To Rafiki: Simpler explanation of GD-MCB hypothesis for CFS

Discussion in 'Fibromyalgia Main Forum' started by richvank, Dec 13, 2008.

  1. richvank

    richvank New Member

    Hi, Rafiki.

    I'm posting a response to your request separately here, in case others might be interested.

    Sorry about all the biochemical gobbledygook! I think that this hypothesis can actually be pretty understandable if it is taken step by step. It's just that there are a lot of steps, and the names of the things involved are unfamiliar to a lot of people. The cause and effect concepts themselves are pretty straightforward.

    I'll try to explain the GD-MCB hypothesis in a simpler way. This will mean that I will be leaving out a lot of details and glossing over some things, so I hope I will be forgiven for that :)-)!

    1. To get an isolated case CFS (I'm not talking here about the epidemics or clusters), you have to have inherited some genetic variations from your parents. These are called polymorphisms or single-nucleotide polymorphisms. We know what some of the important ones are, but we don't know all of them yet. This is a topic that needs more research.

    2. You also have to have some things happen in your life that place demands on your supply of glutathione. Glutathione is like a very small protein, and there is some in every cell of your body, and in your blood. It protects your body from quite a few things that can cause problems, including chemicals that are toxic, and oxidizing free radicals. It also helps the immune system to fight bugs (bacteria, viruses, fungi) so that you are protected from infections by them.

    3. Oxidizing free radicals are molecules that have an odd number of electrons, and are very chemically reactive. They are normally formed as part of the metabolism in the body, but if they rise to high levels and are not eliminated by glutathione and the rest of the antioxidant system, they will react with things they shouldn't, and cause problems. This situation is called oxidative stress, and it is probably the best-proven biochemical aspect of chronic fatigue syndrome.

    4. There are a variety of things in your life that can place demands on your glutathione. These include physical injuries or surgery to your body, exposure to toxic chemicals such as pesticides, solvents, or heavy metals like mercury, arsenic or lead, exposure to infectious agents or vaccinations, or emotional stress that causes secretion of a lot of cortisol and adrenaline, especially if it continues over a long time. Just about anything that "stresses" your body or your mind will place a demand on glutathione. All people experience a variety of stressors all the time, and a healthy person's body is able to keep up with the demands for glutathione by recycling used glutathione molecules and by making new ones as needed. However, if a person's body cannot keep up, either because of extra-high demands or inherited genetic polymorphisms that interfere with recycling or making glutathione, or both, the levels of glutathione in the cells can go too low. When glutathione is properly measured in most people with CFS (such as in the Vitamin Diagnostics methylation pathways panel), it is found to be below normal.

    5. One of the jobs that glutathione normally does is to protect your supply of vitamin B12 from reacting with toxins. If left unprotected, vitamin B12 is very reactive chemically. If it reacts with toxins, it can't be used for its important jobs in your body. A routine blood test for vitamin B12 will not reveal this problem. In fact, many people with CFS appear to have elevated levels of B12 in their blood, while their bodies are not able to use it properly. The best test to reveal this is a urine organic acids test that includes methylmalonic acid. It will be high if the B12 is being sidetracked, and this is commonly seen in people with CFS.

    6. When your glutathione level goes too low, your B12 becomes naked and vulnerable, and is hijacked by toxins. Also, the levels of toxins rise in the body when there isn't enough glutathione to take them out, so there are two unfortunate things that work together to sabotage your B12 when glutathione goes too low.

    7. The most important job that B12 has in the body is to form methylcobalamin, which is one of the two active forms of B12. This form is needed by the enzyme methionine synthase, to do its job. An enzyme is a substance that catalyzes, or encourages, a certain biochemical reaction.

    8. When there isn't enough methylcobalamin, methionine synthase has to slow down its reaction. It's reaction lies at the junction of the methylation cycle and the folate cycle, so when this reaction slows down, it affects both these cycles.

