"It's better to light a candle than curse the darkness"

Stem Cell Therapy for Autism

January 26th, 2010

Sorry to have been gone for so long, but I wanted to take extra time on this topic because….well, because it needs extra time and attention to detail.

In growing numbers, people are taking their autistic children to “clinics” - in Costa Rica, in Germany, in Russia - to get “stem cell” injections. I put “stem cell” inside inverted commas because it is not entirely clear that what these children are receiving are actual stem cells.

And that might be the “good news” in this post - more about that later.

Stem cells have been in the news a lot, especially the past year, since President Obama cleared the way for embryonic stem cell research. So, today, almost everybody above the age of three has heard of them - but how many people really know what they are and what they can (and can’t) do? Not so many, I think (based on what I’ve heard people say about stem cells).

What are stem cells?

Judging by the many and varied things that the lay press have said about stem cells, you might be forgiven for thinking that they are magical little beings that swim to the site of whatever medical problem exists and fix it - sort of like the “nano-machines” that periodically crop up in science fiction stories. However, sad to say, that isn’t the case.

Stem cells are nothing more than a type of cell that can differentiate (develop into) a different type of cell - sometimes many different types of cells (and can proliferate - divide - indefinitely). Far from being magical semi-sentient beings, they are quite prosaic and exist in your bone marrow, under your skin, in your brain - pretty much everywhere in your body. They range from the humble karatinocyte stem cell of your skin - which can only produce karatinocytes (the outer layer of your skin) - to the omnipotent stem cells present in the first few cell divisions after fertilization, which can each develop into a complete organism (see: “identical twins”).

What has some scientists excited about stem cells is the potential to use certain types of them to treat illnesses and injuries that are currently beyond our abilities. In a few cases, we have already seen these therapies work - in most cases, they remain tanalizingly out of reach.

There are a number of different types and degrees of stem cells, which complicates the discussion considerably. The cells of a zygote (fertilized egg) that is still in its first few cell divisions can each become a complete organism (as mentioned above), but before long (a few hours, in most cases), those cells have differentiated to the point where they can’t make an entire organism, but they can still produce cells of any tissue or organ of the body. Once they have “committed” to going down a particular developmental path, they cannot (usually) go back (without our “help”). Eventually, the differentiation process progresses to the point where the cell is terminally differentiated - it has become a liver cell or a neuron and it will not (again, usually) become anything else.

There are two general features of a terminally differentiated cell: it can only divide a few times - at most - and it cannot generate or develop into a different type of cell (again, in biology, there are always the rare exceptions to this and every other rule).

Unipotent and multipotent stem cells:

In order to deal with cell death due to injury or senescence (”wearing out”), most tissues and organs have a pool of unipotent and multipotent stem cells. Unipotent stem cells - as the name implies - can generate one type of cell (e.g. the keratinocyte stem cell can only make keratinocytes); multipotent stem cells can generate a range of related cell types. A good example of multipotent stem cells are the marrow stem cells, which can generate any of the blood cells - red cells, white cells (all types) and platelets - but cannot make, for instance, neurons or skin cells.

Pluripotent stem cells:

This is the type of stem cell that most of the media “hype” is all about. These stem cells can develop into any cell type from any of the three germ cell layers. These are not found in significant numbers beyond infancy, although there have been a number of studies showing that they do persist (in small numbers) into adulthood.

One of the major breakthroughs in stem cell research - and one that might not have happened this soon without the politically-motivated ban on embryonic stem cell research - has been the ability to take adult cells [Note: in stem cell research, cells become "adults" shortly after birth of the organism.] and “reprogramme” them into pluripotent stem cells. This not only gets us around some rather sticky moral and political controversies, it also gets us around the problem of the immune system. More about that in the next section.

Embryonic vs Adult stem cells: 

The next classification of stem cells refers to their origin. Thus we have embryonic stem cells (ESC) that come from the inner cell mass of an embryo, adult stem cells (generally multipotent stem cells) and induced stem cells (iPSC, iMSC) that are made from either adult stem cells or somatic (terminally differentiated) cells.

 

How do stem cell therapies work?

Adult stem cells - generally marrow stem cells, since they are easiest to “harvest” - have been used for some time in the treatment of leukemia and lymphoma. They have even been used - with significantly less success - in the treatment of breast cancer and brain cancer. The reason that bone marrow stem cells are so useful is not because they have some magical anti-cancer activity; they simply allow the oncologists to use much higher doses of chemotherapeutic drugs. One of the limiting factors in chemotherapy for cancer is the bone marrow - higher doses run the risk of killing off too much (or all) of the bone marrow stem cells, killing the patient (usually due to infection from low white blood cell count - red cells and platelets can be transfused).

