Two decades as a cell biologist have convinced me that grown stem cells are drugs

Stem cells grown in culture are a drug.

Agree or disagree?

I believe it is a correct statement. I don’t think it is even a question any more as it was a few months ago.

Yes, I am convinced that the FDA, as supported by a recent federal court ruling, has it right that growing stem cells in culture yields biological drugs.stem cell treatment

Such growth makes stem cells fundamentally different than the endogenous stem cells that exist in our bodies.

In fact not just me, but more broadly stem cell biologists largely concur that growing stem cells in culture substantially increases the risks associated with their potential clinical use.

So why even grow them?

Of all the wonderful properties of stem cells, there is one not so great property that most often goes without saying.

They are very rare.

It is hard to get many true stem cells from the human body so most clinics resort to growing the stem cells prior to use. In this way clinics may boost say 1 million cells into 1 billion cells, which they then transplant. By analogy compare taking a tiny fragment of an aspirin (1/1000th of a full aspirin) versus a full aspirin….of course the whole aspirin will be more powerful. The same idea applies to potential stem cell therapies–1,000x as many cells should be more powerful. Of course with increased power also comes increased risk of side effects.

For sake of argument, let’s say for the moment that we’re going to grow the stem cells to be used for transplant, what happens during this growth process?

The growth-related events are critically important for anyone who cares about stem cells to fully understand.

Sadly it seems the dubious clinics and their supporters either don’t understand this or intentionally sweep it under the rug…or should I say under the gurney.

Why should you believe what I say?

I’ve been growing and studying cells more than 2 decades.

When you grow cells in a lab they change. They can become something quite different than what you started with.

How do they change?

During cell growth in culture in labs, a rapid form of cellular evolution happens.

You don’t even have to believe in human evolution to understand the sense and logic in cellular evolution.

When you grow cells, over time the cells that grow the fastest will inevitably produce progeny that end up taking over the population.

These fast cells grow so much more quickly that they are greatly over-represented in the cell population at the end.

These winners of the cellular evolutionary process that happens during growth in culture even over a relatively short period of time typically share one thing in common.

They become more and more like cancer cells.

A second fact is that with every day that passes during growth, cells tend to acquire more and more mutations as well in their genomes. Thus, the normal genomic sequence of the freshly harvest stem cells from a human patient may be significantly different than the genomic sequence of the cells after growth, which often is abnormal.

As fate would have it the prevalence of mutations increases over time in culture for another reason and that is that some mutations make cells grow faster than their neighboring cells. As a result, mutant cells are often the winners of the cellular evolution that happens during culture described above.

Cells grown in culture are also exposed to a large number of foreign substances during growth that may make the cells more dangerous should they subsequently be transplanted. These substances can range from potentially hazardous chemicals such as endotoxins (terrifically poisonous chemicals made by bacteria) to contaminating proteins that ride piggyback on cells into patients.

Of course not all of this bad stuff always will happen.

But it will happen often enough that growth in culture requires additional validation and safety testing that to my knowledge dubious stem cell clinics never perform prior to transplant into patients. The clinics are either ignorant of these facts of cell biology or they are cutting corners to save themselves money.

I don’t believe in banning growth of cells in culture prior to transplant. Not at all. I believe, however, that it necessitates a higher level of caution by clinics and patients and also more regulatory scrutiny by the FDA.

28 Comments


  1. Paul,
    Thank you for this accurate and excellent post. All those with experience that I know even outside the immediate field like pathologists, neuro-scientists, and geneticists say the very same things that you are saying.

    They have grown cells out and watched this evolution. This was beautifully explained, I can see why you are a professor! MDs are not given the training in this field they need to overcome these obstacles alone.

    I am relieved the FDA was not strong armed into compliance and are promoting the population interests of safety and medicine.

    I hope the FDA will find ways through relationship and positive communication to solve the barriers of cost and extended time barriers before a product is market ready for the sake of needy patients and viable industry but I think none of us wants this at the cost of long term safety.


    • Thanks for your comment, Amy.
      There may be some very powerful stem cell therapies based on cell growth in the future that transform medicine.
      All I’m saying is they need to be more carefully validated and regulated PRIOR to the cells going into patients. Right now many patients are paying large amounts of money to essentially be guinea pigs at a growing number of unregulated stem cell clinics…and the MDs doing this often are not even following up on the patients to scientifically determine the effectiveness and safety of the treatments.


