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In the target article “How molecules became signs” I offer a molecular “thought experiment” that provides a paradigm for resolving the major incompatibilities between biosemiotic and natural science accounts of living processes. To resolve these apparent incompatibilities I outline a plausible empirically testable model system that exemplifies the emergence of chemical processes exhibiting semiotic causal properties from basic nonliving chemical processes. This model system is described as an autogenic virus because of its virus-like form, but its nonparasitic self-repair and reproductive dynamics. The 16 commentaries responding to this proposal recognize its material plausibility but are divided on its value in resolving this basic biosemiotic challenge. In response, I have addressed some of the most serious criticisms raised and have attempted to diagnose the major sources of incompatible assumptions that distinguish the autogenic paradigm from other major paradigms. In particular, I focus on four main issues: the significance of the shift from a cellular to a viral perspective, the relevance of intrinsic versus extrinsic initiation and channeling of interpretive work, the insufficiency of molecular replication as a basis for grounding biological semiosis, and a (universal?) three step scaffolding logic that enables referential displacement of sign vehicle properties without loss of referential continuity (as exemplified by DNA-protein relations). Although I can’t conclude that this is the only way that biosemiotic properties can emerge from physical-chemical relations that otherwise lack these properties, I contend that this approach offers a biologically plausible demonstration that it is possible.

To explore how molecules became signs I will ask: “What sort of process is necessary and sufficient to treat a molecule as a sign?” This requires focusing on the interpreting system and its interpretive competence. To avoid assuming any properties that need to be explained I develop what I consider to be a simplest possible molecular model system which only assumes known physics and chemistry but nevertheless exemplifies the interpretive properties of interest. Three progressively more complex variants of this model of interpretive competence are developed that roughly parallel an icon-index-symbol hierarchic scaffolding logic. The implication of this analysis is a reversal of the current dogma of molecular and evolutionary biology which treats molecules like DNA and RNA as the original sources of biological information. Instead I argue that the structural characteristics of these molecules have provided semiotic affordances that the interpretive dynamics of viruses and cells have taken advantage of. These molecules are not the source of biological information but are instead semiotic artifacts onto which dynamical functional constraints have been progressively offloaded during the course of evolution.

In this review, we describe some of the central philosophical issues facing origins-of-life research and provide a targeted history of the developments that have led to the multidisciplinary field of origins-of-life studies. We outline these issues and developments to guide researchers and students from all fields. With respect to philosophy, we provide brief summaries of debates with respect to (1) definitions (or theories) of life, what life is and how research should be conducted in the absence of an accepted theory of life, (2) the distinctions between synthetic, historical, and universal projects in origins-of-life studies, issues with strategies for inferring the origins of life, such as (3) the nature of the first living entities (the “bottom up” approach) and (4) how to infer the nature of the last universal common ancestor (the “top down” approach), and (5) the status of origins of life as a science. Each of these debates influences the others. Although there are clusters of researchers that agree on some answers to these issues, each of these debates is still open. With respect to history, we outline several independent paths that have led to some of the approaches now prevalent in origins-of-life studies. These include one path from early views of life through the scientific revolutions brought about by Linnaeus (von Linn.), Wöhler, Miller, and others. In this approach, new theories, tools, and evidence guide new thoughts about the nature of life and its origin. We also describe another family of paths motivated by a” circularity” approach to life, which is guided by such thinkers as Maturana & Varela, Gánti, Rosen, and others. These views echo ideas developed by Kant and Aristotle, though they do so using modern science in ways that produce exciting avenues of investigation. By exploring the history of these ideas, we can see how many of the issues that currently interest us have been guided by the contexts in which the ideas were developed. The disciplinary backgrounds of each of these scholars has influenced the questions they sought to answer, the experiments they envisioned, and the kinds of data they collected. We conclude by encouraging scientists and scholars in the humanities and social sciences to explore ways in which they can interact to provide a deeper understanding of the conceptual assumptions, structure, and history of origins-of-life research. This may be useful to help frame future research agendas and bring awareness to the multifaceted issues facing this challenging scientific question., This project/publication was supported by the ELSI Origins Network (EON), which is supported by a grant from the John Templeton Foundation. T.F.’s work on this article was supported by an ELSI Origins Network (EON) Long-Term Visitor Award and by an UNAM-DGAPA-PAPIIT project (IA104717).

