Primate Origin Research Articles

The Primate Origins of Human Social Cognition

ABSTRACT The ability to understand the mental states of other individuals is central to human social behavior, yet some theory of mind capacities are shared with other species. Comparisons of theory of mind skills across humans and other primates can provide a critical test of the cognitive prerequisites necessary for different theory of mind skills to emerge. A fundamental difference between humans and non-humans is language: while language may scaffold some developing theory of mind skills in humans, other species do not have similar capacities for or immersion in language. Comparative work can therefore provide a new line of evidence to test the role of language in the emergence of complex social cognition. Here we first provide an overview of the evidence for shared aspects of theory of mind in other primates, and then examine the evidence for apparently human-unique aspects of theory of mind that may be linked to language. We finally contrast different evolutionary processes, such as competition and cooperation, that may have been important for primate social cognition versus human-specific forms of theory of mind. We argue that this evolutionary perspective can help adjudicate between different proposals on the link between human-specific forms of social cognition and language.

Liminal Light and Primate Evolution

The adaptive origins of primates and anthropoid primates are topics of enduring interest to biological anthropologists. A convention in these discussions is to treat the light environment as binary—night is dark, day is light—and to impute corresponding selective pressure on the visual systems and behaviors of primates. In consequence, debate has tended to focus on whether a given trait can be interpreted as evidence of nocturnal or diurnal behavior in the primate fossil record. Such classification elides the variability in light, or the ways that primates internalize light in their environments. Here, we explore the liminality of light by focusing on what it is, its many sources, and its flux under natural conditions. We conclude by focusing on the intensity and spectral properties of twilight, and we review the mounting evidence of its importance as a cue that determines the onset or offset of primate activities as well as the entrainment of circadian rhythms.

Baboons (Papio anubis) living in larger social groups have bigger brains

The evolutionary origin of Primates' exceptionally large brains is still highly debated. Two competing explanations have received much support: the ecological hypothesis and the social brain hypothesis (SBH). We tested the SBH in (n = 82) baboons (Papio anubis) belonging to the same research centre but housed in groups with size ranging from 2 to 63 individuals. We found that baboons living in larger social groups had larger brains. This effect was driven mainly by white matter volume and to a lesser extent by grey matter volume but not by the cerebrospinal fluid. In comparison, the size of the enclosure, an ecological variable, had no such effect. In contrast to the current re-emphasis on potential ecological drivers of primate brain evolution, the present study provides renewed support for the social brain hypothesis and suggests that the social brain plastically responds to group size. Many factors may well influence brain size, yet accumulating evidence suggests that the complexity of social life might be an important determinant of brain size in primates.

Increased terrestriality in a Neotropical primate living on islands with reduced predation risk

An arboreal lifestyle is thought to be central to primate origins, and most extant primate species still live in the trees. Nonetheless, terrestrial locomotion is a widespread adaptation that has arisen repeatedly within the primate lineage. The absence of terrestriality among the New World monkeys (Platyrrhini) is thus notable and raises questions about the ecological pressures that constrain the expansion of platyrrhines into terrestrial niches. Here, we report the results of a natural experiment, comparing patterns of terrestrial behavior in white-faced capuchin monkeys (Cebus capucinus imitator) living on two islands off the Pacific coast of Panama that lack mammalian predators (island sites) with the behavior of capuchins at three sites in central Panama with more intact predator communities (mainland sites). Surveys with camera traps revealed increased terrestriality in island vs. mainland sites. Capuchin detection rates were higher, the range of party sizes observed was larger, and individuals engaged in a wider range of terrestrial behaviors on the islands lacking mammalian predators. Furthermore, females carrying infants were frequently photographed on the ground at the island sites, but never at the mainland sites. These findings support the long-standing hypothesis that predators constrain the exploitation of terrestrial niches by primates. These results are also consistent with the hypothesis that arboreal locomotion imposes costs that primates will avoid by walking on the ground when predation risk is low.