  2. Paul,

    I mostly disagree on the cell biology, as we have published two safety papers with close follow-up (i.e. few drop outs) and none of this was seen over 3-4 years with MSCs cultured for two weeks in autologous platelet lysate (see http://www.ncbi.nlm.nih.gov/pubmed/19951252 and http://www.ncbi.nlm.nih.gov/pubmed/22023622). The studies you’re referring to either use long-term culture, tumor inducing agents, are in animal models prone to genetic mutation, or animal models without an intact immune system. As you know, at least one study has also shown that even when MSCs pick up mutations during culture, they don’t form tumors-they just don’t work. In addition, none of this has been seen in long-term reports by others-see http://www.ncbi.nlm.nih.gov/pubmed?term=20603892, nor in the expanded MSC trials to date (now totally thousands of patients).

    The argument also misses the mark on how the risk equation should be measured (i.e. based on processing or public health risk)-i.e. whatever the risk of an autologous expanded therapy (likely very low based on the existing published human data), it’s a risk to one individual patient that is consented for that risk. This means that from a public health perspective, it’s exactly equivalent to the risk of any theoretical surgical procedure for which the patient is consented (0-100% morbidity for one individual).

    I certainly agree that if you want to grow cells for production over months in large bioreactors, producing huge number of doses-you need strict control over manufacturing-as that what this is, and that FDA is the right agency to handle that regulation. However that’s not at all similar to an autologous, short-term cell culture. For starters, each patient’s autologous tissue is only as good or as bad as the rest of their health and tissue. There is no drug type dose or potency. Dose-it’s different for every patient as each has cells of different potencies. At best it’s a range, something doctors are used to dealing with every day (should I transplant a little tissue here or because this patient has pretty bad tissue, should it be more more?) More importantly, it completely ignores the fact that even FDA recognizes that any doctor can call up a compounding pharmacy and get any drug chemical combo mixed with new binder, in a new dose, in a new formulation or mixture and apply/give/inject that into a patient. This is not FDA controlled as it’s a single patient care event where the patient is consented for that risk, which again is equivalent from a public health standpoint to the autologous cell therapy example. This is regulated under the practice of medicine and pharmacy, see http://www.fda.gov/ICECI/ComplianceManuals/CompliancePolicyGuidanceManual/ucm074398.htm. In particular this document draws a significant distinction between one on one use by a doctor and pharmacy (which it says FDA will ignore-mostly because of the court case discussed in the document) and when a pharmacist decides to become a manufacturer (which FDA clearly regulates).

    An interview with Bill Haseltine, the inventor of the term ‘Regenerative Medicine” is telling:

    “Surgery is inevitably going to be a big part of what most regenerative medicine technologies will involve, so the question of how one can do surgery at a reasonable cost is certainly one to consider. Looking at the whole field, delivering regenerative medicines can actually involve some of the highest priced labor in the world. Who has a greater labor cost than your doctor? This distinguishes the industry from a pharmaceutical business. The end user (i.e., the patient) is the one actually doing the handwork in the pharmaceutical business; they are the ones opening that bottle every day, reaching in and taking the pill. Equally, the pharmacist and the doctor are
    both engaged in the labor, so that is why the pharmaceutical industry is such a great business. This is not true amongst surgical businesses. I encourage people to think of what this approach could do for regenerative medicine businesses focused around implanting new tissues.”


    • Centeno, again, is a perfect lawyer but his competence in cell biology is more than questionable, given his statements here – he doesn’t even seem to know that even 2-3 population doublings in cell culture can already give rise to abnormal karyotypes. Then the studies that he cites are only remotely related – one would have liked to see studies of cellular integrity PRIOR to administration to willing patients. And then OMG all that tantrum of the value of empirical medicine : (I cite) “At best it’s a range, something doctors are used to dealing with every day (should I transplant a little tissue here or because this patient has pretty bad tissue, should it be more more?)” – pretty scary isn ‘t it ? – if that’s his view of practice of medicine’ in cell therapy – maybe yes, but a middle-age one.


