There have been more than 10,000 studies on soy and or its components since 1991. Those studies can be broken down to endpoints dealing with either nutritional benefits or the metabolic pathways involved with the prevention or treatment of chronic diseases such as cancer, coronary artery diseases, diabetes, multiple sclerosis, muscular dystrophy, and diseases affecting other vital organs. The more advanced studies are involved with DNA, up-regulation or down-regulation of gene expressions, genetic repair mechanisms, and metabolic pathways.

The research has been positive in almost all of the studies. The FDA approved a health claim for the cholesterol-lowering effects of soy protein and the reduction of risk from heart disease. One study on prostate cancer shows soy isoflavones may reduce prostate cancer risks by 50%. Breast cancer studies have been controversial, focusing on the potential increased risk of developing estrogen receptor positive breast cancers (ER+), speeding up the growth of ER+ breast cancers, or as a pharmaceutical company claimed, reducing the effectiveness of Tamoxifen (by way of the isoflavones in soy products). In spite of this last claim, studies show synergism between Tamoxifen and soy. Tamoxifen by itself was 26% effective, soy protein isolate by itself was 36% effective, and the two together were 62% effective. The combination of Tamoxifen and soy resulted in smaller breast tumors than Tamoxifen alone.

Epidemiological studies examining the relationship between soy intake and health outcomes have involved Asian populations and therefore evaluated the intake of traditional fermented foods such as tofu and other soy products that are derived from whole or dehulled soybeans. In contrast, few animal or human intervention studies have involved fermented products or whole soy foods. Instead, soy concentrates, soy isolates, isolated isoflavone mixtures, supplements, or pure genistein are generally used. Some studies have evaluated full-fat or defatted soy flours or textured soy protein (usually mixtures of soy concentrates and soy flour). There are dozens of soy products used for research, and they differ markedly in micro (isoflavone, saponin, phytic acid, phytosterol, vitamin, and mineral content) and macro (protein, fat, and carbohydrate) content.

These differences exist even when comparing similar compounds like soy flours, concentrates, and isolates used in studies. The isoflavone content expressed in a study may not be accurately interpreted, because in fermented soy products, some of the glycoside (40% sugar form) of isoflavones is converted to aglycones (sugar-free form). Researchers often express the isoflavone content of the product fed to subjects without indicating the breakdown between the glycoside and aglycone forms of isoflavones in the product being used. The sugar moiety does not contribute to the biological activity of the isoflavones, and the amount of aglycone present is 60% of the total weight of the aglycone form of isoflavones. Therefore, 100 mg of isoflavones may represent anywhere from 60-100 mg of active isoflavones, depending on the type of soy product.

The level of daidzin and daidzein present in a product may produce significant differences in the results experi-enced by a cancer patient because these two isoflavones produce a potent anticancer compound equol in 30-50% of the people in the United States. Equol is not produced in everyone, because its production is a result of the isofla-vones daidzein and daidzin fermentation by gut microflora. Antibiotics destroy the equol-producing gut microflora. It takes about nine months to re-establish the equol-producing microflora in the gut naturally. Several years ago, the National Cancer Institute announced that "users of antibiotics are at higher risk for cancer." The 4400+ isoflavones in fruits and vegetables are fermented in the intestines, and anticancer metabolites are produced. When beneficial mi-croflora are destroyed by antibiotics, they do not produce equol and other anticancer metabolites. Therefore, users of antibiotics are at higher risk for cancers.

A soy study using soy flour, soy protein concentrate, an isolate, or a fermented soy powder or beverage might mean a difference between 32%, 21%, 3%, or 0% carbohydrate content. Differences in the anticancer compounds, the quantity, and bioavailability can be astronomical. Bioavailability is important with these compounds, because studies show that, with dietary isoflavones, what goes in does not equal what comes out. The excreted isoflavones in humans is less than the total isoflavone consumption. The difference between isoflavone consumption and excretion goes into the cellular tissues and repairs DNA, up-regulates or down-regulates gene expressions, and influences metabolic pathways. Isoflavone compounds generally are 500-3000 daltons in size. Fermentation breaks down these large molecules to individual molecules or smaller molecular clusters that are more bioavailable. Fermentation produces soy metabolites like glyceollins and others that have anticancer properties. Glyceollins are being studied at Tulane University on breast and ovarian cancers.

