Careful now: oral colostrum MAF and Chronic Fatigue Syndrome?

I should perhaps begin this slightly longer than usual post by reiterating my well-trodden caveat on this blog about not giving anything that looks, sounds or smells like medical or clinical advice during my musings. This is a blog [mainly] about peer-reviewed science, nothing more. Added to that, I'm not your Dr Ross and you are not my patient.

So... I've been seeing quite a bit about Gc-MAF (Gc Macrophage Activating Factor) in the news recently. The various headlines about autism and Gc-MAF (see here and see here) have made up the bulk of media coverage but other reports of scientific retractions (see here) have similarly filled some column inches in recent times.

Whilst treading carefully in this area, Gc-MAF has cropped up on this blog a few times based on some of the peer-reviewed literature with autism in mind (see here and see here for further information including what Gc-MAF is). Even Drs Hornig & Lipkin have mentioned Gc-MAF and its precursors in other non peer-reviewed literature (see here). Indeed, given the straddling of autism research and studies on Chronic Fatigue Syndrome (CFS) by Drs Hornig and Lipkin, it is timely that I discuss the paper from Toshio Inui and colleagues [1] (open-access available here) detailing a few case studies suggesting that: "oral colostrum MAF can be used for serious infection and chronic fatigue syndrome (CFS) without adverse effects."

OK. First things first. Oral colostrum MAF is, we are told, a "new form of macrophage-activating factor (MAF) made from colostrum in collaboration with the Tokushima University." Macrophages are known as the 'big eaters' of the immune system getting rid of various molecular debris including viruses, bacteria and the odd 'worn out cell'. The Star Wars version (yes, you heard/read me right) of the role of macrophages can be read in this article [2] by Debra Laskin. Gc-MAF as the name implies is an 'activating factor' for macrophages, also seemingly affected by something called nagalase.

"This new form, referred to as colostrum MAF, is manufactured using bovine colostrum instead of human serum. It is administered orally in an acid-resistant enteric capsule to activate macrophages in the gut-associated lymphoid tissue (GALT) and as a powder in the mouth to activate macrophages in the lymphoid tissue of the mouth and throat."

Given the immune system / macrophage slant to colostrum MAF, the authors moved into the area of CFS and the idea that: "infections and immune dysfunction are thought to play a critical role in the development of the disease." I'll chip in here and reiterate that science does seem to be moving closer to the idea that CFS (and myalgic encephalomyelitis, ME) has origins in organic disease albeit still a little undecided as to what factors are involved. On that basis, two of the three case reports detailed in the Inui paper are on adults with CFS and their experiences of colostrum MAF.

Focusing on those two case reports - both females - they were reported to show some pretty interesting effects concurrent to the use of colostrum MAF. Statements like "reduced malaise" and "being able to do her usual work with more energy like most other people do" are included in the text, even accompanied by "improvements in hair growth on her head." The authors attempt to link such changes to increased phagocytosis. They suggest further work is needed to "elucidate the mechanisms by which MAF has beneficial effects."

These are interesting results but I'm afraid that I need a little more convincing on safety and efficacy yet. Case reports, as I've mentioned in the context of autism (a heterogeneous condition), can provide some really informative data about a specific person diagnosed with a particular condition as a starting point for further investigations more generalised to more people in those specific circumstances. That same logic applies to the Inui findings and the need for further controlled studies on the potential effects of colostrum MAF including specific measures of fatigue and other symptom changes as a result of any intervention(s). This also includes the need for a little more information about the biology behind any reported changes and longer-term, what any effects might be bearing in mind where it comes from. Without casting aspersions, one needs to remember how powerful even a placebo can be (see here).

Insofar as the comments about hair regrowth in relation to CFS, whilst I have heard that hair loss is not uncommon (see here) I can't yet find anything in the peer-reviewed domain specifically about this phenomenon. This doesn't mean that co-occurring issues alongside a diagnosis of CFS might not involve such a symptom but as far as I am aware, it is not a primary part of the [current] diagnostic criteria. In order to avoid any mis-interpretations about colostrum MAF being the next hair growth agent of choice, in future studies I would like to see a little more 'controlled' scientific engagement over such processes.