  3. In my opinion Centeno should have spent his time and money on phase 2 and 3 trials, XXXXXX

    (note, this comment was edited by admin)


  4. These are not adequate or appropriate research papers for safety.

    Safety and Complications Reporting on the Re-implantation of Culture-Expanded
    Mesenchymal Stem Cells using Autologous Platelet Lysate Technique Christopher J. Centeno1, John R. Schultz2, Michelle Cheever3, Brent Robinson*,4, Michael Freeman5 and
    Wayne Marasco6

    This study has a lot of bells and whisltles with catchy graphics and slick wording. It fails to take into account scientific protocal inspite of several authors being MDs and some are clinical epidemiologists

    PICO
    Population : Patients with orthopedic conditions

    Interventions: Direct site injected cultured out 2-3 weeks mesynchemal autologous stem cells

    Controls : None

    Outcomes: Cancer or complications

    Study Design

    Experimental Cross sectional study with no controls

    Taxonomy of Research

    Primary Research Grade reject,

    Design Option
    Properly conducted blinded, randomized RCT with follow up cross sectional study using controls

    Poor quality for reasons of bias, no controls, COI (commercial interests as PI owns the company and pays some of those that conducted the study) No relationship to a normal population is given, cancers and complications are in multiple instances declared to be erroneous without justification or study explanation. Cancer question other than in less than 40 recipients who had area MRI was do you have cancer? Follow up was 2 years or less and blood work was not done except with initial treatment. Cell complications during culturing such as transfer of communicable disease were not discussed. Consents failed to inform patients of all the process and chemical growth factors /methods used. The FDA has banned them from offering this product with an injunction saying it finds no results for efficacy or safety

    Sadly this paper is marched around the internet as ‘proof’ by the authors and others that unregulated stem cells offered through their process is safe and does not cause cancer. I t looks scientific to a patient and they are told you have the right to decide your own stem cells ,they are not a drug. In actuality once these cells are cultured they have significant far reaching implications, more so than many drugs which go through 4 phases to approval


  5. @ FDA permanent injunction holder:
    You are sending a lot of noise without much signal. You consider the experience and work of another scientist with 20 years of experience as nothing and put in his place this inferior evidence?

    Consented risk based on logical fallacies, questionable evidence and straw man arguments using for your foundation your paper that has clear shortcomings is quite brazen. Perhaps you need to review Helsinki and Belmont reports.

    Following it up with a partial quote from Dr. Haseltine is creative. I wonder what he thinks of your paper and your business model?

    You claim you are amenable to some regulation but you have launched media attacks against the FDA using citizens of the USA . The examples you set conveniently exempt anything you are likely to do.

    Has it occurred to you that these activities to promote yourself at the cost of safety have given illegal clinics the motivation to spring up everywhere under the practice of medicine? Some are not even MDs. You could be responsible for innocent persons deaths because they drink the manipulated cells are not drugs kool aid?

    How about a citizens right to safe and lawful medicine? Here is someone who doesn’t seem to have done so well with your organization/ franchise or ICMS safety agency http://www.regenerativemedicinetijuana.com/

    Why don’t you invest your money in promoting science and doing good research instead of preventing the overburdened FDA from doing their job because they have to spend the time attending to your unjustified claims while you trot offshore to keep those pennies coming…


  6. I am thankful for the FDA standing their ground for safety.
    It would be unlikely that safety studies that are industry internal and non FDA approved studies would be approved or considered as valid.

    Even with regulation we are seeing 1.5 and 3 billion dollar fines for improprieties in regards to data transparency. There are also interesting cases where organ bank licensing has been issued without the same oversight and hospitals have used organs that come from questionable sources (took one felon 3 days to get a license!) and now even hospitals advertise on facebook for kidney donors.

    We also have companies, Pharma, med device and biologics that take their products out of the country and do not regard Helsinki, Belmont or FDA and do harm to recipients for which they remain unaccountable and yet they can use this unethically derived data to prop up their case for USA markets.

    These inconsistencies suggest that change is needed . There is little successful recourse for a sick patient who suffers adverse events in a clinical trial in the USA, so that is also not the complete answer but trials are needed. Patients mostly lose or spend years fighting and they end up spending the money they need to pay for their care and also use the mental and emotional energy they need to heal, maintain their immune systems and rebuild their futures.

    When the public reads about these inconsistencies they lose respect and they are left with the choice to trust an FDA they do not know or an MD they meet face to face who hints at the possibility of a solution.

