Philosophical Biology by Sepehr Ehsani
PhilSci-Archive, 2021
Following an analysis of the state of investigations and clinical outcomes in the Alzheimer's res... more Following an analysis of the state of investigations and clinical outcomes in the Alzheimer's research field, I argue that the widely-accepted 'amyloid cascade' mechanistic explanation of Alzheimer's disease appears to be fundamentally incomplete. In this context, I propose that a framework termed 'principled mechanism' (PM) can help with remedying this problem. First, using a series of five 'tests', PM systematically compares different components of a given mechanistic explanation against a paradigmatic set of criteria, and hints at various ways of making the mechanistic explanation more 'complete'. These steps will be demonstrated using the amyloid explanation, and its missing or problematic mechanistic elements will be highlighted. Second, PM makes an appeal for the discovery and application of 'biological principles' (BPs), which approximate ceteris paribus laws and are operative at the level of a biological cell. As such, although thermodynamic, evolutionary, ecological and other laws or principles from chemistry and the broader life sciences could inform them, BPs should be considered ontologically unique. BPs could augment different facets of the mechanistic explanation but also allow further independent nomological explanation of the phenomenon. Whilst this overall strategy can be complementary to certain 'New Mechanist' approaches, an important distinction of the PM framework is its equal attention to the explanatory utility of biological principles. Lastly, I detail two hypothetical BPs, and show how they could each inform and improve the potentially incomplete mechanistic aspects of the amyloid explanation and also how they could provide independent explanations of the cellular features associated with Alzheimer's disease.
Innovative Technologies for Market Leadership, 2020
The mantra that "the best way to predict the future is to invent it" (attributed to the computer ... more The mantra that "the best way to predict the future is to invent it" (attributed to the computer scientist Alan Kay) exemplifies some of the expectations from the technical and innovative sides of biomedical research at present. However, for technical advancements to make real impacts both on patient health and genuine scientific understanding, quite a number of lingering challenges facing the entire spectrum from protein biology all the way to randomized controlled trials should start to be overcome. The proposal in this chapter is that philosophy is essential in this process. By reviewing select examples from the history of science and philosophy, disciplines which were indistinguishable until the mid-nineteenth century, I argue that progress toward the many impasses in biomedicine can be achieved by emphasizing theoretical work (in the true sense of the word "theory") as a vital foundation for experimental biology. Furthermore, a philosophical biology program that could provide a framework for theoretical investigations is outlined.
arXiv, 2018
Ever since the advent of molecular biology in the 1970s, mechanical models have become the dogma ... more Ever since the advent of molecular biology in the 1970s, mechanical models have become the dogma in the field, where a "true" understanding of any subject is equated to a mechanistic description. This has been to the detriment of the biomedical sciences, where, barring some exceptions, notable new feats of understanding have arguably not been achieved in normal and disease biology, including neurodegenerative disease and cancer pathobiology. I argue for a "mechanism-plus-X" paradigm, where mainstay elements of mechanistic models such as hierarchy and correlation are combined with nomological principles such as general operative rules and generative principles. Depending on the question at hand and the nature of the inquiry, X could range from proven physical laws to speculative biological generalizations, such as the notional principle of cellular synchrony. I argue that the "mechanism-plus-X" approach should ultimately aim to move biological inquiries out of the deadlock of oft-encountered mechanistic pitfalls and reposition biology to its former capacity of illuminating fundamental truths about the world.
Metascience, 2018
Review of Denis Noble's "Dance to the Tune of Life: Biological Relativity" (Cambridge University ... more Review of Denis Noble's "Dance to the Tune of Life: Biological Relativity" (Cambridge University Press, December 2016)
arXiv, Sep 30, 2012
All cells must keep time to consistently perform vital biological functions. To that end, the cou... more All cells must keep time to consistently perform vital biological functions. To that end, the coupling and interrelatedness of diverse subsecond events in the complex cellular environment, such as protein folding or translation rates, cannot simply result from the chance convergence of the inherent chemical properties of these phenomena, but may instead be synchronized through a cell-wide pacemaking mechanism. Picosecond vibrations of lipid membranes may play a role in such a mechanism.
