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From the Townsend Letter
October 2016

An Interview with Prof. Marco Ruggiero:
Understanding the GI and Brain Microbiome and the Role of GcMAF in Harmonizing the Immune System with the Microbiome Populations
by Jacques Fernandez de Santos
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JFS: Is it possible that, just by consuming "the dessert cup," certain conditions can be improved in places such as Africa, where access to reliable sources of good protein might be difficult? In this sense, your probiotic product has been distributed for free in Malawi and some Asian countries to children and to people living with HIV/AIDS, with, it seems, very good results.
MR: Probiotic yogurts proved effective in a variety of conditions, in particular where malnutrition and immunodeficiency are present at the same time. In fact, they provide for an excellent source of protein, healthful fats, vitamins, and micronutrients. In addition, all probiotic yogurts contain live cultures that exert positive effects on human health as well as a wealth of proteins and peptides that modulate the immune system, favor the absorption of minerals, decrease inflammation and, in general terms, improve nutritional status. Our Bravo yogurt is peculiar in that it was designed taking into consideration the natural formation of powerful immune-stimulating molecules such as GcMAF. In addition, Bravo contains fermented colostrum, an excellent source of noble proteins and of proline-rich polypeptides (PRP). These molecules are also known as colostrinin and were independently discovered in colostrum and other sources, such as blood plasma, in the US and Poland. In this respect, they resemble the Gc protein, the precursor of GcMAF that also is present in colostrum and in blood. PRPs function as signal-transducing molecules that have the unique effect of modulating the immune system, turning it up when the body comes under attack from pathogens or other disease agents, and damping it when the danger is eliminated or neutralized. In other words, Bravo, which contains fermented colostrum, does not stimulate the immune system in a nonspecific way; it rebalances the immune system, and because of this it has also proved effective in those conditions wherein the immune system is overstimulated, such as with autoimmune diseases. The ferments to prepare the Bravo yogurt were donated to two refuge facilities for children, one in Malawi and one in Thailand, and the yogurt was prepared in loco using local cow milk. So far we have received very encouraging reports, and we hope to be able to help other communities as well.
JFS: Throughout your book, you expound extensively on the importance of proteases in order to assimilate the amino acids that compose the proteins we eat. In parallel, you have worked in the pharmaceutical industry, in the field of proteases. Those inhibitors are widely used to treat HIV infection. The official HIV/AIDS hypothesis states that this is due to the inhibition of proteases of the HIV virus, which once its replication is suppressed, allows the immune system to recover. Within this context, is there another explanation of why this proteases or integrase inhibitors work in immune depressed patients, and could those inhibitors be applied to immune deficiencies not related to HIV in general for short periods of time?

I began working on the enzymes called proteases and their inhibitors. I was a postdoctoral fellow at the Burroughs Wellcome Research Laboratories in North Carolina in the 1980s. With my supervisor, Dr. Eduardo Lapetina, I published a seminal paper that was presented to the National Academy of Sciences of the USA by the Nobel laureate Sir John Vane (Proc Natl Acad Sci U S A. 1986 May;83[10]:3456–3459). In this paper, we describe the effects of a protease inhibitor derived from a certain bacterium called Actinomycetes. This natural inhibitor is called leupeptin and has several interesting properties that may be exploited in the field of natural immunotherapy with particular reference to viral infections. In fact, many viruses, from the influenza viruses to HIV, rely on proteases to be activated and, because of this, protease inhibitors are effective antiviral agents. Leupeptin was demonstrated to be effective against the influenza virus (Antiviral Res. 2011 Oct;92[1]:27–36) but I am not aware of studies of its effects on HIV. However, natural inhibitors of proteases can be found in a number of other natural compounds and may have a role in the natural immunotherapy of viral infections. For example, it is well known that milk and milk-derived products such as Bravo contain inhibitors of the protease called angiotensin converting enzyme, and it is also well known that there are a number of peptides with antiviral properties in fermented milk products such as Bravo (J Proteomics. 2015 Mar 18;117:41–57). In addition to peptides with protease inhibitory activity, milk and its derivatives contain glycosaminoglycans, such as chondroitin sulfate, that are similar to protease inhibitors called kunins and are known to inhibit the binding of HIV to its target cells that are the CD4 lymphocytes (J Nutr. 1995 Mar;125[3]:419–424). It is interesting to notice that this molecule, commonly found in milk and its derivatives, has been demonstrated to be extremely efficient against HIV since the 1990s. In PubMed there are reports describing how a combination of natural substances that included chondroitin sulfate reduced viral load to nondetectable levels in 10 days, a result not even imaginable today with the most advanced antiretroviral drugs (Posit Health News. 1998 Fall[17]:7–11). The following year, in 1999, an Italian researcher working at the Centre for Virology of the Institute Spallanzani in Rome demonstrated that chondroitin sulfate was efficient not only against HIV itself, but also the opportunistic pathogens that are known to infect immunodeficient patients (Antivir Chem Chemother. 1999 Jan;10[1]:33–38). Curiously, none of the research involving natural protease inhibitors such as leupeptin or the inhibitors in milk has received much attention, while this could be an inexpensive and fully natural way to block viral infections and strengthen the immune system. However, I would not be surprised if in the future it is demonstrated that anti-HIV (antiretroviral) drugs also show other effects that may be responsible (momentarily) for the recovery of the immune system independently of their antiretroviral effects. This is a frequent occurrence in medicine; the positive effects of a drug on the outcome of the disease are at first ascribed to some mechanism that is later on demonstrated to not be completely correct. The positive effects remain, but it may be discovered that the reason why the drug worked is completely different from the one that had been previously hypothesized. If we assume that a competent immune system can fight the supposed HIV infection, then it is reasonable to hypothesize that drugs, remedies, or supplements that strengthen the immune system will help in such a fight.
JFS: The dessert cup with the GcMAF protein is an intrinsic part of the vitamin D axis. Is it important to check vitamin D levels and in case of low levels, supplement before taking Bravo or GcMAF?