It is as easy to get carried away with the Inui results as it is to pooh-pooh the findings, particularly in light of all that media coverage of Gc-MAF recently. Throughout the whole history of this compound and now colostrum MAF, there has been a tendency to make some pretty big claims often at the expense of really methodologically sound objective science. Given however the ways and means that a condition like CFS can impact on a person - disable a person - I would suggest that this might be an occasion where sound independent research can come take a lead and put some scientific flesh on the bones on any effect or not.

Music: Carly Rae Jepsen - Call Me Maybe.

----------

[1] Inui T. et al. Oral Colostrum Macrophage-activating Factor for Serious Infection and Chronic Fatigue Syndrome: Three Case Reports. Anticancer Res. 2015 Aug;35(8):4545-9.

[2] Laskin DL. Macrophages and inflammatory mediators in chemical toxicity: a battle of forces. Chem Res Toxicol. 2009 Aug;22(8):1376-85.

----------

Inui T, Kubo K, Kuchiike D, Uto Y, Nishikata T, Sakamoto N, & Mette M (2015). Oral Colostrum Macrophage-activating Factor for Serious Infection and Chronic Fatigue Syndrome: Three Case Reports. Anticancer research, 35 (8), 4545-9 PMID: 26168499

GcMAF and autism continued

"GcMAF treatment was able to normalize the observed differences in the dysregulated gene expression of the endocannabinoid system of the autism group". That is the potentially very important finding from Dario Siniscalco and colleagues* (open-access here) continuing the increasing scientific interest in all-things GcMAF (Gc Macrophage Activating Factor) with autism in mind.

Watson and the shark @ Wikipedia 

A quick recap first: I've talked GcMAF and autism on this blog before (see here and see here) and how activating the 'big eaters' (macrophages) of the immune system might be important for some autism and a variety of other conditions too. The collected literature on GcMAF and autism is small... very small... at the moment comprising one paper by Bradstreet and colleagues [2]. So it is indeed a welcome sight to see some more science being done on this area (with the promise of more to come).

The recent paper by Siniscalco et al is open-access but a few pointers might be useful:

• Blood samples were provided by a small group of participants diagnosed with autism (n=22) and age- and sex-matched asymptomatic controls (n=20). Blood monocyte-derived macrophages (BMDMs) were derived from said samples and dosed with GcMAF.
• At the same time, building on previous work by the authors [3] suggesting involvement of the cannabinoid system (EC) in some cases of autism, authors sought to examine whether the therapeutic effects of GcMAF previously highlighted in autism, might have something to do with the regulation of genes involved with the cannabinoid system. To look at this question, they extracted RNA from the BMDMs to look at the effect of GcMAF on the "transciptional regulation of EC genes". Those genes included CB2R, FAAH, NAPE-PLD and GAPDH.
• The results: quite a few of them but they included: "GcMAF treatment was able to significantly increase gene expressions both NAPE-PLD... and FAAH" in BMDMs from participants with autism. This contrasted with no observed changes in gene expression of any of the EC genes in the control samples.
• Perhaps a little unusually given the meaning of the name GcMAF as a 'macrophage activating factor', "GcMAF was able to trigger overall macrophage deactivation in autistic samples". Based on looking at something called Ki67 involved in cell proliferation, authors reported "a decrease of 23% in GcMAF treated monocyte derived macrophages from autistic children as compared to untreated macrophage cells". This reduction was also noted in the control samples too.

I don't mind telling you that I kinda reached the limits of my very rudimentary knowledge of GcMAF and autism with this paper. I do find that the possibility of involvement of the cannabinoid system to cases of autism to be something really rather interesting as per other results in this area [3] and related research including that potentially impacting on comorbidity such as epilepsy. Linking GcMAF to that system potentially opens up some interesting research avenues.