arXiv, Oct 1, 2013
The advent of molecular biology has led to the identification of definitive causative factors for... more The advent of molecular biology has led to the identification of definitive causative factors for a number of diseases, most of which are monogenic. Causes for most common diseases across the population, however, seem elusive and cannot be pinpointed to a limited number of genes or genetic pathways. This realization has led to the idea of personalized medicine and treating each case individually. Nevertheless, since each common disease appears to have the same endpoint and phenotypic features in all diagnosed individuals, the search for a unifying cause will still continue. Given that multivariate scientific data is of a correlative nature and causation is always inferred, a simple formalization of the general structure of cause and correlation is presented herein. Furthermore, the context in which a causal structure could take shape, termed the 'pericause', is proposed as a tractable and uninvestigated concept which could theoretically play a crucial role in determining the effects of a cause.
arXiv, Jan 11, 2013
The central dogma of molecular biology, formulated more than five decades ago, compartmentalized ... more The central dogma of molecular biology, formulated more than five decades ago, compartmentalized information exchange in the cell into the DNA, RNA and protein domains. This formalization has served as an implicit thematic distinguisher for cell biological research ever since. However, a clear account of the distribution of research across this formalization over time does not exist. Abstracts of >3.5 million publications focusing on the cell from 1975 to 2011 were analyzed for the frequency of 100 single-word DNA-, RNA- and protein-centric search terms and amalgamated to produce domain- and subdomain-specific trends. A preponderance of protein- over DNA- and in turn over RNA-centric terms as a percentage of the total word count is evident until the early 1990s, at which point the trends for protein and DNA begin to coalesce while RNA percentages remain relatively unchanged. This term-based census provides a yearly snapshot of the distribution of research interests across the three domains of the central dogma of molecular biology. A frequency chart of the most dominantly-studied elements of the periodic table is provided as an addendum.
arXiv, Jun 25, 2012
Many open problems in biology, as in the physical sciences, display nonlinear and 'chaotic' dynam... more Many open problems in biology, as in the physical sciences, display nonlinear and 'chaotic' dynamics, which, to the extent possible, cannot be reasonably understood. Moreover, mathematical models which aim to predict/estimate unknown aspects of a biological system cannot provide more information about the set of biologically meaningful (e.g., 'hidden') states of the system than could be understood by the designer of the model ab initio. Here, the case is made for the utilization of such models to shift from a 'predictive' to a 'questioning' nature, and a simple natural-logarithm variation of the logistic polynomial map is presented that can invoke questions about protein trafficking in eukaryotic cells.
Nature Precedings, Apr 1, 2011
The perception of time is an indispensable facet of human consciousness, and may in fact be dynam... more The perception of time is an indispensable facet of human consciousness, and may in fact be dynamically present in primates and other species, albeit with different manifestations. Moreover, contrary to the physical measures of time, cognitive temporal perception may be subjectively affected by both internal and environmental cues. Here we review the evidence for the potential role of the auditory system in shaping the cortical measures of time, and propose possible auditory methods for studying this aspect of consciousness.
COVID / Hepcidin by Sepehr Ehsani
Biology Direct, 2020
The spike glycoprotein of the SARS-CoV-2 virus, which causes COVID-19, has attracted attention fo... more The spike glycoprotein of the SARS-CoV-2 virus, which causes COVID-19, has attracted attention for its vaccine potential and binding capacity to host cell surface receptors. Much of this research focus has centered on the ectodomain of the spike protein. The ectodomain is anchored to a transmembrane region, followed by a cytoplasmic tail. Here we report a distant sequence similarity between the cysteine-rich cytoplasmic tail of the coronavirus spike protein and the hepcidin protein that is found in humans and other vertebrates. Hepcidin is thought to be the key regulator of iron metabolism in humans through its inhibition of the iron-exporting protein ferroportin. An implication of this preliminary observation is to suggest a potential route of investigation in the coronavirus research field making use of an already-established literature on the interplay of local and systemic iron regulation, cytokine-mediated inflammatory processes, respiratory infections and the hepcidin protein. The question of possible homology and an evolutionary connection between the viral spike protein and hepcidin is not assessed in this report, but some scenarios for its study are discussed.
