Using metaphorical considerations to benefit research on the sodium channel fast inactivation mechanism

Despite the prevalence of metaphor in scientific discourse, natural scientists are rarely trained explicitly in its uses or effects. This article outlines the benefits of the deliberate integration of metaphorical considerations into scientific research and teaching. Several fundamental features of metaphor are explained and some of its key uses in the natural sciences are introduced. Accessible examples from the life sciences are used for illustration throughout, and, although citations of the literature on metaphor theory are included to facilitate further reading on the part of the interested reader, no prior knowledge of linguistic theory or its terminology is required to follow this article.

At its core, metaphor explains one thing by equating it to another, as in the example sentence below:

• CRISPR–Cas9 is a pair of scissors for cutting DNA.

Taken literally, this sentence is either nonsensical or simply untrue. As such, a reader must interpret meaning into it. That is to say, that it is primarily the reader, not the author, who defines the meaning attributed to a metaphorical statement. Indeed, there are myriad ways in which this same metaphorical statement could be understood (CRISPR–Cas9 is composed of two interacting parts, divides things in specific places, is directed by a human user, etc.) and it is therefore entirely possible that the same sentence be understood to mean a variety of different things by different people, or even by the same person at different times or in different contextual settings (Hart, 2014). This is not to say that the statement’s author does not intend to convey a specific meaning, simply that those that are understood are not restricted to it.

It is not necessarily the case that a reader is consciously aware of this process of meaning attribution. Rather, from a reader’s perspective, the meaning interpreted into many metaphorical statements arises naturally, almost effortlessly and involuntarily. Consider, as examples, the commonplace statements below:

• Biology is a branch of science.

• Ion channel research is a field of biology.

If I asked a sample of readers to explain precisely what they understood each of these sentences to mean, there would be significant overlap in interpretation, but also a considerable amount of discrepancy (e.g., in what exactly constitutes a scientific field or where precisely the boundaries of a branch of science lie). This process of identifying and assigning our own meanings to metaphor is so commonplace and intuitive to us that multiple metaphors, each with its own diverse set of interpretations, can be combined in a single statement and still be understood almost effortlessly as meaningful, as in the example below:

• Ion channel research is a branch of the field of biology.

In this case, not only must readers construct independent interpretations of the metaphorical terms field and branch, but they must implicitly accept the claim that fields can have branches and interpret what that means as well.

To complicate matters further, indirect metaphors are also widespread in scientific discourse. For example, each of the everyday sentences below is literally untrue or nonsensical and requires a metaphorical understanding of the highlighted terms in order to be meaningful, without explicitly equating two phenomena via the verb “to be”:

• The virus invades the host. (equating a virus with a military force)

• The population rises. (equating a number and a physical object)

• The bacterium prefers warm environments. (equating the bacterium with a human)

The combination of the factors discussed above means that metaphor can be extremely diverse in its manifestation and interpretation. Despite this, most of us are so used to engaging in metaphorical discourse that we can both create and interpret considerable metaphorical complexity without experiencing any difficulty or, indeed, necessarily even realizing that we are using metaphors at all (Dreyfus et al., 2015).

Consider, as an example, the passage below on mRNA vaccines, taken from the official press release accompanying the 2023 Nobel Prize in Physiology or Medicine:

Understanding the terms marked in bold in just this short example text depends upon a number of common metaphorical relations, outlined in Table 1, some of which you may previously have used yourself and not consciously thought of as metaphors until reading this article.

As well as interpreting the individual metaphors listed above, a reader must understand them in combination. For example, a reader must interpret what it might mean for something that takes off to be hindered by roadblocks (not normally something astronauts or pilots are concerned with).

Note also that this extract, which averages more than two metaphors per line, is not taken from an obscure literary novel or a poem intended for a small audience of linguists and students of literature. Rather, it is taken from a text written by one of the world’s most highly respected scientific institutions for the explicit purpose of conveying a specific development in biological research to a large global audience consisting of both technical experts and laypeople.

Given that metaphor is literally false, can be interpreted to mean any number of things to any number of people, is not necessarily interpreted the way it is intended, and can be variously interpreted in combination with other components of a statement, it is reasonable to ask how it can function as an effective means of communication at all. Addressing this issue is the goal of the next section.

Metaphor does not attempt to convey literal truth. Consider the common biological metaphor below:

• DNA is a blueprint.