We agree with Brette's assessment that the coding metaphor has become more problematic than helpful for theories of brain and cognitive functioning. In an effort to aid in constructing an alternative, we argue that joining the insights from the dynamical systems approach with the semiotic framework of C. S. Peirce can provide a fruitful perspective.

We are what we are not: continually, intrinsically, necessarily incomplete in our very nature.Deacon, Incomplete Nature (2012), 535There is no explicit attempt to develop a metaphysical foundation ...

We are extremely grateful that four articulate commentaries have been written in response to our target essay. Not only do they reflect efforts by extraordinary scholars to seriously consider the i...

Contemporary textbooks often define evolution in terms of the replication, mutation, and selective retention of DNA sequences, ignoring the contribution of the physical processes involved. In the closing line of The Origin of Species, however, Darwin recognized that natural selection depends on prior more basic living functions, which he merely described as life’s “several powers.” For Darwin these involved the organism’s capacity to maintain itself and to reproduce offspring that preserve its critical functional organization. In modern terms we have come to recognize that this involves the continual generation of complex organic molecules in complex configurations accomplished with the aid of persistent far-from-equilibrium chemical self-organizing and self-assembling processes. But reliable persistence and replication of these processes also requires constantly available constraints and boundary conditions. Organism autonomy further requires that these constraints and co-dependent dynamics are reciprocally produced, each by the other. In this paper I argue that the different constraint-amplifying dynamics of two or more self-organizing processes can be coupled so that they reciprocally generate each other’s critical supportive boundary conditions. This coupling is a higher-order constraint (which can be distributed among components or offloaded onto molecular structures) that effectively constitutes a sign vehicle “interpreted” by the synergistic dynamics of these co-dependent self-organizing process so that they reconstitute this same semiotic-dynamic relationship and its self-reconstituting potential in new substrates. This dynamical co-dependence constitutes Darwin’s “several powers” and is the basis of the biosemiosis that enables evolution.

Towards a general theory of evolution argues that defining natural selection in terms of “blind variation and selective retention”— as in A-life and replicator selection—ignores the fact that what varies is necessarily part of a far-from-equilibrium physical system that requires physical work to be produced. But natural selection theory is agnostic about the physical-chemical mechanisms underlying the maintenance, repair, and reproduction of organism structures and functions. A more general theory of evolution is proposed that includes an account of a type of process able to reconstitute the organization of the physical system capable of producing that process if damaged.

In the embodied, situated, enacted and distributed approaches to cognition, the coordinative role of language comes to the fore. Language, with its symbolic properties, arises from a multimodal stream of interactive events and gradually gains power to constrain them in a functional and adaptive way. In this article, we attempt to integrate three approaches to information in cognitive systems to provide a theoretical background to the process of development of language as such a coordinator. Ecological psychology provides an explanation for how any behaviors or events become informative through the process of “tuning” to affordances that control individual and collective behavior. The dynamical approach helps to operationalize this control as a functional reduction of degrees of freedom of individual and collective systems. Cognitive semiotics provides a typology of constraints showing their interrelations: it proposes conditions under which informational controls that function as indices and icons may become symbolic, providing a qualitatively different form of constraint, which can be partially ungrounded from the ongoing stream of multimodal events. The article illustrates the proposed processes with examples from actual parent-infant interaction and points to ways of verifying them in a more quantitative way.

