Agential autonomy and biological individuality

What is a biological individual? How are biological individuals individuated? How can we tell how many individuals there are in a given assemblage of biological entities? The individuation and differentiation of biological individuals are central to the scientific understanding of living beings. I propose a novel criterion of biological individuality according to which biological individuals are autonomous agents. First, I articulate an ecological–dynamical account of natural agency according to which, agency is the gross dynamical capacity of a goal-directed system to bias its repertoire to respond to its conditions as affordances. Then, I argue that agents or agential dynamical systems can be agentially dependent on, or agentially autonomous from, other agents and that this agential dependence/autonomy can be symmetrical or asymmetrical, strong or weak. Biological individuals, I propose, are all and only those agential dynamical systems that are strongly agentially autonomous. So, to determine how many individuals there are in a given multiagent aggregate, such as multicellular organism, a colony, symbiosis, or a swarm, we first have to identify how many agential dynamical systems there are, and then what their relations of agential dependence/autonomy are. I argue that this criterion is adequate to the extent that it vindicates the paradigmatic cases, and explains why the paradigmatic cases are paradigmatic, and why the problematic cases are problematic. Finally, I argue for the importance of distinguishing between agential and causal dependence and show the relevance of agential autonomy for understanding the explanatory structure of evolutionary developmental biology.     

Probing catalytically essential domain orientation in histidine kinase EnvZ by targeted disulfide crosslinking

EnvZ, a dimeric transmembrane histidine kinase, belongs to the family of His-Asp phosphorelay signal transduction systems. The cytoplasmic kinase domain of EnvZ can be dissected into two independently functioning domains, A and B, whose NMR solution structures have been individually determined. Here, we examined the topological arrangement of these two domains in the EnvZ dimer, a structure that is key to understanding the mechanism underlying the autophosphorylation activity of the kinase. A series of cysteine substitution mutants were constructed to test the feasibility of chemical crosslinking between the two domains. These crosslinking data demonstrate that helix I of domain A of one subunit in the EnvZc dimer is in close proximity to domain B of the other subunit in the same dimer, while helix II of domain A of one subunit interacts with domain B of the same subunit in the EnvZc dimer. This is the first demonstration of the topological arrangement between the central dimerization domain containing the active center His residues (domain A) and the ATP-binding catalysis assisting domain (domain B) in a class I histidine kinase.     

Forget Evil: Autonomy,the Physician–Patient Relationship,and the Duty to Refer

Aulisio and Arora argue that the moral significance of value imposition explains the moral distinction between traditional conscientious objection and non-traditional conscientious objection. The former objects to directly performing actions, whereas the latter objects to indirectly assisting actions on the grounds that indirectly assisting makes the actor morally complicit. Examples of non-traditional conscientious objection include objections to the duty to refer. Typically, we expect physicians who object to a practice to refer, but the non-traditional conscientious objector physician refuses to refer. Aulisio and Arora argue that physicians have a duty to refer because refusing to do so violates the patient’s values. While we agree with Aulisio and Arora’s conclusions, we argue value imposition cannot adequately explain the moral difference between traditional conscientious objection and non-traditional conscientious objection. Treating autonomy as the freedom to live in accordance with one’s values, as Aulisio and Arora do, is a departure from traditional liberal conceptions of autonomy and consequently fails to explain the moral difference between the two kinds of objection. We outline how a traditional liberal understanding of autonomy would help in this regard, and we make two additional arguments—one that maintains that non-traditional conscientious objection undermines society’s autonomy, and another that maintains that it undermines the physician-patient relationship—to establish why physicians have a duty to refer.     

Dodged debts and the submissive predator: perspectives on Amazonian relations of dependence

This article explores the nature of inter‐ethnic asymmetry and the dynamic of long‐term dependence in Amazonia. Drawing on the case of the Sanema and their neighbouring Ye'kwana, it seeks to gain a deeper understanding of submission and indebtedness with a view to rethinking where the power might lie in such relationships. The association between the two groups, I argue, is motivated by the Sanema's pursuit of manufactured items, access to which the Ye'kwana had historically monopolized. The dynamic entered into in order to procure these goods is one of voluntary deference on the part of the Sanema, a demeanour that is actively pursued because it enables morally valued autonomy and a freedom from ongoing reciprocity. I conclude that this ‘submissive extraction’ can offer new perspectives on the relationship between debt, predation, and freedom.     