The fact also that GcMAF seemed to have a deactivating effect on macrophages is also a point of interest. I hope I'm not mis-interpreting the findings or anything but I do wonder if this would reinforce the fact that other biological effects may need further analysis when it comes to GcMAF and autism. It's also interesting that nagalase activity was not discussed in the Siniscalco paper so perhaps further inspection of those EC genes and their expression with nagalase in mind should be indicated in future work too.

And if you want the authors take on this work, look no further...

Here's a little song for everyone out there.... so said Kiss. And the rest is rock history.

----------

[1] Siniscalco D. et al. The in vitro GcMAF effects on endocannabinoid system transcriptionomics, receptor formation, and cell activity of autism-derived macrophages. J Neuroinflammation. 2014 Apr 17;11(1):78.

[2] Bradstreet JJ. et al. Initial observations of elevated alpha-N-acetylgalactosaminidase activity associated with autism and observed reductions from GC protein—macrophage activating factor injections. Autism Insights. 2012. 4: 31-38.

[3] Kerr DM. et al. Alterations in the endocannabinoid system in the rat valproic acid model of autism. Behav Brain Res. 2013 Jul 15;249:124-32.

----------

Siniscalco D, Bradstreet JJ, Cirillo A, & Antonucci N (2014). The in vitro GcMAF effects on endocannabinoid system transcriptionomics, receptor formation, and cell activity of autism-derived macrophages. Journal of neuroinflammation, 11 (1) PMID: 24739187

Waiting patent-ly: Gc globulin, vitamin D and autism?

As summer inevitably turns to Autumn and the prospect of those colder, darker winter days and nights further encroaches, I find myself again talking about the growing body of research and speculation suggestive of a link between autism (or at least some of the autisms) and the sunshine vitamin - vitamin D - and its related biochemistry.

Autumn @ Wikipedia 

I was brought to this post by an interesting patent application by The Trustees Of Columbia University In The City Of New York regarding an invention by two very well known and renowned scientists: Ian Lipkin and Mady Hornig titled: "Autism-associated biomarkers and uses thereof" (see here*).

Filed earlier this year (2013) the application discusses quite a few things with a focus on vitamin D and autism and in particular: "detecting whether or not there is an alteration in the express of a Gc globulin protein in the subject as compared to a non-autistic subject".

OK, some background just in case you need it. Vitamin D is something of a rock star in health research circles of late. Traditionally thought to be just the stuff needed to help the absorption of calcium, a more varied role has been reported for the sunshine vitamin in recent years covering lots and lots of ailments and conditions. With autism in mind, vitamin D has been the source of quite a bit of speculation** and research (see my previous posts here and here and here). Although requiring further investigation, it would be a brave/foolish (delete as appropriate) person to say that it shows absolutely no link to autism or at least certain facets or cases of autism on the basis of the existing evidence.

Researchers, Ian Lipkin and Mady Hornig, are also highly respected on this blog. Regular readers might remember their names in relation to quite a few topics I've talked about including the old XMRV-CFS/ME de-discovery story (see here) and the fascinating work on autism and Sutterella (see here). Prof Lipkin was also credited in bringing 'science to Hollywood' in his role as an adviser for the film Contagion (see here) and they both share credit for the 'three strikes hypothesis'. Indeed, this is not the first time that their autism work has entered the patent arena (see here).

The recent patent application, I have to admit, was hard going for me in terms of all the details it contained. My trawl for some background information on Gc globulin protein - also I think called vitamin D binding protein (DBP) - revealed that this protein is principally involved in getting vitamin D and its relations around the body among other things***. Specifically the patent is built on: "the finding that increased levels in the Gc globulin GcFl (which is a vitamin D binding protein) can serve as a biomarker for human Autism Spectrum Disorders". This I interpret to mean that too much Gc globulin being present means that too much vitamin D gets bound up with the stuff and levels of free, available vitamin D (and metabolites) might therefore be lower than that required. The patent goes on: "elevated levels of Gc globulin in the umbilical cord plasma of ASD patients were observed relative to control cases".

