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Are there any theories why such an imbalance in chirality of molluscs?

Are there any theories why such an imbalance in chirality of molluscs?



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Most gastropods exhibit sinistral (right hand) winding of their shells. But very few species are anti sinistral. Have there been any theories as to why such a great difference?


Why so many molluscs exhibit sinistral winding?

The estimates of the number of molluscs vary quite greatly between 50,000 and 200,000 species. Of those molluscs species, about 70'000 are Gasteropoda. Gasteropa is most diverse Mollusca phylum.

The winding you describe is present in all Gasteropoda and is often called the torsion. So the answer to why there are so many molluscs that make a torsion is simply, because of phylogenetic independence. The torsion evolved only once in the gastropods. The answer to the more specific question, why is the torsion right handed rather than left handed in all gastropods is 1) phylogenetic independence again. The torsion evolved only once and was therefore either sinistral or anti-sinistral. There is no need for an explanation of why they are all sinistral because the observations are not independent.

Why has the torsion evolved at first place?

One may askbut why did the torsion evolved at first place?. I think the reasons are still to be discovered. The following is a summary of what I read on wikipedia (torsion#evolution)

"Why torsion is bad"

As a result of this torsion, the anus is found next to the mouth which is an obvious hygiene issue and therefore seems rather deleterious. Moreover, there are a whole bunch of issues about organs spinning around and entwining. Also, ventilation seems to be reduced by the torsion which is pretty deleterious.

"Why torsion is good"

However, because there's no "hole" left in the posterior position, the torsion may help preventing sediments. Some have suggested that the torsion may allow to move sensory organs closer to the head. The most likely explanation is that the torsion might have evolved as a defense mechanisms against predation as torsion allow an organism to hide its head behind its shell. Finally, citing from wikipedia:

The evolution of an asymmetrical conispiral shell allowed gastropods to grow larger but resulted in an unbalanced shell. Torsion allows repositioning of the shell, bringing the centre of gravity back to the middle of the gastropod's body, and thus helps prevent the animal or the shell from falling over.

Note also that

Whatever original advantage resulted in the initial evolutionary success of torsion, subsequent adaptations linked to torsion have provided modern gastropods with further advantages.

Why sinistral rather than anti-sinistral

To repeat myself, we only have one single observation of torsion (as it evolved only once) and this observation is either sinistral or anti-sinistral. It sounds therefore quite likely that stochastic processes have driven the evolution of sinistral (rather than anti-sinistral) torsion. In other words, the first mutation allowing for some degree of torsion was probably causing a sinistral torsion and this is it.

But there might eventually be a more functional reason for why torsion evolved to be sinistral. The reasons would then be related to the already existing asymmetry of organs. For example, anti-sinistral torsion may yield to more entwining between the gut and the respiratory system, or to not squeeze too much the one lung, who'd be smaller than the other one due to the presence of circulatory organs. I don't have enough knowledge in the anatomy of the molluscs ancestors to have a good intuition of whether I'd expect sinistral or anti-sinistral torsion to be more beneficial.


Are there any theories why such an imbalance in chirality of molluscs? - Biology

The shadow of symmetry haunts physics. Symmetry is invoked to understand nature concisely, but broken symmetry is invoked to understand nature completely. Physics is filled with examples of shattered symmetries: there is more matter than antimatter, neutrinos only come in the left handed spin flavor, and quantum processes break symmetries constantly, but nature also violates symmetry in chemistry and biology in a very clever manner. Chemistry and biology are subjects I do no normally touch upon, but I am intrigued by the curious circumstance of life on Earth: many molecules are not superimposable upon their mirror images, a property called chirality, and life on Earth has a preference for these chiral mirror configurations. Physics and life is inherently asymmetric.

That something is not identical to its mirror image is a property known as chirality. Hands (etymologically the word chirality is derived from the Greek word for hand), spiral galaxies, and the DNA helix are all examples of chiral objects. In particle physics chirality is a more abstract notion defined by transformations of a particle with respect to a left right of left handed representation in the Poincaré group. In chemistry chirality is well described by analogy to your hands wherein left and right hands cannot be superposed on each other even though the fingers are the same and match up.

This article is an exploration of chirality in biochemistry. I want to ask what makes life chiral, why is life chiral, and how did life become chiral. In order to supplement my limited knowledge of the subject I interviewed a world expert and author of over twenty papers on the subject, Robert Compton, who I must give a deep thanks to for being willing to answer my silly questions.

It is important to accept that the concept of symmetry is tinted by the human notion of harmonious or aesthetically pleasing forms, but the strict mathematical interpretation of symmetry relies upon metrics of geometry. To this end many seemingly symmetric forms in the living natural world are actually examples of broken symmetries: spiral tree trunks, the human form, and sea shells (which generally only coil in one particular direction according to species). The remarkable thing is that this macro asymmetry can be traced back to a micro asymmetry in the chemistry of life. The arrangement of atoms in a molecule defines the function of that molecule, but even molecules with the same chemical configuration can behave differently as in the case of chiral molecules which are like mirror images of the same molecule that come in 'left' and 'right' handed forms. The great asymmetry of life is that all living organisms on Earth almost exclusively utilize the left handed (or levorotatory) configuration for amino acids and the right handed (or dextrorotatory) configuration for sugars belonging to DNA or RNA.

Perhaps it is trivial or obvious that life is chiral when looking at the nautilus, but this obvious chirality is a macroscopic feature which belies the fine arrangement of atoms which defines the chirality of biomolecules.

Different structural forms of compounds with the same molecular formula are known as isomers to chemists. A stereoisomer is an isomeric molecule which has the identical constitution and sequence of bonded atoms, but has a different three-dimensional geometry in space. An enantiomer is one specific steroisomer of the two possible mirror images that are non-superposable. The dominance of the left handed chiral enantiomer in biology is a massive blow to the idea that nature is perfectly symmetric and is an unsolved mystery as to why nature is this way.

Many molecules are chiral, however because molecules are constantly vibrating the instantaneous structure of a molecule may lack the exact structure or symmetry seen in an ideal model. Regardless, enantiomers have identical chemical properties except when they react with other molecules which are also enantiomeric in which case chiral forces yield a difference in behavior. Further, and perhaps more important for biology, particularly astrobiology, is that enantiomers have identical physical properties except with respect to the way they interact with plane-polarized or circularly polarized light or other chiral compounds. A pure enantiomer compound will rotate the plane of a monochromatic plane-polarized light by a certain angle in one direction, say clockwise, while the other enantiomer form of the compound will rotate the light by an equal amount in the opposite direction. Things that rotate light are said to be optically active. Measurements with a polarimeter allow chemists to determine if a compound is chiral or not. Polarization of light by organic compounds was discovered in 1815 by the French physicist and chemist Jean-Baptiste Biot. He found that organically produced chemical solutions consistently rotated plane polarized light, but laboratory synthesized chemicals did not reproduce the rotation. Beyond conjectures he had no explanation for the phenomena.Years later Louis Pasteur preformed a similar experiment with tartaric acid produced from grapes and tartaric acid synthesized in the lab. Pasteur went further and somehow used tweezers and a microscope (I do not conceive to understand how) to separate the tartaric acid crystals which he produced in the laboratory into piles of left and right handed molecules. He found that polarized light was rotated by the left handed molecules that he had selected in the same way the polarized light was rotated by the organic tartaric acid. He concluded that chiral molecules are responsible for the rotation of polarized light.

So chiral molecules rotate light, but actually so does an individual achiral molecule! In an ensemble of achiral molecules each individual molecule may rotate the plane of the polarization, but the net rotation averaged over the ensemble will result in zero rotation. A mixture of two enantiomers in a 1:1 ratio (which is what you get when you create chemicals in the lab) is optically inactive because the rotation results in a zero net polarization rotation. When a reagent or catalyst is optically active the chiral product will also be optically active, or in the presence of chiral forces such as circularly polarized light this may also induce optical activity via enantimoeric excess in the products as well. Generally you can get optically active compounds in two ways 1) The reagent in already optically active. 2) The reaction of achiral but optically inactive precursors in a chiral optically active environment occurs. It takes an optically active molecule or chiral force to produce a product that is optically active.

Most chemical reactions are not enantiomerically selective so that the initial reason for a completely homochiral biology on Earth remains a mystery just as when Biot and Pasteur discovered chirality through optical activity. Of course chirality is simply geometric in nature and thus this geometric asymmetry is what makes life chiral. Any molecule that contains a tetrahedral carbon or other central atom bonded to four different atoms or constituents will exist in enantiomeric forms given that all biological molecules are at least this complicated, then (almost?) all biological molecules exist in enantiomeric forms. It may be that the chirality of biomolcules is simply a consequence of the emergent complexity of basic physics. The conditions necessary for a solution initially containing near equal number of chiral forms to evolve towards pure chirality has been explored (see Frederick Frank 1953) and is plausible. A tiny initial imbalance has spiraled out of control and now each successive generation of biomolecules on Earth is produced by the previous generation of chiral reagents, thus this is the why life is chiral. None of this explains how life is chiral, but a common answer is that because life can be chiral it is chiral.

From this persepctive this topic is not so interesting, honestly. I have come to the conclusion that chriality is as it must be given that each generation of life is spawned from the previous generation under conditions which do have enantiomeric selection forces present. The question is why was left handed chirality chosen for life on our Earth?

Now actually, the chirality of biomolecules is not just a philosophical diversion it a serious issue of biochemistry in balance. There are over 530 synthetic chiral drugs worldwide today. It is technically and economically prohibitive to make enantiomerically pure drugs in all cases. This results in drugs that may have strange, null, or fatal interactions with human subjects. In some cases the difference between two enantiomeric forms is simple, as in the case of the olfactory exciting chemical carvone in one configuration it smells like spearmint and the other configuration like caraway seeds. So, "Perhaps," as Alice said to her cat in Lewis Carroll's Though the Looking Glass, "looking-glass milk isn't good to drink".

  • The weak force. Of the fundamental forces, nuclear, electroweak and gravitational, only the weak force can distinguish between left and right parity particles. The weak force it turns out does not conserve parity (although it does conserve CPT symmetry) during some interactions such as the radioactive beta decay corresponding to the emission of an electron with intrinsic spin 1/2 hbar. Also, the weak force induces a parity-violating energy difference, PVED, between molecules or the interactions of left-handed electrons emitted during beta decay with molecules. So the weak force could preselect a handedness in nature through either beta decay or PVED. The idea is that if one chiral configuration is a lower energy state then nature will prefer that configuration (in fact the exact scaling from thermodynamics is that the reaction rate for the oppositely chiral molecules is proportional to the canonical partition function in physics going as e -PVED/kT where e is the Euler's number, k is Boltzmann's constant, T is the temperature in Kelvin). The difference in energy from the PVED can be theoretically calculated from a Hamiltonian operator that is scaled by the Fermi electroweak coupling constant. The energy difference between chiral configurations is predicted to be small, around 10 -14 Joules per mol which means that not only is this energy difference believed to be minimally important to early life's synthesis, but it is also out of reach of current experimental techniques. However, it turns out that the PVED predicts that the left handed chiral states would be of lower energy, just as they are found dominantly in life on Earth. The weakforce influences chemical reactions because during beta decay, spin polarized electrons produce a an abundance of left-circularly polarized gamma-rays which, if present during the synthesis of biomolecules would tend to create an enantiomeric excess of left handed molecules. However, laboratory experiments have not shown conclusively that this effect is strong enough to matter either. There is some debate as to the exact nature of the PVED which will depend on further experimental measurements. The weakforce seems to preselect a hand in nature, but it is a feeble force.
  • Polarization. Optically active organic molecules being synthesized in the presence of polarized light will be chiral. Sunlight is slightly polarized just before sunrise and after sunset. This averages out to zero, but chemical activity that dominates in the morning/evening or occurs in the presence of shadows could feel a net polarization effect. Also plausible are astronomical sources of polarized light outside the solar system. Supernovae have been known to emit circularly polarized light as have star forming or nebulae regions. These sources while weak would create conditions necessary for the synthesis of homochiral biomolecules.
  • Vorticity. A chemical solution being stirred or agitated results in the synthesis of homochiral biomolecules, however, the handedness of the chirality is random. Certaintly there were chaotic turbulent conditions on the early Earth.