    9. The methylation cycle is found in all the cells of the body (not counting the red blood cells, which are unusual in a lot of ways). The methylation cycle has some important jobs to do. First, it acts as a little factory to supply methyl (CH3) groups to a large number of reactions in the body. Some of these reactions make things like creatine, carnitine, coenzyme Q10, phosphatidylcholine, melatonin, and lots of other important substances for the body. It is not a coincidence that these substances are found to be low in CFS, so that people try taking them as supplements. Not enough of them is being made because of the partial block in the methylation cycle. The methylation cycle also supplies methyl groups to be attached to DNA molecules, and this helps to determine whether the blueprints in the DNA will be used to make certain proteins according to their patterns. The "reading" of DNA is referred to as "gene expression." Methyl groups prevent or "silence" gene expression. Overexpression of genes has been observed in CFS patients, and I suspect this is at least partly due to lack of sufficient methylation to silence gene expression.

    10. Another thing that the methylation cycle does is to regulate the overall use of sulfur in the body. Sulfur comes in from the diet in the form of amino acids in protein (methionine and cysteine) and as taurine and some as sulfate. The methylation cycle regulates the production of the various substances that contain sulfur that are needed by the body. The levels of various sulfur metabolites are often found to be abnormal in people with CFS.

    11. One of the most important sulfur-containing substances in the body is glutathione, so now you can see how this is starting to look like a dog chasing its tail! The thing that causes chronic fatigue syndrome to be chronic, and keeps people ill for years and years, is this interaction between glutathione, vitamin B12, and the methylation cycle. When glutathione goes too low, the effect on vitamin B12 slows down the methylation cycle too much. The sulfur metabolites are then dumped into the transsulfuration pathway (which is connected to ther methylation cycle) too much, are oxidized to form cystine, pass through hydrogen sulfide, and are eventually converted to thiosulfate and sulfate and are excreted in the urine. This lowers the production of glutathione, which requires cysteine rather than cystine, and now there is a vicious circle mechanism that preserves this malfunction and keeps you sick.

    12. That's the basic biochemical mechanism of CFS. I believe that everything else flows from this. As you know, there are many symptoms in CFS. I won't discuss all of them in detail here, but here's how I believe the fatigue occurs: The cells have little powerplants in them, called mitochondria. Their job is to use food as fuel to produce ATP (adenosine triphosphate). ATP acts as a source of energy to drive a very large number of reactions in the cells. For examples, it drives the contraction of the muscle fibers, and it provides the energy to send nerve impulses. It also supplies the energy to make stomach acid and digestive enzymes to digest our food, and many, many other things.

    When glutathione goes too low in the muscle cells, the levels of oxidizing free radicals rise, and these react with parts of the "machinery" in the little powerplants, lowering their output of ATP. So the muscle cells then experience an energy crisis, and that's what causes the fatigue. Over time, because of the lack of enough glutathione, more problems accumulate in the mitochondria, including toxins, viral DNA, and mineral imbalances. These have been observed in the ATP Profiles and Translocator Protein test panels offered by BioLab Medical Unit and Acumen Lab in the UK.

    13. There are explanations that flow from this basic mechanism for other aspects of CFS. I haven't figured out explanations for all of the aspects of CFS, but I do think I understand a large number of them in some detail, and I've been able to explain enough of them that I believe this mechanism will account for the rest as well, if we can figure out the underlying biochemistry. My 2007 IACFS conference poster paper presented outlines of many of these explanations.

    14. The involvement of infections by bacteria, viruses and fungi appears to have two aspects in CFS. First, as mentioned above, infectious agents can act as one of the stressors that initially bring down the level of glutathione and produce the onset of isolated cases of CFS in people who are genetically susceptible. I suspect that the clusters or epidemic occurrences of CFS (such as at Incline Village in the mid-80s) were caused by particularly virulent infectious agents, such as powerful viruses, and the genetic factor is less important in these cases.

    15. Second, when a person's glutathione, methylation cycle, and folate cycle are not operating normally because of the vicious circle described above, the immune system does not function properly. In this case, viruses and bacteria that reside inside our cells and that are always in the body in their dormant, resting states are able to reactivate and produce infections, which the immune system is not able to totally put down. This accounts for the obsrvation that most of the viral and intracellular bacterial infections seen in CFS patients are caused by pathogens that most of the population is carrying around in their dormant states.

    16. Third, when the immune system's defenses are down, a person can catch new infections from others or from the environment, and the immune system is not able to defeat them, so they accumulate over time. Dr. Garth Nicolson has found that the longer a person has been ill, the more infections they have, on the average.

