About 2 million years ago in evolutionary history, just prior to the emergence of the genus Homo, a pivotal event occurred in what was soon to become the human genetic code – inactivation of a gene called CMAH (cytidine monophosphate-N-acetylneuraminic acid hydroxylase). This gene encoded an enzyme which oversees the synthesis of a small sugar molecule called N-Glycolylneuraminic acid – Neu5GC for short. As such, Neu5GC is expressed in the bodies of most non-human mammals, but is not found naturally in humans.
Our species instead evolved to express higher levels of its precursor molecule – Neu5AC – which differs only in the placement of a single hydroxyl (OH) group added onto it by CMAH. Both are negatively charged sugar molecules called sialic acids, which decorate the surfaces of cells in the body.
Although we lack the gene which codes for its production, trace amounts of Neu5GC can still be found in many humans – in those of us who consume animal products in our diet, particularly red meats.
Deactivation of the CMAH gene is believed to confer a protective effect against certain pathogens. A type of malaria which can infect other primates, but not humans, requires an interaction with Neu5GC in order to cause disease. However, lack of CMAH may also explain the negative health effects of meat consumption.
Neu5GC, Chronic Inflammation and Human Cancer
Although it is not naturally produced in the human body, Neu5GC is detectable on the surface of human epithelial cells in meat-eaters – the cells which form a lining around all of our organs and are the most common cell type to give rise to cancer. Once it is ingested, Neu5GC can be metabolised in the human body and is incorporated into human tissues. Higher levels of this alien compound are found in cells of human cancers compared to healthy tissues. Scientists have yet to elucidate the exact pathway by which dietary Neu5GC is taken up into human tissues.
The human immune system is very good at identifying what is part of the human “self” and what is not. Anything that appears foreign, like an invading bacterium, triggers the production of antibodies which label it for destruction. When incorporated into human tissues, Neu5GC is recognised as a foreign threat, and we respond to it like we would to an infection – synthesising anti-Neu5GC antibodies in an attempt to rid it from our system. Continuous ingestion of Neu5GC and production of antibodies against it fosters a state of chronic inflammation – a state which underlies the pathogenesis of many human diseases, including our most relentless and insidious enemy – cancer.
Results from a 2014 study published in PNAS suggest that this meat-derived molecule may be to blame for the well-established red meat cancer connection. When the CMAH gene is knocked out in experimental mice to mimic the human deficiency, and then fed with Neu5GC and anti-Neu5GC antibodies, the mice develop systemic inflammation, along with a five-fold increased risk or cancer occurrence with long-term exposure (1).
Neu5GC is the first identified “xeno-autoantigen” which interacts with so-called “xeno-autoantibodies”. The prefix “Xeno” means “foreign” or “different in origin”, and “auto” means “self”. In other words, the body is producing antibodies to fight against a compound which now resides in its own cells – cells belonging to “self” – but a compound which is foreign in origin.
With continued, long-term meat consumption, these antigen-antibody complexes can promote a state of chronic inflammation known as “xenosialitis”. Neu5GC thus provides a plausible mechanism for the well known epidemiological link between red meat consumption and cancer risk, and may explain the curious human-specificity of this phenomenon.
Other common diseases such as heart disease, obesity and Type 2 diabetes, which are similarly aggravated by chronic inflammation, have also been linked to red meat consumption. Neu5GC, by stimulating a chronic inflammatory state, represents a likely offender in these diseases too. Loss of the CMAH gene in human evolution may in part explain the human-specific susceptibility to heart disease and cancer, to which other meat-eating mammals scarcely fall victim.
There is little doubt that red and processed meat consumption is a threat to human health. Evidence for a cancer link – especially colorectal cancer – is stronger than ever. The World Health Organisation – the leading international body for public health – now classifies processed meat as a Group I carcinogen (definitely causing cancer), placing it in the same category as cigarette smoking, asbestos and radon. Red meat was declared a Group IIa carcinogen (probably causing cancer).
The 2008 World Cancer Research Fund expert report lists red meat among the top 10 factors which influence cancer incidence and progression (2).
One Meat, Many Means
Numerous mechanisms have been proposed to explain the cancer-causing effects of red meat, but no single theory has been agreed upon entirely. Heterocyclic amines, N-Nitroso compounds, polycyclic aromatic hydrocarbons, heme iron and TMAO have all been under inspection. Some of these compounds are activated to cancer-causing forms through cooking processes like grilling, whereas TMAO is formed by microorganisms in the gut when we offer them a meaty meal.
All of these compounds are believed to have DNA-damaging effects, causing mutations which can lead to cancer. Epithelial cells lining the colon are understandably the most susceptible because of their proximity to the digested meal, which can hang around in the colon for several days before being excreted.
One reason why a fibre-rich diet is protective against colon cancer is because dietary fibre speeds the transit of foods through the digestive tract. Less time spent sitting around in the intestine means less contact of colonic epithelial cells to the carcinogenic substance, and less chance of it causing a harmful mutation.
Differing from other prevailing theories, Neu5GC does not directly damage colon cells – rather, it triggers systemic inflammation, suggesting that meat consumption could encourage cancer growth in organs distant from the digestive tract.
Indeed, epidemiological evidence suggests that the red meat cancer connection is not specific to the colon. Results from a large prospective cohort study published in 2018, which included more than 61,000 French men and women, reported an increased overall cancer risk, and breast cancer risk (3).
Sialic acids like Neu5GC are important participants in cancer progression beyond the theory of xenosialitis described above. Elevated levels of sialic acids are detected in cancer cells – a phenomenon called hypersialylation. The alien Neu5GC is particularly favoured over human Neu5AC on tumour cell surfaces.
Hypersialylation is believed to influence the interactions of tumour cells with other cells in their locality in a way which supports metastatic spread – enhancing their ability to migrate out of their primary site and ultimately form additional tumours in distant organs. Hypersialylation might also help cancer cells to evade protective anti-tumour immune defences, thus enhancing tumour growth and survival (4).
R.A. Weinberg’s prominent textbook, “The Biology of Cancer”, has designated Neu5GC as an “area to watch”! Though certainly a compelling theory, it remains unanswered whether circulating levels of anti-Neu5GC antibodies in fact correlate with cancer risk in human populations.
Scientists are continuing to explore the Neu5GC pathway and other emerging theories in an attempt to untangle the complex mechanisms underlying the meat cancer connection. There has been some talk of developing anti-Neu5GC therapies which would rid the molecule from our bodies, or block its entry into human cells. Pursuit of such a drug seems to me counterintuitive, considering that we could simply choose not to introduce Neu5GC into the body in the first place. At least in the meantime, it would be wise for all of us to eliminate, or at least largely reduce our red meat intake in favour of whole plant foods, which are free from Neu5GC and other threatening carcinogens.