Robert N. Compton, Richard M. Pagni, & Volume 48, 2002, Pages 219-261 (2002). The chirality of biomolecules Advances In Atomic, Molecular, and Optical Physics, 48 , 219-261


Introduction

“Feeding is such a universal and commonplace business that we are inclined to forget its importance. The primary driving force of all animals is the necessity of finding the right kind of food and enough of it” (Elton, 1927).

This Special Issue of JEMBE publishes some of the papers delivered at a workshop which brought together scientists interested both in suspension feeding and in the carrying capacity of nearshore marine habitats for the cultivation of bivalve molluscs. It concentrates upon papers on feeding behaviour and on modelling the growth of bivalves. Other presentations, on carrying capacity models, are to be published as a Special Issue of the journal “Aquatic Ecology”. The workshop was held at Plymouth during September 1996 its rationale and justification emerged from two separate but related activities.

Firstly, since 1993, an international consortium of scientists from France, The Netherlands, Spain and the UK have been studying three bivalve species (Crassostrea gigas (Thunberg), Mytilus edulis L. and Cerastoderma edule (L.)) within the Marennes-Oléron Bay in France. The objective has been to understand their feeding behaviours under natural conditions of high but variable concentrations of suspended particulate matter (SPM), and the consequences of these feeding processes for the intensive cultivation of oysters and mussels. The project has been multi-faceted, but one important aim was to incorporate feeding into models of the carrying capacity of the Bay for cultivated shellfish (Héral, 1993), based on the assumption that suspension feeding was a critical factor determining the flux of SPM, and therefore the food available to the bivalves. These experiments yielded new insights into bivalve feeding processes in such high SPM systems (Hawkins et al., 1996, Soletchnik et al., 1996, Urrutia et al., 1996). The TROPHEE Workshop was designed in part to communicate the results of these studies to others and, in particular, to create an opportunity to compare these findings with similar, contemporary studies in North America.

Secondly, an international symposium held under the auspices of NATO, in The Netherlands in 1992 (Dame, 1993), had considered both a wide range of experimental studies of bivalve feeding and a variety of attempts to model these processes both for ecological and aquacultural ends. An important recommendation of this symposium (Grant, 1993) was that a follow-on workshop could prove valuable in exploring similarities and differences amongst the various modelling approaches whilst also helping to identify the critical features of the carrying capacity models and where they might benefit from better descriptions of bivalve feeding behaviour.

At the Plymouth Workshop, scientific papers were presented on bivalve feeding and on carrying capacity studies. In addition, different models of the growth of bivalves were compared at “hands-on” computing sessions using standard data sets for environmental food values derived from studies in the Marennes-Oléron Bay (characterised by high SPM concentrations) and Nova Scotia (a low turbidity site at Upper South Cove see Grant and Bacher, this volume). Papers in this volume by Grant and Bacher and Scholten and Smaal describe the incorporation of these two data sets into different models of growth and production of mussels.

Such interest in modelling the feeding behaviour of suspension-feeding bivalves has grown in recent years in response to two important demands. Firstly, the cultivation of oysters and mussels, in particular, has led to a demand for models of growth which may be used to evaluate the production potential of shellfish growing areas (e.g., Newell and Shumway, 1993 Campbell and Newell, this volume). Such models must contain an explicit and robust description of feeding behaviour which is responsive to variations in both the quantity and quality of food within natural environments. Secondly, our ability to quantify the capacity of such growing areas to cope with intensive modern cultivation practices is increasingly challenged by evidence that the production potential of some traditional shellfisheries is limited by density-dependent effects (e.g., the Bay of Marennes-Oléron in France Héral, 1993). This latter challenge is part of a wider interest in the role of suspension feeders as agents in the ecosystem-scale dynamics of sediment flux, nutrient balance and phytoplankton production in coastal seas (review by Dame, 1996). Models of carrying capacity (Bacher, 1989, Raillard and Ménesguen, 1994) and related ecosystem impacts (Herman, 1993) require quantitative descriptions of rates and efficiencies of suspension feeding. The Plymouth TROPHEE Workshop was designed to explore these interfaces between studies of individual feeding behaviours and the ecological consequences for aquaculture and the carrying capacity of various coastal systems.

However, the study of the physiology of bivalve feeding is currently controversial, largely as a result of publications by Jørgensen (Jørgensen, 1990, Jørgensen, 1996) which cast doubt on the validity of a large body of published work. In this introduction to the papers that follow I have taken the opportunity to address some of these criticisms, by posing three questions and offering some answers. The result is to suggest, contrary to Jorgensen's (Jørgensen, 1996) view, that bivalve suspension feeding is a complex synergy between behavioural, physiological and morphological traits which are responsive to variations in available food. There is still much that we do not know about the mechanisms underlying these responses. Nevertheless, available descriptions of feeding behaviour can support useful initial attempts at modelling bivalve growth. I will also indicate where new approaches to understanding suspension feeding, set in context with available theory, are creating new opportunities for formulating hypotheses of feeding behaviour which will benefit new ecological modelling.


Cell chirality: its origin and roles in left–right asymmetric development

An item is chiral if it cannot be superimposed on its mirror image. Most biological molecules are chiral. The homochirality of amino acids ensures that proteins are chiral, which is essential for their functions. Chirality also occurs at the whole-cell level, which was first studied mostly in ciliates, single-celled protozoans. Ciliates show chirality in their cortical structures, which is not determined by genetics, but by ‘cortical inheritance’. These studies suggested that molecular chirality directs whole-cell chirality. Intriguingly, chirality in cellular structures and functions is also found in metazoans. In Drosophila, intrinsic cell chirality is observed in various left–right (LR) asymmetric tissues, and appears to be responsible for their LR asymmetric morphogenesis. In other invertebrates, such as snails and Caenorhabditis elegans, blastomere chirality is responsible for subsequent LR asymmetric development. Various cultured cells of vertebrates also show intrinsic chirality in their cellular behaviours and intracellular structural dynamics. Thus, cell chirality may be a general property of eukaryotic cells. In Drosophila, cell chirality drives the LR asymmetric development of individual organs, without establishing the LR axis of the whole embryo. Considering that organ-intrinsic LR asymmetry is also reported in vertebrates, this mechanism may contribute to LR asymmetric development across phyla.

This article is part of the themed issue ‘Provocative questions in left–right asymmetry’.

1. Cells are composed of chiral molecules

An object or a system is chiral if it cannot be superimposed onto its mirror image. Our left and right hands represent a familiar and convenient example of chirality (figure 1, top). The left hand is a mirror image of the right one, and they cannot be superimposed no matter how the two hands are oriented.

Figure 1. Chirality in hands, molecules and cells. Chirality is a property of an item that cannot be superimposed on its mirror image, as seen in the left and right hands. Most biological molecules, such as amino acids, are chiral. Cells can also be chiral if they have LR asymmetry and apico-basal polarity.

Chirality is a particularly important concept in biology, because cells are mostly composed of chiral molecules. Small chiral molecules such as amino acids and sugars (figure 1, top) are the building blocks of larger molecules, such as proteins and nucleic acids, which are also chiral. A chiral molecule and its mirror image are called enantiomers one is dextrorotatory (D) and the other is levorotatory (L). Ordinary chemical reactions produce L- and D-molecules in equal amounts, referred to as a racemic mixture. However, related biological molecules have the same chirality most amino acids are L and most sugars are D. This situation is called homochirality, and the homochirality of biological molecules is a characteristic of all living things. D-amino acids are very rare in cells, although some specific activities of D-amino acids have been identified. For example, in the mammalian brain, D-serine acts as a physiological co-agonist of the N-methyl d -aspartate type of glutamate receptor, which is a key excitatory neurotransmitter receptor [1]. However, although the cases in which homochirality is ingeniously used to execute function are uncommon, they demonstrate the importance of chirality in the function of biologically relevant molecules. Interestingly, an enantiomeric excess of L-amino acids was found in the Murchison meteorite, sparking a theory that homochirality has an extraterrestrial origin [2]. In addition, various theories for how a small initial imbalance in enantiomer concentrations could have led to the subsequent production of a single enantiomer have been proposed [3]. For example, the enantioenrichment of biological molecules may have been coupled with the increasing chemical and physical complexity of cells, so the chirality of molecules, including proteins, was intrinsically linked to their functions.

In general, protein functions depend on interactions with other molecules via chiral structures. For a gene to encode a protein with a specific shape, the homochirality of amino acids is required, because L- and D-amino acids will give rise to different three-dimensional protein structures. Thus, the homochirality of amino acids is essential for the basic execution of genetic control. In addition, an enzyme usually has a chiral groove or binding pocket that fits one enantiomer of its substrate but not the other. Thus, the homochirality of biologically active molecules is a critical condition for the molecular functions of organisms.

Chirality may appear less prominent in larger biological structures, although clear exceptions exist. For example, the tail of bacteriophage T4 is a helix with a defined handedness [4], and the structure and motion of prokaryotic flagella are also chiral [5]. However, for most eukaryotic cells, especially metazoan cells, chirality at the single-cell level is not obvious, unlike the marked chirality of the molecules that compose them. Nevertheless, an important role of eukaryotic cell chirality in determining LR asymmetric development in the animal body has recently emerged.

In 1990, Wolpert proposed the ‘F molecule hypothesis’ to explain the development of directional LR asymmetry in the animal body [6]. In this hypothesis, a hypothetical F molecule, which has arms pointing in three dimensions and intrinsic chirality, recognizes the dorsoventral and anteroposterior axes of the embryo and has an activity that arranges it along these two axes. Once the F molecule is placed along the dorsoventral and anteroposterior axes, it defines the LR axis in the embryo by its chirality. More recent evidence indicates that, instead of a chiral molecule like the F molecule directly determining the LR axis in the embryo, chirality at the cellular level dictates the LR asymmetric development in metazoans. However, before exploring the chirality of cells in multicellular eukaryotes and its potential role in complex processes such as LR asymmetric development, we first discuss the chirality found in unicellular eukaryotes, which are a simpler system. In this review, any chirality found at the whole-cell level is referred to as ‘cell chirality’.

