Molecular Genetics

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. (shrink)

Several authors have used the notion of causal specificity in order to defend non-parity about genetic causes (Waters 2007, Woodward 2010, Weber 2017, forthcoming). Non-parity in this context is the idea that DNA and some other biomolecules that are often described as information-bearers by biologists play a unique role in life processes, an idea that has been challenged by Developmental Systems Theory (e.g., Oyama 2000). Indeed, it has proven to be quite difficult to state clearly what the alleged special role (...) of genetic causes consists in. In this paper, I show that the set of biomolecules that are normally considered to be information-bearers (DNA, mRNA) can be shown to be the most specific causes of protein primary structure, provided that causal specificity is measured over a relevant space of biological possibilities, disregarding physical as well as logically possible states of the causal variables. (shrink)

We claim that in contemporary studies in molecular biology and biomedicine, the nature of ‘manipulation’ and ‘intervention’ has changed. Traditionally, molecular biology and molecular studies in medicine are considered experimental sciences, whereas experiments take the form of material manipulation and intervention. On the contrary “big science” projects in biology focus on the practice of data mining of biological databases. We argue that the practice of data mining is a form of intervention although it does not require material manipulation. We also (...) suggest that material manipulation, although still present in in the practice of data mining, fulfill a different epistemic role. (shrink)

Causal selection is the task of picking out, from a field of known causally relevant factors, some factors as elements of an explanation. The Causal Parity Thesis in the philosophy of biology challenges the usual ways of making such selections among different causes operating in a developing organism. The main target of this thesis is usually gene centrism, the doctrine that genes play some special role in ontogeny, which is often described in terms of information-bearing or programming. This paper is (...) concerned with the attempt of confronting the challenge coming from the Causal Parity Thesis by offering principles of causal selection that are spelled out in terms of an explicit philosophical account of causation, namely an interventionist account. I show that two such accounts that have been developed, although they contain important insights about causation in biology, nonetheless fail to provide an adequate reply to the Causal Parity challenge: Ken Waters's account of actual-difference making and Jim Woodward's account of causal specificity. A combination of the two also doesn't do the trick, nor does Laura Franklin-Hall's account of explanation (in this volume). We need additional conceptual resources. I argue that the resources we need consist in a special class of counterfactual conditionals, namely counterfactuals the antecedents of which describe biologically normal interventions. (shrink)

There is no denying the Central Dogma’s impact on the biological sciences. Since the Dogma’s formulation by Francis Crick in 1958, however, many have debated the Dogma’s empirical adequacy. My aim is to move beyond these discussions, and instead consider the Central Dogma’s significance to contemporary biological practice. To do this, I consider four distinct approaches for determining the non-descriptive methodological significance of a scientific principle. I argue that these approaches fail to vindicate the Central Dogma, and that, under many (...) of these approaches, the Dogma amounts to a triviality. (shrink)

The Central Dogma of molecular biology, which holds that DNA makes protein and not the other way around, is as influential as it is controversial. Some believe the Dogma has outlived its usefulness, either because it fails to fully capture the ins-and-outs of protein synthesis (Griffiths and Stotz, 2013; Stotz, 2006), because it turns on a confused notion of information (Sarkar, 2004), or because it problematically assumes the unidirectional flow of information from DNA to protein (Gottlieb, 2001). This paper evaluates (...) an underexplored defense of the Dogma, which relies on the assumption that the Dogma and the Inheritance of Acquired Traits, a principle which dates as far back as Jean Baptiste-Lamarck, are incompatible principles (Smith, 1993; Judson, 1979; Dawkins, 1970; Cobb, 2017; Wilkins, 2002; Graur, 2018). By appealing to empirical evidence in molecular science, I argue that this apparent incompatibility is indeed merely apparent. I conclude by briefly demonstrating how these considerations bear on the topic of conceptual pluralism in the philosophy of science (Stencel and Proszewska, 2018; Lu and Bourrat, 2018). (shrink)

Roughly, the Central Dogma of molecular biology states that DNA codes for protein, not the other way around. This principle, which is still heralded as an important element of contemporary biological theory, has received much critical attention since its original formulation by Francis Crick in 1958. Some have argued that the principle should be rejected, on the grounds that it fails to fully capture the ins-and-outs of protein synthesis, while others have argued that the Dogma is predicated on notions of (...) information that are simply implausible. Yet, despite all this criticism, there is much about the Dogma that has not been said. Existing discussions, for example, gloss over the many distinct, logically independent readings of the Central Dogma that have been defended in the philosophical and biological literature, making it difficult to see which dogma is being criticized. Additionally, this oversight makes it unclear what the overall upshot of these discussions should be taken to be. My aim in this paper is to fix this. (shrink)