The relation of symbolic cognition to embodied and situated bodily dynamics remains one of the hardest problems in the contemporary cognitive sciences. In this paper we show that one of the possible factors contributing to this difficulty is the way the problem is posed. Basing on the theoretical frameworks of cognitive semiotics, ecological psychology and dynamical systems we point to an alternative way of formulating the problem and show how it suggests possible novel solutions. We illustrate the usefulness of this theoretical change in the domain of language development and draw conclusions for computational models of the emergence of symbols in natural cognition and communication as well as in artificial systems.

In this essay, I argue that we ultimately need to re-ground biosemiotic theory on natural science principles and abandon the analogy with human level semiotics, except as this provides clues for guiding analysis. But, to overcome the implicit dualism still firmly entrenched in the biological sciences requires a third approach that is neither phenomenologically motivated nor based on a code analogy. This approach must preserve the centrality of the concept of interpretation (that is ubiquitous in the phenomenological domain) and yet base it in biophysics and mathematical information theory. To accomplish this, we must undertake a thorough re-examination of information theory to determine how it can be extended to deal with issues of real reference and functional significance. I argue below that this requires showing how the concept of entropy (as it is differently defined in thermodynamics and in the information sciences) can be used to explain the relationship between information, meaning and work. Additi...

Although molecules like DNA can be analyzed in terms of their intrinsic information content on the basis of their structural complexity, it is their role in regulating cell metabolism and preserving genetic inheritance that is central. It is a basic tenet of cellular molecular biology that the sequence of nucleotides in a DNA polymer provides information contributing to the structure of proteins and their metabolic interactions and that DNA replication preserves and transmits this information across organism generations. In this respect one can describe DNA structures as being “about” protein structures and indirectly about cell function with respect to a probable environment. It is not merely that we as observers have made this referential assessment. It is intrinsic to cell function and evolution. But there is nothing intrinsic to nucleic acid polymers that makes them intrinsically referential. How a molecule like DNA or RNA could have acquired this property of being “about” other molecules and their interrelationships remains mysterious. In this presentation I will describe a molecular thought experiment that demonstrates how dynamical constraints embodied in a simple molecular system can become spontaneously offloaded onto a molecule’s structural constraints such that this structure separately preserves and re-presents the dynamical constraints that are critical for reconstituting the containing molecular system should it become disrupted. Three variants on this model system provide unambiguous examples of three canonical referential relationships that roughly correspond to iconic, indexical, and symbolic referential relationships. This analysis can help to formalize the relationship between physical-chemical, informational, and semiotic theories of life, as well as provide clues to the origin and nature of molecular genetic information.

The technical concept of information developed after Shannon [22] has fueled advances in many fields, but its quantitative precision and its breadth of application have come at a cost. Its formal abstraction from issues of reference and significance has reduced its usefulness in fields such as biology, cognitive neuroscience and the social sciences where such issues are most relevant. I argue that explaining these nonintrinsic properties requires focusing on the physical properties of the information medium with respect to those of its physical context—and specifically the relationship between the thermodynamic and information entropies of each. Reference is shown to be a function of the thermodynamic openness of the information medium. Interactions between an informing medium and its physical context that drive the medium to a less probable state create intrinsic constraints that indirectly reflect the form of this extrinsic influence. This susceptibility of an informing medium to the effects of physical work is also relevant for assessing the significance or usefulness of information. Significance can be measured in terms of work “saved” due to access to information about certain contextual factors relevant to achieving a preferred target condition.

The classic anthropological hypothesis known as the “obstetrical dilemma” is a well-known explanation for human altriciality, a condition that has significant implications for human social and behavioral evolution. The hypothesis holds that antagonistic selection for a large neonatal brain and a narrow, bipedal-adapted birth canal poses a problem for childbirth; the hominin “solution” is to truncate gestation, resulting in an altricial neonate. This explanation for human altriciality based on pelvic constraints persists despite data linking human life history to that of other species. Here, we present evidence that challenges the importance of pelvic morphology and mechanics in the evolution of human gestation and altriciality. Instead, our analyses suggest that limits to maternal metabolism are the primary constraints on human gestation length and fetal growth. Although pelvic remodeling and encephalization during hominin evolution contributed to the present parturitional difficulty, there is little evidence that pelvic constraints have altered the timing of birth.