2. Cell chirality in protozoans, single-celled organisms

In contrast to multicellular organisms, the protozoans, a diverse group of unicellular eukaryotes, exhibit clear chirality at the cellular level, which has drawn considerable research interest (figure 2, left). The cell chirality in protozoans is an extreme form of cell chirality that may help elucidate the mechanisms of cell chirality formation in metazoans. The ciliates are protozoans that have cilia, which are used for swimming, feeding, sensing and other purposes (figure 2, left). Ciliates exhibit chirality, which is also referred to as ‘handedness’, in their global cortical structures, including the ciliary rows, oral apparatus and contractile vacuole (figure 2, left) [8,9]. The ciliary structure, called the ciliary unit, is positioned in the cell cortex in an asymmetric and polarized (right-handed) manner [7,10]. The ciliary unit is centred over a complex protein structure called the basal body [11,12] (figure 2, right). To examine how polarity forms in ciliates, experimental manipulations were performed to induce atypical ciliary row structures. Stable ciliary phenotypes, including intercalated ciliary rows and mirror-image doublets, can be induced on cells by various techniques, including microsurgery, microbeam laser, thermal shock and chemical shock [13–15]. Notably, such extra sets of ciliary structures can be maintained on the cortex of a clonal cell line for many generations. In addition, in Tetrahymena, clones with a global LR asymmetry the reverse of wild-type (left-handed instead of right-handed) were established [9]. Analyses of these left-handed clones revealed that their LR cortical structure is not owing to a genetic change [9]. Collectively, these observations suggest that the existing cortical structural information of a progenitor cell is repeated in its progeny, propagating the cell's global pattern, including its handedness. These analyses also indicated that nuclear genes are not involved in determining handedness [9]. Thus, a pre-existing chiral structure, rather than specific genetic information for cell chirality formation, dictates the cell chirality in the next generation. These phenomena are referred to as ‘cortical inheritance’ or ‘structural memory’, and were a biological mystery for a long time [7,16–18].

Figure 2. Chirality in ciliates. Right: ciliates show chirality in their global cortical structures, including the ciliary rows, oral apparatus and contractile vacuole. Left: the cortical unit of ciliates, which includes the ciliary rootlet and basal body, is chiral (adapted from [7]). In wild-type ciliates, the ciliary rootlet (cr) extends anteriorly and is positioned to the right relative to the basal body and the cell itself. The transversal microtubule ribbon (tmr) is on the left side of the basal body, and the post-ciliary microtubule ribbon (p-cmr) points posteriorly. Basal bodies are seen from the outside of the cell, and the viewer's right corresponds to the cell's left. Schema is adopted from Beisson [7]. A, anterior P, posterior R, right L, left. (Online version in colour.)

Although the molecular mechanisms underlying cortical inheritance are still not completely understood, the cortical unit appears to play an important role in it. The basal body at the base of the cilium and cytoskeletal appendages (called the ciliary rootlet and microtubule ribbon) make up the cortical unit (figure 2, right) [7,11,12]. The ciliary rootlet normally extends in an anterior direction, and on the right side of the basal body and the cell (figure 2, right). The transversal microtubule ribbon is located on the left side of the basal body, and the post-ciliary microtubule ribbon points in a posterior direction [7]. Thus, the cortical unit is chiral (figure 2, right). During cell division, the basal body is duplicated with strict polarity. The newly formed basal body is inserted into the cortex just anterior to its mother, along the longitudinal row of cortical units (figure 2, right) [7,11,12]. Next, cytoskeletal appendages form at the peribasal site, confined within the cortical unit [7]. Thus, in ciliates, properties of the cortical unit itself are sufficient for self-assembly into high-order subcellular structures, such as cytoskeletal organelles and networks [7].

However, nature is even more complex and interesting than one might think. Even in the mirror-image doublets, the mirror-image (enantiomorphic) form of the cortical unit has never been observed [10]. For example, the position of the ciliary rootlet is not the mirror image in the doublet cell [10]. The mirror image oral primordium begins to self-assemble in the normal (right-handed) part of the doublet [10], and then rotates anticlockwise 180° in its plane, resulting in an imperfect mirror image of the oral apparatus [10]. Therefore, in addition to the self-assembly of cortical units, there must be local cues to induce this planar rotation of the cortex. In addition, it was shown that when regions of the cell are placed in abnormal positions relative to one another, the cell intercalates these regions to restore their normal orientations in the membrane by the shortest permissive route [19–22]. These observations led to the proposal that the reversed anteroposterior axis of the oral apparatus in the mirror part of the doublets may be owing to the abnormal juxtapositioning of right and left marginal cortical units [10]. Regardless of the details, cortical inheritance suggests that the LR asymmetric morphology of a cell is dictated by molecular chirality. That is, these observations demonstrate that the chirality of subcellular structures can direct the chirality at the whole-cell level.

3. Cell chirality and hindgut laterality in Drosophila

Recent studies revealed that cell chirality is not exclusively found only in protozoans, but also exists in metazoans. Cell chirality in a tissue was first discovered in the Drosophila embryonic hindgut, which corresponds to the small and large intestines in mammals (figure 3a) [25,26]. The Drosophila embryonic hindgut is invaginated from an epithelial monolayer and first forms as a bilaterally symmetric structure. During the late 12 and 13 embryonic stages, the hindgut rotates 90° anticlockwise (as viewed from the posterior) and becomes LR asymmetric with dextral looping (figure 3a) [27]. Because the hindgut looping is the first visible sign of LR asymmetry in Drosophila, the directional rotation of the hindgut appears to break the LR symmetry. Taniguchi et al. [25] discovered that before the directional rotation begins, the apical cell surface of the hindgut epithelial cells shows LR asymmetry (figure 3a). These cell surfaces have more leftward-tilted cell boundaries than rightward-tilted ones. Because the hindgut epithelial cells, like other epithelial cells, have apico-basal polarity, their shape is chiral (figure 1, bottom). The cell chirality is evident not only in the overall shape, but also in organelle and protein distributions inside the cells. The centrosomes of hindgut epithelial cells tend to be located in the right-posterior region of the cell, and a cell adhesion molecule Drosophila E-cadherin (DE-cadherin) is more abundant along the rightward-tilted cell boundaries than along the leftward-tilted ones at the apical cell surface [25]. This cell chirality diminishes as hindgut rotation progresses and disappears when the rotation is complete (figure 3a) [25]. The involvement of the cell chirality in promoting the LR asymmetric rotation of the hindgut was supported by an in silico simulation, which showed that the introduction and subsequent dissolution of cell chirality in a model epithelial cell tube is sufficient to recapitulate the directional rotation of the model hindgut [25].

Figure 3. Cell chirality and LR asymmetric morphogenesis in Drosophila. (a) The Drosophila embryonic hindgut shows sinistral looping as the consequence of an LR asymmetric rotation. Before the onset of the rotation, hindgut epithelial cells show chirality with more frequent leftward-tilted cell boundaries than rightward-tilted ones. The chirality disappears when the rotation is completed. Distribution of DE-cadherin (green) also shows chirality. (b) The Drosophila male genitalia undergo a 360° clockwise rotation during the pupal stages. Epithelial cells in the A8a segment of male genitalia show chirality just before and during the LR asymmetric rotation. These cells have more frequent rightward-tilted cell boundaries and a higher expression of Myosin II along the rightward-tilted cell boundaries. Schema is adopted from Sato K et al. [23]. (c) Drosophila adult gut shows LR directional looping. The adult gut develops from larval primordia called the imaginal ring, consisting of H1 and H2 segments. The cell chirality determinant Myo31DF is required only in the H1 segment during larval stages. Cell chirality is observed in the H2 segment only after the H1 segment is eliminated. The handedness determined by Myo31DF in the H1 segment might be conveyed to the H2 segment through atypical cadherins, Dachsous and Fat. Schema is adopted from González-Morales et al. [24].

4. Myosin31DF switches the cell chirality in Drosophila

Myosin31DF (Myo31DF), an orthologue of mammalian MyosinID, is a key molecule for cell chirality in Drosophila. The Myo31DF gene was identified in a Drosophila screen for gene mutations affecting the LR asymmetry of the embryonic gut [27]. In Myo31DF mutants, the embryonic hindgut rotates in the direction opposite to that of wild-type, exhibiting inverted sinistral looping (figure 4) [27]. The cell chirality of the hindgut epithelial cells before the onset of rotation is also inverted in the Myo31DF mutants, supporting the notion that the cell chirality prior to rotation is important for the directional rotation in the hindgut (figure 4) [25]. Rescue experiments of Myo31DF mutants by wild-type Myo31DF showed that the cell chirality is a cell-autonomous property (figure 4). The inversion phenotypes in both hindgut rotation and cell chirality were rescued by over-expressing wild-type Myo31DF in the hindgut epithelial cells [25,28]. When a genetic mosaic was generated by randomly introducing cells expressing wild-type Myo31DF in the Myo31DF mutant hindgut, wild-type cell chirality was formed only in the cells expressing wild-type Myo31DF (figure 4) [28]. These results indicated that cell chirality is intrinsically formed in each cell and that Myo31DF functions to switch the cell chirality from the default (Myo31DF mutant type) to the wild-type direction (figure 4).

Figure 4. Cell chirality is an intrinsic property of individual cells, and Myo31DF switches the direction of cell chirality. Left: wild-type embryos show rightward looping of the hindgut and dextral cell chirality. Middle: in Myo31DF mutant embryos, both the hindgut looping and cell chirality are inverted. Right: when cells expressing wild-type Myo31DF are randomly introduced into the Myo31DF hindgut, only the cells expressing wild-type Myo31DF show the normal dextral chirality, indicating that cell chirality is formed intrinsically in each cell.

Myo31DF is a member of the unconventional myosin I class these molecules consist of an N-terminal head domain containing an ATP-binding motif, a neck domain containing two calmodulin-binding IQ motifs, and a short C-terminal tail domain [27,29,30]. A mutant Myo31DF protein lacking the IQ motifs is unable to rescue the Myo31DF phenotype [29]. Moreover, mutant Myo31DF proteins lacking the ATP-binding motif, IQ motifs or the tail domain fail to induce LR inversion in the hindgut, unlike wild-type Myo31DF [27]. Myo31DF binds β-catenin and an atypical cadherin, Dachsous, and associates with DE-cadherin through β-catenin [24,31]. Myosin 1d (Myo1d) is a rat orthologue of MyoID. Recently, analyses of a Myo1d knockout rat revealed that Myo1d is required for the formation of planar cell polarity in multiciliated epithelial cells, but not for LR asymmetric organ development [32]. Thus, the roles of MyoID family proteins in LR asymmetric organ development are not evolutionarily conserved in mammals, although their biochemical functions in cell chirality may be widely maintained.

5. Cell chirality as a general mechanism of left–right asymmetric development in Drosophila

Myo31DF acts as a general LR determinant in Drosophila [27,29]. In addition to LR inversion in the embryonic gut, Myo31DF mutants exhibit inversion in the looping of the adult gut and testes, and in the rotation of the male genitalia [27,29]. Among these organs, epithelial cells in both the adult gut and the male genitalia show chirality at a point in time related to laterality formation (figure 3b,c). Drosophila male genitalia undergo a 360° clockwise rotation (as viewed from the posterior) during the late pupal stages [33,34]. This rotation is completed through combined 180° rotations of two segments: the A8 anterior (A8a) and A8 posterior. Sato et al. [23] found that epithelial cells in A8a exhibit chirality in their shape and protein distribution. Just prior to and during the directional rotation, these epithelial cells show LR bias, with more frequent rightward-tilted cell boundaries and higher Myosin II expression along the rightward-tilted cell boundaries (figure 3b) [23]. The chirality of the A8a cells is reversed in the Myo31DF mutant [23]. A computer model demonstrated that the biased cell boundary rearrangement, attributed to the biased expression of Myosin II, is important for the directional rotation of the male genitalia [23].