Philosophical investigation in synthetic biology has focused on the knowledge-seeking questions pursued, the kind of engineering techniques used, and on the ethical impact of the products produced. However, little work has been done to investigate the processes by which these epistemological, metaphysical, and ethical forms of inquiry arise in the course of synthetic biology research. An attempt at this work relying on a particular area of synthetic biology will be the aim of this chapter. I focus on the reengineering of (...) metabolic pathways through the manipulation and construction of small DNA-based devices and systems synthetic biology. Rather than focusing on the engineered products or ethical principles that result, I will investigate the processes by which these arise. As such, the attention will be directed to the activities of practitioners, their manipulation of tools, and the use they make of techniques to construct new metabolic devices. Using a science-in-practice approach, I investigate problems at the intersection of science, philosophy of science, and sociology of science. I consider how practitioners within this area of synthetic biology reconfigure biological understanding and ethical categories through active modelling and manipulation of known functional parts, biological pathways for use in the design of microbial machines to solve problems in medicine, technology, and the environment. We might describe this kind of problem-solving as relying on what Helen Longino referred to as “social cognition” or the type of scientific work done within what Hasok Chang calls “systems of practice”. My aim in this chapter will be to investigate the relationship that holds between systems of practice within metabolic engineering research and social cognition. I will attempt to show how knowledge and normative valuation are generated from this particular network of practitioners. In doing so, I suggest that the social nature of scientific inquiry is ineliminable to both knowledge acquisition and ethical evaluations. (shrink)

Griffiths et al. (2015) have proposed a quantitative measure of causal specificity and used it to assess various attempts to single out genetic causes as being causally more specific than other cellular mechanisms, for example, alternative splicing. Focusing in particular on developmental processes, they have identified a number of important challenges for this project. In this discussion note, I would like to show how these challenges can be met.

The perspective revolution of Sigmund Freud: An update.

Neurobiology studies mechanisms of cell signalling. A key question is how cells recognise specific signals. In this context, olfaction has become an important experimental system over the past 25 years. The olfactory system responds to an array of structurally diverse stimuli. The discovery of the olfactory receptors (ORs), recognising these stimuli, established the olfactory pathway as part of a greater group of signalling mechanisms mediated by G-protein-coupled receptors (GPCRs). GPCRs are the largest protein family in the mammalian genome and involved (...) in numerous fundamental physiological processes. The OR family exhibits two characteristics that make them an excellent model system to understand GPCRs: its size and the structural diversity of its members. Research on the OR binding site investigates what amino acid sequences determine the receptor-binding capacity. This promises a better understanding of how the basic genetic makeup of GPCRs relates to their diversification in ligand-binding capacities. (shrink)

Recently, biologists have argued that data - driven biology fosters a new scientific methodology; namely, one that is irreducible to traditional methodologies of molecular biology defined as the discovery strategies elucidated by mechanistic philosophy. Here I show how data - driven studies can be included into the traditional mechanistic approach in two respects. On the one hand, some studies provide eliminative inferential procedures to prioritize and develop mechanistic hypotheses. On the other, different studies play an exploratory role in providing useful (...) generalizations to complement the procedure of prioritization. Overall this paper aims to shed light on the structure of contemporary research in molecular biology. (shrink)

Much of the book is aimed at persuading the reader that genes are not ‘the prime movers in all biological processes’ and that ‘postgenomic genes’ are better understood in a functional sense, as ‘things an organism can do with its genome.' With the main argument in place, the authors examine its impact on a number of philosophical debates. I will discuss three of them: causation, information, and reduction.