The Evolution of Sex: Domains and Explanatory Pluralism

The evolution of sexual reproduction is a striking case of explanatory pluralism, meaning that one needs to refer to more than one explanation in order to adequately account for it. I develop the concept a domain of phenomena in order to analysis this pluralism. Pluralism exists when a phenomenon can be included in more that one homogeneous domain or in a heterogeneous domain. I argue that in some cases domain partitioning can be used to decrease pluralism, but that in the case of sex domains are overlapping and interconnecting, or in other words bear an orthogonal relationship to one another, and hence cannot be partitioned in such a way as to eliminate pluralism.     

Do Organisms Exist?

What is the status of organisms in modern evolutionary biology?I argue that this is a question which centers on the questionof reduction, and towards a complete answer, I pursue issuesthrough three different senses of the term: ontological, methodological,and epistemological. The first sense refers to the ultimatestatus of the entities of the organic world, and in this senseI argue that organisms have no special status. The second senserefers to the question of organization, and I argue that inthe light of modern evolutionary biology organisms do have adistinctive "design-like" organization. The third sense refersto the relationship between theories, in particular to whetherthe theories of the biological sciences can be shown to be logicalconsequences of the theories of the physical sciences. I arguethat such reduction may be possible in principle but difficultin practice. However, from the perspective of the working scientist,this hardly matters. In conclusion, I argue that in some respectsorganisms are not distinctive and in other respects they are.Certainly biologists need not worry for the autonomy of theirsubject.     

Re-Moralizing the Suicide Debate

Contemporary approaches to the study of suicide tend to examine suicide as a medical or public health problem rather than a moral problem, avoiding the kinds of judgements that have historically characterised discussions of the phenomenon. But morality entails more than judgement about action or behaviour, and our understanding of suicide can be enhanced by attending to its cultural, social, and linguistic connotations. In this work, I offer a theoretical reconstruction of suicide as a form of moral experience that delineates five distinct, yet interrelated domains of understanding: the temporal, the relational, the existential, the ontological, and the linguistic. Attention to each of these domains, I argue, not only enriches our understanding of the moral realm but also provides a heuristic for examining the moral traditions and practices that constitute contemporary understandings of suicide.     

Topological organization of the hyaluronan synthase from Streptococcus pyogenes

Since we first reported (DeAngelis, P. L., Papaconstantinou, J., and Weigel, P. H. (1993) J. Biol. Chem. 268, 19181-19184) the cloning of the hyaluronan (HA) synthase from Streptococcus pyogenes (spHAS), numerous membrane-bound HA synthases have been discovered in both prokaryotes and eukaryotes. The HASs are unique among enzymes studied to date because they mediate 6-7 discrete functions in order to assemble a polysaccharide containing hetero-disaccharide units and simultaneously effect translocation of the growing HA chain through the plasma membrane. To understand how the relatively small spHAS performs these various functions, we investigated the topological organization of the protein utilizing fusion analysis with two reporter enzymes, alkaline phosphatase and beta-galactosidase, as well as several other approaches. From these studies, we conclude that the NH2 terminus and the COOH terminus, as well as the major portion of a large central domain are localized intracellularly. The first two predicted membrane domains were confirmed to be transmembrane domains and give rise to a very small extracellular loop that is inaccessible to proteases. Several regions of the large internal central domain appear to be associated with, but do not traverse, the membrane. Following the central domain, there are two additional transmembrane domains connected by a second small extracellular loop that also is inaccessible to proteases. The COOH-terminal approximately 25% of spHAS also contains a membrane domain that does not traverse the membrane and may contain extensive re-entrant loops or amphipathic helices. Numerous membrane associations of this latter COOH-terminal region and the central domain may be required to create a pore-like structure through which a growing HA chain can be extruded to the cell exterior. Based on the high degree of similarity among Class I HAS family members, these enzymes may have a similar topological organization for their spHAS-related domains.     

A single point mutation in a group I WW domain shifts its specificity to that of group II WW domains.