Another organ in which epithelial cells show chirality is the Drosophila adult gut (figure 3c). As Drosophila undergoes metamorphosis, the adult gut is developed from larval primordia called the imaginal ring. The imaginal ring consists of two segments H1 and H2. Epithelial cells in the H2 segment proliferate during the pupal stages and form the adult gut with dextral looping, whereas the H1 segment is eliminated during the pupal stages [24]. Myo31DF activity is required only in H1 during the late larval stages [24]. Interestingly, chirality in the epithelial cell shape is observed only in the H2 segment after the H1 segment is eliminated (figure 3c) [24]. González-Morales et al. proposed that LR bias generated by Myo31DF in H1 is conveyed to H2 through Dachsous, which physically binds to Myo31DF.

In the Myo31DF mutant tissues in which LR asymmetry is the mirror image of wild-type, the cell chirality is also switched from dextral to sinistral (default). Evidence suggests several possible mechanisms for these events. In the epithelium of the Drosophila embryonic hindgut, Myo31DF is required for the chiral distribution of DE-cadherin [22]. Thus, Myo31DF may act as an LR determinant by regulating the chiral distribution or activation of DE-cadherin. Alternatively, Myo31DF may switch the chirality of the structure or function of actin cytoskeleton, given that disrupting the actin cytoskeleton abolishes cell chirality, and that Myo31DF is required for the chiral distribution of Myosin II in Drosophila [22,34].

6. Left–right asymmetry and cell chirality in other invertebrates

Cell chirality–associated phenomena are observed in the blastomeres of various invertebrate species [35]. A spiral cleavage that is conserved in many members of the lophotrochozoan taxa, referred to as Spiralia, often involves chiral blastomeres, especially in the early cleavage stages. In some cases, the chirality of the blastomeres determines the handedness of the embryo.

Snails, which belong to the Mollusca phylum of the lophotrochozoa, undergo spiral cleavage [36–39]. The directional LR asymmetry of snails is easily observed in the coiling direction of the shell, and the spiral cleavage patterns in snails show a stereotypical handedness (figure 5a). In Lymnaea, which belongs to the Pulmonata subclass of molluscs, the blastomere spindles slant clockwise (viewed from the animal pole) at the four-cell stage, then the micromeres are rearranged clockwise at the eight-cell stage (figure 5a) [39]. Thus, each blastomere at the four-cell stage exhibits cell chirality (figure 5a). A formin activity plays a critical role in creating the blastomere chirality in a snail [41], which is reminiscent of a formin-dependent chirality formation seen in mammalian cells, as discussed below [42]. The handedness of the spiral cleavage can be reversed by surgical manipulation at the eight-blastomere stage these embryos exhibit a mirror-image handedness of their entire body [43]. Therefore, the positioning of blastomeres at the eight-cell stage or earlier determines the handedness of the snail body.

Figure 5. Cell chirality in snails and C. elegans. (a) Upper: in Lymnaea, the blastomere spindles slant clockwise as viewed from the animal pole at the four-cell stage, and blastomeres are rearranged clockwise at the eight-cell stage. Bottom: Pulmonata is a snail species with counter clockwise-coiling shells and internal organs that mirror those of Lymnaea. In Pulmonata, blastomere spindles slant anticlockwise as viewed from the animal pole, resulting in a counter clockwise blastomere rearrangement at the eight-cell stage. In both cases, blastomere chirality determines the shell coiling direction and LR asymmetry of the body. Schema is adopted from Shibazaki et al. [39]. (b) Top: in C. elegans, mitotic spindles are skewed during the transition from four cells to six cells. Bottom: at the six-cell stage, changing the LR-asymmetric arrangement of blastomeres to their mirror-image positions results in situs inversus. Thus, in both snails and C. elegans, blastomere chirality is completely responsible for the subsequent LR-asymmetric development. Schema is adopted from Wood & Kershaw [40].

In Pulmonata, mutations affecting the handedness of the shell coiling and internal organs have been found in natural populations [44,45]. In mutants with LR inversion of the shell-coil direction, the early blastomere cleavage pattern is first symmetrical and then becomes a mirror image of the stereotypical cleavage pattern. In Pulmonata evolution, species occasionally emerged with anticlockwise-coiling shells and internal organs that were mirror images of those in the dextrally coiling snails [39]. The spiral blastomere cleavage pattern in these sinistrally coiling species is also the mirror image of the pattern seen in the dextrally coiling snails (figure 5a) [39]. These studies showed that the handedness of the spiral cleavage is correlated with the direction of shell coiling and of the internal organs [39]. Interestingly, the first cleavage in Xenopus is accompanied by a slight anticlockwise torsion of the two blastomeres [46]. A chemical treatment can dramatically increase this cortical anticlockwise torsion, and pharmacological analyses suggested that the torsion requires F-actin [46]. Thus, the cortex of an egg undergoing radial cleavage has intrinsic chirality, supporting the idea that cell chirality is a common property in metazoans.

Caenorhabditis elegans (C. elegans) is an Ecdysozoan model animal that has stereotypic LR asymmetry of the body [40]. As in snails, the first sign of LR asymmetry in C. elegans is an anterior–posterior skewing of the transverse mitotic spindles with predetermined laterality, at the four-cell stage [47] (figure 5b). At the eight-cell stage, the embryo midline tilts rightward from the anterior–posterior axis this positioning is induced by LR-asymmetric blastomere protrusion and migration [48]. These events involve differentially regulated cortical contractility in the sister blastomeres that are bilateral counterparts [48]. Changing the LR-asymmetric blastomere configuration at the six-cell stage to their mirror-image positions causes situs inversus [40] (figure 5b). Thus, as with snails, the relative LR-asymmetric blastomere positioning is completely responsible for the subsequent LR-asymmetric body development in C. elegans [40,43]. That is, intercellular interactions responsible for the subsequent LR-asymmetric development depend on the LR-asymmetric blastomere configuration in the early cleavage stages. In summary, blastomere chirality is a common mechanism driving LR asymmetric development in various invertebrates. Although the molecular mechanisms underlying blastomere chirality formation are not well understood at present, it may have common features with other cases of cell chirality formation, such as the involvement of formin and actin, as discussed below.

7. Cell chirality in vertebrate cultured cells

Cell chirality was recently observed in various vertebrate cultured cells. For example, murine myoblast C2C12 cells, human umbilical vein endothelial cells (hUVECs) and vascular mesenchymal cells (VMCs) show a chirally polarized cell shape when plated on a micropattern [49,50]. Whether the handedness is dextral or sinistral depends on the cell line [49]. Chirality in the nuclear shape and the involvement of E-cadherin in transmitting a chiral bias to neighbouring cells were shown using Madin–Darby canine kidney epithelial cells [51,52].

Cell chirality is also observed in the dynamics of cultured cells. Human promyelocytic leukaemia (HL60) cells, which are neutrophil-like cells, show a leftward-biased migration in the absence of spatial cues [53]. Genetic and pharmacological analyses revealed that microtubules are involved in this process [53]. Fibroblasts from human foreskin seeded on a micropattern and cultured zebrafish melanophores show chiral swirling [42,54]. In these processes, the actin cytoskeleton is important, but microtubules are not [42,54]. Tee et al. studied the detailed molecular mechanisms underlying this fibroblast swirling. They found that fibroblasts seeded on a circular micropattern develop two types of actin fibres, radial and transverse, and that the radial fibres eventually start to tilt unidirectionally, generating the chiral swirling (figure 6) [42]. This process was found to require the radial growth of the radial fibres, which depends on actin's polymerization by formin [42]. Formin appears to give a unidirectional rotation to actin filaments, which results in a rightward tilting of radial fibres when triggered by a slight imbalance in transverse fibres (figure 6). Interestingly, α-actinin-1, an actin filament bundling protein, appears to act as a chirality switch in this system. Over-expressing α-actinin-1 changes the direction of the chiral swirling from anticlockwise to clockwise [42].

Figure 6. Chiral shape and swirling of cultured mammalian cells. Left: cultured murine myoblasts (top) and vascular mesenchymal cells (bottom) demonstrate intrinsic chirality when plated on a substrate with a ring or stripe micropattern. Schemas are adopted from Wan et al. [49] and Chen et al. [50]. Right: fibroblasts from human foreskin seeded on a micropattern show anticlockwise chiral swirling. Radial actin fibres initially situated in a radial pattern eventually start to tilt rightward (top). The clockwise rotation of actin filaments in radial fibres generated by formin may cause the rightward tilting (bottom). Schemas are adopted from Tee et al. [42].

8. Implications

Directional LR asymmetry of the body structure is broadly observed in ecdysozoans, lophotrochozoans and deuterostomes. In addition, cell chirality is observed in these three groups of animals. Thus, it is possible that the mechanisms by which chiral morphology develops, including cell chirality, can be traced back to the ancestral bilateralia. In the cases of cell chirality observed so far, the actin cytoskeleton appears to play a profound role. In particular, formin, which drives the unidirectional rotation of F-actin, is indispensable for the formation of cell chirality in snail, frog and mammalian cells [41,42]. Thus, chirality in the structure or function of actin cytoskeleton may be an important determinant of cell chirality.

During animal development, most cells differentiate and exhibit functions at specific parts of the embryo, which are determined by positional information based on the dorsoventral and anteroposterior axes. Given that some of these cells have intrinsic cell chirality and are positioned in a specific part of the embryo, these cells can define the LR polarity, leading to LR asymmetric development, as found in Drosophila. In this case, chiral cells behave like an F cell, which is equivalent to the F molecule at the cellular level, and drive LR asymmetric development individually in each organ, without establishing an LR axis of the whole embryo (figure 7). This scenario is supported by the absence of any observed LR-asymmetric gene expression in Drosophila. Therefore, cell chirality may serve as a mechanism for inducing organ-intrinsic LR asymmetry in the absence of an established LR axis [23–25].

Figure 7. The ‘F cell’ concept and LR asymmetric development in the absence of an LR axis. Left: in vertebrates, LR morphogenesis occurs according to an established body LR axis. Right: in Drosophila, chiral cells may behave like an F cell, which is analogous to the F molecule—a hypothetical LR determinant—at the cellular level and drive LR asymmetric development in individual organs, without establishing an LR axis of the whole embryo.

In vertebrates, later LR morphogenesis (such as the position and morphology of internal organs) is influenced by an established body LR axis, which is achieved by Nodal signalling [55,56]. In addition, Nodal-independent LR-asymmetric organ morphogenesis was recently reported in a vertebrate. In a zebrafish mutant defective for the Nodal-related gene Southpaw, the left-side–specific gene expression is abolished as expected however, these mutants still show a dextral looping structure in the heart [57]. Moreover, explanted linear heart tubes from chicks or fish develop dextral looping in culture [57–59], indicating that this morphogenesis is independent of the LR body axis that is, that organ-intrinsic mechanisms of LR-asymmetric development like those found in Drosophila may also occur in vertebrates. Given that many types of cells from various organs and organisms show cell chirality, mechanisms driven by cell chirality might be a common platform for the development of organ-intrinsic LR asymmetry.


