it did just that, very convincingly. In the brain of humans it did nothing measurable. Disappointing. Oh well, at least now we know what doesnt work. Cold comfort to the millions suffering from this horrible disease though.” Emphasis mine.
    Now do you know why we can’t just jump into treating people with unproven drugs? Going back to the Science Translation Medicine paper, did you read it? Or just the abstract? Reprogramming fibroblasts to become stem cells took a month. Getting stable transformants took at least a week. Differentiating them into neurons took another month. After all that the median survival time of the SMA mice went from 14 days to 21 days. Admittedly the treated mice grew better than untreated mice, but not as well as wild-type (WT). However, after 14 days they began losing weight whereas the WT mice continued growing.

  27. WilliamLawrenceUtridge says:

    What SteveJ said, and I’m startled you can type out something like that while simultaneously thinking what the Stamina foundation is doing a good thing. The cognitive dissonance must be painful.

  28. @SteveJ
    The mice got therapeutic benefit from the treatment. The transplanted neurons improved muscle growth. The weight loss after 2 weeks is a concern, but I dont think the result was disappointing. It showed that stem cell therapy as viable treatment for a condition thought incurable.

    Treating patients with unproven drugs – that really depends what patient we are talking about. A patient with common cold – no I wouldnt give him any injections of stem cells. A patient with a terminal illness who has no other treatment options? Thats different!

  29. SteveJ says:

    @FastBuckArtist
    So do you admit not having read the paper? Stem cell treatment for SMA is not ready for prime-time. The authors admit as much. “The possibility of motor neuron replacement after the death of endogenous motor neurons is the ideal goal that has to be pursued to treat already symptomatic SMA patients, although such a goal is still a long way in the future.”

    These mice model the most severe form (Type I) of the disease. Most people with Type I SMA don’t live to their 2nd birthdays. Keeping that in mind, the mice were injected with stem-cell derived neuronal cells, not stem cells, when they were 1 day old. All the treated mice were dead after 24 days. The negative control mice were all dead by 16 days. And by dead, I mean they were euthanized because of “problems in feeding, a clear downward progression (mice with 30% weight reduction and severe paralysis), and breathing difficulties…”

  30. weing says:

    “Treating patients with unproven drugs – that really depends what patient we are talking about. A patient with common cold – no I wouldnt give him any injections of stem cells. A patient with a terminal illness who has no other treatment options? Thats different!”

    Primum non nocere still applies. Even in a terminal illness. How do you know that your treatment doesn’t harm if it hasn’t been tested?

  31. @SteveJ

    The lifespan of a mouse is much shorter than a human, about 3 months in the wild and maybe a year in captivity. An extra week in mouse life is equal to a year in human life. It’s significant. The injected corrected neurons clearly substituted the function of genetically faulty neurons.

    I dont understand why you are so negative on this study. It’s the most promising treatment for SMA I have seen so far.

    @weing

    First do no harm is a nice concept, but how many prescription treatments do no harm? They all have adverse side effects. Some extremely harmful. Have you ever had to use Levophed? It’s so toxic the ICU nicknamed it “Leave’em dead”

  32. David Gorski says:

    Primum non nocere still applies. Even in a terminal illness. How do you know that your treatment doesn’t harm if it hasn’t been tested?

    Indeed. And for a terminal patient, every day in the hospital is too large a fraction of his brief remaining life. Every day spent suffering side effects of an unproven treatment robs quality of life in the brief time the patient has left. Every day cut short is a bigger fraction of his remaining life. Maximizing the number of days with high quality of life is very important.

  33. weing says:

    “Have you ever had to use Levophed? It’s so toxic the ICU nicknamed it “Leave’em dead””

    Actually, that’s what we used to call it. It had more to do with the prognosis of the deteriorating situation than the drug’s toxicity.

  34. weing says:

    Oh. And it’s not a concept. It’s a guiding principle. That’s why you have to weigh the risks vs benefits with every prescription and procedure.

  35. mousethatroared says:

    DG “Indeed. And for a terminal patient, every day in the hospital is too large a fraction of his brief remaining life. Every day spent suffering side effects of an unproven treatment robs quality of life in the brief time the patient has left. Every day cut short is a bigger fraction of his remaining life. Maximizing the number of days with high quality of life is very important.”

    Also, from what I’ve heard, from hospice workers and a couple of patient anecdotes, depending upon the illness some terminal patients can make a temporary recovery, live longer and with better quality of life in hospice care (only treatment to alleviate symptoms) than while being aggressively treated for the disease.

    Something I would consider if I was the patient.

  36. Scott says:

    I dont understand why you are so negative on this study. It’s the most promising treatment for SMA I have seen so far.

    Perhaps because it’s IN MICE and nobody has the faintest idea whether it will apply to humans AT ALL?

  37. WilliamLawrenceUtridge says:

    Perhaps because it’s IN MICE and nobody has the faintest idea whether it will apply to humans AT ALL?

    Indeed, truly our ability to cure mice of diseases we gave them in the first place gets better every year. It’s a bleedin’ shame that people aren’t mice.

    FBA, do you know why thalidomide was approved in the first place? It’s because it caused no harm in the animal model it was tested on – rats. From that lesson we learned two things – rodents aren’t people, and one animal model isn’t enough. The charicature you appear to have of science – that you can extrapolate studies directly from mice into humans (with severe and life-limiting diseases) is a false one. Science is full of dead ends, most of which are stacked with the carcasses of rodents. The approach to medical treatment you seem to think appropriate – test every option on sick kids – would contribute very little to science but a lot to the suffering of children.

    The most promising treatment for SMA in mice is a great starting point for further research, not leaps to human treatment. It’s terrible we can’t heal these diseases now, but we need good, solid, well-founded and well-understood research now in order to reliably and effectively treat future sufferers without adding to their suffering.

  38. Chris says:

    WLU:

    FBA, do you know why thalidomide was approved in the first place? It’s because it caused no harm in the animal model it was tested on – rats.

    And the reason it was not approved in the USA in the 1960s was because Dr. Kelsey had done work earlier at the University of Chicago with pregnant rabbits where it was discovered that drugs can affect fetal development. Since thalidomide was being specifically prescribed to pregnant women she wanted the studies on how if affected pregnant animals. None came, and the manufacturer instead tried to harass her, and get approval from her supervisors. See: http://virtualmentor.ama-assn.org/2001/11/prol2-0111.html

  39. SteveJ says:

    @FastBuckArtist
    “The lifespan of a mouse is much shorter than a human, about 3 months in the wild and maybe a year in captivity. An extra week in mouse life is equal to a year in human life. It’s significant. The injected corrected neurons clearly substituted the function of genetically faulty neurons.

    I dont understand why you are so negative on this study. It’s the most promising treatment for SMA I have seen so far.”

    I’m not negative on the study. I am trying to explain that just because stem cell treatment shows promise doesn’t mean that we can use it right now. Or that scientists are blind to the desperate need for treatments. And stem cells aren’t the most promising treatment out there. A adenoviral construct injected directly into the neurons of SMA mice can completely rescue (survival >250 days) them if given early enough. However we don’t know which treatment will work best on people, until we do more testing.

  40. SteveJ says:

    Whoops. I forgot the reference. The paper I saw is “Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN” Nature Biotech 28(3):271-276

Comments are closed.