The chemical composition of soy concentrates or isolates is affected by processing techniques, because water and alcohol washing are used to concentrate the proteins by removing the sugars and oligosaccharides from soy. This removes some of the low-molecular weight peptides (those below 2000 that contain high amounts of sulfur amino acids). Alcohol washing also removes most of the isoflavones and saponins from the product. Research shows alcohol washing may substantially alter the protein matrix and structure. Fermentation breaks down the isoflavones to smaller molecules, produces isoflavone metabolites, and makes them more bioavailable. Spectrographic analysis shows vast differences between Haelan's fermented soy beverage isoflavone spectrum when compared to other commercial isoflavone products being marketed (see Figures 1-4). An analysis of Haelan's fermented soy beverages shows they contain RNA, DNA, polysaccharides, amino acids, isoflavones and their metabolites, the Bowman Birk (BBI) protease inhibitor compound, saponins, phytosterols, and phytic acid compounds in addition to a branched fatty acid compound known as 13 Methyltetradecanoic Acid (MTD-13). This compound is produced solely in Haelan's fermentation process and is not present in other soy products. Studies with the MTD-13 by itself exhibited significant tumor shrinkage in human prostate and liver cancers. Apoptosis in leukemia cells was induced in two hours.

In spite of the positive soy research reports that are reported, articles on the Internet and elsewhere knock soy for controversial reasons. One anti-soy article approves of fermented soy products but is critical of non-fermented soy products. Non-fermented soy products contain growth-stunting compounds and chemotrypsin-inhibiting compounds that affect the consumer's ability to digest proteins. Fermentation removes or de-activates these undesirable compounds. Another article states that the World Health Article provided soy foods to starving people in Sudan, and they were later found to be deficient in minerals. The anti-soy group claimed that the phytates in soy, because of their mineral-binding capacity (which protects us from colon cancers), caused mineral depletion in these Sudanese people. Later studies found that these Sudanese people were deficient in minerals prior to their soy consumption. In spite of the published studies stating there is no mineral deficiency caused by soy, the anti-soy groups continue the myth that soy causes mineral deficiency.

Similarly, a recent study on soy shows soy only affects thyroid function in people who are deficient in iodine. The anti-soy group still claims soy affects thyroid function but forgets to state it is only in those people deficient in iodine. Another contested complaint against soy is that it causes smaller brains in people. This was first presented at an international soy conference I attended in California several years ago. Two female researchers said they tested some elderly Japanese people living in Hawaii, and discerned that those subjects had smaller brains than normal. When asked what they ate during their lifetime, the elderly Japanese subjects answered fish, vegetables, soy, and meat. The researchers concluded that soy must have been the culprit that caused these people to have smaller brains than normal. What else could it have been? I would have directed attention to the fact that these elderly Japanese people were much closer to the nuclear radiation after the atomic bombs destroyed Hiroshima and Nagasaki just prior to the end of World War II. These people may have suffered radiation damage directly as a result of closer proximity to the nuclear blasts or indirectly from eating migratory fish, vegetables, etc. that were possibly damaged by atmospheric deposition of radioactive particles in water and soils involved with their food supply. It is difficult to say what actually caused these elderly Japanese people to have smaller brains. There is no evidence that elderly Japanese or Chinese people have smaller brains associated with their historical consumption of soy. Studies on soy show it reduces the risk of Alzheimer's by 34%, improves blood flow to the brain, and increases brain function in humans.

Without question, soy is controversial. Does soy have a dark side, or is it good? Meat is good, but too much meat is bad. How much soy, if any, is good, or is it all bad? Are some soy products better than others? Do the benefits of soy outweigh the undesirable side effects? How do we determine what is correct? Clinical studies generally give us insight in determining what is factual and what is not. The problem is the soy studies have no uniformity when referring to soy products and components in the scientific literature. In addition, there is a lack of statistical data, and that data involve poorly defined test substances. There is also controversy over the validity of the research models and approaches. Some researchers worry that isoflavones at low levels (below 50 mg) may be estrogenic, whereas the whole soy with higher isoflavone levels is anti-estrogenic. A study on healthy women by Dr. Jane Lu, University of Texas Medical School, Galveston, Texas showed healthy women who consumed the whole soy had lower total circulating levels of estrogens that were 30-40 % lower than women who did not consume the whole soy. Studies in Japan (Nagata et al.) showed that Japanese women who consumed the whole soy had 25% lower levels of circulating estrogens than those who did not consume the whole soy. These results are clearly anti-estrogenic and would be beneficial to those with estrogen receptor-positive cancers.

One published study performed by seven Harvard OB-Gyn oncologists at Massachusetts General Hospital recommended clinical trials with Haelan 951 fermented soy beverages, a commercially available product, for Platinum Chemotherapy-resistant ovarian cancers. This study reported the long-term stabilization of a patient who was previously non-responsive to chemotherapy. Similarly, cancer patient histories with Haelan 951 fermented soy use were evaluated by the National Cancer Institute (NCI) as part of their "Best Case Series." NCI graded several of the reported cases (breast and liver cancers) as being "persuasive" cases. "Persuasive" is the highest NCI rating for a cancer treatment's effectiveness.