III. EVODEVO, GENOMES, AND THE DIVERSIFICATION OF MOLLUSCS

(1) Molluscan organogenesis and body plan evolution

(a) Shells

(b) Musculature and seriality

Together with the recent advances in molluscan phylogeny including the revived Aculifera–Conchifera concept, a wide array of novel data on molluscan genomics and comparative development (EvoDevo) have become available, providing an important window into evolutionary pathways and common ground patterns of various lineages. Accordingly, it was shown that during ontogeny, neomeniomorph aplacophorans recruit their body wall muscles from a complex arrangement of larval muscular subsets that are gradually incorporated into the adult tube-like body (Scherholz et al., 2013 , 2015 ). A number of these larval muscle systems are shared exclusively by neomeniomorphs and polyplacophorans (the chaetodermomorph condition is still unknown) and include a laterally positioned enrolling muscle, a dorsal rectus muscle that spans the anterior–posterior axis of the animal, as well as several ventral longitudinal systems (Fig. 1). While most of these muscular units are retained and elaborated in adult polyplacophorans, they are largely remodelled and incorporated into the developing postmetamorphic body wall musculature of neomeniomorphs (Scherholz et al., 2013 , 2015 ). Interestingly, both, juvenile polyplacophorans and neomeniomorph larvae show a transitory stage of a sevenfold seriality in their dorso-ventral musculature (Wanninger & Haszprunar, 2002 Scherholz et al., 2013 , 2015 ). While in the former the eighth set is added together with the remaining posterior shell plate a considerable time after metamorphosis, multiple pairs are added to the seven primary dorso-ventral muscles in postmetamorphic neomeniomorphs.

A transitory sevenfold seriality shared by aplacophorans and polyplacophorans is also known from chaetodermomorph larvae that show seven rows of epidermal papillae (Nielsen et al., 2007 ), as well as from a reported neomeniomorph ‘postlarva’ with seven rows of spicules (Scheltema & Ivanov, 2002 ). This is congruent with the fossil record, from which aplacophorans (!) with seven shell plates (Sutton et al., 2004 , 2012 ) as well as a sub-group of polyplacophorans, the multiplacophorans, with 17 shell plates arranged in seven (!) rows (Vendrasco, Wood, & Runnegar, 2004 Vinther et al., 2012 a), have been described. Taken together, these data show that the last common aculiferan ancestor had an overall polyplacophoran-like morphology with a suite of highly complex muscle systems and a series of seven dorso-ventral muscles, most likely accompanied by seven shell plates (Fig. 1). The multiplacophorans and some (extinct) aplacophorans (Kulindroplax and Acaenoplax) retained this sevenfold arrangement of shell plates (multiplied in rows 2–6 in multiplacophorans), while extant polyplacophorans acquired an eighth plate secondarily and recent aplacophorans lost their shell plates altogether (Fig. 1). The cylindrical anatomy of aplacophorans constitutes a secondary condition that evolved along with the integration of the individual longitudinal muscle sets into the body wall that eventually resulted in their worm-like phenotype (Scherholz et al., 2013 , 2015 ). Notably, secondary vermification is not limited to the aculiferans but is a recurring phenomenon within molluscan sublineages, e.g., in heterobranch gastropods (e.g. Rhodope, Helminthope Brenzinger, Wilson, & Schrödl, 2011 Brenzinger, Haszprunar, & Schrödl, 2013 ) and teredinid bivalves (shipworms) (Turner, 1966 ).

While the picture of aculiferan evolution and diversification appears to become clearer owing to integrative data sets from various disciplines, the conchiferan condition remains blurry. Not only are conchiferan interrelationships still highly controversial (Haszprunar & Wanninger, 2012 Schrödl & Stöger, 2014 ), but the vast phenotypic diversity of its individual class-level clades renders ground-pattern reconstruction difficult no matter what kind of topology will eventually be agreed on. With their simple single shell and repetitive organ systems including gills, nephridia, commissures, and, most importantly, eight sets of dorso-ventral muscles, the monoplacophorans intuitively make good candidates to be directly compared to the aculiferan condition. Interestingly, fossil bivalves with eight (McAlester, 1965 ) and nautiloid cephalopods with 9 or 10 (Kröger & Mutvei, 2005 ) sets of dorso-ventral muscles are known, while most recent conchiferans only have one (bivalves often have three) (Haszprunar & Wanninger, 2000 ) (Fig. 1). In the light of these findings one may be tempted to propose a gradual ‘de-serialization’ within the Conchifera, starting with a Kimberella-monoplacophoran-like ancestor and terminating with one single dorso-ventral muscle in derived gastropods and recent cephalopods (Haszprunar & Wanninger, 2000 ). However, the uncertainties in conchiferan phylogeny currently hamper a final conclusion. Moreover, it must be borne in mind that muscular development and evolution appears to be a dynamic process in molluscs with a considerable degree of plasticity, rendering assessments of homologous traits versus homoplasies problematic. In addition, details on monoplacophoran ontogeny are still entirely lacking and it thus remains unknown as to how adult seriality develops in this clade and whether or not informative transitory elements occur during development (Wanninger & Wollesen, 2015 ).

(2) Molluscan body axes and morphological novelties

Alongside the emerging patterns of molluscan phenotypic evolution based on morphogenetic and palaeontological data, significant insights have been gained concerning the molecular mechanisms that govern their development (Wanninger & Wollesen, 2015 ). Thereby, the release of the genomes of various gastropods including the Pacific abalone Haliotis discus hannai (Nam et al., 2017 ), the freshwater snail Biomphalaria glabrata (Adema et al., 2017 ), and the basally branching owl limpet Lottia gigantea (Simakov et al., 2013 ) together with several bivalves [e.g. Crassostrea gigas (Thunberg, 1793) (Zhang et al., 2012 ), Patinopecten yessoensis (Jay, 1857) (Wang et al., 2017 ), and other scallop, oyster, and mussel species (Takeuchi et al., 2012 Du et al., 2017 Li et al., 2017 , 2018 Sun et al., 2017 )] and the California two-spot octopus Octopus bimaculoides Pickford & McConnaughey, 1949 (Albertin et al., 2015 ) provided an important framework for studies into key developmental regulators such as Hox and ParaHox genes as well as signalling molecules involved in dorso-ventral axis patterning (bone morphogenetic protein (BMP)/decapentaplegic (Dpp) pathway) and left/right determination (Nodal pathway).

(a) Hox genes, anterior–posterior axes, and molluscan innovations

The finding of non-colinear Hox gene expression in gastropods corroborated an earlier study on the Hawaiian bobtail squid, Euprymna scolopes, where Hox genes similarly were not found to contribute to axial patterning but rather were expressed in distinct organ systems including the gills, arms, funnel, and light organ (Lee et al., 2003 ) (Fig. 3). Again, the genomic architecture of this species still awaits publication, but the recently released genome of the octopus Octopus bimaculoides showed an entirely disrupted Hox cluster, where the various sequences are placed in distant regions on the genome (Albertin et al., 2015 ). Screening of the Octopus genome also revealed hundreds of novel genes that are expressed at high levels in cephalopod-specific structures such as the suckers, skin, or certain neural components. This, together with the finding that in Octopus considerable genome shuffling and expansion of individual gene families such as zinc-finger proteins, chitinases, G-protein-coupled receptors, or protocadherins has taken place [whereby the overall content of gene families is not significantly larger compared to other invertebrates (Albertin et al., 2015 )], indicates that the emergence of the complex cephalopod body plan was likely due to a combination of mechanisms including the evolution of novel genes, multiplication of individual genes, as well as loss-of-function and acquisition of novel functions of conserved gene networks. Importantly, a recent study found that unlike other bilaterians, coleoids, i.e. all cephalopods except for nautiluses, diversify their proteomes to a hitherto unknown extent by RNA editing (Liscovitch-Brauer et al., 2017 ). This recoding appears to be evolutionarily conserved and adaptive among coleoids and may be one reason for their sophisticated cognitive abilities.

As with Octopus, analyses of the genome of four bivalves, namely the Pacific oyster Crassostrea gigas, the pearl oyster Pinctada fucata (Gould, 1850), and two deep-sea mussels, showed a disorganized arrangement of the Hox genes (Zhang et al., 2012 Sun et al., 2017 Wang et al., 2017 ). In C. gigas and P. fucata, the Hox cluster appeared to be split into four or five distinct regions which are all framed by non-Hox sequences (Zhang et al., 2012 Wang et al., 2017 ). Quantitative expression analyses of Crassostrea gigas stages are in line with the split Hox cluster insofar as no temporal correlation was found between expression of a given Hox gene in a certain ontogenetic stage and its relative position to other Hox genes on the genome (Zhang et al., 2012 ). However, in two other bivalves, the scallops Patinopecten yessoensis and Chlamys farreri, the Hox genes do appear to form a true cluster (Li et al., 2017 Wang et al., 2017 ). While precise tempo-spatial expression analyses of Hox genes spanning entire embryonic and larval development are still lacking, transcript localization in gastrulae of Patinopecten yessoensis suggests some degree of staggered expression of four Hox genes (Hox1, Hox4, Lox5, Post2) in this stage, and quantitative analyses revealed staggered temporal expression of individual Hox genes within four (virtual) Patinopecten yessoensis subclusters (Wang et al., 2017 ). This calls for further detailed positional mapping of Hox transcripts in crucial developmental stages by in situ hybridization analyses to assess the degree to which bivalves have retained the polyplacophoran-like anterior–posterior axial expression gradient and/or whether they (also) follow the gastropod–cephalopod pathway of organ-specific Hox gene expression.

Taken together, molluscs, and in particular the conchiferans, appear to show a complex interplay employing multiple changes in genomic architecture and gene functions that most likely contributed to the evolution of lineage-specific morphological novelties. The expected release of additional genomes in the near future will provide an important resource to test which of these molecular mechanisms have contributed to the various apomorphic features of individual molluscan subtaxa.