Literally, a blueprint is physically form-independent, meaning it can appear on paper, on a computer screen, or carved into a rock, is the product of a deliberate, conscious set of design decisions, and is exclusively created and readable by humans (or machines programmed by humans). DNA, by contrast, has a specific physical form, has largely arisen entirely non-deliberately and unconsciously, and was not even known to humans until relatively recently. As such, the statement above is not even approximately literally true and anyone interpreting it as being literally the case would be adjudged to have drastically misunderstood it.

However, despite its lack of literal truth, this statement is understandable, so much so that it is used as an explanation throughout the world’s scientific education systems. A pertinent question at this stage is, therefore, how a metaphor conveys useful, valid meaning without being true. The answer lies in the way metaphors make us think.

This explanation began by stating that metaphors equate one thing with another. We can now add to this statement by recognizing that metaphorically equating concepts does not involve a literal claim based on actual similarity. Consider the examples below:

• The brain is a computer.

• The computer is a brain.

Whilst the first statement is common, the second is rare, if it occurs at all. In this sense, metaphors are directed, describing one phenomenon in terms of another, but not the other way around. The utility of this directedness becomes apparent upon consideration of the types of ideas related via metaphor. Several concepts appearing in example metaphors so far in this article are listed in Table 2:

Some of the items in the left column lie outside direct human experience, as is the case for DNA and CRISPR–Cas9, both of which are far too small for us to detect or interact with directly through our senses, or the brain, which, for the vast majority of the population, is known to exist, but never directly physically accessible. Indeed, although we all have brains and use them continuously, their inner workings are largely a mystery to us. The other two terms, biology and ion channel research, are intangible, purely abstract objects entirely inaccessible to the senses.

By contrast, all of the terms in the right column represent common, concrete, physically tangible objects, which are directly accessible to the senses. Even if a person rarely sees a blueprint, they are likely to know what it is and have extensive experience of other diagrams, drawings, and writing combined to represent spatial information.

More generally, metaphor allows us to reconceptualize the unfamiliar, intangible, and abstract directly in terms of familiar, accessible, and concrete phenomena, which we already understand in detail and can comprehend, relate to, and mentally manipulate much more easily. Taking the DNA is a blueprint metaphor as an example, consider how easy it is to imagine reading a diagram off a piece of paper in comparison to trying to imagine what that same information would physically look like in actual DNA. The directedness of metaphor means we do not have to concern ourselves with whether this reconceptualization is clear if applied the other way around and, as metaphors do not have to be true to be valid, we are able to combine them in literally incompatible or even contradictory ways without issue, as in the example below:

• DNA is a pair of chains and a blueprint for life.

We have now arrived at the answer to the question posed at the end of the previous section, namely that metaphor functions not by conveying truth in a literal sense (DNA is not composed of chains and no chain is a blueprint), but rather by helping us to think about unfamiliar, inaccessible, and abstract concepts more intuitively and easily by equating them to familiar, accessible, concrete ones. As Behn puts it; “They are valuable to scientists not because they represent reality, but because they help scientists think.” (Behn, 1992).

Science requires us to create and develop models of complex, difficult-to-access, and sometimes strongly counterintuitive phenomena in terms which we can understand, manipulate, and communicate easily. As established in the previous section, this is something metaphor is well-adapted to do. Hence, for example, biologists discuss genetics in terms of language, with translation, transcription, and codes, chemists describe atoms as if they were animals, separating them into species and families, and the quantum behavior of molecules is discussed by physicists in terms of manmade structures, such as wells, barriers, and tunnels.

Consider, for example, the role metaphor has played in the development of the atomic theory of matter, which underpins much of what we understand in modern biology. Since the early 19th century, the atomic model has progressed from Dalton’s simple solid sphere to the plum pudding, then the planetary/solar system model before its reconfiguration to include first discrete electron shells and later probability clouds. These metaphorical reconceptualizations of the atom constitute a sequence of responses to new empirical findings and have served to refine the atomic model in a straightforward, tangible, and intuitively accessible way each time the existing paradigm has been called into question.

These metaphors were explicitly constitutive elements of the thought processes of, for example, Bohr and Schrödinger (Burwell, 2018), as they sought to interpret and understand what it was that their groundbreaking experimental findings meant for our understanding of the atom. These same metaphors have in turn allowed successive generations of researchers and students a simple way to conceptualize the structure of matter as well as grapple with the key questions they raise, such as how the charge is distributed within an atom or how electrons can form chemical bonds, all without the need for technical data, jargon, or access to expensive equipment.

