Positive Health Online

BioBran MGN-3, a natural food supplement made from rice bran and Shitake mushroom enzymes, has been clinically shown to enhance significantly the activity of the immune system without any side effects.

Introduction

BioBran MGN-3 was developed in 1992 by Hiroaki Maeda, Director of Research and Development at Daiwa Pharmaceutical Co. Ltd in Tokyo. Maeda's area of interest is in finding natural phytonutrient solutions for both human health and agriculture, and in the late 1980s he turned his attention to polysaccharides, which have been known to strengthen immune response. Then, working in conjunction with Daiwa Pharmaceutical, headed by Yasuo Ninomiya, and Mamdooh Ghoneum, Professor of Immunology at Drew University of Medicine and Science in Los Angeles, Maeda later developed a complex of short-chain polysaccharides (primarily arabinoxylan and other hemicelluloses) which he named BioBran MGN-3 (M - Maeda, G - Ghoneum, N - Ninomiya, 3 - third generation product). Small quantities of this food-based compound, which is made by breaking down rice bran using Shitake mushroom enzymes, have been clinically shown to stimulate the immune system (see box) when taken as a food supplement.

The Immune System

The immune system is the collective army of a trillion white blood cells, the bone marrow, antibodies and the thymus gland that identifies and then destroys the millions of microbes (bacteria, viruses, parasites, fungi) that penetrate our bodies every day. This system also needs to eliminate 500 to 10,000 of our own cells that have become genetically abnormal or cancerous.[1] In fact, the immune system is considered every bit as complex as our nervous system, and is not only able to produce a matching antibody for every one of the millions of different infective agents, but is able to remember how to produce these decades later.

Central to the immune system are the lymphocytes, which include the T cells (70-80%), B cells (5-10%) and NK cells (15-20%). These cells, which work in conjunction with one another, are able to identify and destroy almost every intruder or infected/cancerous cell in the body.

NK cells are of particular interest and importance because, unlike other white blood cells, they are able to work more or less independently, without special instructions from the immune system, to recognize and destroy many types of cancerous and virally infected cells. They are therefore considered the body's first line of defence for these types of disease.

When the body is stressed or in a diseased state, the immune system can become overloaded and the activity of these protector cells becomes sluggish. This can often be compounded by some medical treatments - such as chemotherapy in the case of cancer - which further depress the immune system. A weak immune system is less able to prevent cancer cells and infections from taking hold and spreading in the body.

Physiological Effects of Dietary Fibre

The benefits of a high-fibre diet have been known for at least a century. Originally believed to be nutritionally worthless, and therefore removed from many food products, research is revealing many new benefits of fibre. These include:

1. Improved lipid metabolism (cholesterol-lowering effects): Dietary fibre decreases total cholesterol levels by inhibiting the reabsorption of cholesterol in the intestinal tract, and by reducing LDL-cholesterol levels through increased bile production;

2. Improved sugar metabolism (amelioration of diabetes): Dietary fibre suppresses elevated blood sugar levels after meals, which leads to reduced insulin needs. It also reduces fluctuations in blood sugar levels, making them easier to control;

3. Inhibition of toxic effects of hazardous substances in food: Dietary fibre absorbs and eliminates hazardous substances found in the digestive tract and helps to prevent the exfoliation of the mucosa of the digestive tract caused by hazardous substances. In fact, a high-fibre diet has been shown to reduce colon and bowel cancer significantly;

4. Enhancement of the immune system: A significant number of near-indigestible polysaccharides have been shown to stimulate the immune system.[2],[3] In the area of mushroom polysaccharides,[4-6] these include the drug derivatives: Lentinan, derived from Shitake mushrooms; Krestin, from Kawaratake mushrooms; and Sizofiran, from Suehirotake mushrooms. Echinacea,[7] Noni juice, and other natural health supplements are also believed to derive much of their immunomodulatory effect from their polysaccharide component.