arXiv, 2020
The spike glycoprotein of the SARS-CoV-2 virus, which causes COVID-19, has attracted attention fo... more The spike glycoprotein of the SARS-CoV-2 virus, which causes COVID-19, has attracted attention for its vaccine potential and binding capacity to host cell surface receptors. Much of this research focus has centered on the ectodomain of the spike protein. The ectodomain is anchored to a transmembrane region, followed by a cytoplasmic tail. Here we report a distant sequence similarity between the cysteine-rich cytoplasmic tail of the coronavirus spike protein and the hepcidin protein that is found in humans and other vertebrates. Hepcidin is thought to be the key regulator of iron metabolism in humans. An implication of this preliminary observation is to suggest a potential route of investigation in the coronavirus research field making use of an already-established literature on the interplay of local and systemic iron regulation, cytokine-mediated inflammatory processes, respiratory infections and the hepcidin protein. The question of possible homology and an evolutionary connection between the viral spike protein and hepcidin is not assessed in this report, but some scenarios for its study are discussed.
Prion Protein Biology by Sepehr Ehsani
Biological Reviews, 2021
The quest to determine the function of a protein can represent a profound challenge. Although thi... more The quest to determine the function of a protein can represent a profound challenge. Although this task is the mandate of countless research groups, a general framework for how it can be approached is conspicuously lacking. Moreover, even expectations for when the function of a protein can be considered to be 'known' are not well defined. In this review, we begin by introducing concepts pertinent to the challenge of protein function assignments. We then propose a framework for inferring a protein's function from four data categories: 'inheritance', 'distribution', 'interactions' and 'phenotypes' (IDIP). We document that the functions of proteins emerge at the intersection of inferences drawn from these data categories and emphasise the benefit of considering them in an evolutionary context. We then apply this approach to the cellular prion protein (PrPC), well known for its central role in prion diseases, whose function continues to be considered elusive by many investigators. We document that available data converge on the conclusion that the function of the prion protein is to control a critical post‐translational modification of the neural cell adhesion molecule in the context of epithelial‐to‐mesenchymal transition and related plasticity programmes. Finally, we argue that this proposed function of PrPC has already passed the test of time and is concordant with the IDIP framework in a way that other functions considered for this protein fail to achieve. We anticipate that the IDIP framework and the concepts analysed herein will aid the investigation of other proteins whose primary functional assignments have thus far been intractable.
Scientific Reports, Jan 18, 2017
The prion protein (PrP) evolved from the subbranch of ZIP metal ion transporters comprising ZIPs ... more The prion protein (PrP) evolved from the subbranch of ZIP metal ion transporters comprising ZIPs 5, 6 and 10, raising the prospect that the study of these ZIPs may reveal insights relevant for understanding the function of PrP. Building on data which suggested PrP and ZIP6 are critical during epithelial-to-mesenchymal transition (EMT), we investigated ZIP6 in an EMT paradigm using ZIP6 knockout cells, mass spectrometry and bioinformatic methods. Reminiscent of PrP, ZIP6 levels are five-fold upregulated during EMT and the protein forms a complex with NCAM1. ZIP6 also interacts with ZIP10 and the two ZIP transporters exhibit interdependency during their expression. ZIP6 contributes to the integration of NCAM1 in focal adhesion complexes but, unlike cells lacking PrP, ZIP6 deficiency does not abolish polysialylation of NCAM1. Instead, ZIP6 mediates phosphorylation of NCAM1 on a cluster of cytosolic acceptor sites. Substrate consensus motif features and in vitro phosphorylation data poi...