These are potentially big words. At the time of writing (September 2013) I was unable to find anything in the peer-reviewed research literature looking at Gc globulin in relation to autism, let alone anything suggesting that increased levels of the protein might be the stuff of biomarkers. That's not to say that there may not be something waiting in the pre-publication arena about this, as per the patent talking about proteomic analysis of "umbilical cord blood plasma samples from children diagnosed with autism (n=l 1 cases) and children without evidence of developmental disorder (n=12 controls)". Proteomics you say?

Further down the patent I noted other points. So: "administering to the subject a therapeutic amount of GcMAF, thereby treating or preventing autism or an ASD". Without getting into any debates about treatment and prevention (which seems to be a common theme as per the MAR autism letter recently), Gc-MAF is another interesting part of this application. Regular readers might have seen my post on Gc-MAF and nagalase in relation to autism (see here) and the early-day connections being made there (see here also).

A quick non-expert look at the connection between Gc globulin and Gc-MAF reveals that Gc globulin is the precursor to Gc-MAF****. I think (and it is just that) the patent is suggesting that because greater than usual quantities of vitamin D might be bound up with Gc globulin, there are knock-on immune effects resulting from this vitamin D deficiency, ergo: "administering to the subject a therapeutic amount of GcMAF, thereby treating or preventing the vitamin D deficiency-related immune deficit." Onwards, the assumption is that this might have an effect on the presentation of autism too. Again, with my non-expert hat on, administration of Gc-MAF does seem to affect Gc globulin activity (at least in the lab and using cells from patients with systemic lupus erythematosus*****). Don't quote me on that by the way.

There is quite a bit more information included in this patent which I can't cover here in one post. As if you needed more evidence that vitamin D deficiency might be quite prevalent in autism (and across different geographies) I would also refer you to the recent papers by Duan and colleagues****** & Gong and colleagues******* based in China. That being said, if the Lipkin/Hornig patent turns out to be correct at least for some on the autism spectrum, simply adding more vitamin D into the diet or supplementing or increasing sunshine exposure when a deficiency is present alongside high levels of Gc globulin, might not necessarily be the most desirable course of action.

Finally, I should point out that this is a patent application and not peer-reviewed science so whilst being as enthused as I am about the potential for this line of inquiry, one has to take a step back. As with all patent applications, the aim is protection; protection for the your work, the intellectual property of your work and indeed, the commercialisation of your work from being copied by others presumably for profit. Autism has seen its fair share of patents down the years, over 98,000 at the time I looked, and whilst many would love to see these patents actually produce some real-life benefits for people with autism and their families, the question is: how many actually do?

----------

* Autism-associated biomarkers and uses thereof. The Trustees Of Columbia University In The City Of New York. WO2013130953 A2. Application number PCT/US2013/028589. Filed: March 1 2013. Published: September 6 2013.

** Cannell JJ. Autism, will vitamin D treat core symptoms? Med Hypotheses. 2013 Aug;81(2):195-8. doi: 10.1016/j.mehy.2013.05.004.

*** Haddad JG. Plasma vitamin D-binding protein (Gc-globulin): Multiple tasks. J Steroid Biochem Mol Biol. 1995; 53: 579-582.

**** Nagasawa H. et al. Gc Protein (Vitamin D-binding Protein): Gc Genotyping and GcMAF Precursor Activity. Anticancer Res. 2005; 25: 3689-3696.

***** Yamamoto N. et al. Deglycosylation of serum vitamin D3-binding protein by alpha-N-acetylgalactosaminidase detected in the plasma of patients with systemic lupus erythematosus. Clin Immunol Immunopathol. 1997 Mar;82(3):290-8.

****** Duan XY. et al. Relationship between vitamin D and autism spectrum disorder. Zhongguo Dang Dai Er Ke Za Zhi. 2013 Aug;15(8):698-702.