By taking out some of the patient’s own bone marrow stem cells and saving them, they can be re-infused after the chemotherapy has been completed - in essence, they “re-seed” the marrow. This allows them to use much higher chemotherapy doses, which (in some situations) can make the difference between a relapse and a remission.

A similar process is used - experimentally, for now - in the treatment of multiple sclerosis [1]. Multiple sclerosis is an auto-immune disease, where a group of immune cells are reacting to the patient’s own tissues (the myelin covering of their nerves, in this case). Recent advances in cell identification and sorting have allowed researchers to isolate only stem cells from the marrow (and none of the terminally differentiated cells that are causing the problem). After the stem cells are removed, the patient receives a course of chemotherapy (and occasionally radiation) to kill off the immune system, after which the stem cells are re-infused to “re-seed” the marrow with (hopefully) healthy cells. This appears to be somewhat promising in limited trials to date, but it is far from established therapy.

A bit more experimental is the use of stem cells to repair damaged tissues, such as heart muscle, nerves (spinal cord) and brain. To do this you need pluripotent stem cells (or you need to extract the stem cells from the tissue/organ - a technique that hasn’t been developed yet). You can use either embryonic stem cells (ESC) or induced pluripotent stem cells (iPSC). So far, the few clinical trials using stem cells for cardiac disease are either in the early stages or not yet started.

Early on in stem cell research - before the discovery of techniques to induce terminally-differentiated adult cells to become pluripotent stem cells - it was thought that only embryonic stem cells were pluripotent. But studies (and a few clinical trials) using embryonic stem cells ran into problems with the immune system. Embryonic stem cells (unless they were harvested from the patient’s umbilical cord blood or a genetically identical donor) are foreign to the recipient, so there is the problem of rejection so familiar in organ transplants, where the recipient’s immune system attacks the stem cells. If the stem cells are (or differentiate into) immune cells, they can even turn about and attack the recipient’s cells, a phenomenon known as graft vs host disease. Either situation calls for immune suppression, which limits the usefullness of embryonic stem cells.

The advantage of using iPSC’s is that they are (usually) the patient’s own cells, so there is essentially zero chance of rejection or immune reaction. Of course, if the problem is a genetic one, there is probably little point in using the patient’s own cells, since they will carry the same mutation.

Unfortunately, iPSC’s carry some “baggage”, as well - literally. In order to “reprogramme” adult cells to become iPSC’s, certain genes - that have been permanently inactivated in terminally differentiated cells (and even in multipotent stem cells) - need to be “turned on”.  Initially, this was done using lentiviral vectors - retroviruses that had been “engineered” to carry non-inactivated versions of the four critical genes (Oct3/4, Sox2, c-Myc and Klf4) into the cells and insert them into the DNA [2]. This worked very well, but the problem is that lentiviruses are rather….indiscriminate about where they insert themselves, so there is a chance that they will do so in a place that inactivates a critical gene. This is why so many of the lentiviruses are known as oncoviruses (cancer-causing viruses). As you might imagine, this limited the use of iPSC’s to experimental animals.

More recently (2008), a research team has managed to convert embryonic fibroblasts to iPSC’s without using a viral vector, using plasmids [3] and even more recently, another team managed to do it with proteins alone [4]. Both of these techniques are - needless to say - still being refined and are not ready for clinical trials.

So, if anybody is getting “stem cell therapy” today, it is either from their own bone marrow (and will produce only blood cells) or it is from embryonic stem cells (and carries the risk of rejection and/or graft vs host disease).

 

Risks of stem cell therapy:

The risks of stem cell therapy are hard to quantify because it is difficult to separate the risks of the other parts of the therapy from the risks of the stem cells. This is because most of the patients who have undergone stem cell therapy to date have received bone marrow stem cells (their own or someone else’s) and have also received large doses of chemotherapy and/or radiation, which muddies the water as far as following the risks of stem cell infusions goes. However, there are some “brave maverick doctors” in places like Russia who are injecting embryonic stem cells into the spinal fluid of children with ataxia-telangiectasia (and, apparently, other genetic neurological disorders). The outcome of one of these children was reported in PLoS Medicine:

“In May 2001 at the age of 9 y, in March 2002 at the age of 10y, and in July 2004 at the age of 12 y, he was taken by his parents to be treated in Moscow with repeated transplantation of fetal stem cells.”

Approximately one year after his last stem cell treatment, he was seen in hospital:

“…[he] presented to the Sheba Medical Center in February 2005 with recurrent headaches. On examination he had severe neurological deficits characteristic of AT, affecting mainly his motor functions and making him wheelchair bound.”