    We are all socially conditioned to trust and not to question an MD’s judgement. If we are vulnerable and in pain or have no other options it is no contest. Most will assume the doctor has ethics, is honest, he/she is compliant, the lab is clean and the treatment is good even when it is not. If the doctor says it is safe and they have a chance and are fortunate to have the funding to broker the deal they will go for it regardless of FDA. Even if the MD is legally barred from performing a procedure within the USA, the medic or the staff or a designate can still see patients in a USA office, recommend treatment offshore and then go and perform it or have others they hire do this for them. How safe is? There are concerns when there are complications plus there is the additional bodily insult of extended travel.

    Most will continue to support the medic even when treatment harms them or is unsuccessful as they invested in the process and gave their trust and to consider otherwise is questioning their own judgement which is yet another loss. By the time they figure out they have been taken advantage of it is too late. If a family member has helped pay for the treatment it is even more serious as none of us wants to tell a family member that their help was harmful or did not good. If any seek legal redress they will be outspent and intimidated plus since this intervention is so new tying the adverse events to the cell therapy in a court of law will not be easy.

    If they are fortunate and treatment succeeds they will not look back, most of us would give everything we have for the health of someone we love. For those that care about science, patients and ethics the system needs innovation and the exercising of integrity compassion and wisdom from all stakeholders. History does not show a good track record for self regulation in the health industry. Their needs to be a cooperative effort for change with the needs and concerns of all stakeholders understood and validated without unfair power advantages or hostility


  7. Guys, use your real names and I’ll address all of your issues specifically. Hiding behind pseudonyms in a debate means you have a reason to hide your identity and shouldn’t be tolerated as it makes it too easy to say irresponsible things.

    However, one example that will help define the debate further is Genzyme Carticel. This was approved in 1997 and is an autologous culture in FBS for 2-3 weeks based on a surgical chondrocyte sample taken from a knee. The focus is cartilage repair of an OCD. Recent research has shown that cartilage biopsies contain an MSC population. Dowthwaite et al first described a progenitor cell population on the surface of bovine cartilage.[2] Williams et al obtained human cartilage biopsies from femoral condyles in the same manner as Brittberg. These were digested and plated as in the Carticel procedure. In this study they then used a finbronectin adhesion assay to select adherent cells. They note that it is well documented that full depth chondrocytes in monolayer culture lose their rounded cell configuration and phenotype. In addition, their study demonstrated that this loss of phenotype is associated with an MSC-like progenitor population.[3] Koelling also isolated a similar population of progenitor cells in cartilage.[4] Chang has found that these mesenchymal progenitor cells in cartilage constitute approximately 4-6% of the cells taken from a Carticel type biopsy of adult and elderly knees.[5] Pretzel performed various immunofluorescence tests and found between 11-16% of normal and osteoarthritic cartilage cells were CD105+/CD166+ progenitor cells.[6] Interestingly, the CD166+ cells had many of the same characteristics of MSCs and these were found almost exclusively in the middle and superficial cartilage zone most likely to be biopsied by a surgeon (22-24% concentration). Khan recently noted that the Brittberg ACI procedure (Carticel) predated the discovery of MSCs in cartilage and as a result, his opinion this procedure utilizes MSCs for its effect.[7]

    So we have a procedure that has been done since 1997 and has been used in tens of thousands of patients safely. It does, based on the most recent scientific evidence, clearly culture MSCs. It was approved with less data than has been developed for our procedure (in fact based on a single case series without any controls). It’s approval documents show that it’s release criteria is about the same or less stringent (since we use periodic flow cytometry) than our current procedure. There isn’t a single published case report on any serious complication related to the use of these cultured cells (outside of obvious surgical issues) since 1997.