    17. Other things that accumulate over time are various types of toxins, because the detox system depends to a large extent on the sulfur metabolism, and it will not be operating properly as long as the person has CFS. The body stores much of these toxins in fat, but as the levels get higher, they begin cause problems throughout the biochemistry of the cells. Many people with CFS have been tested for toxins (most commonly the heavy metal toxins, which are the most easily tested) and they are commonly found to be elevated.

    18. The longer a person is chronically ill with CFS, the more toxins and infections accumulate in their body, and the more symptoms they experience. This explains why the disorder changes over time, and why some people become extremely debilitated after being ill for many years.

    19. The main key to turning this process around is to help the methionine synthase enzyme to operate more normally, so that the partial block in the methylation cycle and the folate cycle are lifted, and glutathione is brought back up to normal. That is what the simplified treatment approach is designed to do, and so far, the evidence is that it does do these things in most people who have CFS. I recommend that people with CFS have the Vitamin Diagnostics methylation pathways panel run to find out if they do in fact have a partial methylation cycle block and glutathione depletion before deciding, with their doctors, whether to try this treatment. This also provides a baseline so that progress can be judged later on by repeating it every few months during the treatment. Symptoms may not be a good guide to judge progress during treatment, because detoxing and die-off can make the symptoms worse, while in fact they are exactly what is needed to move the person toward recovery.

    20. The main question I'm working on now is what else needs to be done to bring people to recovery? I don't have complete answers to this question yet. Many people may recover from this treatment alone, but it is proving to be a slow process, and we will need more time to see how this will work out. It does appear that people who suffer from illness due to toxic molds do need to remove themselves from environments where these are present. The small amount of evidence I have so far suggests that people who have Lyme disease will need to have that treated in addition. I'm not sure about certain viral infections. They may also need to be treated. We still have a lot to learn, but I'm convinced that the mechanism I have described above is the core of the abnormal biochemistry in CFS, and correcting it needs to be cornerstone of the treatment.

    I hope this is helpful.

    Rich Van Konynenburg
  2. deliarose

    deliarose New Member


    As you know I've been treating a methylation cycle block for coming up on two years now & while I have made terrific progress, I am still some way from the finish line.. presumably because having been sick so long I have a large toxic, viral, & bacterial load.

    So here's my question & I think it will be familiar.. because I have tried to pin you down on this multiple times.

    I am considering adding Valtrex to my regime at some point. I have elevated IGG titers and at some point they may even turn into IGM titers as has occurred with other infections over the past 2 years.

    Anyhoo I know you cannot comment on individual cases, but what are the downsides of using an antiviral -- specifically Valtrex -- in a long-term sick PWC?

    I guess I am concerned that the drug could place an additional burden on the liver and the adrenals.. and in verteran PWCs, these organs are probably not in good shape.

    I know it's all about trade-offs. You seeem to think that restoring the methylation and folate cycles and the levels of glutathione may be sufficient to get EBV and other infections under control.

    But there's also the timing issue: how much longer would this take, vs using a pharmaceutical to speed up the process.

    I don't suppose there's any data on this, but I would be interested in your thoughts however speculative.

    One more thing: another poster related that Dr Ablashi seems to think there is some risk of resistance with the way Dr. Lerner uses antivirals.. ie over many years in some cases.

    Have you seen any data on what the threshold is for resistance in using antivirals?

    As you probably know, some DAN! docs don't seem to have any problem putting autistic kids on antivirals for several years.

    Ok: I promise not to pester you with this issue again! I may just have to figure this out by trial and error.

    Thanks again for all your work. I'm so much better these days. I hardly recognise the person I was 2 years ago.

  3. Rafiki

    Rafiki New Member

    This is not only helpful, it is downright fascinating.

    Thank you for explaining it in a way which is not only understandable but also respectful of the intelligence of your grateful audience. You showed great sensitivity; I never once felt dumb.

    This will take me some time to fully comprehend but I now have the building blocks in a nice comprehensible row.

    I have been reluctant to experiment with any treatment other than antibiotics which I discovered, quite accidentally, were temporarily useful -- "temporarily" now makes perfect sense. A lot of things make sense within the paradigm you describe.

    I'm very grateful for your time and will now reread many of your other pieces armed with Methylation For Dummies. I feel hopeful, really hopeful!

