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"Varki, Ajit"
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Denial : self-deception, false beliefs, and the origins of the human mind
Describes why humans are able to deny reality and ignore their own inevitable deaths to the detriment of the entire species and what might be done to change this mindset.
Book
Glycan-based interactions involving vertebrate sialic-acid-recognizing proteins
All cells in nature are covered by a dense and complex array of carbohydrates. Given their prominence on cell surfaces, it is not surprising that these glycans mediate and/or modulate many cellular interactions. Proteins that bind sialic acid, a sugar that is found on the surface of the cell and on secreted proteins in vertebrates, are involved in a broad range of biological processes, including intercellular adhesion, signalling and microbial attachment. Studying the roles of such proteins in vertebrates has improved our understanding of normal physiology, disease and human evolution.
Journal Article
Uniquely human evolution of sialic acid genetics and biology
Darwinian evolution of humans from our common ancestors with nonhuman primates involved many gene-environment interactions at the population level, and the resulting human-specific genetic changes must contribute to the \"Human Condition.\" Recent data indicate that the biology of sialic acids (which directly involves less than 60 genes) shows more than 10 uniquely human genetic changes in comparison with our closest evolutionary relatives. Known outcomes are tissue-specific changes in abundant cell-surface glycans, changes in specificity and/or expression of multiple proteins that recognize these glycans, and novel pathogen regimes. Specific events include Alu-mediated inactivation of the CMAH gene, resulting in loss of synthesis of the Sia N-glycolylneuraminic acid (Neu5Gc) and increase in expression of the precursor N-acetylneuraminic acid (Neu5Ac); increased expression of α2-6-linked Sias (likely because of changed expression of ST6GALI); and multiple changes in SIGLEC genes encoding Sia-recognizing Ig-like lectins (Siglecs). The last includes binding specificity changes (in Siglecs -5, -7, -9, -11, and -12); expression pattern changes (in Siglecs -1, -5, -6, and -11); gene conversion (SIGLEC11); and deletion or pseudogenization (SIGLEC13, SIGLEC14, and SIGLEC16). A nongenetic outcome of the CMAH mutation is human metabolic incorporation of foreign dietary Neu5Gc, in the face of circulating anti-Neu5Gc antibodies, generating a novel \"xeno-auto-antigen\" situation. Taken together, these data suggest that both the genes associated with Sia biology and the related impacts of the environment comprise a relative \"hot spot\" of genetic and physiological changes in human evolution, with implications for uniquely human features both in health and disease.
Journal Article
Sialic acid–binding immunoglobulin-like lectins (Siglecs) detect self-associated molecular patterns to regulate immune responses
The mammalian immune system evolved to tightly regulate the elimination of pathogenic microbes and neoplastic transformed cells while tolerating our own healthy cells. Here, we summarize experimental evidence for the role of Siglecs—in particular CD33-related Siglecs—as self-receptors and their sialoglycan ligands in regulating this balance between recognition of self and non-self. Sialoglycans are found in the glycocalyx and extracellular fluids and matrices of all mammalian cells and can be considered as self-associated molecular patterns (SAMPs). We also provide an overview of the known interactions of Siglec receptors and sialoglycan-SAMPs. Manipulation of the Siglec-SAMP axis offers new therapeutic opportunities for the treatment of inflammatory conditions, autoimmune diseases and also cancer immunotherapy.
Journal Article
Multiple changes in sialic acid biology during human evolution
Humans are genetically very similar to “great apes”, (chimpanzees, bonobos, gorillas and orangutans), our closest evolutionary relatives. We have discovered multiple genetic and biochemical differences between humans and these other hominids, in relation to sialic acids and in Siglecs (Sia-recognizing Ig superfamily lectins). An inactivating mutation in the CMAH gene eliminated human expression of N-glycolylneuraminic acid (Neu5Gc) a major sialic acid in “great apes”. Additional human-specific changes have been found, affecting at least 10 of the <60 genes known to be involved in the biology of sialic acids. There are potential implications for unique features of humans, as well as for human susceptibility or resistance to disease. Additionally, metabolic incorporation of Neu5Gc from animal-derived materials occurs into biotherapeutic molecules and cellular preparations - and into human tissues from dietary sources, particularly red meat and milk products. As humans also have varying and sometime high levels of circulating anti-Neu5Gc antibodies, there are implications for biotechnology products, and for some human diseases associated with chronic inflammation.
Journal Article
Diversity in cell surface sialic acid presentations: implications for biology and disease
Sialic acids (Sias) are typically found as terminal monosaccharides attached to cell surface glycoconjugates. They play many important roles in many physiological and pathological processes, including microbe binding that leads to infections, regulation of the immune response, the progression and spread of human malignancies and in certain aspects of human evolution. This review will provide some examples of these diverse roles of Sias and briefly address immunohistochemical approaches to their detection.