Personalized genomics companies (PG; also called ‘direct-to-consumer genetics’) are businesses marketing genetic testing to consumers over the Internet. While much has been written about these new businesses, little attention has been given to their roles in science communication. This paper provides an analysis of the gene concept presented to customers and the relation between the information given and the science behind PG. Two quite different gene concepts are present in company rhetoric, but only one features in the science. To explain (...) this, we must appreciate the delicate tension between PG, academic science, public expectation, and market forces. (shrink)

Considerable variation exists not only in the kinds of transposable elements (TEs) occurring within the genomes of different species, but also in their abundance and distribution. Noting a similarity to the assortment of organisms among ecosystems, some researchers have called for an ecological approach to the study of transposon dynamics. However, there are several ways to adopt such an approach, and it is sometimes unclear what an ecological perspective will add to the existing co-evolutionary framework for explaining transposon-host interactions. This (...) review aims to clarify the conceptual foundations of transposon ecology in order to evaluate its explanatory prospects. We begin by identifying three unanswered questions regarding the abundance and distribution of TEs that potentially call for an ecological explanation. We then offer an operational distinction between evolutionary and ecological approaches to these questions. By determining the amount of variance in transposon abundance and distribution that is explained by ecological and evolutionary factors, respectively, it is possible empirically to assess the prospects for each of these explanatory frameworks. To illustrate how this methodology applies to a concrete example, we analyzed whole-genome data for one set of distantly related mammals and another more closely related group of arthropods. Our expectation was that ecological factors are most informative for explaining differences among individual TE lineages, rather than TE families, and for explaining their distribution among closely related as opposed to distantly related host genomes. We found that, in these data sets, ecological factors do in fact explain most of the variation in TE abundance and distribution among TE lineages across less distantly related host organisms. Evolutionary factors were not significant at these levels. However, the explanatory roles of evolution and ecology become inverted at the level of TE families or among more distantly related genomes. Not only does this example demonstrate the utility of our distinction between ecological and evolutionary perspectives, it further suggests an appropriate explanatory domain for the burgeoning discipline of transposon ecology. The fact that ecological processes appear to be impacting TE lineages over relatively short time scales further raises the possibility that transposons might serve as useful model systems for testing more general hypotheses in ecology. (shrink)

The paper intends to find the more probable age of proto-human, which in turn could help in finding the timeline of proto-language. In the hominid line of evolution, the rise of modern humans plays a significant role and its role is also owing to the fact of their uniqueness due to language. Different disciplines are put together to solve the mystery of language of human. In an attempt to understand how old, language could be, the paper makes an attempt to (...) find it by first locating the timeline of the proto-human, using the Minimalist program of Chomsky. The search goes with Cartesian discontinuity notion and uses paleoanthropology and genetics to find the age of proto-human. (shrink)

A recent literature review of commentaries and ‘state of the art’ articles from researchers in psychiatric genetics (PMG) offers a consensus about progress in the science of genetics, disappointments in the discovery of new and effective treatments, and a general optimism about the future of the field. I argue that optimism for the field of psychiatric molecular genetics (PMG) is overwrought, and consider progress in the field in reference to a sample estimate of US National Institute of Mental Health funding (...) for this paradigm for the years 2008 and 2009. I conclude that the amounts of financial investment in PMG is questionable from an ethical perspective, given other research and clinical needs in the USA. (shrink)

It appears that all the detailed steps of evolution stored in DNA that are read, transcribed, and translated in every developmental and growth process of each individual cell depend on RNA-mediated processes, in most cases interconnected with other RNAs and their associated protein complexes and functions in a strict hierarchy of temporal and spatial steps. Life could not function without the key agents of DNA replication, namely mRNA, tRNA, and rRNA. Not only rRNA, but also tRNA and the processing of (...) the primary transcript into the pre-mRNA and the mature mRNA are clearly descended from retro-“elements” with obvious retroviral ancestry. They seem to be remnants of viral infection events that did not kill their host but transferred phenotypic competences to their host and changed both the genetic identity of the host organism and the identity of the former infectious viral swarms. In this respect, noncoding RNAs may represent a great variety of modular tools for cellular needs that are derived from persistent nonlytic viral settlers. (shrink)

Comparative genomicists seem to be convinced that the unit of measurement employed in their studies is a gene that drives the function of cells and ultimately organisms. As a result, they have come to some substantive conclusions about how similar humans are to other organisms based on the percentage of genetic makeup they share. I argue that the actual unit of measurement employed in the studies corresponds to a structural rather than a functional gene concept, thus rendering many of the (...) implications drawn from comparative genomic studies largely unwarranted, if not completely mistaken. †To contact the author, please write to: Department of Philosophy, University of Utah, 215 South Central Campus Drive, Carolyn Tanner Irish Humanities Building, 4th Floor, Salt Lake City, UT 84112; e‐mail: monika.piotrowska@utah.edu. (shrink)