    Your generosity is nearly as impressive as your theory!

    Peace out,
  4. richvank

    richvank New Member

    Hi, Delia.

    I'd like very much to be able to answer your questions, but I just don't know enough to do so. What little I know about use of antivirals in CFS has come from those who use them, including Drs. Montoya and Lerner.

    Concerning Valtrex, Dr. Lerner spoke at the most recent IACFS conference in January, 2007. I recall him emphasizing the importance of drinking a lot of fluids when taking Valtrex, in order to protect the kidneys. I gather that if the resulting acyclovir becomes too concentrated in the urine, it will precipitate out in the kidneys.

    For what it's worth, here's the abstract of a paper he published in 2007 on the use of Valtrex for EBV in CFS. I don't have a copy of the full paper. It might help to answer your questions.

    In Vivo. 2007 Sep-Oct;21(5):707-13.Links
    Valacyclovir treatment in Epstein-Barr virus subset chronic fatigue syndrome: thirty-six months follow-up.Lerner AM, Beqaj SH, Deeter RG, Fitzgerald JT.
    Department of Medicine, William Beaumont Hospital, Royal Oak, MI, USA.

    BACKGROUND: We hypothesized that subset classification of Epstein-Barr virus (EBV) in chronic fatigue syndrome (CFS) is required. At first, a blinded-random placebo-controlled trial of valacyclovir in EBV CFS subset was performed (Group 1), and this EBV subset was followed for thirty-six months (Group 2). Patients were given valacyclovir at 14.3 mg/kg every 6 hours. The validated Energy Index (EI) point score assessing physical functional capacity, Holter monitor, multigated (radionuclide) MUGA rest/stress ventriculographic examination, EBV serum IgM viral capsid antibodies (VCA), and EBV early antigen diffuse (EA) were followed. After six-months, Group 1 CFS patients receiving valacyclovir experienced an increased mean least square EI point score +1.12 units (122 kcal/day), while the placebo cohort increased +0.42 EI units (65 kcal/day). EI point scores at Group 2 increased progressively. Sinus tachycardias decreased and abnormal cardiac wall motion improved. Serum antibody titers to EBV VCA IgM decreased. Patients resumed normal activities.

    PMID: 18019402 [PubMed - indexed for MEDLINE]

    Here's the abstract of his earlier paper:

    Drugs Today (Barc). 2002 Aug;38(8):549-61. Links
    A six-month trial of valacyclovir in the Epstein-Barr virus subset of chronic fatigue syndrome: improvement in left ventricular function.Lerner AM, Beqaj SH, Deeter RG, Dworkin HJ, Zervos M, Chang CH, Fitzgerald JT, Goldstein J, O'Neill W.
    School of Medicine, Wayne State University, Detroit, MI, USA.

    This study was designed to determine safety and efficacy of a 6-month trial of valacyclovir in single-virus Epstein-Barr virus (EBV) persistent infection. Phase I of this study used four specific criteria to define a subset of patients with chronic fatigue syndrome (CFS). In the second phase, myocardial dynamics were measured by MUGA rest/stress radionuclide ventriculographic (RVG) examinations pre- and posttreatment with valacyclovir. In phase I, a trial was performed in 19 consecutive CFS patients with the following diagnostic conditions: patients met criteria for diagnosis of CFS; they had had CFS for less than 1 year. They demonstrated repetitively abnormal oscillating T waves (ischemic or flat) at 24-h Holter monitoring; and they had elevated serum IgM antibody titers to EBV viral capsid antigen and/or total diffuse early antigen as measured by the enzyme-linked immunosorbent assay method. The treatment group comprised 10 CFS patients with no serum antibodies to human cytomegalovirus, but the control group (nine CFS patients) had, additionally, high titers of serum antibodies (IgG) to conformational structural antigens of human cytomegalovirus. Both the parallel treatment and control CFS groups received valacyclovir 1.0-1.5 gm q.6.h. for 6 months. This valacyclovir dose achieved serum acyclovir C(max) of > 7 microm and high antiviral activity versus EBV (IC(50) of 4.4-13.3 m). In phase II, six additional CFS patients met the same four criteria as the 19 CFS patients in phase I. They had, however, been ill for a mean of 55.8 months. Thus, 25 CFS patients comprise this study. The studies were carried out at a single outpatient practice in Birmingham, MI, U.S.A. Before initiating valacyclovir, and after 6 months of treatment, clinical and laboratory observations were made. The CFS Energy Index point score (Table I) was used to record each CFS patient's functional capacity at baseline and after 1, 3 and 6 months of valacyclovir. Energy Index point scores, as well as EBV and human cytomegalovirus serum antibody titers were assessed. In the second phase, left ventricular dynamics were repeated after 6 months of treatment with valacyclovir. We concluded that the 16 CFS patients (included in both phases of this study) with EBV-persistent infection (EBV single-virus subset) are improved after 6 months of continuous pharmacokinetic dosing with valacyclovir. Nine CFS patients with EBV/human cytomegalovirus co-infection did not benefit from 6 months of similar treatment. Valacyclovir is not an effective anti-human cytomegalovirus antiviral drug. Unimproved CFS patients with co-infections EBV and human cytomegalovirus may require combined treatment with valacyclovir and another drug more active against human cytomegalovirus. This preliminary trial, with a small number of patients, may be critical to an appropriately designed larger, double-blind, placebo-controlled trial. Copyright 2002 Prous Science

