Exit, O Sodium!

Abstract

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Since Ole H. Peterson’s 2021 editorial “When a Discovery Is a Rediscovery: Do We Know the History of Our Own Subject?” highlighted the lack of rigor in reporting historical background in research papers,^1^ the importance of proper referencing and understanding the history of our research fields has been repeatedly emphasized^2,3^ in Function. Historical distance, untimely discovery in an unreceptive environment, inaccessibility of original literature, language barriers, and/or citation bias can all contribute to obscuring readily available facts,1–  5 ultimately leading to their oblivion. Surprisingly, however, sometimes the errors are being propagated even though are visible to all.

The origins of scientific terms in biomedicine, some of which go back to the antiquity, are no less prone to being forgotten than original discoveries. For instance, it is difficult to resolve what holiness, mice, and fish have in common with the sacral bone (os sacrum—the “holy” bone),^6^ muscle (musculus—a little mouse),^7^ or the big toe—hallux (supposedly originating from hal(l)ex, hal(l)ec, or al(l)ec—a fish sauce in ancient Rome),^7^ respectively. Given the uncertain origins of these terms, contradictory interpretations, such as that of the name of the saphenous vein, which could mean both the obvious and the hidden vein,^8^ are hardly surprising. However, it is less clear why recent, well-documented scientific coinages should be misinterpreted and almost completely replaced by wrong forms.

A low intracellular concentration of Na^+^ and a high intracellular concentration of K^+^ is a fundamental characteristic of living cells. In animal cells, asymmetric ion distribution is maintained by an Na^+^-K^+^ pump,9–  12 a P-type ATPase that catalyses the reaction: ATP + H_2_O + 3Na^+^(in) + 2K^+^(out) → ADP + P_i + 3Na^+^(out)_ + 2K^+^(in).^13,14^ In yeast and protists, an Na^+^-K^+^ pump does not exist, and it was long assumed that an H^+^ pump, a V-type ATPase, is primarily responsible for actively maintaining ion gradients.^15^ However, in 1991, a new putative P-type ATPase, which is now known to catalyse the reaction ATP + H_2_O + Na^+^(in) → ADP + P_i + H^+^ + Na^+^(out)_,^16–^  ^19^ was described in Saccharomyces cerevisiae.^15^ Clearly, the yeast also possessed a primary active Na^+^ extrusion system! In the classical tradition, the gene encoding the newly described ATPase was promptly named ENA1 from exitus natrii,^15^ meaning the exit of sodium. Later, other related ATPases were described, and it is now evident that there is a family of Na^+^-extruding ATPases20–  22 that transport Na^+^ in fungi,^15^ protists,^23^ and plants.^16^

The official gene names, which unambiguously denote a single, specific gene, are frequently abbreviations (eg, GAPDH) of the name of the encoded protein (eg, glyceraldehyde-3-phosphate dehydrogenase). However, in cases such as ENA1, the link between the name of the gene (ENA1) and the encoded protein (sodium/potassium exporting P-type ATPase 1) is not obvious. Indeed, the name of the gene ENA1 does not make any intuitive sense unless the history of its discovery is known. While the acronym ENA1 caught on quickly, the Latin phrase exitus natrii, from which it originated, was mentioned only occasionally,24–  26 but was typically not referred to in research papers for nearly 20 yr27–  30 after its discovery.^15^ In a reverse trend, the acronym is often explained in more recent sources, possibly to explain why a gene for a sodium P-type ATPase (a sodium pump) was called ENA1.

Interestingly, however, exitus natrii has been wrongly, but consistently, transmuted into exitus natru in sources ranging from research papers and reviews^20^,31–  44 to student theses,45–  61 books,^62,63^ encyclopedias (eg, Na^+^-ATPase in Protozoan Parasites | Encyclopedia MDPI), and even genome and other online databases (eg, Saccharomyces Genome Database, BioCyc Pathway/Genome Database Collection, YeastPhenome.org, Alliance of Genome Resources, and Pathway Genome Databases of Agriculturaly Important Bacteria Sequenced by the USDA). A simple Google search returns hundreds of hits for ^“^exitus natru,^”^ but only a couple for “exitus natrii.” The use of exitus natru instead of exitus natrii is so pervasive that it even appears in abstracts of various research papers.^20,32,41^

