Stem Cell Therapy for Autism

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).

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Anti-Viral Nonsense

There are some “alt-med” treatments for autism that are like the zombies in B-grade horror movies. You think they’re dead, but as soon as you turn your back, they’re up and shambling around, searching for…..well, they’re usually looking for money, so they don’t fit the zombie analogy that well.

Chelation, secretin and HBOT have all been shown to be no more than profit centers for “alternative” practitioners, but my contacts in the “biomed” world tell me that they are still being prescribed (and inflicted) on autistic children. Apparently, it’s going to take more than decapitation or a stake through the heart to put these undead therapies in the ground for good.

Which brings me to the undead therapy that has – I would have thought – the best reason to be dead, buried and resting in peace: acyclovir/valacyclovir.

For the past few years, I had been living in blissful ignorance of the ongoing use of acyclovir and valacyclovir in the “treatment” of autism. Sure, they were “hot stuff” a few years ago, back when some misguided practitioners were using them to treat “chronic measles infection”. But I thought that people had wised up and realised that these anti-viral drugs have absolutely no effect on measles and – in plain fact – can’t have any effect on the measles virus.

Fast forward to a few months ago, when a worn-out mom asked me if I thought that acyclovir would be as effective as valacyclovir for the treatment of chronic measles.

My initial thought was that they would be equally ineffective, but I managed to keep that thought from being voiced. Instead I asked, “Are you sure that your doctor is using valacyclovir for measles?” The answer was chilling – the undead zombie of “valacyclovir for chronic measles” had risen from its restless grave.

 

Before I go any further, it might be useful to explain what acyclovir and valacyclovir are, how they work and what their side-effects are.

How acyclovir and valacyclovir work:

The “parent” drug is acyclovir, which was first licensed for use in the US back in 1982 (it is currently off-patent). Valacyclovir (USFDA approved 1995) is simply acyclovir with valine (an amino acid) bound to it to improve its uptake from the gastrointestinal tract (55% vs 10-20% for acyclovir). The valine is cleaved from valacylovir by esterases in the liver, releasing the active drug, acyclovir. So, when it comes to efficacy and side effects, the two drugs are pretty much identical. When it comes to cost, valacyclovir is more expensive, though there is a generic form.

Acyclovir (and, thus, valacyclovir) works by interacting with the enzyme thymidine kinase. This enzyme takes thymidine deoxynucleoside and phosphorylates it to TMP, which then is further phosphorylated to TTP, which is a component of DNA. Herpes viruses happen to make their own thymidine kinase, which they need because they replicate in non-dividing cells (e.g. neurons) that don’t produce TTP (but do produce ATP, CTP and GTP, needed for RNA synthesis). Herpes viruses also make ribonucleotide reductase, which can convert these ribonucleic acids them all to the deoxy- form needed for DNA.

OK, maybe that was more information than some people wanted. The “short form” is that herpes viruses make their own thymidine kinase because, in “resting” cells (i.e. non-dividing cells), the cellular thymidine kinase is “switched off”.

The reason that acyclovir works against the herpes viruses and doesn’t simultaneously kill all the cells of the patient is that the viral thymidine kinase is not as specific – as “fussy” – about its substrate as the cellular (human) thymidine kinase; it will take the acyclovir molecule and phosphorylate it. The cellular enzyme, however, isn’t perfect, it will also phosphorylate acyclovir, but at only 1% the rate of the viral thymidine kinase.

Once acyclovir is phosphorylated by thymidine kinase, cellular enzymes further phosphorylate it to the triphosphate form and then the viral (or cellular) DNA polymerase can add it to the growing DNA chain (it “looks” like GTP). Once added, however, it lacks the 3′ -OH needed to add the next nucleotide and the DNA chain stops prematurely (premature termination). Needless to say, if the virus cannot replicate its genome, it can’t form new viruses and can’t infect. That’s how acyclovir and valacyclovir work.

Side effects:

Remember that the herpes virus thymidine kinase activates acyclovir 100 times faster than the cellular (human) enzyme. Well, that’s why acyclovir is relatively non-toxic. That, of course, is “relative to other anti-viral agents”, which is rather like saying “safer than swimming with sharks”. Still, acyclovir is pretty safe, apart from the rare renal failure seen during longer treatment.

Considering how dangerous herpes virus infections can be (and how painful), acyclovir and valacyclovir have very favorable risk:benefit ratios… IF they are being used to treat a herpes virus infection (more about that later).

What about measles?

Yes, what about measles? You’ll have noticed that I didn’t mention anything about measles. Or other viruses, for that matter. Well, as it turns out, acyclovir (and its close relative, valacyclovir) don’t have any effect on measles. Even though acyclovir has been used in the treatment of HIV/AIDS, it is primarily to suppress herpes virus. Acyclovir isn’t even effective against all herpes viruses – CMV and EBV aren’t that susceptible.

So, why isn’t acyclovir effective against measles? You’ll recall that I discussed how acyclovir interferes with DNA synthesis, blocking the replication of the herpes virus genome. Measles virus (wild type and vaccine strain) has an RNA genome. That’s right, it doesn’t make DNA. Not even a bit. So a drug that interferes with DNA synthesis is pretty much useless against measles.

Let me repeat that: measles is an RNA virus without a DNA stage, so drugs like acyclovir and valacyclovir – which interfere with DNA synthesis – have no effect on measles.

However, the side-effects from acyclovir and valacyclovir are present whether or not the drug is given for a rational reason.

“But it works!”:

Inevitably, someone will reply “But valacyclovir helped my child recover from autism!” It may be true that their child’s improvement happened after the valacyclovir was started, there is no plausible physiological reason that the improvement can be tied to the drug. Coincidences happen, and for every person I’ve heard say that valacyclovir “recovered” their autistic child (1), I’ve heard twenty or more say that it had no effect.

Summary:

Acyclovir and valacyclovir are relatively safe anti-viral drugs that are effective against herpes simplex virus (types 1 and 2) and, to a lesser extent, varicella/herpes zoster/chicken pox. They are also somewhat effective against the herpes viruses cytomegalovirus (CMV) and Epstein-Barr virus (EBV).

Acyclovir and valacyclovir are not effective against measles virus (or mumps or rubella or polio or….) or any other RNA virus. In fact, they aren’t effective against anything other than the herpes viruses.

If your child’s doctor has prescribed or recommended acyclovir or valacyclovir to treat “chronic measles infection” or autism or, for that matter, anything other than a herpes virus infection, you should seek an independent second opinion.

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