Metaphors and the models of which they form an essential part enable novel perspectives and conceptualizations to emerge as they are interpreted and reinterpreted. Over time, they may be used to generate hypotheses and pose research questions, the exploration of which may in turn require the metaphors’ further adaptation to accommodate new evidence emerging from the laboratory or the field, as visualized in Fig. 1.

Having established a general understanding of the mechanisms of scientific metaphor, this article now moves on to a detailed discussion of its productive application to the sodium channel fast inactivation (FI) mechanism.

Whilst a considerable amount of information is available on the structures surrounding sodium channels (Fig. 2), as well as their functions and roles in the cell, the exact nature of the sodium channel FI mechanism remains unclear. The complexity of the physical structure of these channels is such that a range of visualizations and models exists, each complex in its own right and highlighting a different aspect of its character.

In addition, each of these models requires technical expertise to produce, understand, and manipulate as well as being heavily reliant on visual information, meaning none of them is easy to express in spoken or written form. This makes discussion and manipulation of such models inherently cumbersome as well as exclusive to a relatively small audience of technical experts. As such, sodium channels, and the FI mechanism in particular, constitute precisely the kind of complex, sensorily inaccessible phenomena suited to metaphorical description.

The primary function of the sodium channel is to allow sodium ions to pass through the membrane and enter the cell. It opens in response to changes in voltage across the cell membrane, and the structural basis of this activation gate has been described in detail (Catterall, 2023; Körner and Lampert, 2020). A few milliseconds after opening, the channel is closed again via the FI mechanism. The three amino acids constituting the IFM motif are known to play a crucial role in this, binding to the IFM pocket and initiating a process within the channel, which stops the ion flow. In light of recent structural data, the mechanism underlying this process is currently under investigation and a suitable description is being sought.

Indeed, attempts have been made to provide simple mechanical metaphors for the FI mechanism, with the ball-and-chain (Armstrong and Bezanilla, 1977), hinged lid (Goldin, 2003), and, more recently, the door wedge (Li et al., 2021), most often used in the literature (Fig. 3). However, several aspects of the structural gating mechanism are not considered. In particular, the emergence of new empirical data indicating that the IFM binding pocket is potentially located at a considerable distance from the opening of the channel and the identification of a dual ring-like structure at the channel’s intracellular opening (Liu et al., 2023) poses challenges to each of the metaphorical descriptions listed above.

Ideally, a metaphor intended to convey the current state of knowledge of the FI mechanism, as well as open avenues for new discoveries, would reflect certain structural features. FI only occurs after the channel is activated by voltage and during its permeation by sodium ions, which it halts via a mechanism located close to the intracellular side of the pore. Three amino acids, I, F, and M, form the IFM motif crucial to this mechanism (the “ball” in the “ball-and-chain” metaphor). While the IFM is located on a relatively mobile part of the intracellular side of the channel, its binding pocket is located at some distance from the permeation pathway, on the outside of the channel’s pore.

Such a metaphor would also imbed the molecular mechanism in a broader physiological context in which sodium channel FI is necessary to allow the action potential of a nerve fiber to end within milliseconds, thereby allowing rapid bodily reactions e.g. to painful stimuli. Malfunctioning FI, which fails to initiate a series of nociceptive signals, can result in debilitating, chronic pain disorders.

This paper proposes a systematic approach to applying metaphorical thinking to the FI mechanism, stripping down its complexity to provide an intuitive and easily explained way to conceptualize it.

The FI mechanism can be divided into two constituent parts, namely the mechanism at the intracellular mouth of the channel and the link between that mechanism and the IFM/pocket. A schematic representation is given in Fig. 4.

This analysis adopts this division and explores metaphorical approaches to describing both components. However, before doing so, it is necessary to consider how metaphorical considerations of the FI mechanism may be impacted by two established metaphors, namely the channel and the gate. Both of these terms have proven highly successful in facilitating understanding of the structures they describe and are deeply ingrained in the terminology and literature of the subject. Nonetheless, assumptions about the nature of these structures may stem from their typical conceptualization as channels and gates. For example, a physical channel, such as a riverbed or a canal, typically has fixed, or only very slowly changing, location, shape, and dimensions. Equally, a gate normally has a fixed shape and is used to close a specific opening by blocking it fully.

