Since the end of 2014, the Internet has been ablaze with headlines declaring that there is clear evidence of a sialic acid compound, N-glycolylneuraminic acid (Neu5Gc), that explains the epidemiologic association of consumption of red meat and cancer. Media attention seems to have been heralded by a recent report published in the Proceedings of the National Academy of Sciences (Samraj et al., 2014).
This group has been studying tumor glycomics (i.e., cancer biomarkers) based on complex carbohydrate structures (sialic acids) attached to proteins and lipids. Sialic acids represent a family of nine-carbon acidic monosaccharides that occur naturally at the end of sugar chains attached to the surfaces of cells and soluble proteins. The linked monosaccharides are glycans, and N-Linked glycans are attached in the endoplasmic reticulum of the cell to the nitrogen in the side chain of asparagine.
Glycans appear to play a role in a number of processes, including sub-cellular and cellular trafficking, intercellular adhesion, signaling, and microbial attachment. In the human body, the highest concentration of sialic acid is N-acetylneuraminic acid (Neu5Ac) that occurs in the brain.
In mammals, there are two major types of sialic acid: N-acetylneuraminic acid (Neu5Ac) and N-glygolylneuraminic acid (Neu5Gc), which differ by one oxygen atom. Humans have only the “Ac” version; other mammals also have the “Gc” version. Although the Ac and Gc versions are very similar in structure, the single oxygen atom difference appears to be recognized by the human immune system, which develops antibodies to the nonhuman type of sialic acid.
The present widely publicized research suggests that polyclonal antibodies to Neu5Gc epitopes that are derived from exogenous/dietary sources (i.e., red meat and milk products) are accumulated in human tissue and commensal bacteria and in turn elicit inflammation and angiogenesis that lower the threshold for cancer. While conducted meticulously and in stages over much of the last decade, the conclusions that are drawn both by the investigators and by the press seem significantly overextended.
Threats to validity include the fact that there are likely tens of thousands of antigens from plants and animals that are presented in normal dietary patterns. One study (Vaughan et al., 2010) identified 4,500 allergy-related B-cell epitopes derived from 270 different allergens in plant, animal, airborne, and drug sources. Undoubtedly, antibodies are elicited in the vast majority of instances, which likely do not result in clinically significant reactivity or inflammation. Only about 10% are recognized by IgE production, i.e., symptomatic inflammation.
Another perspective can be drawn by considering the enormous populations that are vaccinated against various infectious agents and who reliably produce measurable evidence of seroconversion/immunity without any morbidity or enduring inflammation.
In terms of experimental method, that antibody production was not elicited with exposure to control antigens leads us to question the provocative adequacy and appropriateness of the control antigen. Direct exposure of tumor cells to anti-Neu5Gc autoantibodies seems to stack the experimental deck profoundly in favor of an accelerated disease state.
Finally, one must be cautious in translating data developed in animal models. Based on some quick calculations, it appears as if the studied mice were fed an amount nearly 100 times larger than any potential dietary exposure by humans. Also, this dose was consumed daily for about 50% of the typical lifespan of the mice; it is unlikely that humans would consume beef (which has the highest concentration of Neu5Gc) daily for half of their life expectancy. Moreover, exposure in the experimental system via peritoneal lavage is not the same as ingestion via the gastro tract and within a food matrix. The hypothesis that one compound that is innate in a food may pose a health hazard must include consideration of its effects within the entire food matrix. When eaten in a typical quantity and with other foods, health risk may be mitigated. It is interesting to note that Neu5Gc antibodies appear to be important for humans to combat a variety of viral infections. There is also evidence that without this unique sugar, there is an increased risk of GI infections.
The 2010 Dietary Guidelines for Americans noted that red meat can provide a variety of important nutrients, particularly among at-risk populations. There is no reason to eliminate a food that has enormous nutritive value. In summary then, while the current research on Neu5Gc raises some interesting and important questions for future research on this unique sugar in red meat, the leap to proclaiming that it promotes inflammation or cancer at the current dietary consumption levels is an unsupported and unreasonable leap.
Roger Clemens, Dr.P.H., CFS,
Adjunct Professor, University of Southern California
School of Pharmacy, Los Angeles, Calif.