Frontiers in Cell and Developmental Biology, 2014
Knowledge of phenotypic changes the cellular prion protein (PrP(C)) contributes to may provide no... more Knowledge of phenotypic changes the cellular prion protein (PrP(C)) contributes to may provide novel avenues for understanding its function. Here we consider data from functional knockout/down studies and protein-protein interaction analyses from the perspective of PrP's relationship to its ancestral ZIP metal ion transporting proteins. When approached in this manner, a role of PrP(C) as a modulator of a complex morphogenetic program that underlies epithelial-to-mesenchymal transition (EMT) emerges. To execute EMT, cells have to master the challenge to shift from cell-cell to cell-substrate modes of adherence. During this process, cell-cell junctions stabilized by E-cadherins are replaced by focal adhesions that mediate cell-substrate contacts. A similar reprogramming occurs during distinct organogenesis events that have been shown to rely on ZIP transporters. A model is presented that sees ZIP transporters, and possibly also PrP(C), affect this balance of adherence modes at bot...
PLoS ONE, 2013
The cellular prion protein (PrPC) was recently observed to co-purify with members of the LIV-1 su... more The cellular prion protein (PrPC) was recently observed to co-purify with members of the LIV-1 subfamily of ZIP zinc transporters (LZTs), precipitating the surprising discovery that the prion gene family descended from an ancestral LZT gene. Here, we compared the subcellular distribution and biophysical characteristics of LZTs and their PrP-like ectodomains. When expressed in neuroblastoma cells, the ZIP5 member of the LZT subfamily was observed to be largely directed to the same subcellular locations as PrPC and both proteins were seen to be endocytosed through vesicles decorated with the Rab5 marker protein. When recombinantly expressed, the PrP-like domain of ZIP5 could be obtained with yields and levels of purity sufficient for structural analyses but it tended to aggregate, thereby precluding attempts to study its structure. These obstacles were overcome by moving to a mammalian cell expression system. The subsequent biophysical characterization of a homogeneous preparation of the ZIP5 PrP-like ectodomain shows that this protein acquires a dimeric, largely globular fold with an α-helical content similar to that of mammalian PrPC. The use of a mammalian cell expression system also allowed for the expression and purification of stable preparations of Takifugu rubripes PrP-1, thereby overcoming a key hindrance to high-resolution work on a fish PrPC.
Journal of Molecular Biology, 2012
We recently documented the co-purification of members of the LIV-1 subfamily of ZIP (Zrt‐, Irt‐li... more We recently documented the co-purification of members of the LIV-1 subfamily of ZIP (Zrt‐, Irt‐like Protein) zinc transporters (LZTs) with the cellular prion protein (PrPC) and, subsequently, established that the prion gene family descended from an ancestral LZT gene. Here, we begin to address whether the study of LZTs can shed light on the biology of prion proteins in health and disease. Starting from an observation of an abnormal LZT immunoreactive band in prion-infected mice, subsequent cell biological analyses uncovered a surprisingly coordinated biology of ZIP10 (an LZT member) and prion proteins that involves alterations to N-glycosylation and endoproteolysis in response to manipulations to the extracellular divalent cation milieu. Starving cells of manganese or zinc, but not copper, causes shedding of the N1 fragment of PrPC and of the ectodomain of ZIP10. For ZIP10, this posttranslational biology is influenced by an interaction between its PrP-like ectodomain and a conserved metal coordination site within its C-terminal multi-spanning transmembrane domain. The transition metal starvation-induced cleavage of ZIP10 can be differentiated by an immature N-glycosylation signature from a constitutive cleavage targeting the same site. Data from this work provide a first glimpse into a hitherto neglected molecular biology that ties PrP to its LZT cousins and suggest that manganese or zinc starvation may contribute to the etiology of prion disease in mice.
Prion, 2012
The evolutionary origins of vertebrate prion genes had remained elusive until recently when multi... more The evolutionary origins of vertebrate prion genes had remained elusive until recently when multiple lines of evidence converged to the proposition that members of the prion gene family represent an ancient branch of a larger family of ZIP metal ion transporters. A follow-up investigation which explored the mechanism of evolution in more detail led to the surprising conclusion that the emergence of the prion founder gene likely involved the reverse transcription of a spliced transcript of a LIV-1 ZIP predecessor gene. The objective of this perspective is to discuss the possible significance of this reunion of ZIP and prion gene subfamilies for understanding the biology of the prion protein in health and disease. While a recent review article broadly introduced this area of research, the emphasis here is to comment on some of the more pertinent concepts, experimental paradigms, ongoing developments and challenges.