(b) The Dpp/BMP pathway and dorso-ventral patterning

Bilaterian animals are not only characterized by a distinct anterior–posterior axis but also by defined dorsal and ventral body regions. The underlying regulatory network that commonly determines dorso-ventral polarity is the Dpp/BMP signalling pathway (De Robertis & Sasai, 1996 Ferguson, 1996 De Robertis & Kuroda, 2004 Ashe & Briscoe, 2006 Lowe et al., 2006 Cebria, Salo, & Adell, 2015 ). Briefly, the morphogen-encoding gene Dpp (the invertebrate homolog of the vertebrate Bmp2/4) is largely expressed dorsally in protostome animals, while its antagonists such as Chordin or Noggin have a predominantly ventral expression domain (Tan, Huan & Liu, 2017 ). This system is inverted in chordates with ventral BMP expression and dorsal expression of the antagonists. In extracellular regions of higher Dpp/BMP concentration, these proteins bind to receptors on the cell surface, resulting in the phosphorylation of so-called SMADs (proteins related to the Drosophila mothers against decapentaplegic and the Caneorhabditis elegans small worm phenotype protein families), that subsequently migrate into the cell nucleus where they activate downstream target genes (Anderson & Darshan, 2008 ). One result of this gene/protein cascade is, among others, the formation of the longitudinal neural cords of the central nervous system in regions of suppressed Dpp/BMP signalling, i.e. where the concentration of Dpp/BMP antagonists is high, thus defining the dorsal side of chordates and the ventral side of protostomes (Miller-Bertoglio et al., 1997 Furthauer, Thisse, & Thisse, 1999 Hild et al., 1999 Kondo, 2007 ). In molluscs, Dpp has been shown to be expressed in the shell field of bivalves (Kin, Kakoi, & Wada, 2009 Tan, Huan, & Liu, 2017 ) and gastropods (Nederbragt, Van Loon, & Dictus, 2002 Koop et al., 2007 Iijima et al., 2008 Hashimoto, Kurita, & Wada, 2012 ), thus in dorsal ectodermal domains similar to other protostomes. However, since no further data were available, the question whether these expression patterns hint towards a novel function of Dpp in molluscan shell formation or whether Dpp is (also) involved in establishing neural and dorso-ventral identity remained elusive. To this end, a recent experimental study on the model gastropod Ilyanassa obsoleta revealed that Dpp is intensely expressed on the dorsal side and co-localized with phosphorylated SMADs, indicating that BMP-signalling is functional on the dorsal side (Lambert et al., 2016 ). When Dpp was knocked down, no dorsal identity developed, resulting in a rather ‘ventralized’ embryo. Surprisingly, however, and different to other protostomes, ectopic activation of the Dpp/BMP pathway led to the formation of additional neural tissues in the gastropod and not to their repression, as would have been predicted from findings in other bilaterian animals (Lambert et al., 2016 ). This would suggest that the Dpp/BMP pathway in Ilyanassa obsoleta comprises a combination of ancestral (specification of the dorso-ventral axis) and novel (induction of neuroectoderm formation) functions. Since no further data are available for other molluscan taxa, it is currently impossible to assess the broader implications of these findings for molluscan body plan evolution. However, the study demonstrates that, similar to the Hox genes, the Dpp/BMP pathway seems to exhibit a certain degree of plasticity within Mollusca.

The adult scaphopod and cephalopod body plans have traditionally been thought to have evolved by secondary elongation of the dorso-ventral axis, probably from a monoplacophoran-like ancestor, which eventually became dominant over the anterior–posterior one (Naef, 1928 Yochelson, Flower, & Webers, 1973 Kröger, Vinther, & Fuchs, 2011 ). Expression pattern analyses and experiments involving components of the Dpp/BMP pathway similar to that performed in Ilyanassa obsoleta may provide cues in favour or against this classical hypothesis of molluscan phenotypic evolution.

(c) The Nodal pathway and body plan asymmetries

Although bilaterian animals are by definition characterized by a single primary symmetry plane, many representatives are not symmetrical at all with respect to the morphology and position of certain organ systems in their body. In molluscs, body asymmetry is most obvious in gastropods, where ontogenetic torsion – a process where the body region comprising the head and foot rotates by 180° relative to the mantle cavity – results in a U-shaped gut, intercrossing visceral nerve cords (streptoneury), and an anteriorly positioned mantle cavity (Wanninger et al., 1999 Wanninger, Ruthensteiner, & Haszprunar, 2000 Page, 2006 ). This event has been partly reversed during the evolution of heterobranch gastropods, resulting in an asymmetrically positioned mantle cavity, heart, gills, hindgut, and other features, usually on the right side (dextrally, i.e. clockwise-coiling individuals). Early work on the pulmonates Biomphalaria glabrata (ram's horn snail) and Lymnaea stagnalis (pond snail), that both have sinistrally and dextrally coiling individuals, revealed that handedness is maternally inherited (Boycott & Diver, 1923 Sturtevant, 1923 Boycott et al., 1930 ), with the dextral phenotype being dominant over the sinistral one (Shibazaki, Shimizu, & Kuroda, 2004 Liu et al., 2015 ). As predicted by studies on deuterostomes, asymmetric expression of genes of the Nodal signalling pathway, Nodal and Pitx, was found in various gastropods depending on their chirality: in the dextral limpet Lottia gigantea, both genes are exclusively expressed on the right side, while in sinistral Biomphalaria glabrata specimens both genes are expressed on the left side (Grande & Patel, 2009 ). This finding is consistent with studies on two other gastropods, Ilyanassa obsoleta (Say, 1822) and Crepidula fornicata (Linnaeus, 1758), where mRNAs are asymmetrically distributed already at early cleavage stages (Lambert & Nagy, 2002 Henry et al., 2010 Rabinowitz & Lambert, 2010 ). Inhibition of Nodal signalling before the blastula stage in Biomphalaria glabrata resulted in loss of Pitx expression and non-chiral individuals with an uncoiled, tubular shell (Grande & Patel, 2009 ). Experimental manipulation of the genetically determined spiral cleavage program in Lymnaea stagnalis (by shifting the micromeres by 90° at third cleavage and thereby artificially producing sinistralized and dextralized embryos, respectively) was accompanied by reversed Nodal/Pitx expression. The resulting fertile females maintained the externally imposed chirality but in turn produced offspring with the genetically determined handedness and not the one forced upon their mothers (Kuroda et al., 2009 ).

A detailed look into the earliest symmetry-breaking events upstream of Nodal signalling revealed that in Lymnaea stagnalis one of two identified diaphanous-related formin genes, Ldia2, is expressed asymmetrically as early as in two-cell-stage embryos (Davison et al., 2016 ). The definite role of formin in establishing chirality in Lymnaea stagnalis was confirmed by inhibitory experiments applied to genetically dextral embryos after the second cleavage, whereby the formin-dependent formation of actin-containing components of the cytoskeleton was disrupted. This resulted in embryos with four, non-chirally arranged micromeres similar to wild-type sinistral embryos (Davison et al., 2016 ). These findings demonstrate that chirality is already established at a molecular level in this gastropod in early cleaving embryos and thus long before morphologically detectable asymmetries occur. Dia was also found to be involved in left–right patterning in the African clawed frog, Xenopus laevis, thus suggesting a conserved role of formin in establishing chirality in bilaterians (Davison et al., 2016 ). Interestingly, however, in two other pulmonate snail genera where both chiral patterns do occur, Euhadra and Partula, dia is not involved in left–right patterning (Davison et al., 2016 ). This points towards a complex regulatory network underlying the establishment of body plan asymmetries in gastropods. Importantly, these findings once more confirm the commonly emerging picture that developmental pathways and gene functions appear to be highly plastic in molluscs, with a strong tendency towards co-option as well as loss-of-function events occurring even at low hierarchical taxonomic levels.


Are there any theories why such an imbalance in chirality of molluscs? - Biology

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On “Darwinian Mysteries” or Molluscs as Models in Evolutionary Biology: From Local Speciation to Global Radiation

Matthias Glaubrecht 1,*

1 Department of Malacozoology, Museum of Natural History, Leibniz Institute for Research in Evolution

* Corresponding author: [email protected]

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Evolutionary biology is not only a biological subdiscipline but also a synthetic theory based on comprehensive scientific achievements. However, to date biodiversity, which is far from being fully documented, and the evolutionary processes leading to it are two of the least understood phenomena in evolutionary biology. Surprisingly, decades after the Modern Synthesis and centuries after the commencement of research in biological systematics, we are still unable to satisfyingly answer apparently simple yet fundamental questions. Here termed “Darwinian mysteries”, these are for example, how many species inhabit Earth today, what are species, where are they distributed, and how did biodiversity originate. While many contributions in malacology center around morphology, anatomy, and phylogenetic relationships within and among constituent taxa, molluscs only rarely have been utilized explicitly as models for the study of general aspects in evolutionary biology. However, this particular group, with its many features and facets, is highly suitable for providing fundamental insights into the mechanisms that generate biodiversity, pattern in historical biogeography, and the underlying processes of speciation and radiation. Here, I discuss some aspects of these fundamental questions that are of relevance for evolutionary biology, hoping that the influence of malacology within evolutionary biology will increase in the future.


Chiral magnetic effect generates quantum current

IMAGE: This photos shows nuclear theorist Dmitri Kharzeev of Stony Brook University and Brookhaven Lab with Brookhaven Lab materials scientists Qiang Li, Genda Gu, and Tonica Valla in a lab where. view more

Credit: Brookhaven National Laboratory

UPTON, NY--Scientists at the U.S Department of Energy's (DOE) Brookhaven National Laboratory and Stony Brook University have discovered a new way to generate very low-resistance electric current in a new class of materials. The discovery, which relies on the separation of right- and left-"handed" particles, points to a range of potential applications in energy, quantum computing, and medical imaging, and possibly even a new mechanism for inducing superconductivity--the ability of some materials to carry current with no energy loss.

The material the scientists worked with, zirconium pentatelluride, has a surprising trait: When placed in parallel electric and magnetic fields, it responds with an imbalance in the number of right- and left-handed particles--a chiral imbalance. That imbalance pushes oppositely charged particles in opposite directions to create a powerful electric current.

This "chiral magnetic effect" had long been predicted theoretically, but never observed definitively in a materials science laboratory at the time this work was done.

In fact, when physicists in Brookhaven's Condensed Matter Physics & Materials Science Department (CMP&MS) first measured the significant drop in electrical resistance, and the accompanying dramatic increase in conductivity, they were quite surprised. "We didn't know this large magnitude of 'negative magnetoresistance' was possible," said Qiang Li, a physicist and head of the advanced energy materials group in the department and a co-author on a paper describing these results just published in the journal Nature Physics. But after teaming up with Dmitri Kharzeev, the head of the RIKEN-BNL theory group at Brookhaven and a professor at Stony Brook, the scientists had an explanation.

Kharzeev had explored similar behavior* of subatomic particles in the magnetic fields created in collisions at the Lab's Relativistic Heavy Ion Collider (RHIC, https:/ / www. bnl. gov/ rhic/ ), a DOE Office of Science User Facility where nuclear physicists explore the fundamental building blocks of matter. He suggested that in both the RHIC collisions and zirconium pentatelluride, the separation of charges could be triggered by a chiral imbalance.

To test the idea, they compared their measurements with the mathematical predictions of how powerful the increase in conductivity should be with increasing magnetic field strength.

"We looked at the data and we said, 'Gee, that's it!' We tested six different samples and confirmed that no matter how you do it, it's there as long as the magnetic field is parallel to the electrical current. That's the smoking gun," Li said.

Right- or left-handed chirality is determined by whether a particle's spin is aligned with or against its direction of motion. In order for chirality to be definitively established, particles have to behave as if they are nearly massless and able to move as such in all three spatial directions.

While free-flowing nearly massless particles are commonly found in the quark-gluon plasma created at RHIC, this was not expected to occur in condensed matter. However, in some recently discovered materials, including "Dirac semimetals"--named for the physicist who wrote the equations to describe fast-moving electrons--nearly massless "quasiparticle" versions of electrons (and positively charged "holes") propagate through the crystal in this free manner.

Some aspects of this phenomenon, namely the linear dependence of the particles' energy on their momentum, can be directly measured and visualized using angle-resolved photoemission spectroscopy (ARPES).

"On first sight, zirconium pentatelluride did not even look like a 3D material," said Brookhaven physicist Tonica Valla, who performed the measurements with collaborators at the Advanced Light Source (ALS) at Lawrence Berkeley National Laboratory and at Brookhaven's National Synchrotron Light Source (NSLS, https:/ / www. bnl. gov/ ps/ nsls/ about-NSLS. asp) -- two additional DOE Office of Science User Facilities. "It is layered, similar to graphite, so a quasi-2D electronic structure would be more expected. However, as soon as we did the first ARPES measurements, it was clear that the material is a 3D Dirac semimetal."