Not all fine-branch locomotion is equal: Grasping morphology determines locomotor performance on narrow supports

Fine-branch models have long played a central role in primate evolutionary research. Nevertheless, recent studies of positional behavior in nonprimate arboreal mammals have challenged the idea that synapomorphic primate features, such as grasping extremities, uniquely facilitated access to the fine-branch zone. We test the alternative hypothesis that grasping extremities specifically improve locomotor performance in a fine-branch environment by examining how support diameter influences locomotor mechanics in one sciurid rodent (Sciurus carolinensis) and two platyrrhine primates (Callithrix jacchus and Saimiri boliviensis). These species were chosen to broadly model different stages in the evolution of primate grasping morphology. The results showed that transitioning from broad to narrower supports required the greatest kinematic adjustment in squirrels and the least adjustment in squirrel monkeys, with marmosets displaying an intermediate level of adjustment. Moreover, on any given support, squirrels' locomotor mechanics differed from marmosets' in a manner consistent with a greater need for stability, despite superficial ecomorphological similarities between sciurid rodents and callitrichine primates. Morphological analyses of autopodial size and proportions suggest that variation in locomotor performance more closely tracked variation in overall hand and foot size rather than digit length per se. Indeed, a broad comparative analysis revealed that for their body mass, primates have longer hands than similarly sized arboreal rodents and marsupials (although only the primate-rodent comparison was significant after incorporating phylogenetic relatedness). Inclusion of fossil stem primates (plesiadapiforms) and euprimates (adapiforms) in these analyses suggests that this primate-wide grade shift in relative autopodial size must have occurred early in the evolutionary history of the group. Overall, our findings show that basal primate morphological adaptations may have specifically facilitated improved locomotor performance in a fine-branch niche, rather than merely permitting access to the environment. As such, future adaptive hypotheses of primate origins should incorporate the import of primate-like morphology on locomotor performance as well.

Palm fruit colours are linked to the broad-scale distribution and diversification of primate colour vision systems.

A long-standing hypothesis in ecology and evolution is that trichromatic colour vision (the ability to distinguish red from green) in frugivorous primates has evolved as an adaptation to detect conspicuous (reddish) fruits. This could provide a competitive advantage over dichromatic frugivores which cannot distinguish reddish colours from a background of green foliage. Here, we test whether the origin, distribution and diversity of trichromatic primates is positively associated with the availability of conspicuous palm fruits, i.e. keystone fruit resources for tropical frugivores. We combine global data of colour vision, distribution and phylogenetic data for more than 400 primate species with fruit colour data for more than 1700 palm species, and reveal that species richness of trichromatic primates increases with the proportion of palm species that have conspicuous fruits, especially in subtropical African forests. By contrast, species richness of trichromats in Asia and the Americas is not positively associated with conspicuous palm fruit colours. Macroevolutionary analyses further indicate rapid and synchronous radiations of trichromats and conspicuous palms on the African mainland starting 10 Ma. These results suggest that the distribution and diversification of African trichromatic primates is strongly linked to the relative availability of conspicuous (versus non-conspicuous) palm fruits, and that interactions between primates and palms are related to the coevolutionary dynamics of primate colour vision systems and palm fruit colours.

The frugivorous insectivores? Functional morphological analysis of molar topography for inferring diet in extant treeshrews (Scandentia)

AbstractThe ecology, and particularly the diet, of treeshrews (order Scandentia) is poorly understood compared to that of their close relatives, the primates. This stems partially from treeshrews having fast food transit times through the gut, meaning fecal and stomach samples only represent a small portion of the foodstuffs consumed in a given day. Moreover, treeshrews are difficult to observe in the wild, leading to a lack of observational data in the literature. Although treeshrews are mixed feeders, consuming both insects and fruit, it is currently unknown how the relative importance of these food types varies across Scandentia. Previous study of functional dental morphology has provided an alternative means for understanding the diet of living euarchontans. We used dental topographic metrics to quantify aspects of functional dental morphology in a large sample of treeshrews (n = 58). We measured relief index, Dirichlet normal energy, and three-dimensional orientation patch count rotated, which quantify crown relief, occlusal curvature, and complexity, respectively. Our results suggest that treeshrews exhibit dental morphology consistent with high levels of insectivory relative to other euarchontans. They also suggest that taxa such as Dendrogale melanura and Tupaia belangeri appear to be best suited to insectivory, whereas taxa such as T. palawanensis and T. gracilis appear to be best adapted to frugivory. Our results suggest that Ptilocercus lowii is characterized by a dentition better adapted to insectivory than the early primate Purgatorius. If P. lowii represents a good modern analogue for primitive euarchontans, this contrast would support models of primate origins that include a shift to greater frugivory.