Scientific anomalies are observations and facts that contradict current scientific theories and they are instrumental in scientific theory change. Philosophers of science have approached scientific theory change from different perspectives as Darden (Theory change in science: Strategies from Mendelian genetics, 1991) observes: Lakatos (In: Lakatos, Musgrave (eds) Criticism and the growth of knowledge, 1970) approaches it as a progressive “research programmes” consisting of incremental improvements (“monster barring” in Lakatos, Proofs and refutations: The logic of mathematical discovery, 1976), Kuhn (The structure (...) of scientific revolutions, 1996) observes that changes in “paradigms” are instigated by a crisis from some anomaly, and Hanson (In: Feigl, Maxwell (eds) Current issues in the philosophy of science, 1961) proposes that discovery does not begin with hypothesis but with some “problematic phenomena requiring explanation”. Even though anomalies are important in all of these approaches to scientific theory change, there have been only few investigations into the specific role anomalies play in scientific theory change. Furthermore, much of these approaches focus on the theories themselves and not on how the scientists and their experiments bring about scientific change (Gooding, Experiment and the making of meaning: Human agency in scientific observation and experiment, 1990). To address these issues, this paper approaches scientific anomaly resolution from a meaning construction point of view. Conceptual integration theory (Fauconnier and Turner, Cogn Sci 22:133–187, 1996; The way we think: Conceptual blending and mind’s hidden complexities, 2002) from cognitive linguistics describes how one constructs meaning from various stimuli, such as text and diagrams, through conceptual integration or blending. The conceptual integration networks that describe the conceptual integration process characterize cognition that occurs unconsciously during meaning construction. These same networks are used to describe some of the cognition while resolving an anomaly in molecular genetics called RNA interference (RNAi) in a case study. The RNAi case study is a cognitive-historical reconstruction (Nersessian, In: Giere (ed) Cognitive models of science, 1992) that reconstructs how the RNAi anomaly was resolved. This reconstruction traces four relevant molecular genetics publications in describing the cognition necessary in accounting for how RNAi was resolved through strategies (Darden 1991), abductive reasoning (Peirce, In: Hartshorne, Weiss (eds) Collected papers, 1958), and experimental reasoning (Gooding 1990). The results of the case study show that experiments play a crucial role in formulating an explanation of the RNAi anomaly and the integration networks describe the experiments’ role. Furthermore, these results suggest that RNAi anomaly resolution is embodied. It is embodied in a sense that cognition described in the cognitive-historical reconstruction is experientially based. (shrink)

Systems biology is a vigorous and expanding discipline, in many ways a successor to genomics and perhaps unprecendented in its combination of biology with a ...

Systems biology is largely tributary to genomics and other “omic” disciplines that generate vast amounts of structural data. “Omics”, however, lack a theoretical framework that would allow using these data sets as such (rather than just tiny bits that are extracted by advanced data-mining techniques) to build explanatory models that help understand physiological processes. Systems biology provides such a framework by adding a dynamic dimension to merely structural “omics”. It makes use of bottom-up and top-down models. The former are based (...) on data about systems components, the latter on systems-level data. We trace back both modeling strategies (which are often used to delineate two branches of the field) to the modeling of metabolic and signaling pathways in the bottom-up case, and to biological cybernetics and systems theory in the top-down case. We then argue that three roots of systems biology must be discerned to account adequately for the structure of the field: pathway modeling, biological cybernetics, and “omics”. We regard systems biology as merging modeling strategies (supplemented by new mathematical procedures) from data-poor fields with data supply from a field that is quite deficient in explanatory modeling. After characterizing the structure of the field, we address some epistemological and ontological issues regarding concepts on which the top-down approach relies and that seem to us to require clarification. This includes the consequences of identifying modules in large networks without relying on functional considerations, the question of the “holism” of systems biology, and the epistemic value of the “systeome” project that aspires to become the cutting edge of the field. (shrink)