PLoS ONE, 2011
The evolutionary origin of prion genes, only known to exist in the vertebrate lineage, had remain... more The evolutionary origin of prion genes, only known to exist in the vertebrate lineage, had remained elusive until recently. Following a lead from interactome investigations of the murine prion protein, our previous bioinformatic analyses revealed the evolutionary descent of prion genes from an ancestral ZIP metal ion transporter. However, the molecular mechanism of evolution remained unexplored. Here we present a computational investigation of this question based on sequence, intron-exon, synteny and pseudogene analyses. Our data suggest that during the emergence of metazoa, a cysteine-flanked core domain was modularly inserted, or arose de novo, in a preexisting ZIP ancestor gene to generate a prion-like ectodomain in a subbranch of ZIP genes. Approximately a half-billion years later, a genomic insertion of a spliced transcript coding for such a prion-like ZIP ectodomain may have created the prion founder gene. We document that similar genomic insertions involving ZIP transcripts, and probably relying on retropositional elements, have indeed occurred more than once throughout evolution.
Progress in Neurobiology, 2011
Prion diseases are fatal neurodegenerative diseases of humans and animals which, in addition to s... more Prion diseases are fatal neurodegenerative diseases of humans and animals which, in addition to sporadic and familial modes of manifestation, can be acquired via an infectious route of propagation. In disease, the prion protein (PrPC) undergoes a structural transition to its disease-causing form (PrPSc) with profoundly different physicochemical properties. Surprisingly, despite intense interest in the prion protein, its function in the context of other cellular activities has largely remained elusive. We recently employed quantitative mass spectrometry to characterize the interactome of the prion protein in a murine neuroblastoma cell line (N2a), an established cell model for prion replication. Extensive bioinformatic analyses subsequently established an evolutionary link between the prion gene family and the family of ZIP (Zrt-, Irt-like protein) metal ion transporters. More specifically, sequence alignments, structural threading data and multiple additional pieces of evidence placed a ZIP5/ZIP6/ZIP10-like ancestor gene at the root of the PrP gene family. In this review we examine the biology of prion proteins and ZIP transporters from the viewpoint of a shared phylogenetic origin. We summarize and compare available data that shed light on genetics, function, expression, signaling, post-translational modifications and metal binding preferences of PrP and ZIP family members. Finally, we explore data indicative of retropositional origins of the prion gene founder and discuss a possible function for the prion-like (PL) domain within ZIP transporters. While throughout the article emphasis is placed on ZIP proteins, the intent is to highlight connections between PrP and ZIP transporters and uncover promising directions for future research.
PLoS ONE, 2009
In the more than twenty years since its discovery, both the phylogenetic origin and cellular func... more In the more than twenty years since its discovery, both the phylogenetic origin and cellular function of the prion protein (PrP) have remained enigmatic. Insights into a possible function of PrP may be obtained through the characterization of its molecular neighborhood in cells. Quantitative interactome data demonstrated the spatial proximity of two metal ion transporters of the ZIP family, ZIP6 and ZIP10, to mammalian prion proteins in vivo. A subsequent bioinformatic analysis revealed the unexpected presence of a PrP-like amino acid sequence within the N-terminal, extracellular domain of a distinct sub-branch of the ZIP protein family that includes ZIP5, ZIP6 and ZIP10. Additional structural threading and orthologous sequence alignment analyses argued that the prion gene family is phylogenetically derived from a ZIP-like ancestral molecule. The level of sequence homology and the presence of prion protein genes in most chordate species place the split from the ZIP-like ancestor gene at the base of the chordate lineage. This relationship explains structural and functional features found within mammalian prion proteins as elements of an ancient involvement in the transmembrane transport of divalent cations. The phylogenetic and spatial connection to ZIP proteins is expected to open new avenues of research to elucidate the biology of the prion protein in health and disease.
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Philosophical Biology by Sepehr Ehsani
COVID / Hepcidin by Sepehr Ehsani
Prion Protein Biology by Sepehr Ehsani