    PMID: 12582420 [PubMed - indexed for MEDLINE]

    Sorry I don't have more information.


  5. acer2000

    acer2000 New Member


    What have you found with respect to the people who haven't responded to the 5 supplements you talk about? I tried them for 3 months and it produced no change in my symptoms. No worse felling, no better. I also take the metagenics "multigenics" vitamin with 5-MTHF as well as B-12 "extreme" sublingual from Prohealth (has 4 or 5 types of B12 in it) to no effect. Have you been finding that people who don't respond to the methylation protocol have something else consistently wrong? And what might that be?

    As an aside, I didn't have any reaction to Valcyte either, but felt better on Zithromax pretty quickly... Just curious what your take would be on this..


  6. Rafiki

    Rafiki New Member

    I can't resist asking a question.

    Can you explain why so many of us never seem to get colds or flu following coming down with ME using the Methylation Block hypothesis? If you cannot, it makes very little difference to me but I've long been curious about this aspect of the illness.

    Thanks much, answer or no,
  7. richvank

    richvank New Member

    Hi, Rafiki.

    Here's my hypothesis for that:

    When there is glutathione depletion, partial methylation cycle block, and a folate trap, for which there is now good evidence in many cases of CFS, we can expect that the immune system will be dysfunctional, because all three of these are known to hinder the operation of the immune system. In particular, what is called the cell-mediated immune response is suppressed. This is the response that involves the Th1 cells and the cytotoxic T cells. This type of response is particularly needed to fight viral infections and also intracellular bacterial infections. It is no coincidence that these are the types of infections that are commonly found limping along in people with CFS.

    Normally, when a healthy immune system detects reactivation of a virus that has been in its dormant state, such as the Epstein--Barr virus, it does certain things rapidly in order to perform a "holding action" on the viruses, while in the meantime it builds up a knockout punch in the form of a cell-mediated immune response. The short-term holding action is not specific to the particular virus. The cell-mediated response is very specific, but it takes a few days to mobilize. Normally, the holding action only has to do its job for a few days, and then the cavalry arrives in the form of a newly cloned army of cytotoxic T cells that know just what they are looking for, and they destroy the cells that have the active viruses inside them.

    In a person with CFS, basically, the cavalry never arrives, because the cells for the army are never cloned, as a result of the problems I listed above. But the immune system still "knows" the viruses are there, and thus it stays activated, it keeps calling for help by sending out chemical signals called cytokines, and it keeps up the holding action as well as it can. There is thus sort of an ongoing guerrilla war between the weakened immune system and the viruses, and nobody has a clear win. That's why people with CFS can feel as though they have the "flu" more or less constantly.

    Now, when the person with CFS is exposed to cold or flu viruses coming in from the outside, their cells are already in this "holding action" state, and I think that's why these viruses coming from the outside are not able to get a foothold.

    To get a little more technical, the holding action consists of responses in the cells that are stimulated by interferon alpha and beta. These interferons are generated when long double-stranded RNA is detected, which is characteristic of viruses. The interferons induce the buildup of RNase-L, PKR kinase, and Mx. These in turn make the cells very resistant to the replication of viruses. Mx is actually specific to influenza viruses.