Il arrive qu’une complexite extreme mette le modele de la selection naturelle au defi d’expliquer quoi que ce soit. Depuis Darwin, l’aptitude humaine au langage est incessamment citee en exemple-type de ce cas de figure. Et ceux qui ont souligne les problemes poses par cette faculte si specifiquement humaine n’etaient pas tous des critiques du darwinisme. On sait l’argument avance par Alfred Russel Wallace, co-instigateur de la theorie de la selection naturelle, et repute plus darwiniste que ...

Kalevi Kull and colleagues recently proposed eight theses as a conceptual basis for the field of biosemiotics. We use these theses as a framework for discussing important current areas of debate in biosemiotics with particular reference to the articles collected in this issue of Zygon.

Explaining the extravagant complexity of the human language and our competence to acquire it has long posed challenges for natural selection theory. To answer his critics, Darwin turned to sexual selection to account for the extreme development of language. Many contemporary evolutionary theorists have invoked incredibly lucky mutation or some variant of the assimilation of acquired behaviors to innate predispositions in an effort to explain it. Recent evodevo approaches have identified developmental processes that help to explain how complex functional synergies can evolve by Darwinian means. Interestingly, many of these developmental mechanisms bear a resemblance to aspects of Darwin's mechanism of natural selection, often differing only in one respect (e.g., form of duplication, kind of variation, competition/cooperation). A common feature is an interplay between processes of stabilizing selection and processes of relaxed selection at different levels of organism function. These may play important roles in the many levels of evolutionary process contributing to language. Surprisingly, the relaxation of selection at the organism level may have been a source of many complex synergistic features of the human language capacity, and may help explain why so much language information is “inherited” socially.

Theses on the semiotic study of life as presented here provide a collectively formulated set of statements on what biology needs to be focused on in order to describe life as a process based on semiosis, or signaction. An aim of the biosemiotic approach is to explain how life evolves through all varieties of forms of communication and signification (including cellular adaptive behavior, animal communication, and human intellect) and to provide tools for grounding sign theories. We introduce the concept of semiotic threshold zone and analyze the concepts of semiosis, function, umwelt, and the like as the basic concepts for theoretical biology.

Lacking a plausible model for the emergence of telos (purposive, representational, and evaluative relationships, as in life and consciousness) from simple material and energetic processes, the sciences operate as though all teleological relationships are physically epiphenomenal. Alternatively, in religion and the humanities it is as- sumed either that telos influences the material world from an outside or transcendental source or that it is a fundamental and ineffable property of things. We argue that a scientifically sound and intu- itively plausible model for the physical emergence of teleological dy- namics is now realizable. A methodology for formulating such a model and an exemplar case—the autocell—are presented. An autocell is an autocatalytic set of molecules that produce one another and also pro- duce molecules that spontaneously accrete to form a hollow container, analogous to the way virus capsules form. The molecular capsules that result will spontaneously enclose some of the nearby molecules of the autocatalytic set, keeping them together so that when the au- tocell is broken open autocatalysis will resume. Autocells are thus self-reconstituting, self-reproducing, and minimally evolvable. They are not living and yet have necessary precursor attributes to telos, in- cluding individuality, functional interdependence of parts, end-di- rectedness, a minimal form of representation, and a normative (evaluational) relationship to different environmental properties. The autocell thus serves as a missing link between inanimate (nonlife) and animate (living) phenomena. We conclude by discussing the chal- lenges that a natural origin for telos poses for religious thought.