These results agreed nicely with the ones on conductivity and explained why the chiral magnetic effect was observed in this material.

In the absence of magnetic and electric fields, zirconium pentatelluride has an even split of right- and left- handed quasiparticles. But adding parallel magnetic and electric fields introduces a chiral preference: The magnetic field aligns the spins of the positive and negative particles in opposite directions, and the electric field starts the oppositely charged particles moving--positive particles move with the electric field, negative ones against it. If the two fields are pointing in the same direction, this creates a preference for positive and negative particles that are each moving in a direction aligned with their spin orientation--right-handed chiral particles--but with positive and negative particles moving away from one another. (If the magnetic field orientation is flipped relative to the electric field, the preference would be for left-handed particles, but still with opposite charges separating.)

"This chiral imbalance gives a big boost to the separation of the oppositely charged particles, which can be connected through an external circuit," Kharzeev said. And once the chiral state is set it's hard to alter, "so very little energy is lost in this chiral current."

The dramatic conductivity and low electrical resistance of Dirac semimetals may be key to potential applications, including "quantum electricity generators" and quantum computing, Li said.

"In a classic generator, the current increases linearly with increasing magnetic field strength, which needs to be changing dynamically. In these materials, current increases much more dramatically in a static magnetic field. You could pull current out of the 'sea' of available quasiparticles continuously. It's a pure quantum behavior," Li said.

Separating the two chiral states could also give a new way of encoding information--analogous to the zeros and ones of computing. And because the chiral state is very stable compared with other electrical states, it's much less prone to interference from external influences, including defects in the material. It could therefore be a more reliable material for quantum computing, Li said.

Kharzeev has some other ideas: "The resistance of this material drops as the magnetic field strength increases, which could open up a completely different route toward achieving something like superconductivity--zero resistance," he said. Right now the materials show at least some reduction in resistance at temperatures as high as 100 Kelvin--in the realm of the best high-temperature superconductors. But there are many different types of Dirac semimetals to experiment with to explore the possibility of higher temperatures or even more dramatic effects. Such low-resistance materials could help overcome a major limit in the speed of microprocessors by reducing the dissipation of current, Kharzeev added.

"In zirconium pentatelluride and other materials that have since been discovered to have the chiral magnetic effect, an external magnetic field is required to start reducing resistivity," Valla said. "However, we envision that in some magnetic materials, the electrical current could flow with little or no resistance in a direction parallel with the material's internal magnetic field. That would eliminate the need for external magnetic fields and would offer another avenue for dissipationless transport of electrical current."

Kharzeev and Li are also interested in exploring unusual optical properties in chiral materials. "These materials possess collective excitations in the terahertz frequency range, which could be important for wireless communications and also in imaging techniques that could improve the diagnosis of cancer," Kharzeev said.

Getting back to his nuclear physics roots, Kharzeev added, "The existence of massless quasiparticles that strongly interact makes this material quite similar to the quark-gluon plasma created in collisions at RHIC, where nearly massless quarks strongly interact through the exchange of gluons. So this makes Dirac semimetals an interesting arena for testing some of the ideas proposed in nuclear physics."

"This research illustrates a deep connection between two seemingly unrelated fields, and required contributions from an interdisciplinary team of condensed matter and nuclear physicists," said James Misewich, the Associate Laboratory Director for Energy Science at Brookhaven Lab and a professor of physics at Stony Brook University, who played the central role of introducing the members of this research team to one another. "We're fortunate to have scientists with expertise in these fields here at Brookhaven and nearby Stony Brook University, and the kind of collaborative spirit to make such a project come to fruition," he said.

This research was supported by the DOE Office of Science (BES). Research at RHIC is primarily supported by the Office of Science (NP).

Brookhaven National Laboratory is supported by the Office of Science of the U.S. Department of Energy. The Office of Science is the single largest supporter of basic research in the physical sciences in the United States, and is working to address some of the most pressing challenges of our time. For more information, please visit science.energy.gov.

One of ten national laboratories overseen and primarily funded by the Office of Science of the U.S. Department of Energy (DOE), Brookhaven National Laboratory conducts research in the physical, biomedical, and environmental sciences, as well as in energy technologies and national security. Brookhaven Lab also builds and operates major scientific facilities available to university, industry and government researchers. Brookhaven is operated and managed for DOE's Office of Science by Brookhaven Science Associates, a limited-liability company founded by the Research Foundation for the State University of New York on behalf of Stony Brook University, the largest academic user of Laboratory facilities, and Battelle, a nonprofit applied science and technology organization.

An electronic version of this news release with a photo: http://www. bnl. gov/ newsroom/ news. php?a= 11811. Prior to the embargo, reporters will be required to enter a password for access. The case-sensitive password is: BNLnews

Scientific paper: "Observation of the chiral magnetic effect in ZrTe5" [http://dx. doi. org/ 10. 1038/ nphys3648] Note that this link will not work until after the embargo lifts.

* Related work at RHIC: Scientists See Ripples of a Particle-Separating Wave In Primordial Plasma [https:/ / www. bnl. gov/ newsroom/ news. php?a= 25735]

Media contacts: Karen McNulty Walsh, (631) 344-8350, [email protected], or Peter Genzer, (631) 344-3174, [email protected]

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Are there any theories why such an imbalance in chirality of molluscs? - Biology

Snails are the only animal group to ordinarily produce mirror-image forms. They have the potential to be an unequalled natural genetic resource in understanding chirality, including the invariant LR asymmetry of other animal groups.

A formin gene is associated with variation in LR asymmetry in two snail species, although the mutation is pathological in both. The genes that produce chiral variation without pathology are still wholly unknown changes in gene expression or of accessory factors are likely.

Understanding LR asymmetry in snails will involve studies of early embryology and genomics, alongside whole-animal studies on the impact of natural and sexual selection.

Chiral variation in snails may be enabled by the dichotomous nature of spiralian cleavage (dextral or sinistral), combined with the action of selection on the outward shell phenotype.

In seeking to understand the establishment of left–right (LR) asymmetry, a limiting factor is that most animals are ordinarily invariant in their asymmetry, except when manipulated or mutated. It is therefore surprising that the wider scientific field does not appear to fully appreciate the remarkable fact that normal development in molluscs, especially snails, can flip between two chiral types without pathology. Here, I describe recent progress in understanding the evolution, development, and genetics of chiral variation in snails, and place it in context with other animals. I argue that the natural variation of snails is a crucial resource towards understanding the invariance in other animal groups and, ultimately, will be key in revealing the common factors that define cellular and organismal LR asymmetry.


The UnDisciplined Deep Dive: Looking To The Stars To Understand Evolution

Most of life’s intricacies can be explained by evolution — as organisms encounter new challenges, subsequent generations evolve a­nd become better equipped to survive.

But one evolutionary peculiarity has baffled scientists since its discovery in 1848, with no evident reason as to why life developed the way it did. The mystery is “chirality,” a scientific property that can be thought of in terms of human “handedness.” Just as a person has two hands that look symmetrically identical but can’t replace one another, a molecule is chiral if it has two structurally similar forms that cannot be superimposed on top of one another.

As it turns out, life favors one side.

“We know for a fact that long ago — we’re talking back to the origin of life — somehow there was a choice made, just by the laws of physics and chemistry, to use homochiral systems and molecules,” said David Deamer, a biomolecular engineering professor at the University of California Santa Cruz.

Why was that choice made? A new theory, published in Astrophysical Journal Letters on May 20, may help put that question to rest.

While scientists tend to look for Earthly pressures to explain evolution, physicists Noémie Globus and Roger Blandford believe the answer may be nothing short of cosmic.

On the one hand

DNA is an example of a chiral molecule. The famous double helix curves to the right in living organisms but has a defunct twin that curves to the left. This classifies DNA, along with other important biological molecules such as amino acids and RNA, as “homochiral,” meaning it exists today in only one form of handedness.

Racemic mixtures — sets of molecules that display both right and left-handed chiral forms — can be created in a lab, but chiral molecules don’t play well with their counterparts. If a wrong-handed sugar were to be inserted into a piece of DNA, for instance, the entire strand would cease to function.

Humans are chiral beings and can be harmed if this “handedness” is incongruous in consumable substances such as medications. In the mid-20th century, before scientists understood the importance of distinguishing between chiral molecules and their mirrors, a mix-up in a drug called thalidomide, intended to reduce morning sickness, caused some pregnancies to end in miscarriages and others to produce children with severe birth defects.

“When we produce drugs in laboratories, we produce 50-50 of each mirror image, and one of them can have the intended effects, but the other can be lethal,” Globus said.

Looking to Occam

As is often the case in biomedical science, fixing the problem proved easier than understanding why it exists in the first place. Over the years, drug developers have come up with a number of ways to separate and produce molecules with only the intended chiral arrangement. But the question nonetheless vexed researchers – particularly those who were looking at the mystery through the lens of classical evolution.

“You’ve probably heard the term Occam’s razor, which is a sort of philosophical thing that says if you have a complicated explanation and a simple explanation, choose the simple explanation,” Deamer said. “Most scientists take Occam’s razor into consideration, and the simplest idea would be that there is no cause for it.”

Or, at least, no Earthly explanation. And it turns out that’s what Louis Pasteur figured, too. The renowned biologist first uncovered the phenomenon of chirality in 1848 while inspecting tartaric acid build up in wine vats. Unable to provide an explanation that would satisfy his understanding of biology, Pasteur later proposed that some mysterious, dissymmetric cosmic force was behind the homochirality of many biomolecules.

A continuous cosmic shower

Globus and Blandford’s paper and its proposed experiments build on Pasteur’s early postulation. The researchers believe the cause of homochirality may lie in the interaction between cosmic rays and ancient helical molecules — the initial building blocks of life.

When cosmic rays hit Earth’s atmosphere, they break down into secondary particles called muons, which in turn break down to magnetically polarized electrons. This, the hypothesis suggests, is where the dissymmetric forces promote one chiral form over the other. The researchers believe because of their uniform polarization, “spin-polarized” particles cause more damage to a certain chiral form than its mirror, thus promoting evolution-favoring mutation in one chiral form and the eventual disappearance of the other.

“In the long run, if you have a different mutation rate between life and its mirror image… if you induce this bias which is permanent — because cosmic rays are falling continuously on us — then you can make a preference in the long term,” Globus said.

Deamer, who has gained fame for his novel ideas about the origins of life on Earth, was smitten with the hypothesis. No other scientists have thought about the problem in this way, he said.

“So that’s why we’re having this conversation, because everybody loves new ideas,” Deamer said. “And Noémie, to her credit, is trying to test it.”

Recreating early Earth

The testing itself will be an interdisciplinary effort, requiring collaboration among scientists from different fields including physics and biology.

Deamer, who served as an adviser for Globus on the paper, helped come up with an initial way to begin testing the theory. The scientists plan to conduct an Ames test, which is designed to assess the mutagenic effect of substances on the bacteria salmonella. In the experiment, the scientists will subject the helical bacteria to opposite forms of polarized radiation to discover if there is a difference in the amount of damage each inflicts.

“Here’s the most important point: If the spin-polarized electrons are in one direction, they may not produce this effect, because it is the wrong direction to produce damage in the DNA,” Deamer said. “But if the spin polarization is in the right direction to interact with the DNA, they will be more mutagenic than the spin polarized in the other direction. And that would be a first and very nice, very strong test, I think, of her idea.”