    So when a cold or flu virus enters a cell that is primed in this way, it doesn't have much of a chance. Even though the dysfunctional immune system can't totally knock out the original reactivated viruses, it is often able to keep new invaders out, using this holding action.

  8. richvank

    richvank New Member

    Hi, anchorholds.

    I don't know how treatment to lift the methylation cycle block would affect your heart. I don't know what problems your heart has. Some people do have toxic heavy metals in their hearts. Some with CFS have viral infections, as Dr. Lerner has shown. Many with CFS appear to have diastolic dysfunction, as Dr. Cheney has found. I think you would have to have some sophisticated echocardiography to find out what's going on with your heart.

    I think it's possible that your response to methylcobalamin injections might have been due to methylation of mercury. I don't favor use of methylcobalamin in people who are likely to have large body burdens of inorganic mercury, because methylcobalamin is the only substance in biological systems that is known to be able to methylate mercury. Methylmercury can cross the blood-brain barrier and enter the central nervous system. It acts as a neurotoxin. I know that methylmercury is used successfully in autistic children, but I suspect that their mercury is mostly from thimerosol that used to be in the vaccines, which is ethylmercury, another organic form, and it unfortunately already had a chance to enter their brains. Babies and little children usually don't have mercury fillings in their teeth, but adults with CFS have often had them for many years, while they have been ill, and their glutathione has been too low to take it out the mercury as they inhale it into their bodies from their fillings. So they have built up inventories of inorganic mercury in their bodies. There are other ways of getting inorganic mercury into the body also, such as living near a coal-fired power plant. The mercury that comes from eating fish is organic methylmercury.

    Your response to the OSR sounds like an allergic reaction. Perhaps the immune system recognized the OSR molecule, with or without bound merury, as being foreign, and generated antibodies to it. I'm sorry that OSR didn't work for you. I heard Prof. Haley speak about it at the AutismOne conference in Chicago last May. He sounded pretty optimistic.

    (Incidentally, I've always been curious about your webname. Does it by any chance come from a certain church hymn, i.e. "My Anchor Holds"?)

  9. richvank

    richvank New Member

    Hi, A.

    I haven't had a chance to study those who don't respond in much detail yet, but hope to soon.

    We're dealing with a very heterogeneous population in CFS, so those who don't respond could have a variety of things going on.

    Sounds like you have a pretty interesting case. Have you done any metabolic testing, such as urine organic acids tests, or amino acids tests, or a methylation pathways panel? I think those are the best types of tests for getting an overall perspective on a case.

  10. acer2000

    acer2000 New Member

    Hi Rich,

    Yeah I have done some of that testing. I did a MAP and UAA, and my Dr. does a UAA and Blood AA from Labcorp when he does labs (not sure why). I can detail the tests if you want or send them to you... if you'd like to "study" them... :) I'm not really sure what to look for except the obvious indicators of low B12.

  11. richvank

    richvank New Member

    Hi, A.

    I can't promise how soon I would be able to study your test results, because I'm way overcommitted at the moment, but if you send them to me, I will try to look them over and give you some comments. I am interested to try to understand why the treatment wasn't effective for you. My ultimate goal is something like "No PWC left behind!" My email address is richvank at aol dot com, and my fax number is (925) 449-7723.

    [This Message was Edited on 12/16/2008]
  12. richvank

    richvank New Member

    Hi, A.

    Sorry, I put down the wrong number for my fax. I've corrected it. It should be (925) 449-7723.

  13. acer2000

    acer2000 New Member

    OK rich, thanks
  14. sleepyinlalaland

    sleepyinlalaland New Member

    I ran across the following article on a science news website and to my challenged mind it SEEMS to be referring to the same disfunction you are describing. I know that many times people on these boards have wondered about the connection of CFS to autism, schizophrenia and other neurological disorders (in this article they refer to them as "excitability disorders").

    I wish I could summarize and simplify the following article, but I can only understand it well enough to guess that there is a relationship to the glutathione depletion theory. It is long, but I think may be of interest. Then again, maybe its what you've just said much more clearly in the beginning post.