A scientifically adequate theory of semiotic processes must ultimately be founded on a theory of information that can unify the physical, biological, cognitive, and computational uses of the concept. Unfortunately, no such unification exists, and more importantly, the causal status of informational content remains ambiguous as a result. Lacking this grounding, semiotic theories have tended to be predominantly phenomenological taxonomies rather than dynamical explanations of the representational processes of natural systems. This paper argues that the problem of information that prevents the development of a scientific semiotic theory is the necessity of analyzing it as a negative relationship: defined with respect to absence. This is cryptically implicit in concepts of design and function in biology, acknowledged in psychological and philosophical accounts of intentionality and content, and is explicitly formulated in the mathematical theory of communication (aka "information theory"). Beginning from the base established by Claude Shannon, which otherwise ignores issues of content, reference, and evaluation, this two part essay explores its relationship to two other higher-order theories that are also explicitly based on an analysis of absence: Boltzmann's theory of thermodynamic entropy (in Part I) and Darwin's theory of natural selection (in Part II). This comparison demonstrates that these theories are both formally homologous and hierarchically interdependent. Their synthesis into a general theory of entropy and information provides the necessary grounding for theories of function and semiosis.

The emergence paradox The evolutionary perspective turned the classic worldview on its head. Since Roman times the world was understood to be hierarchic in structure, explained by transcendent Mind at the top. From there the Great Chain of Being cascaded down through angels, humans, frogs, protozoa, and finally stones. Inverting the Chain of Being, switched mind from being the ultimate explanation of things, to being the mystery to be explained. As an early critic of Darwin protested, this theory assumes that “Absolute Ignorance” is the ultimate artificer, even of life and mind. However, the notion that the distinctive properties of life and mind were produced by blind mechanism from inanimate matter runs counter to a fundamental assumption of Western thought. It is expressed in the oft-quoted dictum of the Roman poet-scientist Lucretius: “ex nihilo nihil fit,” from nothing, nothing [can be] produced. Later, the principle was expressed another way by mediaeval philosopher-theologians who borrowed a maxim derived from Roman secular law: “Nemo dat quod non habet,” no one gives what he does not have. This maxim articulated their conviction that no creation can have more perfect characteristics than the cause that gave rise to it. To imagine that modern science and philosophy have now fully abandoned this principle would be mistaken. The First Law of Thermodynamics states that neither matter nor energy can be created nor destroyed, and the Second Law tells us that ultimately orderliness always gives way to disorder. Physical change always and only involves a rearrangement of material and energetic properties that are already there. No chemical transformation will turn lead into gold, and perpetual motion machines, constantly recycling the same capacity to do work, are impossible. Because the capacity to do work depends on the Second Law—the spontaneous breakdown of ordered states—in the

A simple molecular system (“autocell”) is described consisting of the reciprocal linkage between an autocatalytic cycle and a self-assembling encapsulation process where the molecular constituents for the capsule are products of the autocatalysis. In a molecular environment sufficiently rich in the substrates, capsule growth will also occur with high predictability. Growth to closure will be most probable in the vicinity of the most prolific autocatalysis and will thus tend to spontaneously enclose supportive catalysts within the capsule interior. If subsequently disrupted in the presence of new substrates, the released components will initiate production of additional catalytic and capsule components that will spontaneously re-assemble into one or more autocell replicas, thereby reconstituting and sometimes reproducing the original. In a diverse molecular environment, cycles of disruption and enclosure will cause auto-cells to incidentally encapsulate other molecules as well as reactive substrates. To the extent that any captured molecule can be incorporated into the autocatalytic process by virtue of structural degeneracy of the catalytic binding sites, the altered autocell will incorporate the new type of component into subsequent replications. Such altered autocells will be progenitors of “lineages” with variant characteristics that will differentially propagate with respect to the availability of commonly required substrates. Autocells are susceptible to a limited form of evolution, capable of leading to more efficient, more environmentally fitted, and more complex forms. This provides a simple demonstration of the plausibility of open-ended reproduction and evolvability without self-replicating template molecules (e.g., nucleic acids) or maintenance of persistent nonequilibrium chemistry. This model identifies an intermediate domain between prebiotic and biotic systems and bridges the gap from nonequilibrium thermodynamics to life.