WW domains can be divided into three groups based on their binding specificity. By random mutagenesis, we switched the specificity of the Yes-associated protein (YAP) WW1 domain, a Group I WW domain, to that of the FE65 WW domain, which belongs to Group II. We showed that a single mutation, leucine 190 (betaB5) to tryptophan, is required to switch from Group I to Group II. Although this single substitution in YAP WW1 domain is sufficient to precipitate the two protein isoforms of Mena, an in vivo ligand of FE65, we showed that an additional substitution, histidine 192 (betaB7) to glycine, significantly increased the ability of YAP to mimic FE65. This double mutant (L190W/H192G) precipitates eight of the nine protein bands that FE65 pulls down from rat brain protein lysates. Based on both our data and a sequence comparison between Group I and Group II WW domains, we propose that a block of three consecutive aromatic amino acids within the second beta-sheet of the domain is required, but not always sufficient, for a WW domain to belong to Group II. These data deepen our understanding of WW domain binding specificity and provide a basis for the rational design of modified WW domains with potential therapeutic applications.     

Evolution of MHC class I genes in the European badger (Meles meles)

The major histocompatibility complex (MHC) plays a central role in the adaptive immune system and provides a good model with which to understand the evolutionary processes underlying functional genes. Trans-species polymorphism and orthology are both commonly found in MHC genes; however, mammalian MHC class I genes tend to cluster by species. Concerted evolution has the potential to homogenize different loci, whereas birth-and-death evolution can lead to the loss of orthologs; both processes result in monophyletic groups within species. Studies investigating the evolution of MHC class I genes have been biased toward a few particular taxa and model species. We present the first study of MHC class I genes in a species from the superfamily Musteloidea. The European badger (Meles meles) exhibits moderate variation in MHC class I sequences when compared to other carnivores. We identified seven putatively functional sequences and nine pseudogenes from genomic (gDNA) and complementary (cDNA) DNA, signifying at least two functional class I loci. We found evidence for separate evolutionary histories of the α1 and α2/α3 domains. In the α1 domain, several sequences from different species were more closely related to each other than to sequences from the same species, resembling orthology or trans-species polymorphism. Balancing selection and probable recombination maintain genetic diversity in the α1 domain, evidenced by the detection of positive selection and a recombination event. By comparison, two recombination breakpoints indicate that the α2/α3 domains have most likely undergone concerted evolution, where recombination has homogenized the α2/α3 domains between genes, leading to species-specific clusters of sequences. Our findings highlight the importance of analyzing MHC domains separately.     

Functional analysis of the ligand binding site of EGF-receptor utilizing chimeric chicken/human receptor molecules.

The epidermal growth factor (EGF)-receptor is composed of an extracellular ligand-binding region connected by a single transmembrane region to the cytoplasmic kinase domain. In spite of its importance for understanding signal transduction, the ligand-binding domain of the EGF-receptor is not yet defined. We describe the identification of a major ligand-binding domain of the EGF-receptor by utilizing chimeras between the human EGF-receptor and the chicken EGF-receptor. This approach is based on the fact that murine EGF binds to the chicken EGF-receptor with 100-fold lower affinity as compared to the human EGF-receptor. Hence, the substitution of various domains of the chicken EGF-receptor by domains of the human EGF-receptor may restore the higher binding affinity towards EGF, characteristic of the human receptor. We show that chimeric chicken/human EGF-receptor, which contains domain III of the extracellular region of the human receptor, behaves like the human EGF-receptor with respect to EGF binding affinity and biological responsiveness. However, a chimeric chicken/human EGF-receptor containing domains I and II of the human receptor behaves like the chicken rather than the human EGF-receptor. Moreover, two different monoclonal antibodies which compete for the binding of EGF to EGF-receptor recognize specifically domain III of the human EGF-receptor. It is concluded that domain III which is flanked by the two cysteine-rich domains is a major ligand-binding domain of the EGF-receptor.     

Mechanically unfolding proteins: the effect of unfolding history and the supramolecular scaffold

The mechanical resistance of a folded domain in a polyprotein of five mutant I27 domains (C47S, C63S I27)(5)is shown to depend on the unfolding history of the protein. This observation can be understood on the basis of competition between two effects, that of the changing number of domains attempting to unfold, and the progressive increase in the compliance of the polyprotein as domains unfold. We present Monte Carlo simulations that show the effect and experimental data that verify these observations. The results are confirmed using an analytical model based on transition state theory. The model and simulations also predict that the mechanical resistance of a domain depends on the stiffness of the surrounding scaffold that holds the domain in vivo, and on the length of the unfolded domain. Together, these additional factors that influence the mechanical resistance of proteins have important consequences for our understanding of natural proteins that have evolved to withstand force.     