    ScienceDaily (Dec. 17, 2008) — Rice University researchers have found a potential clue to the roots of epilepsy, autism, schizophrenia and other neurological disorders.

    While studying the peripheral nerves of the Drosophila, aka the fruit fly, Rice doctoral student Eric Howlett discovered an unanticipated connection between glutamate – an amino acid and neurotransmitter in much of the food we eat – and phosphoinositide 3-kinase (PI3K), an enzyme that, Howlett found, regulates the activity of neurons.

    Howlett and his colleagues, graduate student Curtis Chun-Jen Lin, research technician William Lavery and Michael Stern, a professor of biochemistry and cell biology, discovered that negative feedback mediated by PI3K regulates the excitability of neurons, an issue in a number of ailments that include neurofibromatosis, and that a mutation in a glutamate receptor gene common to both the fruit fly and humans has the ability to disrupt that regulatory mechanism.
    Howlett found the Drosophila’s metabotropic glutamate receptor (DmGluRA) gene, when mutated, increased the excitability of the neuron by preventing PI3K from doing its job.

    The study is the culmination of four years of work that built upon research by Marie-Laure Parmentier and her team at the University of Montpelier, France, to connect glutamate to regulatory functions in the fruit fly.

    “As science often goes, we didn’t set out with this hypothesis,” said Howlett, who began the project on funding obtained by Stern from the Department of Defense to study neurofibromatosis. “This all came about as a control for a completely different experiment, and we said, ‘Wow, this is some interesting stuff.’”

    What he saw was that the overexpression of PI3K in motor neurons had a dramatic effect. “I noticed under the scope that these nerves were really big, and electrophysiologically, they were really slow. That wasn’t what I expected, and it set me on a path of trying to find out what was going on.”

    Howlett’s breakthrough was identifying the negative feedback loop that acts to maintain neuronal excitability at normal levels. “What we found was that glutamate, which is released due to neuronal activity, feeds back onto metabotropic glutamate receptors on the same neurons that released it in the first place. This leads to the activation of PI3K and ultimately to the dampening of the amount of glutamate that is released.” Without that regulation, he said, things inside the cell can go terribly wrong.

    “He put his heart and soul into this,” said Stern of Howlett’s exploration of the neuronal chain. “He was working on PI3K because that has a key role in neurofibromatosis. The Department of Defense is very interested in how PI3K is regulated in the nervous system because of its role in tumor formation.”

    Discovering the negative feedback loop that keeps neurons stable was key, said Stern, but not the end of the investigation. “We know that glutamate activates mGluR and PI3K, but we don’t know how,” he said. “There are almost certainly a number of intermediates that remain to be identified, and we have several candidates we’re looking into.

    “We’re finding a mechanistic link among these molecules that hadn’t been previously appreciated,” Stern said.

    “Obviously the next step would be to test whether these same molecules are playing similar roles in mammalian neurons,” said Howlett, who will leave Rice in the spring to pursue postdoctoral cancer research at Virginia Commonwealth University. A native Houstonian, he earned his bachelor’s in biology at the University of Houston-Clear Lake.

    Howlett said mGluRs had already been targeted in possible treatments for schizophrenia, epilepsy and other “excitability” diseases, so it’s not a stretch to think his research could lead to even more strategies in treating neurological ailments.

    “Actually, all of the molecules involved in our model have been implicated in one way or another with neurological diseases, but no one has been able to link them together into a coherent explanation of the diseases,” he said. “Our model provides a novel framework that could really go a long way toward doing that.”

  15. richvank

    richvank New Member

    Hi, sleepy.

    Thanks for posting this article. It looks like an interesting discovery. I think it will take some more study to see how it fits into the mechanisms of various diseases and disorders.

    In CFS and autism, the brain suffers from excitotoxicity, which means that neurons are firing nerve impulses too easily and too rapidly. This involves the glutamate receptors on neurons, and there might be a connection there with this new research result involving glutamate and PI3K.

    Thanks again.

  16. winsomme

    winsomme New Member


    i have been reading some of the stuff over at the "mb12valtrex" group over on yahoo groups and it seems that some of their thinking about valtrex is that it may help the functioning of the methylation cycle....something in regards to adenosine..

    do you have knowledge on Valtrex and the methylation cycle?