******* Gong ZL. et al. Serum 25-hydroxyvitamin D levels in Chinese children with autism spectrum disorders. Neuroreport. 2013 Oct 1. [Epub ahead of print]

----------

Cannell JJ (2013). Autism, will vitamin D treat core symptoms? Medical hypotheses, 81 (2), 195-8 PMID: 23725905

GcMAF, nagalase and autism

I think it might be worth starting this blog post with (a) reference to my very well-trodden caveat of not making any medical recommendations on this blog and (b) a little bit of a description of some of the key terms connected with the paper by Jeff Bradstreet and colleagues* (open-access) on nagalase, GcMAF and autism bearing in mind my amateur status in this area. I might also add, don't shoot the messenger.

I'm the big eater @ Wikipedia  

Macrophages. It all begins with monocytes, white blood cells produced in bone marrow from hematopoietic stem cells. Monocytes grow into different types of macrophages.

Macrophages, known as the big eaters of the immune system, are present in every cell of the body and include microglia (in the brain).

As part of their big eating duties, macrophages enjoy dining out on the odd invading pathogen or cell programmed for destruction as well as telling other immune cells what to do. A sort of Mr Creosote if you will (without the bucket). If you want the Star Wars version of macrophages (I'm not kidding) ... here you go (open-access).

Macrophages are activated by Gc-MAF (Gc Macrophage Activating Factor). The production of Gc-MAF is affected by nagalase (alpha-N-acetylgalactosaminidase) encoded by the gene NAGA. Nagalase affects the Gc protein (vitamin D3 binding protein) which has a knock-on effect blocking the production of Gc-MAF. The more nagalase activity, the less Gc-MAF is a rough-and-ready way to look at it. Less Gc-MAF equates as less macrophage activation according to this logic and some potential onward effects for immune function.

Why is it important? Well in cancer research, there is some preliminary chatter that tumors might be able to affect Gc-MAF function by way of altering nagalase activity (open-access)**. Such is the effect of increased nagalase and depressed Gc-MAF function that this has been put forward as a potential explanation of why cancers are able to 'avoid' the immune system and so develop unchecked. There is also some very preliminary evidence that giving supplemental Gc-MAF as an injection might affect cancer growth in animal models*** and human participants**** although this is still an area of some controversy given that one lab seems to be producing all the research.

So what's the logic of this area with autism in mind? I can't claim to be able to provide a definitive answer but one suggestion from press releases such as this one, are the reports of high levels of nagalase activity to be present in quite a few of the cohorts with autism looked at. Remember, nagalase negatively affects levels of Gc-MAF so potentially disrupting the activation of macrophages. Outside of malignant cells, there is a suggestion that elevated nagalase activity might be part and parcel of issues with immune function in cases of autism onwards to things like the presence of some kind of viral activity. Indeed this last point on viruses and nagalase I assume comes from other results on the use of Gc-MAF in the clearance of HIV infection***** bearing in mind replication is still required for this area of work.

So eventually we get back to the paper from Bradstreet and colleagues and in more detail:

• Described as a chart review, 40 participants with autism who sought testing for nagalase activity, pre- and post assessment of nagalase following Gc-MAF injections were followed.
• Diagnosis of participants was determined by having already received a DSM-IV diagnosis of autism independent of the study together with some in-house assessments on the severity of presentation.
• Blood draws signalled the start of the nagalase activity assessment which was shipped to a lab already versed in looking for the enzymatic activity. 
• Gc-MAF was injected on a weekly basis covering an average of 14 injections to get those macrophages stimulated, and nagalase activity assessed again.
• Results: nagalase activity was generally higher in the autism group than the various reference ranges cited by the assaying laboratory.
• Nagalase activity levels dropped in quite a few participants following Gc-MAF administration (24 of 40 decreased to within laboratory reference ranges) and "uncontrolled observations of GcMAF therapy indicated substantial improvements in language, socialization and cognition". Before we get too carried away though, lets remember those words "uncontrolled observations". 
• Importantly (very importantly) no significant side-effects were reported, bearing in mind reports of elevated body temperature occurred post infusion and words like "By the second month, no patients experienced significant febrile events" were used.
• The authors conclude that more research is required in this area.