A study performed in Germany on the breast cancer cell line BT474 with Doxorubicin (chemo for breast cancers) showed a 4.6% cancer cell survival rate with 5% by volume chemotherapy treatment. The Haelan 951 fermented soy produced a 4.8% cancer cell survival with 3% by volume in the blood. Doxorubicin at .5% resulted in an 82% cancer cell survival but, when combined with the 3% fermented soy, resulted in a cancer cell kill five times stronger than the Doxorubicin produced by itself. The synergistic effect of the combination is partly explained by the fact that the fermented soy increased pro-apoptotic conditions in the cancer cells and raises the level of P21 in cancer cells. Re-activation of the P53 tumor suppressor protein produces higher levels of P21 in cancer cells. Additional insight into the synergism between soy and chemotherapy treatments was reported by Karmanos Cancer Center, University of Michigan in Detroit. Their report says, "all cancer cells within two hours of being hit with chemotherapy try to mutate. The mutation pathway of the cancer cell is Nuclear Factor Kappa Beta (NF-Kb), and the soy isoflavones shut off the mutation capability completely, and you get eight to ten times greater cancer cell kill than chemotherapy does by itself."

With glowing reports like this extolling the benefits of soy, why is there confusion on determining if soy is beneficial for the treatment of estrogen-positive breast, ovarian, and prostate cancers? At the heart of the estrogen receptor-positive breast cancer controversy are a few studies that are out of synch with the thousands of positive cancer studies on soy. The controversy began when a study at the University of Illinois removed the ovaries from rats, implanted estrogen receptor-positive (ER+) breast cancers and then gave them a low level of genistein (one of 12 isoflavones in soybeans). Under these conditions, the tumor grew. The word quickly spread, "don't give soy products to ER+ breast cancer patients because soy makes those cancers grow. Later studies showed that when Tamoxifen alone was used under the same conditions, the tumors also grew. When higher levels of genistein were used, the tumors shrank. When the whole soy was used, the tumors shrank. When the ovaries were left in the rats, those that received the soy were better off than the control group that did not receive the soy. After looking at thousands of incomparable soy studies, the position presented by Dr. Mark Messina, representing the soy industry, is that women have no problem with consuming the "whole" soy but should be cautious about consuming isolates of soy.

The National Cancer Institute (NCI) spent $20 million looking at anticancer compounds in fruits and vegetables and found five classes of superstar anticancer compounds, all of which are in the whole soybean. Those are isoflavones, protease inhibitors, saponins, phytosterols, and phytic acid compounds. There are six major and six minor isoflavones in the isoflavone group. After identifying these anticancer compounds, the NCI spent $2.9 million studying them. The results were published in the Journal of the National Cancer Institute on April 17, 1991. This publication spurred the extensive cancer research on soy. It is easy to recognize that a whole soy product may have all of these soy anticancer compounds in them, whereas soy supplement products may only contain a few of isoflavones in them and none of the other anticancer compounds naturally found in the whole soybean.

Dr. Ann Kennedy, David Brandon, and Irvin Liener, in studies at the University of Pennsylvania, noted that the soybean BBI protease inhibitor (BBI) either inhibits or prevents development of experimentally induced colon, oral, lung, liver, and esophageal cancers. Results suggest an important role for trypsin inhibition in suppression of the promotional stage of carcinogenesis. These compounds prevent conversion of normal cells to malignant state even at very late stages in carcinogenesis and cause an irreversible suppressive effect on the carcinogenic process. In addition, these compounds have been shown to suppress oncogene expression and inhibit carcinogen-induced protease activity. Kennedy commented that the lowest effective dietary levels of protease inhibitors used in their animal studies (0.1%) could be achieved in humans by modifying the diet to include soy products. An analysis of tofu has revealed that the protease-inhibitor content varied significantly between the samples from four to 30 micrograms of BBI per gram of product. There is a wide variation of BBI content among varieties of soybeans. Studies show Haelan 951 contains the highest BBI content of any commercially available soy product. Studies show BBI benefits muscular dystrophy, multiple sclerosis, and cancer patients.