However, there are also many other ways an opening can be sealed. For example, constriction or compression of the channel walls could reduce the size of the mouth of the channel and make it impassable, just as the pull string of a bag stops things falling out of it or a clamp applied to a capillary stops the flow of blood. Equally, the configuration or shape of the channel walls could change, making the sodium ions the equivalent of round pegs unable to pass through a square hole. This would make the mouth of the channel impassable to sodium ions, without the need to posit a separate object, such as a ball or lid, to close it.

Recent research suggests that there may be “leaky” states in which some sodium ions pass through the channel despite the gate being closed (Liu et al., 2023). It is difficult to imagine how this would be possible if the channel were fully plugged by a ball, whereas it is much more intuitively easy to imagine, for example, a partially constricted opening slowing the flow of ions, but not stopping it entirely. An integral part of metaphors such as the gate or ball-and-chain is that they allow a fixed channel to be in one of the two states, closed or open. Other metaphors may, however, be more appropriate in allowing a gradation or variety of states to exist and be “open” to varying degrees or in different ways.

Other mechanisms may also be considered in relation to the two rings at the mouth of the channel, described by Liu et al. (2023). For example, there are a number of ways in which a relative movement of these rings, such as a lateral offset introducing a kink in the channel, could make the mouth of the channel impassable to sodium ions, without the need to posit an external object to block it. Equally, there may be parts of the channel that can be allowed to move or be immobilized, similar to applying the brake to a water wheel or the rotating shaft of a screw compressor.

Fundamentally, it is worthwhile to ask questions such as “How gate-like is the gate?” and “Which characteristics of a channel does the opening in the membrane actually exhibit?” One major advantage of metaphorical reconceptualization is that it both requires and facilitates the reexamination of such implicit assumptions as the fixed shape of the channel and the separate nature of the gate, which may otherwise unintentionally mask or exclude potentially fruitful lines of inquiry.

As well as modeling the mechanism at the mouth of the channel, its connection to the IFM pocket is to be considered and, ideally, described as part of the same metaphor. Empirical evidence has been found (Li et al., 2021) that the IFM pocket lies at a considerable distance from the mouth of the channel, posing problems for previously proposed metaphors such as the hinged lid, as it fails to incorporate this separation or provide a mechanism for how the motion of the IFM into the pocket leads to a change at the distant gate mouth.

At its heart, this link constitutes a way for a movement by one component, the IFM, to induce action at a distance via a single, direct connection. The ball-and-chain attempts this but is challenged by several issues, such as a lack of clarity about the location of the ball during the active and inactive states.

Various ways of using a relatively small motion of one component to produce movement in another component at a distance arise in everyday contexts. Examples include mechanical systems such as pulling a bicycle brake, flicking an electrical switch to turn on a fan, and employing hydraulics to pump up a paddling pool. These three familiar activities involve direct mechanical forces, electrical signals, and fluid dynamics, respectively, as the mechanisms of transmission between the moving components. Each of these in turn represents a potentially useful source of metaphors relating to how the link between the IFM pocket and channel functions and it may be fruitful to consider metaphors not restricted to purely mechanical means of transmission.

One, often productive, approach to identifying new metaphors for scientific phenomena is not to look at the complex technical detail of the structures being described, but at the functions they perform and seek familiar systems with similar functions in the world around us. For example, the flushing mechanism of a Western-style sitting toilet constitutes a familiar, intuitively manipulable, and widespread technology involving action at a distance, the release of a flow across a defined boundary, and a mechanism for stopping that flow again a short time later (Fig. 5).

Structural and functional parallels between this mechanism and that of sodium channel FI exist, allowing metaphorical relationships such as those listed in Table 3 to be considered.

In this example, the handle is the IFM, the connection between the handle and plug is the link, and the plug is the channel-closing mechanism. However, as metaphors can be mixed and combined in novel ways, the metaphor can be adapted to reflect different understandings of its component parts. For example, the mechanical handle mechanism can be exchanged for an electrical switch or a motion sensor. Such changes can be incorporated into the metaphor without loss of understandability and comparing or contrasting various such conceptualizations can often provide insight in its own right.

Indeed, due to the clear distinction between the individual components in this metaphor, it is possible to posit entirely different mechanisms for each of them while maintaining the broader metaphor with no loss of clarity. As such, the valve could be described as a hinged, ball-shaped lid attached to a chain, if combining existing metaphors familiar to the reader to assist in facilitating a shift in understanding were a priority. Alternatively, if it were desirable to model the mechanism as a relative motion of the two rings at the channel’s inner mouth, the valve could be described, for example, as an iris aperture similar to a camera lens, or as a bottle’s screw top. As Wilczek puts it; “No one perspective exhausts reality, and different perspectives may be valuable, yet mutually exclusive.” (Wilczek, 2015).