MR: The issue of how much vitamin D we need is a truly complex one. So complex that a few years ago, the famous nephrology journal Kidney International, of the Nature Publishing Group, invited me to write a commentary titled "Chronic Kidney Disease and Vitamin D: How Much Is Adequate?" (2009 Nov;76[9]:931–933). There I put forward the idea that the adequate intake of vitamin D has to be reevaluated. In fact, the current indications refer to the biological effects of vitamin D on bone and calcium metabolism, with particular reference to the prevention of rickets. However, such a limited interpretation of the biological effects of vitamin D is now obsolete, and even the designation of the molecule is erroneous. Today we know that it is not a vitamin but a hormone, and that it regulates practically all the aspects of cell physiology and therefore is involved in almost all types of disease. If you search for "vitamin D and cancer treatment" in PubMed, you will find more than 5000 published articles, and the same happens if you search, for example, for "vitamin D and cardiovascular disease," where you find more than 4000 articles. However, as of today, no one is able to state with certainty what the adequate amount of vitamin D is in each particular condition and whether the amount to treat a disease is the same as that to prevent the same disease. Things are even more complicated if we consider that each individual has a different response to vitamin D because of variations (polymorphisms) in the gene that codes for the receptor of vitamin D. We published several papers on this issue, and, for example, we demonstrated that women harboring a variation of the gene show a significantly higher risk of metastases and recurrences of breast cancer (Oncol Res. 1998;10[1]:43–46). There are physicians in Germany who inject intravenously very high amounts of vitamin D, in the range of 400,000 International Units (IU), in the course of cancer treatment and, interestingly, do not report adverse effects. Personally, I try to expose myself to the sun as frequently as possible since in 30 minutes of exposure my skin produced more than 10,000 IU of endogenous vitamin D. When I don't have this opportunity, I take the same amount of vitamin D as a supplement but, as I have written, the response and consequently the dosage vary in each individual. The response to any treatment involving stimulation or rebalancing of the immune system needs adequate amounts of vitamin D; and, in case of doubt, supplementation may be required. (In PubMed, "vitamin D and immune system" yields 3459 papers!)
JFS: Speaking of heparin, as it is widely mentioned in
Your Third Brain, is your team still studying it in order to find ways to administer it to patients, since it appears to have very important properties and it is a very effective molecule to fight cancer cells by inhibiting their replication?
MR: I began working on heparin in 1985 when I was a young post-doc at the Laboratory of Molecular Biology of the University of Firenze, Italy; and I published a paper in the Biochemical Journal, which was among the most famous scientific journals in those days (1985 Apr 1;227[1]:57–65). In that paper, we described a rather strange association between endogenous heparin and phosphatidylcholine, a major constituent of the cell membrane. While the use of heparin as an anticoagulant drug is very well assessed, the role of endogenous heparin and in particular in the bloodstream remains a mystery, one of the few mysteries in today's physiology. Back in the 1980s, we postulated that endogenous heparin might have had roles other than the well-known anticoagulant activity, and, given our interest in the biology of cancer, we begun studying whether heparin was a naturally occurring anticancer agent. We published the first paper demonstrating that it is indeed an anticancer agent in 1991, when we showed that heparin inhibited the proliferation of carcinoma cells (FEBS Lett. 1991 Apr 9;281[1–2]:141–144). Two years later, we demonstrated that such an anticancer effect was not limited to carcinoma cells, but it could be observed in a variety of cells transformed by different oncogenes, which are genes whose mutations are known to cause cancer (Cell Biol Int. 1993 Aug;17[8]:781–786). Therefore, we concluded that the role of the heparin that in the bloodstream is related to the natural control of cancer, the so-called anticancer surveillance, a term which indicates the physiological mechanisms that defend us from the cancer cells that constantly arise in the body. Rather obviously, the heparin that is commercially available cannot be used as an anticancer drug as it is, since it would cause bleeding because of its anticoagulant activity. Because of this, for the following 20 years, we kept on studying its physiological assembly in the human body with the goal of discovering the secret of how endogenous heparin can protect from cancer without causing bleeding. We eventually found out that the key lies in its association with plasma proteins. In other words, when the endogenous heparin associates with certain proteins in the plasma, the properties of the proteins and of heparin change dramatically and novel biological properties, such as the anticancer activity, arise. We also found out that heparin regulated gene expression, another apparent oddity considering that the DNA is negatively charged and heparin is the biological molecule with the highest concentration of negative charges. Therefore, according to the principles of electrostatics, DNA and heparin should repel each other. On the contrary, we demonstrated that heparin, once bound to certain proteins, dramatically changes its overall electrostatic behavior and is transported inside the cells, where it can interact with molecules such as DNA, therefore influencing the functioning of the genes (Biochem Biophys Res Commun. 1986 Oct 15;140[1]:294–301).
JFS: "Miraculous" molecules such as GcMAF apparently have many abilities, although the real one would to be the carrier for the good molecules doing the real job. Actually GcMAF could be replaced somehow, as the important aspect is its carrying ability. Could you please further explain this important aspect to better understand this molecule?