The health benefits gained from any soy product depend on many factors. There are more than 10,000 varieties of soybeans. The phytochemical content in soybeans varies 50%, depending on the minerals in the soil, and an additional 50%, depending on the age of the beans when they are picked. Processing greatly affects the resulting end product. Storage and processing of the soybeans affects the concentrations and bioavailability of the surviving compounds in the end product. To demonstrate the difference between commercially available soy isoflavone products and Haelan 951 fermented soy beverages, the following comparisons are presented. In summary, all soy products are not created equally, and the benefits derived are not the same. This makes it very difficult to evaluate the soy studies that are researched. The studies with Haelan 951 fermented soy are easier to evaluate because the same product was used in all the studies. The results achieved with this product may not be achieved with other commercial soy products of lesser quality.

Figure 1: 1H NMR spectrum of Haelan 951 and genistin; corresponding proton groups and signals marked by arrows (red and green).

To determine the actual amount of isoflavones relative to the total contents of a soy capsules, high-field NMR spectroscopy was used as described above to non-destructively identify via integration the proportions of low molecular weight metabolites in the sample solution, combined in groups. This required identifying the isoflavones in the 1H NMR spectrum of Haelan 951. This was achieved, for example, by taking the 1H NMR spectrum of genistin, the genistein glucoside and identifying the respective signals in the NMR spectrum of Haelan 951 (see Figure 2, red and green arrows). The orange arrows in the Haelan spectrum represent saturated fatty acids such as 13 MTD. The proportion of isoflavones is clearly identifiable in the Haelan 951 spectrum.

Figure 2 shows the isoflavone content in each product via orange and green bars. Product 1 contains hardly any detectable amounts of the soy isoflavones. In addition, the middle portion of the spectrum indicates that Product 1 largely consists of only one simple sugar and fatty acids.

Figure 2: 1H NMR spectra of Product 1 and Haelan 951

Figure 3 displays a comparison of the spectra of Product 2 and Haelan 951. Again, in addition to revealing the marginal amount of aromatic compounds in Product 2, Figure 3 illustrates that the compared Product 2 largely consists of sugars and fillers.

Figure 3: 1H NMR spectra of Product 2 and Haelan 951

Conclusion
We need to recognize all soy products are not created equal. In addition, we need to recognize most soy studies were not "soy" studies but studies with isolated components taken from the soybean. A study with genistein is not an isoflavone study or a soy study. It is a study with genistein (one of the 12 isoflavones in soy) and should be reported as a study with genistein. The study should state the genistein concentration, form (glycoside or aglycone), and conditions used in the study. Interpretation of the many reported "soy studies" has been difficult because the soy products or components of the soy used in the studies were not the same and were poorly identified. We can't compare apples to oranges. Amid the inconsistent results in "soy" studies, we do find consistency in the studies with Haelan's fermented soy on cancers and other health benefits. The results are consistent because the same "soy product" was used in the studies. Results of these studies have been consistent, superior, and duplicated in humans. Haelan's processing and inclusion of the vast spectrum of anticancer compounds found in the whole soybean have demonstrated synergism that are not matched in studies with only one or a few of these isolated compounds.

Consumers need to recognize there are little or no isoflavones in many commercial products. In addition, sugars and fillers represent a major component of many commercial isoflavone products. Spectrographic comparisons between Haelan 951 and commercially available isoflavone products show Haelan contains not only greater amounts of the isoflavones but a vast spectrum of other anticancer compounds that are not present in soy isoflavone products. The comparison of the isoflavone portions in the 1H NMR spectra shown in Figure 4 reveals that in addition to the known isoflavones genistin, genistein, daidzein, etc., Haelan 951 contains a number of interesting compounds not specifically characterized so far that have likely been generated in the special fermentation process.

Pilot studies on tumor cells and subsequently on a group of patients with breast, ovarian, or prostate carcinoma demonstrated a positive influence of Haelan 951 in terms of reduced tumor growth and significant improvement of the patients' general condition. Dr. Doris Bachg's working group at Gemeinschaftspraxis fur Laboratoriumsmedizin, Recklinghausen, Germany, was able to demonstrate on a genetic level that Haelan 951 enhances the expression of P21, which leads to a stop of the cell cycle and thus suppresses cancer growth in prostate, ovarian, and breast cancer patients alike. P21 is located at a prominent position in the cell cycle and is activated by P53.

Haelan 951 consists of many components, the number of which has been significantly increased via the special type of fermentation when compared to an untreated simple soy extract. In mixtures of so many soy components, it is always unclear which of the many soy constituents is responsible for an observed effect: is it one component or a facultative effect of several substances, or does the mixture only work indirectly by triggering a type of placebo effect at some place in the metabolism (metabolome) via a comparatively insignificant substance? Clinical trials and research on Haelan are ongoing.

Figure 4: A comparison of the isoflavone content in Product #1 and Haelan 951
In addition, many other beneficial compounds in Haelan are identified.