While the first three benefits do not require absorption of the fibre through the intestinal wall, the fourth benefit - immuno-enhancement – most certainly does. The components of the fibre must be able to be absorbed into the blood and come into contact with cells responsible for immunity, such as the lymphocytes and macrophages, for this effect to be realized. Of course, this is an immediate problem because dietary fibre, which mostly consists of long-chain polysaccharide molecules tightly bound together, is mostly indigestible to humans.

In 1990, Daiwa Pharmaceutical began research into methods of processing fibre that significantly increase its absorption. The ability of different processes and starting ingredients to optimize any immuno-stimulation effect was then examined. What Daiwa came up with was a process whereby the long-chain polysaccharides in rice bran are lysed or broken down by the action of Shitake mushroom enzymes (Hyphomycetes mycelia). The compound, called BioBran MGN-3, consists of small-chain hemicelluloses (30,000 to 50,000 molecular weight) whose primary component is arabinoxylan. BioBran MGN-3 is water soluble, and has a low enough molecular weight (30,000 to 50,000 units) to pass undigested through the wall of the small intestine and directly into the blood.

Physiological Effect of BioBran Supplementation

When taken as a food supplement, BioBran MGN-3 increases the activity of the body's lymphocytes or white blood cells - more specifically T and B cell and especially NK cell function. With supplementation, NK cell activity is increased by more than 300%, B cell activity by more than 250% and T cell activity by 200%. The precise mechanism by which BioBran MGN-3 is able to do this is still uncertain, but it is thought that these hemicellulous compounds stimulate increased production of the body's own natural cytokines – including interleukins, interferons and tumour necrosis factors. (Cytokines are messenger proteins that allow cells to communicate with one another. They are not only able to inhibit virus replication and cancer proliferation directly, they are also the immune system's throttle: increase the body's own natural production, and the activity of lymphocytes which comprise the backbone of the immune system increases.)

As research shows that the biggest increase in immune function with BioBran MGN-3 is in NK cell activity, and as NK cells specifically target many types of cancer and viral-infected cells, this supplement has a promising role in the treatment of cancer[8] and also HIV,[9] hepatitis B and C,[10] viral ME[11] and other viral infections. (It has also been shown to be helpful with diabetic conditions,[12],[13] but, for the purposes of this short review, we will focus primarily on cancer as most of the research with BioBran MGN-3 has so far been done in this area.) NK cells are able to destroy cancerous and virally infected cells by attaching to the infected cell's membrane and injecting cytoplasmic granules (perforin). These dissolve (lyse) the infected cell, and the NK cell is then free to move on to another infected cell. A single NK cell can repeat this process with up to 27 cells in its lifetime.

BioBran MGN-3 appears to increase NK activity by encouraging the formation of these cytoplasmic granules (the NK cells' ammunition). This appears to be mediated by its ability to encourage the natural production of IFN-3 and TNF-K,[14-17] and can be assessed using a four-hour radioactive chromium-release assay which measures how many cancer cells the NK cell sample can destroy in the given period of time. The reason that this test is used is because it gives a more accurate indication of immune system activity, rather than simply counting lymphocyte numbers. The blood of cancer patients typically has less than half the NK cell activity of a healthy immuno-competent person,[18] and often a lot less than that, especially if conventional treatments such as chemotherapy or radiotherapy have knocked out the immune system.

Figure 1 gives simple graph that shows the effect of high dose MGN-3 on NK cell activity over a period of two weeks, after which supplementation was stopped.[19] As you can see, increase in NK cell activity is relatively rapid. Although intake was stopped after two weeks for this experiment, the NK activity is still well above the control level a few weeks later.

Lack of Toxicity and Hyporesponsiveness

BioBran MGN-3 has shown itself to be completely non-toxic, which is unusual for a substance that can enhance the immune system. Recently, synthetic interferon and interleukin-2 (IL-2) have made headlines as promising cancer drugs because of their ability to stimulate the immune system. However, these synthetic drugs can cause severe side effects, including kidney failure, capillary leaking syndrome and nausea/vomiting. (Good results have been obtained combining low levels of IL-2 with BioBran MGN-3.17)

Required drug toxicity tests[20] and human trials using doses up to 45mg/kg/day over a six-month period have found no abnormalities in blood chemistry or living enzymes (SGOT and SGPT).19 In fact, safety wise, BioBran MGN-3 is on a par with foods consumed in an ordinary diet (LD 50-30 grams per kilogram). This makes it an extremely safe food supplement.

