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.

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