Whilst no such metaphorical construct is a perfect description and each has its specific limitations, such as how universally familiar or intuitively compatible given technologies may be, the flexibility of such combinations is one of metaphor’s major strengths as an explanatory and conceptual tool. Indeed, although familiarity and tangibility are foundational components of metaphorical description, metaphorical scaffolds are not restricted to the real or even the possible. It is perfectly acceptable, as with blueprints made of chains or fields with branches, to mix metaphorical terms in ways not possible to recreate in the real world and still find significant explanatory or conceptual value in them.

The familiar phenomena utilized by metaphors do not exist in isolation. Rather, they are embedded in our broader understanding of the world around us. As such, when a metaphor draws an equivalence between phenomena, this relationship is nested within an expansive network of other associations and concepts. For instance, in the example metaphor above, the toilet is not only a common item with components coincidently suited to the description of the FI mechanism, but also more broadly associated with flows, blockages, organic material, and bodily functions. These shared associations serve to strengthen the connection drawn by the metaphor, potentially leading to useful intuitions and making the metaphor itself more easily understood. This also applies to other common systems or technologies within the same field, such as the mechanism of a sink stopper depicted in Fig. 6. The consideration and comparison of such distinct but related metaphors can be useful in raising pertinent questions about the conceptualizations and potential interpretations they promote.

In addition to this, contextual norms may contribute to the clarity and ease with which a metaphor can be interpreted. For example, sodium channels are almost universally depicted and described as vertically oriented, with the flow of sodium ions portrayed as occurring vertically downwards. Whilst there is no physical reason for this beyond convention, it coincides helpfully with both the toilet flush and sink stopper metaphors, in which vertical downward movement is also the standard model.

Metaphorical reconceptualization prompts researchers to call into question assumptions underlying existing understanding of scientific phenomena. This is essential both to the development of robust understanding on the part of individual researchers and to the large-scale conventionalization and acceptance of scientific models (Amin et al., 2018). Equally, a novel metaphor may raise research questions relating to the phenomena under study and thereby induce a change of perspective, or even a whole paradigm.

As well as its value to subject experts, metaphor can have a marked effect on the teaching and spread of scientific understanding. By shifting the discussion of scientific phenomena such as the FI mechanism away from inaccessible, cumbersome, and non-intuitive models such as those in Fig. 2, and toward conceptualizations understandable with considerably less technical expertise or specialist training, metaphor can make them accessible and engaging to a far wider audience. This has significant implications for science education as well as science communication and public outreach work (Gupta et al., 2010).

Lowering the technical knowledge barrier to fields such as ion channel research also paves the way for truly novel interdisciplinary research. This allows new insights, perspectives, and approaches to be brought to bear on the subject, as in this article, primarily written by a linguist untrained in biology and with no prior knowledge of sodium channel research.

In addition, metaphorical consideration is a purely intellectual activity. Research and training in technical fields such as ion channel research are typically resource intensive, requiring high-tech laboratories, materials, and equipment, as well as the staff and infrastructure needed to run and maintain them. As such, the ability of metaphor to contribute to progress in the field without inducing such costs can be regarded as a significant benefit.

Ultimately, metaphor runs through all of natural science, is intimately connected to both its history and development, and impacts the ways individuals understand and communicate it. As such, a basic understanding of the mechanisms at play in metaphorical language and an awareness of where and how it is at play in a particular field are valuable tools for any professional scientist, student, or educator.

David A. Eisner served as editor.

Warm thanks go to Aura Heydenreich and Klaus Mecke at the ELINAS Center for Literature and Natural Science at Friedrich-Alexander-University Erlangen-Nürnberg for organizing the exciting interdisciplinary conference at which the authors met and this collaboration began. We would like to thank Jannis Körner and Aylin Kesdoğan for their input and background research on sodium channel fast inactivation literature. Thanks also go to the organizers and participants of the first Worldwide Sodium Channel Conference 2024 for the overwhelmingly positive response to the presentation of this topic, which motivated the writing of this article.

A. Lampert received funding by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation LA 2740/6-1).

Author contributions: P. Hull: Conceptualization, Visualization, Writing - original draft, Writing - review & editing, A. Lampert: Conceptualization, Data curation, Funding acquisition, Investigation, Project administration, Visualization, Writing - review & editing.