Social animals are provisioned with prosocial orientations that operate to transcend self-interest. Morality, as used here, describes human versions of such orientations. We explore the evolutionary antecedents of morality in the context of emergentism, giving considerable attention to the biological traits that undergird awareness and our emergent human forms of mind. We suggest that our moral frames of mind emerge from our primate prosocial capacities, transfigured and valenced by our symbolic languages, cultures, and religions.

The lack of supply and access to human tissue has prompted the development of xenotransplantation as a potential clinical modality for neural cell transplantation. The goal of the present study was to achieve a better understanding of the immune factors involved in neural xenograft rejection in primates. Initially, we quantified complement mediated cell lysis of porcine fetal neurons by primate serum and demonstrated that anti-C5 antibody treatment inhibited cell death. We then developed an immunosuppression protocol that included in vivo anti-C5 monoclonal antibody treatment, triple drug therapy (cyclosporine, methylprednisolone, azathioprine) and donor tissue derived from CD59 or H-transferase transgenic pigs and applied it to pig-to-primate neural cell transplant models. Pre-formed aGal, induced aGal and primate anti-mouse antibody (PAMA) titers were monitored to assess the immune response. Four primates were transplanted. The three CD59 neural cell recipients showed an induced anti-aGal response, whereas the H-transferase neural cell recipient exhibited consistently low anti-aGal titers. Two of these recipients contained surviving grafts as detected by immunohistochemistry using selected neural markers. Graft survival correlated with high dose cyclosporine treatment, complete complement blockade and the absence of an induced PAMA response to the murine anti-C5 monoclonal antibodies.

There have been more theories of consciousness than you can shake a stick at, but this is the first to depend as much on what isn't there as on what is. There's more. Its originator, Terrence W. Deacon believes his counterintuitive theory will help us better understand emotions, brain functions – and even our early origins

Neural and stem cell transplantation is emerging as a potential treatment for neurodegenerative diseases. Transplantation of specific committed neuroblasts (fetal neurons) to the adult brain provides such scientific exploration of these new potential therapies. Huntington's disease (HD) is a fatal, incurable autosomal dominant (CAG repeat expansion of huntingtin protein) neurodegenerative disorder with primary neuronal pathology within the caudate–putamen (striatum). In a clinical trial of human fetal striatal tissue transplantation, one patient died 18 months after transplantation from cardiovascular disease, and postmortem histological analysis demonstrated surviving transplanted cells with typical morphology of the developing striatum. Selective markers of both striatal projection and interneurons such as dopamine and c-AMP-related phosphoprotein, calretinin, acetylcholinesterase, choline acetyltransferase, tyrosine hydroxylase, calbindin, enkephalin, and substance P showed positive transplant regions clearly innervated by host tyrosine hydroxylase fibers. There was no histological evidence of immune rejection including microglia and macrophages. Notably, neuronal protein aggregates of mutated huntingtin, which is typical HD neuropathology, were not found within the transplanted fetal tissue. Thus, although there is a genetically predetermined process causing neuronal death within the HD striatum, implanted fetal neural cells lacking the mutant HD gene may be able to replace damaged host neurons and reconstitute damaged neuronal connections. This study demonstrates that grafts derived from human fetal striatal tissue can survive, develop, and are unaffected by the disease process, at least for 18 months, after transplantation into a patient with HD.

We used brain imaging to study long-term neurodegenerative and bioadaptive neurochemical changes in a primate model of Parkinson disease. We gradually induced a selective loss of nigros- triatal dopamine neurons, similar to that of Parkinson disease, by creating oxidative stress through infusion of the mitochondrial complex 1 inhibitor MPTP for 14 ± 5 months. Repeated evaluations over 3 years by positron emission tomography (PET) demonstrated progressive and persistent loss of neuronal dopamine pre-synaptic re-uptake sites; repeated magnetic resonance spectroscopy (MRS) studies indicated a 23-fold increase in lactate and macromolecules in the striatum region of the brain for up to 10 months after the last administration of MPTP. By 2 years after the MPTP infusions, these MRS striatal lactate and macromolecule values had returned to normal levels. In contrast, there were persistent increases in striatal choline and decreases in N- acetylaspartate. Thus, these combined PET/MRS studies demonstrate patterns of neurochemical changes that are both dynamic and persistent long after selective dopaminergic degeneration.