Research has also shown that, provided BioBran MGN-3 is regularly included in the diet, this stimulation of the immune system need not decrease over time. This lack of attenuation or hyporesponsiveness with prolonged use is extremely unusual for immunomodulatory substances and means that BioBran MGN-3 continues to be an effective supplement over an extended period of time - which is important for long-term treatment. NK activity usually peaks around one or two months after being on a high dose, after which it can be maintained with a smaller maintenance dose. The speed at which this peak is reached depends on the amount taken each day.

Research with Cancer Patients

There are now over 15 published studies[21] in scientific journals to support the claim that BioBran MGN-3 is one of the most effective and safe immunomodulator available, and the number of studies increases every year.

The chief researcher of BioBran MGN-3 and its effects in the body has and continues to be Dr Mamdoo Ghoneum - a world authority in the emerging field of cancer immune therapy which focuses on immunomodulators' (often called biological response modifiers or BRMs) ability to activate the body's own defence systems to kill cancer cells. Ghoneum received his PhD at the University of Tokyo in radioimmunology and then worked at UCLA School of Medicine in cellular and molecular immunology. He is currently head of immunology at the Charles Drew University of Medicine and Science in California.

Ghoneum has spent most of his professional life studying NK cell activity and substances that are able to modify immune function, and has focused much of his research in the last 15 years on BioBran MGN-3 because it is the most effective and promising immunomodulator he has come across. In his own words, "I abandoned all other projects, including NIH-funded research, in order to focus entirely on this substance."[22]

One of the first in vivo studies Ghoneum undertook with cancer patients was with five breast cancer patients, the results of which were presented at the AACR Special Conference in Maryland in November 1995. Three grams of BioBran MGN-3 were administered to these five patients alongside the conventional chemotherapy.

Within a week or two, NK cell activity started to be enhanced, and with continued supplementation it was able to rise from a baseline range of 12.7%-58.3% to 41.8%-89.5%. Within six to eight months, two of the patients were in complete remission, and another two were in remission after submission of the abstract to the conference.

The next significant study involved 27 cancer patients18 with different types of malignant tumours: seven with breast cancer; seven with prostate cancer; eight with multiple myeloma; three with leukaemia; and two with cervical cancer. Once again, patients were receiving 3 grams of BioBran MGN-3 a day as a supplement to their conventional treatments. Again, NK cell activity was measured using the 51Cr release assay test using K562 cancer cells as the target. Within just two weeks, NK cell activity had increased significantly:

• Breast cancer - increase of 154% to 332%;
• Prostate cancer - increase of 174% to 385%;
• Multiple myeloma - increase of 100% to 214%;
• Leukaemia - increase of 100% to 214%;
• Cervical cancer - increase of 100% to 275%.

This is unusual as the majority of cancer patients have very low NK cell activity baselines18 which itself is a risk factor for malignancy or metastases quite apart from a negative prognostic indicator[23] (which indicates that BioBran MGN-3 may be useful for healthy individuals[24] or those with a risk of disease as a preventative supplement). This increase in NK cell activity continued and has been maintained for five years[25] with continued supplementation - an indication of BioBran MGN-3's lack of hyporesponsiveness.

More recent studies show the same increase in NK cell activity and immunological function; this is all very well, but does this lead to actual clinical improvement? Ghoneum states that the clinical data so far collected indicate that BioBran MGN-3 supplementation correlates with reductions in tumour markers and other pathology indicators which has led to long-term stabilization or remission of disease in the majority of cases (>85%).[22] The complete clinical data for all patients treated since 1995, including haematology and pathology reports, as well as incidence of remission and length of survival, are in the process of being collected and analysed.[22] In the meantime, a large collection of case studies serves as an indication that a lot more research would be well worth undertaking in this area (see case studies below).