Calcitonin receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

This receptor family comprises a group of receptors for the calcitonin/CGRP family of peptides. The calcitonin (CT), amylin (AMY), calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on CGRP, AM, AMY, and CT receptors [122, 67]) are generated by the genes CALCR (which codes for the CT receptor) and CALCRL (which codes for the calcitonin receptor-like receptor, CLR, previously known as CRLR). Their function and pharmacology are altered in the presence of RAMPs (receptor activity-modifying proteins), which are single TM domain proteins of ca. 130 amino acids, identified as a family of three members; RAMP1, RAMP2 and RAMP3. There are splice variants of the CT receptor; these in turn produce variants of the AMY receptor [122], some of which can be potently activated by CGRP. The endogenous agonists are the peptides calcitonin, α-CGRP (formerly known as CGRP-I), β-CGRP (formerly known as CGRP-II), amylin (occasionally called islet-amyloid polypeptide, diabetes-associated polypeptide), adrenomedullin and adrenomedullin 2/intermedin. There are species differences in peptide sequences, particularly for the CTs. CTR-stimulating peptide (CRSP) is another member of the family with selectivity for the CT receptor but it is not expressed in humans [87]. olcegepant (also known as BIBN4096BS, pKi~10.5) and telcagepant (also known as MK0974, pKi~9) are the most selective antagonists available, showing selectivity for CGRP receptors, with a particular preference for those of primate origin. CLR (calcitonin receptor-like receptor) by itself binds no known endogenous ligand, but in the presence of RAMPs it gives receptors for CGRP, adrenomedullin and adrenomedullin 2/intermedin.

Vertical support use and primate origins

Adaptive scenarios of crown primate origins remain contentious due to uncertain order of acquisition and functional significance of the clade’s diagnostic traits. A feature of the talus bone in the ankle, known as the posterior trochlear shelf (PTS), is well-regarded as a derived crown primate trait, but its adaptive significance has been obscured by poorly understood function. Here we propose a novel biomechanical function for the PTS and model the talus as a cam mechanism. By surveying a large sample of primates and their closest relatives, we demonstrate that the PTS is most strongly developed in extant taxa that habitually grasp vertical supports with strongly dorsiflexed feet. Tali of the earliest fossils likely to represent crown primates exhibit more strongly developed PTS cam mechanisms than extant primates. As a cam, the PTS may increase grasping efficiency in dorsiflexed foot postures by increasing the path length of the flexor fibularis tendon, and thus improve the muscle’s ability to maintain flexed digits without increasing energetic demands. Comparisons are made to other passive digital flexion mechanisms suggested to exist in other vertebrates. These results provide robust anatomical evidence that the habitual vertical support use exerted a strong selective pressure during crown primate origins.

Ontogeny of Orbit Orientation in Primates.

Orbit orientation in primates has been linked to adaptive factors related to activity pattern and size-related variation in structural influences on orbit position. Although differences in circumorbital form between anthropoids and strepsirrhines appear to be related to interspecific disparities in levels of orbital convergence and orbital frontation, there is considerable overlap in convergence between suborders. Unfortunately, putative links between convergence and frontation across primates, and consequent arguments about primate and anthropoid origins, are likely to be influenced by allometry, the size range of a respective sample, and adaptive influences on encephalization and activity patterns. Such a multifarious system is less amenable to interspecific treatment across higher-level clades. An ontogenetic perspective is one way to evaluate transformations from one character state to another, especially as they pertain to allometric effects on phenotypic variation. We characterized the ontogeny of orbital convergence and frontation in 13 anthropoid and strepsirrhine species. In each suborder, correlation and regression analyses were used to test hypotheses regarding the allometric bases of variation in orbital orientation. Growth trajectories were analyzed intra- and inter-specifically. Frontation decreased postnatally in all taxa due to the negative scaling of brain vs. skull size. Further, interspecific variation in relative levels of frontation was linked to corresponding ontogenetic transpositions in encephalization that differed within both suborders. In strepsirrhines, postnatal increases in convergence were largely due to the negative allometry of orbit vs. skull size. In contrast, convergence in anthropoids varied little during growth, being unrelated to ontogenetic variation in either relative orbit or interorbit size. Anat Rec, 302:2093-2104, 2019. © 2019 American Association for Anatomy.