In other words, they are looking for proof that these polarized particles can precipitate damage — and thus mutation — in helical molecules, as they believed happened billions of years ago.

“It is really exciting,” Globus said. “If the bacteria would respond to polarized radiation of opposite polarities, I would be thrilled.”

Answers beget questions

Proof is an elusive quarry. Even if the experiments work, Deamer cautions that—while drawing a step closer to validation—the theory will remain largely unproved.

“If the experiment works,” Deamer said, “that will be novel and interesting. Whether it is significant is a different matter… There is going to be a lot more work going back in time, because we just don’t know how much cosmic radiation was coming into the Earth back then we don’t know about the atmosphere. So there’s a whole bunch of unknowns.”

Deamer noted that the hypothesis begins with the premise that helical molecules existed to be radiated, “and yet a helical molecule already has to be homochiral, or it can’t be helical,” he continued. “So there’s a big gap in the story right there — where did the first helical molecules arise?”

Richard Rosenberg, a senior chemist at Argonne National Laboratory, believes spin-polarized particles could indeed be behind the homochirality we see on Earth today — but in his view, it's likely low-energy particles.

Cosmic rays are a form of high-energy radiation that thermalize when they interact with a solid, said Rosenberg, who has studied and written about theories similar to that of Globus and Blandford. “In other words,” he said, “they cascade about, lose their energy, lose their spin polarization, and they create a lot of low-energy electrons which aren’t polarized, which don’t have one polarization more than the other.”

Rosenberg noted, however, that he wasn't dismissing the new theory outright. “I’m not saying that it is out of the question or anything," he said, "but it makes it less probable.”

Here — and there?

Questions regarding chiral preference are not limited to Earth. In fact, Globus first became interested in the subject during college, when one of her professors was tasked with studying the chirality of amino acids found on a meteorite as part of the Rosetta space probe launch.

The scientists discovered there were more left-handed amino acids than right-handed ones on the meteorite. And researchers are now studying other cosmic bodies, trying to discover if homochirality may truly extend further than the confines of Earth.

These findings have far-reaching implications, and some researchers believe that meteorites delivered the biased amino acids to Earth and thus were the cause of biological homochirality.

Brett McGuire, an assistant professor of chemistry at MIT, is not so sure.

McGuire was part of the team that uncovered the first chiral molecule in interstellar space in 2016 — a discovery which may allow scientists to better study how the imbalance of chiral amino acids on meteorites came to be.

However, he is not convinced that the meteorite theory is correct — or even that homochirality is due to cosmic forces.

“There are a number of possibilities that all have — I wouldn't say an equal likelihood — but they are all reasonable possibilities,” he said. “I would not place a bet on any of them versus any of the others. I think that there is no strong evidence pointing us in one direction or the other.”

McGuire said that’s precisely why it’s important to do studies like the one Globus and Deamer are undertaking. “Maybe that really is the answer,” he said. “It certainly could be. And we need to figure out what the most efficient pathway is.”

Trying to find the actual cause of homochirality requires first testing theories in a lab — like Globus and Blandford plan to do — and then trying to piece together what conditions were like billions of years ago to see if the theory matches up with the circumstance.

But there is another challenge: Even if something works theoretically, it doesn’t mean that’s what actually nudged life toward homochirality.

“In fact, probably all of them would work to some degree,” McGuire said of the multitude of theories that have been discussed. “So which one was the dominant force that drove it in one direction or the other?”

Star search

According to Globus, NASA is currently planning a mission to Europa, one of Jupiter’s moons, to study molecules on its surface. Although the planetary body is icy and has little atmosphere, if cosmic rays were to interact with the moon’s ice and create muons with the same polarization as the ones on Earth, they could potentially produce the same homochiral effect on molecules there.

If that were so, it would strengthen their theory.

“This is why we actually like this mechanism,” Globus said. “If it can make a differential effect on mutation of life in every form, then it should work everywhere — everywhere you can have this polarized component.”

And that, she noted, would include life elsewhere in the universe.

Daedan Olander is a student in the Department of Journalism and Communication at Utah State University. The UnDisciplined Deep Dive is funded by a grant from the Maxium and Doreen LaPlante Fund for Health and Science Journalism.


Chiral magnetic effect generates quantum current

Nuclear theorist Dmitri Kharzeev of Stony Brook University and Brookhaven Lab with Brookhaven Lab materials scientists Qiang Li, Genda Gu, and Tonica Valla in a lab where the team measured the unusual high conductivity of zirconium pentatelluride. Credit: Brookhaven National Laboratory

Scientists at the U.S Department of Energy's (DOE) Brookhaven National Laboratory and Stony Brook University have discovered a new way to generate very low-resistance electric current in a new class of materials. The discovery, which relies on the separation of right- and left-"handed" particles, points to a range of potential applications in energy, quantum computing, and medical imaging, and possibly even a new mechanism for inducing superconductivity—the ability of some materials to carry current with no energy loss.

The material the scientists worked with, zirconium pentatelluride, has a surprising trait: When placed in parallel electric and magnetic fields, it responds with an imbalance in the number of right- and left-handed particles—a chiral imbalance. That imbalance pushes oppositely charged particles in opposite directions to create a powerful electric current.

This "chiral magnetic effect" had long been predicted theoretically, but never observed definitively in a materials science laboratory at the time this work was done.

In fact, when physicists in Brookhaven's Condensed Matter Physics & Materials Science Department (CMP&MS) first measured the significant drop in electrical resistance, and the accompanying dramatic increase in conductivity, they were quite surprised. "We didn't know this large magnitude of 'negative magnetoresistance' was possible," said Qiang Li, a physicist and head of the advanced energy materials group in the department and a co-author on a paper describing these results just published in the journal Nature Physics. But after teaming up with Dmitri Kharzeev, the head of the RIKEN-BNL theory group at Brookhaven and a professor at Stony Brook, the scientists had an explanation.

Kharzeev had explored similar behavior of subatomic particles in the magnetic fields created in collisions at the Lab's Relativistic Heavy Ion Collider (RHIC), a DOE Office of Science User Facility where nuclear physicists explore the fundamental building blocks of matter. He suggested that in both the RHIC collisions and zirconium pentatelluride, the separation of charges could be triggered by a chiral imbalance.

To test the idea, they compared their measurements with the mathematical predictions of how powerful the increase in conductivity should be with increasing magnetic field strength.

"We looked at the data and we said, 'Gee, that's it!' We tested six different samples and confirmed that no matter how you do it, it's there as long as the magnetic field is parallel to the electrical current. That's the smoking gun," Li said.

Right- or left-handed chirality is determined by whether a particle's spin is aligned with or against its direction of motion. In order for chirality to be definitively established, particles have to behave as if they are nearly massless and able to move as such in all three spatial directions.

While free-flowing nearly massless particles are commonly found in the quark-gluon plasma created at RHIC, this was not expected to occur in condensed matter. However, in some recently discovered materials, including "Dirac semimetals"—named for the physicist who wrote the equations to describe fast-moving electrons—nearly massless "quasiparticle" versions of electrons (and positively charged "holes") propagate through the crystal in this free manner.

Some aspects of this phenomenon, namely the linear dependence of the particles' energy on their momentum, can be directly measured and visualized using angle-resolved photoemission spectroscopy (ARPES).

"On first sight, zirconium pentatelluride did not even look like a 3D material," said Brookhaven physicist Tonica Valla, who performed the measurements with collaborators at the Advanced Light Source (ALS) at Lawrence Berkeley National Laboratory and at Brookhaven's National Synchrotron Light Source (NSLS, https://www.bnl.gov/ps/nsls/about-NSLS.asp)—two additional DOE Office of Science User Facilities. "It is layered, similar to graphite, so a quasi-2D electronic structure would be more expected. However, as soon as we did the first ARPES measurements, it was clear that the material is a 3D Dirac semimetal."

These results agreed nicely with the ones on conductivity and explained why the chiral magnetic effect was observed in this material.

In the absence of magnetic and electric fields, zirconium pentatelluride has an even split of right- and left- handed quasiparticles. But adding parallel magnetic and electric fields introduces a chiral preference: The magnetic field aligns the spins of the positive and negative particles in opposite directions, and the electric field starts the oppositely charged particles moving—positive particles move with the electric field, negative ones against it. If the two fields are pointing in the same direction, this creates a preference for positive and negative particles that are each moving in a direction aligned with their spin orientation—right-handed chiral particles—but with positive and negative particles moving away from one another. (If the magnetic field orientation is flipped relative to the electric field, the preference would be for left-handed particles, but still with opposite charges separating.)

"This chiral imbalance gives a big boost to the separation of the oppositely charged particles, which can be connected through an external circuit," Kharzeev said. And once the chiral state is set it's hard to alter, "so very little energy is lost in this chiral current."

Potential applications

The dramatic conductivity and low electrical resistance of Dirac semimetals may be key to potential applications, including "quantum electricity generators" and quantum computing, Li said.

"In a classic generator, the current increases linearly with increasing magnetic field strength, which needs to be changing dynamically. In these materials, current increases much more dramatically in a static magnetic field. You could pull current out of the 'sea' of available quasiparticles continuously. It's a pure quantum behavior," Li said.

Separating the two chiral states could also give a new way of encoding information—analogous to the zeros and ones of computing. And because the chiral state is very stable compared with other electrical states, it's much less prone to interference from external influences, including defects in the material. It could therefore be a more reliable material for quantum computing, Li said.

Kharzeev has some other ideas: "The resistance of this material drops as the magnetic field strength increases, which could open up a completely different route toward achieving something like superconductivity—zero resistance," he said. Right now the materials show at least some reduction in resistance at temperatures as high as 100 Kelvin—in the realm of the best high-temperature superconductors. But there are many different types of Dirac semimetals to experiment with to explore the possibility of higher temperatures or even more dramatic effects. Such low-resistance materials could help overcome a major limit in the speed of microprocessors by reducing the dissipation of current, Kharzeev added.

"In zirconium pentatelluride and other materials that have since been discovered to have the chiral magnetic effect, an external magnetic field is required to start reducing resistivity," Valla said. "However, we envision that in some magnetic materials, the electrical current could flow with little or no resistance in a direction parallel with the material's internal magnetic field. That would eliminate the need for external magnetic fields and would offer another avenue for dissipationless transport of electrical current."

Kharzeev and Li are also interested in exploring unusual optical properties in chiral materials. "These materials possess collective excitations in the terahertz frequency range, which could be important for wireless communications and also in imaging techniques that could improve the diagnosis of cancer," Kharzeev said.

Getting back to his nuclear physics roots, Kharzeev added, "The existence of massless quasiparticles that strongly interact makes this material quite similar to the quark-gluon plasma created in collisions at RHIC, where nearly massless quarks strongly interact through the exchange of gluons. So this makes Dirac semimetals an interesting arena for testing some of the ideas proposed in nuclear physics."

"This research illustrates a deep connection between two seemingly unrelated fields, and required contributions from an interdisciplinary team of condensed matter and nuclear physicists," said James Misewich, the Associate Laboratory Director for Energy Science at Brookhaven Lab and a professor of physics at Stony Brook University, who played the central role of introducing the members of this research team to one another. "We're fortunate to have scientists with expertise in these fields here at Brookhaven and nearby Stony Brook University, and the kind of collaborative spirit to make such a project come to fruition," he said.