Although not explicitly stated in the case report, the stem cell treatments were apparently not working, based on their description of his condition. What they found, however, was worse than “not working”:

“MRI performed in February 2005 to investigate the headaches revealed a right infratentorial lesion slightly compressing the brain stem and another lesion at the cauda equina (Figure 1A and 1B). The lesions grew slowly as evidenced by repeat MRIs in June and July 2006. In September 2006 at the age of 14 y, surgery was performed and a tumor localized at L3–4 level attached to the cauda equina nerve roots was removed. Additional ’satellite’ lesions were identified attached to nerve roots rostral to the main lesions (Figure 2A and 2B).”

In short, this lad had two separate brain and spinal cord tumours. Under the microscope, these tumours were not cancerous, but looked like disorganized neural tissue. When they were tested genetically, the tumours did not match the patient’s genetic markers. They were, in fact, from two separate donors.

 Although this child received embryonic stem cells from two different donors, there is no reason why the same problem couldn’t happen with either autologous embryonic stem cells (i.e. from stored cord blood) or iPSC’s. In fact, one of the defining characteristics of pluripotent stem cells (embryonic, adult or induced) is there ability to form teratomas - tumors containing tissues from all three embronic layers (ectoderm, endoderma and mesoderm).

 

What about using stem cells in autism?

Part of the problem with using stem cells to treat autism is that we don’t know what we are treating. Despite the enthusiastic promotion of various “theories” about what causes autism, there is no generally agreed upon pathology or “lesion” to treat. Even genetic studies fail to show one single genetic cause of autism, suggesting that what we call “autism” is a number of different disorders with a similar (or not so similar) appearance. Injecting stem cells in the vague hope that they will find the problem and fix it is foolish. Stem cells have no more idea of how to “fix” autism than we do - which is to say, “none”.

The “good news” I referred to above is that, based on the descriptions of what they are doing, the clinics where parents are taking their autistic children for “stem cell therapy” are using - at best - multipotent blood stem cells. The descriptions are more promotional than informational, so it is entirely possible that their “techniques” are yielding no stem cells whatsoever. This is “good” because infusing real pluripotent stem cells into the blood or (worse yet) into the spinal fluid carries the risk of creating tumors without any known (or even suspected) potential for benefit.

In the event that someone invokes the concept of “neuroinflammation” as a reason to try stem cell therapy, I’d like to point out that, to date, effective stem cell treatments for “neuroinflammation” and autoimmunity have involved also giving large doses of cytotoxic drugs to kill the errant immune system cells prior to re-infusing the patient’s stem cells. Explain how that would work without the cytotoxic drugs (or radiation) and you’ll get a Nobel Prize in Medicine.

I fervently hope that none of these clinics are using viral vectors to create or “activate” pluripotent stem cells, as this carries a known risk of carcinogenic transformation. I know that they aren’t using any of the non-viral techniques because they are too new and too complicated. I suspect that they are simply re-infusing the patient’s own blood. And I hope that they are using good sterile technique when they do so.

At best, “stem cell therapy” for autism is offering false hope; at worst….. who knows?

 

Prometheus

UPDATE: See this article in the Milwaukee Journal Sentinal about the sales techniques used by a stem cell therapy center.

References:

[1] Capello E, Vuolo L, et al. Autologous haematopoietic stem-cell transplantation in multiple sclerosis: benefits and risks. Neurol Sci. (2009); 30(Suppl 2):S175-S177

[2] Takahashi K,Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. (2006);126:663–676

[3] Okita K, Nakagawa M, et al. Generation of mouse induced pluripotent stem cells without viral vectors. Science. (2008); 322:949-953

[4] Zhou H, Wu S, et al. Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell. (2009); 4(5):381-384

Filed under: Autism Science, Autism Treatments

18 Responses to “Stem Cell Therapy for Autism”

  1. A Photon In The Darkness » Blog Archive » Stem Cell Therapy for Autism | My Autism Site | All About Autism Says:

    [...] Read this article: A Photon In The Darkness » Blog Archive » Stem Cell Therapy for Autism [...]

  2. Clay Says:

    Thanks for explaining that, Prometheus. I had been wondering about that.

  3. _Arthur Says:

    I’ll stick to RNA yeast extract, then.

    Or Vegemite.

  4. Lindsay Says:

    Wow, I had no idea there really were people hawking phony “stem-cell” treatments for autism … I saw a Google ad mentioning “stem cell therapy for autism” and thought it had to be a hoax, or random computer-generated gibberish, since there obviously couldn’t be any such thing.

    And yes, I’m quite confused as to how you’d use stem cells to “cure” autism anyway, even if stem-cell technology *AND* our understanding of autism were to suddenly advance far enough to make such a cure possible — grow a whole new brain? Paging Dr. Frankenstein!

  5. Tom Says:

    If these clinics are using donor tissue, I hope they have screened for common infectious diseases like HIV or hepatitis but I doubt it.