How to interpret the “molecular gene” concept is discussed in this paper. I argue that the architecture of biological systems is hierarchical and multi-layered, exhibiting striking similarities to that of modern computers. Multiple layers exist between the genotype and system level property, the phenotype. This architectural complexity gives rise to the intrinsic complexity of the genotype-phenotype relationships. The notion of a gene being for a phenotypic trait or traits lacks adequate consideration of this complexity and has limitations in explaining the (...) genotype-phenotype relationships. I explore ways toward an integrative interpretation of the gene in the context of multi-layered biological systems. A gene, I argue, should be interpreted as a functional unit that is responsible for the trans-generation passage of the capacity to dynamically produce a biochemical activity or biochemical activities. At the molecular level, a gene is a genetic unit, a stretch of DNA sequence, which dictates the behavior and the dynamic production of the encoded cellular component(s). Embedded in a gene’s quadruple DNA code are the regulatory signals, such as those for RNA splicing and/or editing, as well as for transcription factor binding. A regulatory signal can be recognized by the gene expression machinery in one state, but not in another. The confusion caused by RNA splicing, editing, and a gene’s selective tissue distribution pattern is addressed. Instead of a context-dependent definition of the gene, I argue for the view that it is the same gene displaying multiple meanings, subject to differential interpretation by the cellular machinery in different states. In other words, the same gene gives rise to different products and expression levels under different conditions. (shrink)

Evidence from molecular genetics bolsters the claim that color is not a perceptuolinguistic and behavioral universal. Neurobiology continues to fill in many details about the flow of color information from photon reception to central processing in the brain. Humans have the most acute color vision in the biosphere because of natural selection and adaptation, not coincidence.

The study of mental illness by the methods of molecular genetics is still in its infancy, but the use of genetic markers in psychiatry may potentially lead to a Virchowian revolution in the conception of mental illness. Genetic markers may define novel clusters of patients having diverse clinical presentations but sharing a common genetic and mechanistic basis. Such clusters may differ radically from the conventional classification schemes of psychiatric illness. However, the reduction of even relatively simple Mendelian phenomena to molecular (...) genetics has been shown to be a surprisingly complex and problematic enterprise. Mental illnesses exist at many levels of including social, environmental, and developmental interactions. Reductionistic shifts in the classification of such a disease entity will have to address the interlevel dynamics that take place within the structure of theories of mental illness. The question of how molecular analysis of psychiatric disease will impact on the structure of existing theories and classification systems is the central topic of this paper. (shrink)

Certain correspondences appear between the classifications and between the classes of various entities at molecular genetic level: types of fundamental correspondences between classifications and between classes of normal entities, on the one hand, and of mutant entities on the other hand; ranks of correspondences between classifications and between classes of entities. The concept of universality of the genetic code was reformulated on the basis of the above correspondences.

The present paper has two aims. First, we reconstruct the core of molecular genetics (MOLGEN) i.e. the array of theoretical assumptions which underly all or most applications of molecular genetics. Second, we define a reduction relation p reducing character-factor genetics (CFG) to MOLGEN. That p is a reduction relation is proved by establishing that p satisfies the two major conditions which are discussed in the literature as necessary or ‘essential’ for reduction. This substantiates the claim that molecular genetics is ‘better (...) than’ or ‘more progressive-than’ character-factor genetics-which is commonly held true today. The paper continues, and relies heavily on the definitions given in part 1 (Balzer and Dawe [1985]). The enumeration of the definitions and sections in the present paper continues that of part 1. References to definitions with numbers smaller than 8 and to sections number I-4 always refer to part 1. (shrink)

Taking reduction in the traditional deductive sense, the programmatic claim that most of genetics can be reduced by molecular genetics is defended as feasible and significant. Arguments by Ruse and Hull that either the relationship is replacement or at best a weaker form of reduction are shown to rest on a mixture of historical and logical confusions about the nature of the theories involved.

Within the sedimentation diagram of infective RNA preparations isolated from Tobacco Mosaic Virus, undegraded molecules form a sharp peak with a molecular weight corresponding to the total RNA content of the virus particle. Degradation kinetics by ribonuclease is of the linear, single-target type, indicating that the RNA is single-stranded. The intact RNA of a virus particle thus forms one big single-stranded molecule. Quantitative evaluation of the effect degradation by RNA-ase on the infectivity of the RNA shows that the integrity of (...) the entire molecule is required for its biological activity. (shrink)

Upon separation of the protein from the nucleic acid component of tobacco mosaic virus by phenol, using a fast and gentle procedure, the nucleic acid is infective in assays on tobacco leaves. A series of qualitative and quantitative control experiments demonstrates that the biological activity cannot depend on residual proteins in the preparation, but is a property of isolated nucleic acid which is thus the genetic material of the virus.