Journal Article
From “Serum Sickness” to “Xenosialitis”: Past, Present, and Future Significance of the Non-human Sialic Acid Neu5Gc
The description of \"serum sickness\" more than a century ago in humans transfused with animal sera eventually led to identification of a class of human antibodies directed against glycans terminating in the common mammalian sialic acid
Glycolylneuraminic acid (Neu5Gc), hereafter called \"Neu5Gc-glycans.\" The detection of such glycans in malignant and fetal human tissues initially raised the possibility that it was an oncofetal antigen. However, \"serum sickness\" antibodies were also noted in various human disease states. These findings spurred further research on Neu5Gc, and the discovery that it is not synthesized in the human body due to a human-lineage specific genetic mutation in the enzyme
. However, with more sensitive techniques Neu5Gc-glycans were detected in smaller quantities on certain human cell types, particularly epithelia and endothelia. The likely explanation is metabolic incorporation of Neu5Gc from dietary sources, especially red meat of mammalian origin. This incorporated Neu5Gc on glycans appears to be the first example of a \"xeno-autoantigen,\" against which varying levels of \"xeno-autoantibodies\" are present in all humans. The resulting chronic inflammation or \"xenosialitis\" may have important implications in human health and disease, especially in conditions known to be aggravated by consumption of red meat. In this review, we will cover the early history of the discovery of \"serum sickness\" antibodies, the subsequent recognition that they were partly directed against Neu5Gc-glycans, the discovery of the genetic defect eliminating Neu5Gc production in humans, and the later recognition that this was not an oncofetal antigen but the first example of a \"xeno-autoantigen.\" Further, we will present comments about implications for disease risks associated with red meat consumption such as cancer and atherosclerosis. We will also mention the potential utility of these anti-Neu5Gc-glycan antibodies in cancer immunotherapy and provide some suggestions and perspectives for the future. Other reviews in this special issue cover many other aspects of this unusual pathological process, for which there appears to be no other described precedent.
Journal Article
Human species-specific loss of CMP-N-acetylneuraminic acid hydroxylase enhances atherosclerosis via intrinsic and extrinsic mechanisms
Cardiovascular disease (CVD) events due to atherosclerosis cause one-third of worldwide deaths and risk factors include physical inactivity, age, dyslipidemia, hypertension, diabetes, obesity, smoking, and red meat consumption. However, ∼15% of first-time events occur without such factors. In contrast, coronary events are extremely rare even in closely related chimpanzees in captivity, despite human-like CVD–risk-prone blood lipid profiles, hypertension, and mild atherosclerosis. Similarly, red meat-associated enhancement of CVD event risk does not seem to occur in other carnivorous mammals. Thus, heightened CVD risk may be intrinsic to humans, and genetic changes during our evolution need consideration. Humans exhibit a species-specific deficiency of the sialic acid N-glycolylneuraminic acid (Neu5Gc), due to pseudogenization of cytidine monophosphate-N-acetylneuraminic acid (Neu5Ac) hydroxylase (CMAH), which occurred in hominin ancestors ∼2 to 3 Mya. Ldlr
−/− mice with human-like Cmah deficiency fed a sialic acids (Sias)-free high-fat diet (HFD) showed ∼1.9-fold increased atherogenesis over Cmah wild-type Ldlr
−/− mice, associated with elevated macrophage cytokine expression and enhanced hyperglycemia. Human consumption of Neu5Gc (from red meat) acts as a “xeno-autoantigen” via metabolic incorporation into endogenous glycoconjugates, as interactions with circulating anti-Neu5Gc “xeno-autoantibodies” potentiate chronic inflammation (“xenosialitis”). Cmah
−/−
Ldlr
−/− mice immunized with Neu5Gc-bearing antigens to generate human-like anti-Neu5Gc antibodies suffered a ∼2.4-fold increased atherosclerosis on a Neu5Gc-rich HFD, compared with Neu5Ac-rich or Sias-free HFD. Lesions in Neu5Gc-immunized and Neu5Gc-rich HFD-fed Cmah
−/−
Ldlr
−/− mice were more advanced but unexplained by lipoprotein or glucose changes. Human evolutionary loss of CMAH likely contributes to atherosclerosis predisposition via multiple intrinsic and extrinsic mechanisms, and future studies could consider this more human-like model.
Journal Article
A red meat-derived glycan promotes inflammation and cancer progression
A well known, epidemiologically reproducible risk factor for human carcinomas is the long-term consumption of “red meat” of mammalian origin. Although multiple theories have attempted to explain this human-specific association, none have been conclusively proven. We used an improved method to survey common foods for free and glycosidically bound forms of the nonhuman sialic acidN-glycolylneuraminic acid (Neu5Gc), showing that it is highly and selectively enriched in red meat. The bound form of Neu5Gc is bioavailable, undergoing metabolic incorporation into human tissues, despite being a foreign antigen. Interactions of this antigen with circulating anti-Neu5Gc antibodies could potentially incite inflammation. Indeed, when human-like Neu5Gc-deficient mice were fed bioavailable Neu5Gc and challenged with anti-Neu5Gc antibodies, they developed evidence of systemic inflammation. Such mice are already prone to develop occasional tumors of the liver, an organ that can incorporate dietary Neu5Gc. Neu5Gc-deficient mice immunized against Neu5Gc and fed bioavailable Neu5Gc developed a much higher incidence of hepatocellular carcinomas, with evidence of Neu5Gc accumulation. Taken together, our data provide an unusual mechanistic explanation for the epidemiological association between red meat consumption and carcinoma risk. This mechanism might also contribute to other chronic inflammatory processes epidemiologically associated with red meat consumption.
Journal Article