Sepehr Ehsani

This paper’s aim is to provide a normative notion of relative completeness that pinpoints cell-biological part–part interactions as a critical niche for the integration of mechanistic explanations with the explanatory features of lawlike generalizations. Using a critiquing account of mechanisms that determines whether and how a given mechanistic explanation could become relatively more complete, I highlight the critical role of part–part interactions in the cell. Mechanistic explanations, which are a mainstay of causal accounts in cell biology, are underpinned in large part by a network of such interactions (e.g. protein–protein or protein–nucleic-acid). In studies that attempt to discover these interactions, there is a tacit assumption that an ‘interaction’ is constituted simply by the proximity between and/or enzymatic changes imparted on the interacting parts. As very few substantive theoretical accounts of what may actually constitute an ‘interaction’ in the context of the cell have been put forth, I develop an account of protein–protein interactions (a key type of part–part interactions in the cell with implications for other types of cellular interactions) toward making the explanation more complete. In doing so, I first map out four aspects relevant to the sequence of events taking place in at least a significant proportion of protein–protein interactions, and, second, propose (i) interaction-enabling properties of proteins and (ii) interaction-enabling properties of the proteins’ environment as elements that could be explained by relevant lawlike generalizations. These generalization-based explanations could answer contrastive why-this-and-not-that type of questions pertaining to different aspects of a protein–protein interaction of interest in a mechanistic explanation, which would otherwise be difficult to answer in cell-biological mechanistic terms. This approach illustrates how part–part interactions in a mechanism could be explained by lawlike generalizations, with the eventual goal of making the overall explanation more fruitful and informative.

This paper’s aim is to provide a normative notion of relative completeness that pinpoints cell-biological part–part interactions as a critical niche for the integration of mechanistic explanations with the explanatory features of lawlike generalizations. Using a critiquing account of mechanisms that determines whether and how a given mechanistic explanation could become relatively more complete, I highlight the critical role of part–part interactions in the cell. Mechanistic explanations, which are a mainstay of causal accounts in cell biology, are underpinned in large part by a network of such interactions (e.g. protein–protein or protein–nucleic-acid). In studies that attempt to discover these interactions, there is a tacit assumption that an ‘interaction’ is constituted simply by the proximity between and/or enzymatic changes imparted on the interacting parts. As very few substantive theoretical accounts of what may actually constitute an ‘interaction’ in the context of the cell have been put forth, I develop an account of protein–protein interactions (a key type of part–part interactions in the cell with implications for other types of cellular interactions) toward making the explanation more complete. In doing so, I first map out four aspects relevant to the sequence of events taking place in at least a significant proportion of protein–protein interactions, and, second, propose (i) interaction-enabling properties of proteins and (ii) interaction-enabling properties of the proteins’ environment as elements that could be explained by relevant lawlike generalizations. These generalization-based explanations could answer contrastive _why-this-and-not-that_ type of questions pertaining to different aspects of a protein–protein interaction of interest in a mechanistic explanation, which would otherwise be difficult to answer in cell-biological mechanistic terms. This approach illustrates how part–part interactions in a mechanism could be explained by lawlike generalizations, with the eventual goal of making the overall explanation more fruitful and informative.

The past decade has brought to the fore the critical need to constantly envision and consider various scenarios where ongoing trends and sudden changes could together alter the provision of healthcare and the direction of medical research. This book brings together scholars whose areas of expertise represent different themes that are essential to understanding how healthcare might change and evolve over the next decade. What lessons can one take away from current and past developments? The themes explored by the book rest on four pillars. The first is the rapid pace and ubiquity of technological advances in areas such as artificial intelligence, machine learning, additive manufacturing and wearable electronics. The second pillar concerns healthy aging, longevity and the management of chronic diseases. The third is the imperative to remain cognizant of the ethical dimensions of medical decisions, adapting bioethics to ongoing changes in healthcare provision. Finally, the fourth pillar relates to how uncertainty in different domains of medical knowledge can be mitigated and translated into clinical practice. For example, how should uncertainty with the results of clinical trials for a new treatment be dealt with? What cost-benefit analyses would be most appropriate for the situation? Chapter authors identify respective challenges and promising opportunities, discussing how these could contribute to envisioning the future scope of healthcare when it comes to providing medical, economic and ethical values to human societies. Chapters 1, 4, 12, and 20 are available open access under a Creative Commons Attribution 4.0 International License via link.springer.com.

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.

This paper is about interpreting the aim of Plato's Sophist in a linguistic framework and arguing that in its attempt at resolving the conundrum of what the true meaning and essence of the word "sophist" could be, it resembles a number of themes encountered in contemporary linguistics. I think it is important to put our findings from the Sophist in a broader Platonic context: in other words, I assume—I think not too unreasonably—that Plato pursued (or at least had in mind) a number of overall projects ('OP' for short) throughout some or most of the dialogues, while each one of the dialogues would in addition have more specific projects ('SP') as part of its individual blueprint. To be sure, the OPs, if they actually existed, might have evolved from the earlier-written to later dialogues, but their foundational premises should have remained intact. In Section A, I provide evidence for reading the Sophist on a linguistic basis. In Section B, I focus on two OPs that I think are relevant to our discussion, one having to do with language and meaning acquisition, and the second concerning the "mind" or a "thought faculty". Ultimately, in Section C, I will use the OPs to contextualise two (related) SPs in the Sophist: (i) identifying cases of intentional referrals for names versus (ii) identifying internal references when searching for word meanings without particular referable instances. At the end of this section, I will draw close parallels between this interpretation of the dialogue and a congruous project of modern 'generative' linguistics.

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.

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.

Advances in biology, at least over the past two centuries, have mostly relied on theories that were subsequently revised, expanded or eventually refuted using experimental and other means. The field of theoretical biology used to primarily provide a basis, similar to theoretical physics in the physical sciences, to rationally examine the frameworks within which biological experiments were carried out and to shed light on overlooked gaps in understanding. Today, however, theoretical biology has generally become synonymous with computational and mathematical biology. This could in part be explained by a relatively recent tendency in which a "data first", rather than a "theory first", approach is preferred. Moreover, generating hypotheses has at times become procedural rather than theoretical, therefore perhaps inadvertently leading some hypotheses to become perfunctory in nature. This situation leaves our understanding enmeshed in data, which should be disentangled from much noise. Given the many unresolved questions in biology and medicine, big and small, ranging from the problem of protein folding to unifying causative frameworks of complex non-Mendelian human diseases, it seems apt to revive the role of pure theory in the biological sciences. This paper, using the current biomedical literature and historical precedents, makes the case for a "philosophical biology" (philbiology), distinct from but quite complementary to philosophy of biology (philobiology), which would entail biological investigation through philosophical approaches. Philbiology would thus be a reincarnation of theoretical biology, adopting the true sense of the word "theory" and making use of a rich tradition of serious philosophical approaches in the natural sciences. A philbiological investigation, after clearly defining a given biological problem, would aim to propose a set of empirical questions, along with a class of possible solutions, about that problem. Importantly, whether or not the questions can be tested using current experimental paradigms would be secondary to whether the questions are inherently empirical or not. These issues will be illustrated using a range of specific examples. The final goal of a philbiological investigation would be to develop a theoretical framework that can lead observational and/or interventional experimental studies of the defined problem, a framework that is structured, generative and expandable, and, crucially, one that simplifies some aspect(s) of the said problem.