Macroevolutionary effects on primate trophic evolution and their implications for reconstructing primate origins

The visual-predation hypothesis proposes that certain derived features shared by crown primates reflect an insectivorous ancestry. Critics of this idea have argued that because insectivory is uncommon among extant primates it is unlikely to have been a major influence on early primate evolution. According to this perspective, the low frequency of insectivory indicates that it is an apomorphic deviation from the mostly conserved primate ecological pattern of herbivory. The present study tests two alternative hypotheses that are compatible with an insectivorous ancestor: (1) that trophic evolution was biased, such that herbivory evolved repeatedly with few shifts back to insectivory, and (2) that insectivorous lineages have diversified at a lower rate than herbivorous lineages owing to differential trophic effects on speciation and extinction probabilities. Model-based analysis conducted using trait data for 307 extant primate species indicates that rates of transition into and out of insectivory are similar, rejecting the hypothesis of biased trophic evolution. On the other hand, the hypothesis of asymmetric diversification is supported, with insectivorous lineages having a lower rate of diversification than herbivorous lineages. This correlation is mediated by activity pattern: insectivory occurs mostly in nocturnal lineages, which have a lower diversification rate than diurnal lineages. The frequency of insectivory also appears to have been shaped by repeated transitions into ecological contexts in which insectivory is absent (large body size) or rare (diurnality). These findings suggest that the current distribution of trophic strategies among extant primates is the result of macroevolutionary processes that have favored the proliferation and persistence of herbivory relative to insectivory. This conclusion implies that the low frequency of insectivory is not necessarily evidence against the visual-predation hypothesis.

MiRTrace reveals the organismal origins of microRNA sequencing data

We present here miRTrace, the first algorithm to trace microRNA sequencing data back to their taxonomic origins. This is a challenge with profound implications for forensics, parasitology, food control, and research settings where cross-contamination can compromise results. miRTrace accurately (> 99%) assigns real and simulated data to 14 important animal and plant groups, sensitively detects parasitic infection in mammals, and discovers the primate origin of single cells. Applying our algorithm to over 700 public datasets, we find evidence that over 7% are cross-contaminated and present a novel solution to clean these computationally, even after sequencing has occurred. miRTrace is freely available at https://github.com/friedlanderlab/mirtrace.

The ethnoprimatology of the Maijuna of the Peruvian Amazon and implications for primate conservation

BackgroundIn Amazonia, primates are not only an important food source but they also hold significant cultural and symbolic value for many indigenous groups. We document the relationship between primates and community members of the Maijuna indigenous community of Sucusari in the Peruvian Amazon and describe how ethnoprimatological studies provide a better understanding of the significance of primates in people’s lives. Additionally, we explore how ethnoprimatological studies can help inform and enhance primate conservation initiatives.MethodsSemi-structured interviews were conducted with 50 residents of the community of Sucusari to assess the classification, cultural significance and traditional uses, beliefs, ceremonies and stories of primates within the Sucusari River basin.ResultsPrimates play an important role in the lives of individuals in the Sucusari community. They are distinguished by their arboreal lifestyle, and among the 11 species reported in the area, seven (Lagothrix lagotricha, Alouatta seniculus, Pithecia monachus, Callicebus spp., Saimiri sciureus, Leontocebus nigricollis) are highly recognized and culturally salient. Primates are used as food, medicine, pets, domestic tools and in the production of handicrafts. They are primarily hunted for local consumption, with larger primates such as L. lagotricha being preferred. Lagothrixlagotricha was also the most commonly reported pet species and the only observed pet primate in the community during surveys. Maijuna traditional beliefs include ancestral dietary taboos for A. seniculus, which are referred to as sorcerer monkeys, but this taboo is no longer fully adhered to. Maijuna traditional stories associated with primates describe the origin of primates found in Sucusari.ConclusionPrimates are embedded in the intricate sociocultural system of the community of Sucusari. Better understanding the relationship between primates and people can help to focus conservation efforts on primate species of particularly high sociocultural importance as well as ecological value, such as L. lagotricha. We highly recommend the inclusion of ethnoprimatological studies into primate conservation initiatives to accomplish more effective conservation planning, ultimately integrating the goals of biodiversity conservation with the cultural and economic needs of indigenous and local communities.