Exitus natru is usually explained as meaning the exit of sodium, implying that natru is the genitive. However, natrium, the Neo-Latin for sodium, follows the second Latin declension (neuter):

In accordance with this convention, PubChem, an open chemistry database at the National Institutes of Health (NIH), uses natrii in the Latin names of over 300 sodium compounds and substances, while natru does not occur once in this context. Obviously, the exit of sodium should be translated into Latin as exitus natrii as written by the discoverers of ENA.^15^ The origin of natru in the scientific literature is therefore unclear. It is possible that it derives from the closely related classical term nitrum, meaning soda. Nitrum was derived from the ancient Greek νίτρον, whose genitive is νίτρου (pronounced nitru), which is similar to natru. However, nitrum is not a synonym for sodium, so such a usage would be difficult to justify. And even if it were, the correct form would be exitus nitru not exitus natru. On the other hand, the particular type of the italic font used in the original publication yields ii, which look almost exactly like u,^15^ suggesting that natrii may simply have been misread as natru.

In a further twist, exitus natru is sometimes explained as “exit sodium,”^31,34,38,41,45,47,49,50,57,58,63^ which would make exitus a verb (an imperative) and by extension natru a vocative (O sodium!). The latter translation would certainly have amused Winston Churchill, who, in his memoir My Early Life,^64^ wittily described the bewilderment at having to learn the vocative of the first Latin declension:

ChatGPT also seems to know Latin very well. When asked what exitus natrii means, it replies that “‘Exitus natrii’ translates to ‘exit of sodium’ in English.” In contrast, ChatGPT claims: “The phrase ‘exitus natru’ itself doesn’t seem to correspond directly to a known Latin expression or word.” When asked again about the meaning of the word natru, ChaptGPT insists: “As of my last knowledge update in January 2022, ‘natru’ doesn’t appear to be a recognized Latin word.”

Bioscientific and medical terminology is full of mythological, even somewhat mystical expressions of uncertain origin. (One needs to go no further than pondering what is so sacred about the sacral bone.) Without wishing to pass judgment on the plausibility of anyone wanting to address sodium, exitus is a noun, meaning exit, and therefore clearly cannot be used to command sodium to exit the cell. The imperative of the verb exire (ie, to exit) is exi (ie, exit!), while the correct vocative case of natrium is natrium. “Exit, O sodium!” would therefore be translated as exi, natrium. Maintaining a low intracellular sodium concentration may be an imperative for every living cell, but the Latin imperative was obviously not used to denote ENA.

To dissect linguistic errors, to which we are admittedly all prone, could be seen as an overzealous pedantry. After all, it is just a wrong word. Has that ever done any harm? Nevertheless, we believe that the case of exitus natru, although innocuous in itself, highlights a larger problem. Firstly, although the correct term exitus natrii appears in the original 1991 paper on ENA1  ^15^, the paper continues to be misquoted, which appears to suggest that what is quoted is not necessarily always read. Secondly, exitus natru, although incorrect for linguistic reasons, continues to find its way into publications. While bioscientists are not required to use Latin and ancient Greek, nor are they expected to be familiar with the intricacies of their vocabulary and grammar, it is surprising that linguistic errors have not been detected at various stages of the publication process.

That a new term that has drifted away from its original form should take precedence in contemporary literature is hardly surprising. Since the language of life sciences is a dynamic, living entity, it has always been subject to the evolution of existing terms and a constant influx of neologisms. For example, the term natrium, for which there is no original ancient equivalent, was first coined by Berzelius in the 1800s.^65^ Moreover, the persistent use of corrupted or incorrect forms often prevails and becomes generally accepted, as an old maxim “usus (est) tyrannus” (ie, custom is a tyrant) nicely sums up. Exitus natru could therefore be here to stay. In this case, however, it should at least be recognized that exitus natru does not stand for the exit (of) sodium in standard Latin. An alternative etymology of natru, which we may have inadvertently overlooked, would also be appreciated.

Researchers might perceive ourselves as critical seekers after truth, forming our opinions exclusively on the basis of objective experimental data and their continuous critical (re)appraisal. However, when a word that is not only misquoted but also grammatically incorrect spreads through the scientific literature with such apparent ease, we should pause and ask ourselves whether something similar happens, at least occasionally, not only to the misperceptions of the histories of our research fields but also to the misinterpretations of research data that we all so cherish.