OK. With the science hat on, one reiterates that this was a very, very preliminary case review and although Gc-MAF was "checked for sterility in-house and externally by the UK Health Protection Agency" apparently, this is still a compound under investigation and is still very experimental. I've not specifically made mention of Gc-MAF on this blog before this post. That being said, I have talked about nagalase in relation to some speculations on the now de-discovered work on XMRV and chronic fatigue syndrome (CFS).

There are some obvious questions raised from the findings reported by Bradstreet. So, assuming all that Gc-MAF does and how it apparently does it, the whole 'underactive immunity' side of autism comes into play. Indeed I'm immediately drawn back to the work by Harumi Jyonouchi and colleagues on SPAD and immunodeficiency detected in their cohort and the possible link with gastrointestinal (GI) dysfunction. That and the low IgA findings also observed on more than one occasion in cases of autism. Of course balancing all that with other findings indicative of other issues with immune function in cases of autism such as an overactive immune system and the whole autoimmunity side of things. I should perhaps also stress that I am not equating autism with HIV or cancer or anything else based on the description of these findings.

Perhaps just as important is the whole viral infection link being implied in some cases of autism by this work. I know this starts to take us into some quite uncomfortable territory with autism in mind as per the study by Mady Hornig and colleagues****** (including virus hunter Ian Lipkin) on a (mostly) lack of measles virus in reply to studies like the one from Kawashima and colleagues*******. I'm not really in a position to offer an expert opinion as to whether this is proof positive that specific viruses are or aren't involved in autism, over an above the multitude of viruses everyone comes across in a lifetime, albeit with an immune response in full working order and the focus being on autisms not autism. Think also back to that most classical autism-viral connection which looked at rubella******** quite a few years back. And then all those ancient remnants of viruses which we all carry in our genome and have been recently looked at with autism in mind and whether there are any connections to be made or not.

Irrespective of any controversy this might unearth - which I assume it probably will - the Bradstreet results are peer-reviewed results and hence worthy of further independent analysis. Perhaps Prof. Lipkin might once again step up to this task?

[Update: you may also want to have a look at the second time Gc-MAF has cropped up on the autism  research circuit too.]

-----------

* Bradstreet JJ. et al. Initial observations of elevated alpha-N-acetylgalactosaminidase activity associated with autism and observed reductions from GC protein—macrophage activating factor injections. Autism Insights. 2012. 4: 31-38.

** Korbelik M. et al. The value of serum alpha-N-acetylgalactosaminidase measurement for the assessment of tumour response to radio- and photodynamic therapy. Br J Cancer. 1998; 77: 1009-1014.

*** Yamamoto N. & Nataparaju VR. Immunotherapy of BALB/c mice bearing Ehrlich ascites tumor with vitamin D-binding protein-derived macrophage activating factor. Cancer Res. 1997 Jun 1;57(11):2187-92.

**** Yamamoto N. et al. Immunotherapy of metastatic breast cancer patients with vitamin D-binding protein-derived macrophage activating factor (GcMAF). Int J Cancer. 2008; 122: 461-467.

***** Yamamoto N. et al. Immunotherapy of HIV-infected patients with Gc protein-derived macrophage activating factor (GcMAF). J Med Virol. 2009; 81: 16-26.

****** Hornig M. et al. Lack of association between measles virus vaccine and autism with enteropathy: a case-control study. PLoS ONE. 2008; 3: e3140.

******* Kawshima H. et al. Detection and sequencing of measles virus from peripheral mononuclear cells from patients with inflammatory bowel disease and autism. Dig Dis Sci. 2000; 45: 723-729.

******** Chess S. Follow-up report on autism in congenital rubella. J Autism Child Schizophr. 1977; 7: 69-81.

----------

James Jeffrey Bradstreet, Emar Vogelaar, & Lynda Thyer (2012). Initial observations of elevated alpha-N-acetylgalactosaminidase activity associated with autism and observed reductions from GC protein—macrophage activating factor injections Autism Insights