Blackfellas and Whitefellas: the Concepts of Domain and Social Closure in the Analysis of Race-Relations

In presenting data on social relations between Aborigines and Whites at a north Australian Aboriginal settlement, this paper develops the concepts of domain and social closure as important in the study of power and race-relations. Previous Australian studies in this area have not treated adequately, the substantive nature and theoretical significance of spatial and social separation between Aborigines and Whites. I argue that Aborigines retain some autonomy within a ‘Blackfella domain’, through effecting a form of exclusionary social closure.     

Use of hemopexin domains and monoclonal antibodies to hemopexin to probe the molecular determinants of hemopexin-mediated heme transport

Plasmin cleaves rabbit serum apohemopexin (Mr = 60,000) at a single site producing a heme-binding domain (I, Mr = 35,000) and a second domain (II, Mr = 25,000) (W. T. Morgan and A. Smith (1984) J. Biol. Chem. 259, 12001-12005). The absorbance spectra of heme-domain I are indicative of a bis-histidyl coordination complex with the central heme iron atom. Chemical modification of the 5 histidine residues of apo-domain I with diethylpyrocarbonate abolished heme binding, supporting this assignment. Upon binding heme, domain I migrates more rapidly in sucrose gradients, and, in sedimentation velocity experiments, the s value of domain I increases from 3.17 +/- 0.04 to 3.71 +/- 0.09, a notably large increase which indicates that the domain becomes much more compact. This conformational change which plays a pivotal role in hemopexin function requires the bis-histidyl coordination with heme iron and leads to a tighter association between domain I and domain II shown by the co-migration of heme-domain I and domain II in sucrose gradients. In turn, the association of heme-domain I with domain II increases the thermal stability of the heme-domain I chromophore. Results of binding studies using mouse hepatoma cells and isolated domains indicate that domain I not only binds heme but also plays a vital part in the hemopexin-receptor interaction. The change in conformation of domain I upon heme binding and the association between domains I and II induced by heme are both notable determinants of the strength of the hemopexin-receptor interaction, but an intact "hinge region" between the domains is not necessary for receptor binding. The importance of both domains in bringing about the transport function of hemopexin is confirmed by the ability of three (two specific for domain I and one for domain II) of seven monoclonal antibodies raised against hemopexin to inhibit the hemopexin-receptor interaction.     

Covert moral bioenhancement,public health,and autonomy

In a recent article in this journal, Parker Crutchfield argues that if moral bioenhancement ought to be compulsory, as some authors claim, then it ought to be covert, i.e., performed without the knowledge of the population that is being morally enhanced. Crutchfield argues that since the aim of compulsory moral bioenhancement is to prevent ultimate harm to the population, compulsory moral bioenhancement is best categorized as a public health issue, and should therefore be governed by the norms and values that apply in public health settings. In this article, I argue for two related claims. First, I question the extent to which compulsory moral enhancement should be considered a public health issue that ought to be governed by the norms and values that apply in public health settings. Second, I argue that Crutchfield's argument that covert moral bioenhancement would better respect people's autonomy than an overt program overlooks two important autonomy‐based reasons that, in fact, favor an overt moral enhancement program over a covert one.     

Species and kinds: a critique of Rieppel's "one of a kind" account of species

A major issue in philosophical debates on the species problem concerns the opposition between two seemingly incompatible views of the metaphysics of species: the view that species are individuals and the view that species are natural kinds. In two recent papers in this journal, Olivier Rieppel suggested that this opposition is much less deep than it seems at first sight. Rieppel used a recently developed philosophical account of natural kindhood, namely Richard Boyd's "homeostatic property cluster" theory, to argue that every species taxon can be conceived of as an individual that constitutes the single member of its own specific natural kind. In this paper I criticize Rieppel's approach and argue that it does not deliver what it is supposed to, namely an account of species as kinds about which generalized statements can be made.     

Developmentally regulated cytokeratin gene in Xenopus laevis.

We have determined the sequence of cloned cDNAs derived from a 1,665-nucleotide mRNA which transiently accumulates during Xenopus laevis embryogenesis. Computer analysis of the deduced amino acid sequence revealed that this mRNA encodes a 47-kilodalton type I intermediate filament subunit, i.e., a cytokeratin. As is common to all intermediate filament subunits so far examined, the predicted polypeptide, named XK70, contains N- and C-terminal domains flanking a central alpha-helical rod domain. The overall amino acid homology between XK70 and a human 50-kilodalton type I keratin is 47%; homology within the alpha-helical domain is 57%. The N-terminal domain, which is not completely contained in our cDNAs, is basic, contains 42% serine plus alanine, and includes five copies of a six-amino-acid repeating unit. The C-terminal domain has a high alpha-helical content and contains a region with sequence homology to the C-terminal domains of other type I and type III intermediate filament proteins. We suggest that different keratin filament subtypes may have different functional roles during amphibian oogenesis and embryogenesis.     