Alzheimer's disease (AD) is the most common neurodegenerative disorder that causes cognitive deficits in the elderly. Its neuropathology is characterized by amyloid deposition and specific cholinergic degeneration. To address the link between amyloid formation and cholinergic loss, we examined histologically the amyloid precursor protein (APP) changes following selective immunolesion of the basal forebrain cholinergic system with 192 IgG-saporin in rats at 6 months post-lesion. In such rats with cognitive deficits observed in Morris water maze tests, we found increased levels of APP by optical density measurements in regions of cholinergic denervation. APP elevation and performance in the water maze task correlate with reduction of acetyl-cholinesterase (AChE) activity in the frontal cortex and CA3 subfield of hippocampus. The data indicate that loss of cholinergic innervation can affect APP expression.

Despite decades of research that has revolutionized the neurosciences, efforts to explain the major features of human brain evolution are still mostly based on superficial gross neuroanatomical features (e.g. size, sulcal patterns) and on theories of selection for high-level functions that lack precise neurobiological predictions (e.g. general intelligence, innate grammar). Beyond its large size we still lack an account of what makes a human brain different. However, advances in comparative neuroanatomy, developmental biology, and genetics have radically changed our understanding of brain development. These data challenge classic ideas about brain size, intelligence, and the addition of new functions, such as language, and they provide tools with which we can test hypotheses about how human brains diverge from other primate brains.

The movement disorder in Parkinson's disease results from the selective degeneration of a small group of dopaminergic neurons in the substantia nigra pars compacta region of the brain. A number of exploratory studies using human fetal tissue allografts have suggested that transplantation of dopaminergic neurons may become an effective treatment for patients with Parkinson's disease and the difficulty in obtaining human fetal tissue has generated interest in finding corresponding non-human donor cells. Here we report a post-mortem histological analysis of fetal pig neural cells that were placed unilaterally into the caudate-putamen brain region of a patient suffering from Parkinson's disease. Long-term (over seven months) graft survival was found and the presence of pig dopaminergic neurons and other pig neural and glial cells is documented. Pig neurons extended axons from the graft sites into the host brain. Furthermore, other graft derived cells were observed several millimeters from the implantation sites. Markers for human microglia and T-cells showed only low reactivity in direct proximity to the grafts. This is the first documentation of neural xenograft survival in the human brain and of appropriate growth of non-human dopaminergic neurons for a potential therapeutic response in Parkinson's disease.

The presence and specificity of axon guidance cues in the mature brain were examined by transplanting several types of xenogeneic neural cells from fetal pig brains into adult rat brains with selective neuronal loss. Committed neuronal phenotypes from cortical, mesencephalic and striatal fetal regions were implanted in homotopic or ectopic central nervous system locations. Using specific neurofilament and neural markers, axonal target selection by transplanted fetal neurons was determined throughout the central nervous system. Different types of donor neurons grew axons specifically to appropriate adjacent and distant host brain regions from ectopic or homotopic brain implantation sites and independent of the pattern of prior selective neuronal loss. Since the fetal donor neurons could orient axonal growth towards their normal synaptic termination zones, it shows that the adult brain also elaborates highly specific signals for axon guidance. These results obtained by xenotransplantation also demonstrate that the adult brain exhibits a latent potential for long-distance axon guidance that is evolutionarily conserved. These and related studies indicate that the necessary processes for connection of specific neurocircuitry also exist in the adult central nervous system, if axonal growth inhibition is overcome.