MR: First of all, we have to understand what GcMAF means: it is a macrophage activating factor (and this describes its function) derived from a protein called Gc (from group component; that is, a component of human plasma). The Gc protein is also known as vitamin D binding protein because one of its functions is to bind vitamin D and carry it to the target cells. The functions of the Gc protein have been known for years, long before the observation that it also could activate macrophages. It was very well known that the Gc protein binds actin, a cellular protein that is released when cells die. Therefore, the Gc protein works as a scavenger that prevents the accumulation of actin coming from dead cells that could be very toxic. In addition, it was known that the Gc protein also binds fatty acids such as oleic acid. We could make an analogy and say that the Gc protein is a big truck that can carry away toxic waste (the actin from dead cells), as well as vitamin D and oleic acid to their cellular targets. The Gc protein also carries another molecule with a rather fancy name: alpha-N-acetylgalactosamine. This is a sugar that is present in milk (hence the name with the suffix -galactose), and it is bound to one of the amino acids of the Gc protein. We observed that the function of activating macrophages is due to a molecular triad that happens to be carried by the Gc protein. This molecular triad is composed of alpha-N-acetylgalactosamine, vitamin D, and oleic acid.
Continuing analogies with vehicles, now we can say that the Gc protein is like a taxi that carries a three-person surgical team to the hospital so that they can perform their duties. These three people/molecules are the alpha-N-acetylgalactosamine, vitamin D, and oleic acid that need to be carried all together at the same time if they are to activate macrophages. The kind of taxi, or whether it is a limousine or a piece of junk, is rather irrelevant as long as it can carry the team to the hospital. Now, imagine that GcMAF is nothing other than a taxi carrying the three-people team to the hospital; we have found a way to replace the Gc protein that derives from blood with another class of molecules called glycosaminoglycans. It is as if we have replaced the taxi that moves slowly in the traffic with a helicopter; it can carry the three-person team to the hospital much faster and more efficiently. In addition, let's assume that the team is needed in more than one hospital; here it means that more than one macrophage needs to be activated. With a regular taxicab, once they have finished in the first hospital, the three members board the taxi that, slowly and with the uncertainty of traffic, carries them to the next hospital. With the helicopter, the transfer of the surgical team from a hospital to the next will be much more rapid and efficient and a greater number of patients will benefit. When I invented this "helicopter" that is the next generation of GcMAF, I followed this very reasoning, and I had the advantage of having worked on glycosaminoglycan for the previous 30 years. This is the reason why this next-generation MAF (here the Gc prefix is no longer necessary) is so powerful and versatile.
JFS: Besides GcMAF-carrying ability, you mention many others, such as inhibition of breast cancer cells, as well as protection of human cells from damage inflicted by heavy metals. Once the vitamin D axis is reestablished, there is an awakening of macrophages and natural killers. Is that correct? Are there other mechanisms by which GcMAF function?