Ghoneum does emphasize that, although BioBran MGN-3 is a useful adjunct to conventional treatments, it is not a replacement. Conventional treatments are able to reduce substantially the number of cancer cells in the body, either through surgery, chemotherapy or radiotherapy – a process called debulking. As Ghoneum has stated, "MGN-3 cannot and should not replace debulking therapy, especially in cases of advanced malignancies. In these cases, even an extremely active immune response is easily overwhelmed by the huge numbers of cancer cell present. Instead, I recommend that cancer patients with solid tumours begin MGN-3 immunotherapy concurrently with, or immediately following, debulking therapies. With this strategy we have the best chance of winning what essentially becomes a war of numbers."[22] However, as most cytotoxic therapies are themselves immunosuppressive, any cancer cells left after treatment go essentially unchallenged by the immune system, which is why remissions are often short lived.[22]

It is also important to take into account the quality of life of a patient. Most of Ghoneum's papers and many of the case studies repeatedly indicate that BioBran MGN-3 significantly increases the quality of life (QOL) in patients with low immunity. This increase in QOL is most obvious with patients on conventional treatments such as chemotherapy and radiotherapy, which are renowned for inducing side effects such as extreme nausea, weakness, loss of hair and general poor health. BioBran MGN-3 is able to help mitigate some of these side effects by increasing immune strength.[26]

Case Studies[27]

Case 1 - Stomach Cancer

In March 1996, a 53-year-old female patient was diagnosed with terminal stage stomach cancer that had severely metastasized.

Abdominal surgery was attempted, but when the doctors opened the abdomen they realized that there was nothing they could do as the tumours were too numerous and extensive to remove. Chemotherapy was suggested but declined, as it would not have been very effective in this situation.

Shortly after this time, the patient started taking 3 grams of BioBran MGN-3 per day. Within one week her appetite, which had waned, started to return and she had more energy to walk around the house. Over the next six months, she visited the hospital once a week for check-ups and had X-rays taken periodically. At the end of this period her X-rays showed a substantial reduction in tumour shadow and it was agreed to perform another operation. This operation was successful because of the major reduction in the tumours present, and it was the first time that the doctors in question had seen such a substantial recovery.

Case 2 - Lung Cancer

A 67-year-old male was diagnosed in August 1996 with lung cancer (squamous cell carcinoma) and tuberculosis (Mycobacterium tuberculosis). After treatment of the tuberculosis, the lower half of his right lung was excised, removing the tumour. The patient left hospital in January 1997, after irradiation treatment. However, in June, he consulted the doctor again complaining of pain in his right breast, and it was found that the tumour had spread to the ribs of the right chest and into the bones of the entire body. From July, sustained-release morphine was administered as an analgesic, as this was all the doctors could do. Meanwhile, at the end of May 1997, BioBran MGN-3 supplementation was started at 3g per day. The tumour marker ICPP, which was originally 16.8ng/ml, had reduced to 6.7ng/ml by June the following year. NK cell activity, which was as low as 9% when the disease recurred, gradually increased to a healthy level.

Case 3 - Prostate Cancer

A 60-year-old male with prostate cancer, diagnosed in 1994, was unable to have surgery due to moderate aortic stenosis and was reluctant to have radiation as the long-term prognosis with this treatment in his particular situation was very poor. He was therefore put onto hormone therapy to try to control the spread of the cancer. The patient started BioBran MGN-3 supplementation at 3g per day in April, and by October nine biopsies showed a negative result - his cancer was in remission. The hormone therapy was stopped in October. Since that time the patient's NK cell activity and health have remained high (apart from a brief drop due to the stress of having his house destroyed in a mountain fire).

Case 4 - Breast Cancer

A 44-year-old female was diagnosed with breast cancer in December 1994. She received surgery and chemotherapy, after which her NK cell activity baseline was 39.9% as of May 1995. One month after starting BioBran MGN-3 supplementation, it was 48.9%. By October 1995 it was 83.5%. Since then this level has been maintained and all follow-up mammograms have shown no sign of relapse.