  17. richvank

    richvank New Member

    Hi, Bill.

    Sorry, I don't know about that.

    The only connection I can come up with is that Valtrex inhibits herpes virus DNA synthesis, while methylation can inhibit viral gene expression. If you find out more about a connection between Valtrex and the methylation cycle, I would be interested.

  18. winsomme

    winsomme New Member


    from what i can find, Dr Jill James found that adenosine levels are abnormal in autism. they did a small study with acyclovir and found that the adenosine levels normalized with the treatment.

    here is an excerpt from a longer piece (the link is the full text with diagrams) by the founder of the "mb12valtrex" group:

    The Methylation / Adenosine Connection

    Methylation, a key to health, detoxification and neurotransmitter and DNA replication, is often impaired in children with autism [4]. One of these impairments, found by Jill James PhD. and observed by other researchers and physicians, is the abnormal levels of adenosine. Adenosine has the unique status of being a neurotransmitter and a metabolite involved in methylation. Adenosine is also an important anti-inflammatory.

    This metabolic diagram, provided by Jill James Ph.D., shows where abnormal levels of adenosine can disrupt methylation, raise levels of SAH (a marker and cause of oxidative stress) and lower levels of glutathione (the body’s most important antioxidant).

    Dr. Sid Baker, in cooperation with Jill James Ph.D., conducted a pilot study of 10 children with autism. Nine children were treated with acyclovir and one child was not treated.

    Note: Valtex is quickly converted to acyclovir in the intestines and the liver5. From a viral treatment perspective many viruses that Valtrex can affect can also take up residence in the liver. Valtrex is also more bioavailable than oral acyclovir6 (more similar to IV acyclovir) and has what seems to be a safer side-effect profile.

    In all the 9 children adenosine levels were seemingly improved. Some children had higher levels of adenosine and they were lowered. Some children had lower levels and they were raised. The untreated child’s level remained unchanged. This striking normalizing effect is not very common in medicine.

    There are very few tools to modulate adenosine and it appears that Valtrex is one of them. Mild Hyperbaric Oxygen Therapy (1.3 ATA) may be the only other therapy that I understand may affect adenosine. The only lab I am aware of that can test for adenosine levels is Jill James’ lab at University of Arkansas which is not publically available.

    There is still much to learn about why Valtrex and other antiviral therapies help so many children. Additionally, there does not seem to be a way of measuring adenosine that is easily available to the general population. This, combined with parent reports of children who improve with negative viral testing continues to suggest that an antiviral trial may be the best method to see if your child would be a responder.

  19. richvank

    richvank New Member

    Hi, Bill.

    Thanks for posting this.

    Adenosine is one of several metabolites that are measured on the Vitamin Diagnostics methylation pathways panel, which is publicly available with a doctor's or chiropracter's order, for $300. It may be possible to order an adenosine measurement from them separately, at lower cost. I'll repeat the contact information for this lab below.

    I've seen results of this panel from quite a few PWCs now. Some start with high adenosine, some low, and some normal. I don't yet understand all the factors that control the adenosine level.

    Generally speaking, after a few months of treatment with the simplified treatment approach for lifting the partial methylation cycle block, the low adenosine values have come up, some into the normal range, some still below it. The high values have mostly stayed about the same or have even gone up a little, but changes are still occurring, so I don't know what the final values will be.

    Here's the contact info for Vitamin Diagnostics:

    Methylation Pathways Panel

    This panel will indicate whether a person has a partial methylation cycle block and/or glutathione depletion. I recommend that this panel be run before deciding whether to consider treatment for lifting the methylation cycle block. I am not associated with the lab that offers this panel.

    The panel costs $300 and requires an order from a physician or a chiropractor. The best way to order the panel is by fax, on your clinician’s letterhead.

    Available from:

    Vitamin Diagnostics, Inc.
    Rt. 35 & Industrial Drive
    Cliffwood Beach, NJ 07735
    Phone:+1 (732) 583-7773
    Fax: +1 (732) 583-7774)

    Lab Director: Tapan Audhya, Ph.D. (pronounced tapPAN owDEEah)
    (usually at the lab on Tues. and Wed. from 1 to 3 p.m., Eastern time)

    Dr. Audhya is willing to help clinicians with interpretation of the panel by phone.