MR: Molecules such as the old GcMAF or next-generation MAF have multiple actions, for the very simple reason that they operate at the most basic genetic level and influence the working of a number of genes that in turn influence a great number of physiologic functions. This translates in a long list of possible clinical applications. Just to name a few, the next-generation MAF could be used to restore the immune system, which is rather obvious, but also to fight several chronic conditions wherein the use of vitamin D, oleic acid, and glycosaminoglycans has already proved effective. I am referring to neurological disorders such as Parkinson's and Alzheimer's diseases, multiple sclerosis, amyotrophic lateral sclerosis, and brain aging, or to dermatological conditions such as psoriasis. Another possible area of intervention is related to cardiovascular conditions, since all three members of this "surgical dream team" have been shown to be effective in the prevention and treatment of cardiovascular conditions – and of course cancer. We do not know as yet the minimum length of treatment with this novel, rather revolutionary MAF, but we can safely assume that once the underlying disorders have been addressed, a minimum maintenance dose should be all that is required.
JFS: Stimulation of nitric oxide looks like a significant ability of GcMAF molecule, as it has an important effect on the circulatory system. Could you expand on the importance of this aspect and how it relates to cardiovascular health?

MR: Nitric oxide (NO) is a very interesting molecule; it was even awarded the title of "Molecule of the Year" by the journal Science in 1992. In those days, its fame was mainly due to its role in the mechanism of action of Viagra. In fact, among many other actions, NO cause vasodilation, and the increase in blood flow in different organs may be exploited for different scopes. For example, it had been known for decades that nitrates that release NO are very useful in increasing the coronary blood flow and can solve an attack of angina pectoris. Increased blood flow in the cavernous bodies of the penis fights erectile dysfunction; Viagra essentially works by blocking the degradation of NO, thus favoring its action. Later on, it was discovered that NO also has other interesting functions that could be exploited in the treatment of proliferative diseases such as cancer. In fact, NO selectively kills cancer cells because it causes a type of damage to cancer cells' DNA that they cannot repair. In other words, NO has the same effect on the DNA of healthy cells and cancer cells, but the cancer cells are unable to repair the damage inflicted by the NO, whereas the healthy cells do have not such a difficulty. We discovered that macrophages, when they are activated by GcMAF or the next-generation MAF, release NO, and such a release can easily be demonstrated by looking at the blood flow with a common ultrasound system (Anticancer Res. 2014 Jul;34[7]:3569–3578). Thus, we may have found something very close to the long-sought-after "magic bullet." In oncology, before the advent of the "smart bombs," magic bullet referred to a molecule that could kill only cancer cells, leaving healthy cells unharmed – at variance with what commonly happens with conventional chemotherapy. The principle is rather simple: we activate the macrophages with the old GcMAF or, even better, the next-generation MAF. The macrophages go on a "search and destroy" mission; that is, they look for cancer cells or cells infected by viruses. Once they have found such an abnormal cell, the macrophages bind to it and release NO that causes irreversible damage to the DNA of the cancer cell. As far as the role of the NO released by the activated macrophages in cardiovascular health is concerned, we must take into consideration that a constant, physiological activation of macrophages can be achieved with probiotic products such as Bravo, which in this way may contribute to the maintenance of health. In fact, Bravo not only contains naturally produced GcMAF, but it also has some live microbes such as Lactobacillus rhamnosus that are known to activate macrophages per se (Microbiol Immunol. 2012 Nov;56[11]:771–781).

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