A domain sharing model for active site assembly within the Mu A tetramer during transposition: the enhancer may specify domain contributions.

The functional configuration of Mu transposase (A protein) is its tetrameric form. We present here a model for the organization of a functional Mu A tetramer. Within the tetramer, assembly of each of the two active sites for Mu end cleavage requires amino acid contributions from the central and C-terminal domains (domains II and III respectively) of at least two Mu A monomers in a trans configuration. The Mu enhancer is likely to function in this assembly process by specifying the two monomers that provide their C-terminal domains for strand cleavage. The Mu B protein is not required in this step. Each of the two active sites for the strand transfer reaction is also organized by domain sharing (but in the reverse mode) between Mu A monomers; i.e. a donor of domain II (also the recipient of domain III) during cleavage is a recipient of domain II (and the donor of domain III) during strand transfer. The function of the Mu B protein (which is required at the strand transfer step) and that of the enhancer element may be analogous in that their interactions with Mu A (domain III and domain I alpha respectively) promote conformations of Mu A conducive to strand cleavage or strand transfer.     

The Social Mobility of the Haratine and the Re-Working of Bourdieu's Habitus on the Saharan Frontier, Morocco

In this article, I examine the practical relevance of Bourdieu's notion of Habitus in understanding the relationship between the acquisition of land and the transformation of political and social relations of subordination in the stratified communities of southern Morocco. First, I claim that the acquisition of land by the Haratine, a subordinate and low-status ethnic group, means more than just a simple economic transaction, and land serves as the very basis for changing the political relations of subordination. Second, I argue that the Haratine strategy of land acquisition was made possible by the intervention of the central state in the local power structure during and after the French colonial period. When these transformations were coupled with labor possibilities made available by national and transnational migration, the market game was opened to the Haratine, who could draw on the accumulation to improve their political and social standing. This also meant that the autonomy of the local community was lost forever, and the traditional nobility of Berbers and Arabs was no longer able to exclude the subalterns by extra-economic or legal means. [Arabs, Berbers, Bourdieu, Habitus, Haratine, Morocco]     

Trypanosome cyclic nucleotide phosphodiesterase 2B binds cAMP through its GAF-A domain

Trypanosoma brucei, the causative agent of sleeping sickness in humans and livestock, expresses at least three cAMP-specific class I phosphodiesterases (PDEs), all of which are essential for survival of the parasite. These PDEs have either one or two N-terminal GAF domains, which in other proteins function as signaling domains. However, neither the functional roles nor ligands for these domains in trypanosome PDEs are known. The present study shows that TbPDE2B, which contains two tandem GAF domains, binds cAMP with high affinity through its GAF-A domain. A purified recombinant N terminus + GAF-A domain binds cAMP with an affinity (Ki) of approximately 16 nM. It also binds cGMP but with a 15-fold lower affinity of approximately 275 nM. The TbPDE2B holoenzyme has a somewhat lower affinity (approximately 55 nM) for cAMP but a greatly lower affinity (approximately 10 microM) for cGMP. This suggests that both the selectivity and affinity for a ligand can be determined not only by the nature of the binding domain but also by the adjacent domains. Additionally, binding of cAMP to the holoenzyme showed positive cooperativity, with a Hill coefficient value of 1.75. However, binding of cGMP to the holoenzyme did not show any cooperativity, suggesting differences in the conformational changes caused by binding of these two cyclic nucleotides with the protein. Point mutation of a key predicted binding site residue (T317A) resulted in a complete loss of high affinity cAMP binding. This mutation increased the apparent Km of the mutant enzyme for substrate without altering the Vmax. A truncated catalytic domain construct of TbPDE2B also exhibited an increased Km, strongly suggesting that cAMP binding to the GAF-A domain can regulate TbPDE2B by allowing the full activity of the enzyme to be expressed. These properties of the GAF-A domain of TbPDE2B thus suggest that it could be a new target for anti-trypanosomal drugs.