The Enigmatic Metallothioneins: A Case of Upward-Looking Research

Abstract

In the mid-1950s, Bert Lester Vallee and his colleague Marvin Margoshes discovered a molecule referred to today as metallothionein (MT). Meanwhile, MTs have been shown to be common in many biological organisms. Despite their prevalence, however, it remains unclear to date what exactly MTs do and how they contribute to the biological function of an organism or organ. We investigate why biochemical research has not yet been able to pinpoint the function(s) of MTs. We shall systematically examine both the discovery of and recent research on Dr. Vallee’s beloved family of MT proteins utilizing tools from philosophy of science. Our analysis highlights that Vallee’s initial work exhibited features prototypical of a developing research tradition: it was upward-looking, exploratory, and utilized mere interactions. Since the 1960s, MT research has increasingly become intervention- and hypothesis-based while it remained largely upward-looking in character. Whilst there is no reason to think that upward-looking research cannot successfully yield structure-function mappings, it has not yet been successful in the case of MTs. Thus, we suggest it might be time to change track and consider other research strategies looking into the evolution of MTs. Recent studies in mollusks render research in this direction worthy of pursuit.

The Bioinorganic Chemistry of Mammalian Metallothioneins

“…The necessity to pursue investigations about the origin of MTs has been pointed out. 448 An answer to this question imposes constraints on the myriad of causal functions and distinguishes a proper function from an accidental or adventitious function, an issue that is critically important when analyzing the many functions proposed for MTs. Molecular biologists conceive of function as specific, coordinated activities that serve a purpose.…”

“…It is linked to teleology: Why was the part selected in evolution? The necessity to pursue investigations about the origin of MTs has been pointed out . An answer to this question imposes constraints on the myriad of causal functions and distinguishes a proper function from an accidental or adventitious function, an issue that is critically important when analyzing the many functions proposed for MTs.…”

Bert Vallee—A 20th Century Adventure(r) in Zincology

“…In this Special Issue, Abdin et al therefore revisit the discovery of metallothionein (MT) from the angle of philosophy of science to provide a clear historical and contemporary summary of research conducted on MT by Bert Vallee and his colleagues [20]. In their manuscript, the authors from natural sciences and philosophy join forces to analyse the research conducted on MTs.…”

“…In their manuscript, the authors not only try to disambiguate a 60 year-old question about the function of MTs [20], they also pose the question whether traditional mechanistic explanations are sufficient or indeed exclusive in modern science. Alternative explanations, such as teleological explanations dealing with a specific function or purpose of a protein within a wider physiological context, may at first glance seem antiquated.…”

Metallothionein 2A with Antioxidant and Antitumor Activity Is Upregulated by Caffeic Acid Phenethyl Ester in Human Bladder Carcinoma Cells

“…Metallothioneins (MTs), initially identified from a horse kidney cortex in 1957, are a group of small cysteine-rich proteins [ 1 ]. Four main gene subfamilies of MTs (metallothionein 1 [ MT1 ], metallothionein 2A [ MT2 A ], metallothionein 3 [ MT3 ], and metallothionein 4 [ MT4 ]) are expressed in humans, and a cluster of MT genes is located on the chromosome 16q12-22 [ 2 , 3 ]. MTs were exploited as bio-environmental markers for predicting heavy metal contamination due to the nature of metal binding [ 4 , 5 ].…”