    BTW-Hi Amy, Hi Danilo…

    1. Brittberg, M., et al., Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med, 1994. 331(14): p. 889-95.
    2. Dowthwaite, G.P., et al., The surface of articular cartilage contains a progenitor cell population. J Cell Sci, 2004. 117(Pt 6): p. 889-97.
    3. Williams, R., et al., Identification and clonal characterisation of a progenitor cell sub-population in normal human articular cartilage. PLoS One, 2010. 5(10): p. e13246.
    4. Koelling, S., et al., Migratory chondrogenic progenitor cells from repair tissue during the later stages of human osteoarthritis. Cell Stem Cell, 2009. 4(4): p. 324-35.
    5. Chang, H.X., et al., Age-related biological characterization of mesenchymal progenitor cells in human articular cartilage. Orthopedics, 2011. 34(8): p. e382-8.
    6. Pretzel, D., et al., Relative percentage and zonal distribution of mesenchymal progenitor cells in human osteoarthritic and normal cartilage. Arthritis Res Ther, 2011. 13(2): p. R64.
    7. Khan, W.S. and U.G. Longo, ACI and MACI procedures for cartilage repair utilise mesenchymal stem cells rather than chondrocytes. Med Hypotheses, 2011.


    • Moniker use to comment on a blog does not invalidate facts Chris. In my opinion, given the litigious history, it’s the best way to participate under these circumstances. XXXXXXXX

      Comment edited for content


    • I agree with Super here and would also point out that this is not a debate, Debates have rules and you have already broken them. A good debate and debaters could take either side and look objectively at its merits and flaws. All would learn from the debate.
      It should not matter as Super says what the moniker is, the importance is in the facts presented. Going off on social status, education, lack of experience or competence of the one with an opposing view is just smallness.
      Carticel is not the same forms of expansion as Paul was speaking about and there is not enough long term data to predict population safety for other procedures


  8. Here are a host of arguments (both scientific and public health) against turning cultured cells into drugs, not made by me, but by a host of big players who opposed these regulations:

    -American Society of Clinical Oncology-[A real “barn burner” of a letter]-https://www.box.com/s/oa9d02pnmbk7g2a2sluh

    -Biotech Industry Org-https://www.box.com/s/3tb6ccqh6gep8y3hld3g

    -Northwestern Univ Transplant Program-https://www.box.com/s/k9jhy0ohvvtjpfdab1r0

    -Osiris [they now have allogenic cultured MSC products]-https://www.box.com/s/2j6o53nk8i5ntdr4y49h

    -American Red Cross-https://www.box.com/s/k1s1kxgrn3gj3boab1t1

    -Anthony Atalia, Hyman-Phelps-Reprogenesis-https://www.box.com/s/hb7ae5tfm7h9789b88lx


    • All of those papers are over a decade old and have no bearing on the current issue at hand or scientific developments and regulatory challenges that have taken place over the last 15+ years. Posting links that easily punch holes in your own argument is an insulting waste of everyone elses’ time, but I’m sure you already knew that.


  9. Dr. Knoepfler:
    First of all, thanks for the forum you gave the ICMS a couple of months ago. I am writing today as a Plastic Surgeon who works with adipose tissue as a way of delivering SVF (Stromal Vascular Fraction Cells).
    The problem is that in the case of SVF cells the FDA is coflating the issue of autologous SVF cells not grown in culture with: 1) autologous cells grown in culture for a limited number of cell division cycles (As in Centeno’s case), 2) Allogeneic cells subjected to multiple and serialized growth cycles, 3) Inmmortalized Allogeneic cell lines (IPS).
    The safety issues for each of these categories are vastly different. From our own work at ICMS trying to establish standards and safety guidelines for the handling of these cellular therapies, the requirements for each are very different.
    The FDA rationale for including them all under the same regulatory rubric is that stem cells, whether SVF, autologous cultured cells, allogeneic cultured cells, etc. act like a drug. If it is true that SVF acts “like a drug” because it releases cytokines that cause surrounding tissues to alter their behavior, so it is for all our grafts, like skin grafts, bone grafts, etc. which release their own cytokines and stimulate surrounding tissues to change their behavior.
    This is a semantic trap that if followed to its logical conclusion would lead to the regulation of simple fat grafting as a drug.
    Fat tissue contains a high proportion of stem cells per gram of tissue, up to 1million cells/cc. Thus a harvest of 200cc’s of adipose tissue could yield therapeutic doses in the same operative session without resorting to tissue culture. Indeed, clinically treating radiated breast tissue with fat grafting alone shows dramatically the drug like effects of SVF residing in fat grafts.
    Indeed, the whole issue of how you concentrate the SVF from fat leads one to the slippery slope of increasing concentrations of SVF in a gram of fat. Where does one draw the line?
    In summary, I find that even experienced researchers with 20 years of experience like yourself tend to discuss the issue of stem cells as it was “one thing” whereas in reality we are talking of various cell populations, each with its own risk profile. I think that even you would agree that the risk profile of freshly isolated autologous SVF reinjected in the same operative session is in a different category than that of cultured autologous cells, or even allogeneic IPS cells.