Case 5 - Breast Cancer

A 50-year-old female with breast cancer, treated with surgery and chemotherapy, had worked as an X-ray technician and was diagnosed as having breast cancer in March 1991. She had conventional therapy. One year later, her tumour marker for the breast cancer was 3.4, and her NK cell activity was extremely low at 5%. BioBran MGN-3 was administered, and within seven months her CEA level had decreased to 1.7. Two months later, her NK cell activity was 58%, a tenfold increase from her previous count. She is still taking the BioBran and her immune function remains normal. Follow-up mammograms suggest that she is free of cancer.

Case 6 - Multiple Myeloma

A 56-year-old male with multiple myeloma (MM), was treated with radiation and chemotherapy. The individual had a history of smoking and drinking and had been diagnosed with the cancer in the summer of 1994. Clinical test data showed that the Benz-Jones protein (BJP), a marker for MM, of a 24-hour yield was 934mg a day. Lumbar X-rays showed bone deficiency throughout his entire body and several oppressed bone fractures of the lumbar spine. The patient suffered serious lumbar pain from the disease. He was given radiation at 3000R following chemotherapy, at which time he also began taking 3g of BioBran MGN-3 per day. After two weeks, his baseline level of 20% had risen to 71%, which was then maintained. His BJP value also decreased from 934mg per day to 0mg per day. The patient has been in complete remission for the past five years and is now back at work.

Conclusions

BioBran MGN-3 is certainly an effective and safe immunomodulator with an impressive track record in the short time that it has been available. Mamdooh Ghoneum, head of Immunology at the Charles Drew University of Medicine and Science, has described it as the most effective immunomodulator he has come across, and BioBran MGN-3 is rapidly becoming the leading immune system supplement used worldwide.

Numerous published studies have shown that BioBran MGN-3 is able to boost significantly the physiological parameters of the immune system - such as NK cell activity, T cell and B cell activity, TNF-K and IFN-3 production - but quite how increases in these parameters translate to actual disease survival percentages will need several large-scale double-blind trials lasting several years to decide.

However, this raises an important consideration, for any double-blind trial with an effective immunomodulator may be diminishing the chance of recovery for the percentage of its participants receiving the placebo. That said, smaller scale trials continue to take place every year in Japan and the USA, with trials planned shortly in Europe. Overall, the growing body of evidence for the efficacy of this natural product is encouraging.

References

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9. Ghoneum M. Anti-HIV activity in vitro of MGN-3, an activated arabinoxylan from rice bran. Biochemical and Biophysical Research Communications. 243: 25-29. 1998.
10. Research conducted by Ghoneum, M. Unpublished to date. Alternatives For the Health Conscious Individual. 7(15). Sept 1998.
11. Kenyon J. A Descriptive questionnaire-based study on the use of BioBran (MGN-3) in chronic fatigue syndrome. Townsend Letter for Doctors and Patients. Nov 2001.
12. Ohara, Onai and Maeda H. Modified rice bran, MGN-3, improves glucose tolerance in niddm adult rats given Streptozotocin as neonates. (Unpublished, but visit http://www.jafra.gr.jp/nid-e.html for info.)
13. Ohara, Tabuchi, Onai and Econ. Effects of modified rice bran on serum lipids and taste preference in Streptozotocin-induced diabetic rats. Nutrition Research. 20(1): 59-68. 200.
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20. AMA Laboratories Inc., New York. Ref No: WP96-BERN1/LD504881.DP/ Reference: Acute Oral Toxicity. FHSLA, 16 CFR 1500.3.
21. Visit http://www.jafra.gr.jp/arabino-e.htm for a listing of many of them.
22. Ghoneum M. One sizeable step for immunology, one giant leap for cancer patients. Townsend Letter for Doctors and Patients. pp58-62. Jan 2000.
23. Whiteside T and Herberman R. Human natural killer cells in health and disease. Clinical Immunotherapeutics. 1(1): 56-66. 1994.
24. Levy SM. Persistently low natural killer cell activity in normal adults. Nat Immun Cell Growth Regul. 8: 173-86. 1998.
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26. McAllister E. Healing evidence of MGN-3. Well Being Journal. 2000.
27. All case studies supplied by Daiwa Pharmaceutical and Dr M Ghoneum.