  6. Prometheus Says:

    Tom,

    From the descriptions I’ve received of what goes on in the “stem cell” clinics (again, based only on non-scientific parental reports and a limited number of clinics), it would appear that the infusion consists of diluted blood (from the patient).

    This is one situation where the best outcome would be if the clinics were “scamming” the parents, since a well-intentioned attempt to actually produce and inject induced pluripotent stem cells into the spinal fluid of children could have dire long-term consequences.

    Prometheus

  7. Autism and Stem Cells | Ashlar-Online.com Says:

    [...] via Prometheus [...]

  8. Alex Says:

    Where exactly are these clinics? No need to crow if you don’t have the seed.

  9. Prometheus Says:

    Alex,

    You may have missed the part where I mentioned that clinics adminstering “stem cells” for the treatment of autism can be found in Costa Rica, Germany and Russia. A quick Google search for “autism” and “stem cell” reveals that there are also clinics in China, Thailand and Mexico. No doubt, I could find more places if I spent a bit more time.

    If you are asking for their names and addresses, you’ll have to look them up yourself - I don’t want to give them any free advertisment.

    Prometheus

  10. Stephanie Says:

    It seems odd to hope it’s all a scam, but that seems the best of the available alternatives. Which is sad, but not too surprising.

  11. late_but_here Says:

    I wanted to add a nerdy non-autism comment, that in the very basic science camps, we want to study various stem cells, not because of some very immediate medical application, but simply to better understand how they work, since there are serious lessons about certain genes awaiting us, and those lessons influence our thinking, about cancer for example (that’s my situation). We are not looking for astonishing and simple breakthroughs where we just inject cells and poof, magic happens, just more understanding. I don’t see that getting said in public very often.

    More generally we also want to understand how organs (like adrenal glands) get made, which again impacts our thinking about the genes involved, and yes, there are some other folks out there who ‘just’ want to be able to make replacement parts like heart valves from your own stem cells.
    The important genes/proteins/processes in stem cells are heavy hitters, and we can hardly imagine more knowledge of them failing to be crucial. Maybe that is hard to sell without going deep into specific examples though.

  12. Prometheus Says:

    Late_but_here,

    I had a couple of paragraphs about that in my post, but took them out because it disrupted the “flow”.

    Personally, I think that the therapeutic use of stem cells is often used as an “excuse” to research their basic principles. If you mention that stem cells might yield some amazing medical therapy “in the future”, medical-oriented funding sources are more likely to fund your research.

    From where I sit in the biology research landscape, the most interesting part about stem cell research is finding out how a single cell can generate a multi-cellular organism (like us) with just the information encoded in its DNA.

    I was at a cell-signaling conference where I spoke with a major stem-cell researcher who stated:

    “Stem cell-based therapies are the future of medicine - and they always will be.”

    Prometheus

  13. Stephanie Says:

    Late_but_here & Prometheus,

    I think another reason why the therapeutic application is pushed in the mainstream media is because so many people cannot divorce “stem cell” with “embryonic stem cell.” For many people, if you’re going to “harvest babies,” then you need to have some believable (by them) life-saving goal as the ends that justifies the means. Otherwise, if you’re just doing it to satisfy your own curiosity, then you’re just monsters.

  14. MJ Says:

    First FDA-Approved Stem Cell Trial in Pediatric Cerebral Palsy

    http://www.sciencedaily.com/releases/2010/02/100211121812.htm

  15. Autism Blog - Stem Cell Therapy for Autism « Left Brain/Right Brain Says:

    [...] For those who would like a rundown of stem cells, their use and the potential problems, I refer you to Promtheus’ A Photon In The Darkness blog and his post, Stem Cell Therapy for Autism. [...]

  16. nayeema bashar Says:

    I feel stem cell therapy still offers hope for many parents like myself in the near future.

  17. Prometheus Says:

    Nayeema Bashar,

    Can you tell me on what you base your “feelings” about stem cell therapy?

    I will grant that it may offer “hope”, but does it offer any real chance of improvement or cure? Based on my review of the literature and discussions with stem cell researchers (and autism researchers), I don’t see any reason why stem cell therapy could help in autism.

    If you have access to information that supports the use of stem cells therapy in autism, I’d be interested to know about it.

    I hope you’re not basing your feelings on the paper by Ichim et al. That paper is pure speculation with no supporting data. It also makes several assumptions that are demonstrably wrong.

    Prometheus

  18. Prometheus Says:

    From WFJAG:

    “Off thread, but, thought you’d be interested since you blogged about “stem cell treatments” offered in Costa Rica in the past. See, FEATURE - Costa Rica puts brakes on popular stem cell tourism (Reuters Mon Jun 7, 2010)
    http://in.reuters.com/article/idINIndia-49088520100607

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