  10. Amy,

    XXXX

    Your premise that patients trust doctors is also a logical fallacy in that first it’s an Ad hominem attack in disguise. It’s also a false analogy in that this phenomenon is not at all unique to stem cells. There are bad doctors just as there are bad scientists, lawyers, and Indian chiefs. In particular, this discussion was about Paul’s assertion that based on his experience at the lab bench, stem cells should have strict regulation. I think as Ricardo brought up, you can bifurcate this argument into two concepts. Paul uses the concept most comfortable to a bench scientist-the degree of processing and changes to the cells. In fact this is the concept FDA chose for it’s regulation. While this makes sense for cells grown to millions of doses in a bio-reactor, it fails to make common sense from a public health standpoint when applied to doctors seeing one unique patient. In that case, the risk of any autologous stem cell therapy is equivalent to any surgical risk.

    Your research/drug trial concepts for patient protection are also not supported by the seminal document for the US system-The Belmont Report, nor are they supported by the International Document-Helsinki. The latter sums it up the best:

    “In the treatment of a patient, where proven interventions do not exist or have been ineffective, the physician, after seeking expert advice, with informed consent from the patient or a legally authorized representative, may use an unproven intervention if in the physician’s judgment it offers hope of saving life, reestablishing health or alleviating suffering. Where possible, this intervention should be made the object of research, designed to evaluate its safety and efficacy. In all cases, new information should be recorded and, where appropriate, made publicly available.”

    What you’re really quoting about patient protections is taken out of context for effect. Belmont places this higher burden on patients who are involved in a research study where the goal is not to cure or mitigate disease and thus they need extra protection. This is because whether or not any individual recovers is simply unimportant to the end goal of the study. Quite the opposite, what physicians do (as described in Helsinki and Belmont) is to treat one person with a duty to heal. In doing that, sometimes the research is helpful, sometimes it doesn’t apply to Mr. Smith-as a result, physicians are trained to use whatever it takes (including innovative care if no good traditional option exists) to help the patient.

    Note, comment edited for content (XXXXX)


    • Paul was talking about safety with cells not just safety in bio-reactors but cells that are manipulated The FDA is about SAFETY for human participants. To tun this into a manufacturing dichotomy is not useful.


    • Public health risk 1-100% says nothing. That is life as it is, we are born, we all die, medicine happens along the way . FDA is looking at safety within a specific perimeter: human cells that are manipulated. They need real numbers for safety , these come with perimeters like appropriate conditions cGMP labs, etc.

      Big concepts like logical fallacy and ad hominem attacks in disguise LOL…best to read up so you can use them logically


    • If anyone chooses to practice as an MD and a scientist simultaneously then the ethics for both apply.

      For the trial the emphasis is on does this work or not and that is why we have ethics to protect participants so they do not become treated like the ends to the mean,

      As an MD there is the do no harm plus doing whatever is needed to intervene on behalf of a the patient in your care .
      If you wear both hats you are subject to the laws and ethical conduct in both camps .


  11. I’d agree with Ricardo on complexity of the problem. We can’t call all type of cells by the same name and agency should not regulate them in the same way.

    To me, cells are not drugs. Biologically and chemically these are completely different things. When public and mass media say “cells are drugs” they mean “cells are regulated by FDA as drugs”. So, we are discussing regulation but not biological or chemical definitions. In terms of regulation, I think and I proposed it many times, that different types of cell therapy should be regulated in different way. So, some – yes, some – no. For example, I’d regulate gene modified cells as drugs (irrespective to their maturation) or iPS/ES-cell derivatives as drugs.

    The hardest one is autologous adult stem/ progenitor cells non-modified genetically. This is a subject of big debate. Almost all discussions we have on our forums – all about this category. But, I think, it should be clearly defined at the beginning what are we all talking about. Within this issue we can divide cells cultured and non-cultured. To add more complexity to the issue – non-cultured cells could be minimally and non-minimally manipulated. For example, freshly isolated bone marrow mononuclear cells mixed with (A) FDA-approved drug, (B) non-FDA-approved drug; in case of (B) – incubated with a drug for 1-2 hours (C) or mixed in infusion solution at a bed side (D). How should A, B, C, D regulated? Same way or different? If different – at what degree? The next question – Is there any therapeutic cell product, except hematopoietic graft which is clearly defined by FDA as minimally manipulated? Fresh SVF derivation from fat associated with use of enzymes, but cells are not cultured. Should it be regulated in the same way as cultured for 2 weeks adipose-derived MSC?

    The next series of questions – FDA authority. I don’t know much about it, but I think, it also complex. For example, should FDA regulate only manufacturing (ensuring safety and quality of the product) or everything? Should FDA regulate all cell clinical trials? Should manufacturing be only strictly GMP-grade? How can we define manufacturing in autologous cell non-gene-modified products?

    Finally, FDA regulation is an experience of just one country. It could be good, could be bad. Why should we be so obsessed about it?


    • Alexey, yes that is my question too. If the cells are working so well and the FDA is the only barrier to widespread implementation and efficacy then why are we not seeing good research standard peer reviewed efficacy studies from other developed countries without an FDA?

      I agree here “In terms of regulation, I think and I proposed it many times, that different types of cell therapy should be regulated in different way. So, some – yes, some – no. For example, I’d regulate gene modified cells as drugs (irrespective to their maturation) or iPS/ES-cell derivatives as drugs.”


      • Alexey, you raise some important points. I do, however, disagree on the issue of whether cultured stem cells are drugs. I think they are drugs.


  12. Agree Alexey, complex issues. The FDA has come up with one way to deal with this-based on the level of manipulation (let’s call it an event). When that event involves manufacturing (i.e. the distribution of a million doses) this makes quite a bit of sense from a public health perspective. This was the intended purpose of the FDA’s 1271 regulation, as evidenced by the fact that prior to 2006, this definition of “more than” minimally manipulated was directed at a manufacturing event. However, as Ricardo brought up, once you extend this manufacturing concept to autologous cells (as FDA did in 2006 by changing the word “another” [into another human] to “a” [into a human]), the manufacturing event concept no longer makes sense from a public health perspective. This is because the event is now a single procedure, so the public health implication is suddenly equal to that of any other surgical procedure that may also have very high morbidity or even mortality.


  13. Paul- As you know, my lab’s done extensive molecular analysis of human iPSCs and hESCs to determine what happens when the cells are kept in culture. I agree that evolution in the dish takes place- survival of the fittest…I use those terms in my seminars. However, saying that these cells turn cancerous is factually incorrect. We see deletions of “tumor suppressor” genes and duplications of “oncogenic” genes, loss of X-inactivation in human cells, loss of imprinting. But remember, many of the “oncogenes” that we speak of are genes associated with embryonic development, as well as cancers. It makes sense that these cells would be pressured to become more “pluripotent”-like as they adapt to culture. Our culture methods encourage that. But so far no one has seen any increase in tumorigenesis by derivatives of hESCs or iPSCs because of any of these molecular aberrations. It would be a good project for someone to do thoroughly.


    • Jeanne, To me this is a huge concern and one that needs extensive study. People do have abnormal lab results after cell transplant and these people don’t know if they are a stress episode or single DNA break away from cancer and if in fact they are fine and once the lab result are clean they are out of the woods. I wonder what animal studies show?


  14. Very interesting exchange once again. Paul, I have an additional 2 decades of experience culturing various types of stem cells and agree with what you describe. I also would add contact of the cells with high concentrations of oxygen, which was shown to be a mutagenic factor some years ago by Peter Cerutti.

    Clinical trials are required not only to demonstrate safety of a therapy, but also efficacy. Even for approved therapies, we have learned that safety monitoring is an ongoing concern. However, my major concern is that with cultured cells, there should be regulation of the procedure. In this respect cells are similar to drugs in that they must be prepared under GMP conditions with strict QA/QC and SOPs, even if they are autologous.

    I believe that it is another discussion when we discuss efficacy and cost/risk/benefit analyses. Is the procedure worth the money, risk etc. I think this is a very important question, especially when we are concerned with medical tourism.


  15. Question. Doesn’t exposure to and/or culture in FBS of human MSCs lead to their essentially permanent contamination with cow proteins? It seems the FDA would view that by definition as more than minimal manipulation.

Comments are closed.