Rethinking the Origin of Primates by Reconstructing Their Diel Activity Patterns Using Genetics and Morphology

Phylogenetic inference typically invokes nocturnality as ancestral in primates; however, some recent studies posit that diurnality is. Here, through adaptive evolutionary analyses of phototransduction genes by using a variety of approaches (restricted branch/branch-site models and unrestricted branch-site-based models (BS-REL, BUSTED and RELAX)), our results consistently showed that ancestral primates were subjected to enhanced positive selection for bright-light vision and relatively weak selection for dim-light vision. These results suggest that ancestral primates were mainly diurnal with some crepuscularity and support diurnality as plesiomorphic from Euarchontoglires. Our analyses show relaxed selection on motion detection in ancestral primates, suggesting that ancestral primates decreased their emphasis on mobile prey (e.g., insects). However, within primates, the results show that ancestral Haplorrhini were likely nocturnal, suggesting that evolution of the retinal fovea occurred within ancestral primates rather than within haplorrhines as was previously hypothesized. Our findings offer a reassessment of the visual adaptation of ancestral primates. The evolution of the retinal fovea, trichromatic vision and orbital convergence in ancestral primates may have helped them to efficiently discriminate, target, and obtain edible fruits and/or leaves from a green foliage background instead of relying on mobile insect prey.

Evidence for a primate origin of zoonotic Helicobacter suis colonizing domesticated pigs.

Helicobacter suis is the second most prevalent Helicobacter species in the stomach of humans suffering from gastric disease. This bacterium mainly inhabits the stomach of domesticated pigs, in which it causes gastric disease, but it appears to be absent in wild boars. Interestingly, it also colonizes the stomach of asymptomatic rhesus and cynomolgus monkeys. The origin of modern human-, pig- or non-human primate-associated H. suis strains in these respective host populations was hitherto unknown. Here we show that H. suis in pigs possibly originates from non-human primates. Our data suggest that a host jump from macaques to pigs happened between 100 000 and 15 000 years ago and that pig domestication has had a significant impact on the spread of H. suis in the pig population, from where this pathogen occasionally infects humans. Thus, in contrast to our expectations, H. suis appears to have evolved in its main host in a completely different way than its close relative Helicobacter pylori in humans.

Major Questions in the Study of Primate Origins

Numerous factors have stimulated new enthusiasm for understanding the process of primate origins, including new fossil discoveries, improvements to methods for analyzing molecular data, and technological advances. These novel approaches have led to a better appreciation of the complexities of early primate evolution. Eight fundamental questions provide a framework for thinking about these issues. Among these topics are the phylogenetic position of Primates in Mammalia and the membership of particular fossil groups in the order. Also of central interest are questions about early primate ecology and anatomy such as the ancestral body mass, diet, locomotor mode, interactions with predators, and brain size and form. And finally, considerations of the paleontological record need to be informed by the most relevant living models, which help flesh out the story that is being told by fossils. Although much is known about all of these areas, fundamental questions still remain.

Postcrania of the most primitive euprimate and implications for primate origins

The fossil record of early primates is largely comprised of dentitions. While teeth can indicate phylogenetic relationships and dietary preferences, they say little about hypotheses pertaining to the positional behavior or substrate preference of the ancestral crown primate. Here we report the discovery of a talus bone of the dentally primitive fossil euprimate Donrussellia provincialis. Our comparisons and analyses indicate that this talus is more primitive than that of other euprimates. It lacks features exclusive to strepsirrhines, like a large medial tibial facet and a sloping fibular facet. It also lacks the medially positioned flexor-fibularis groove of extant haplorhines. In these respects, the talus of D. provincialis comes surprisingly close to that of the pen-tailed treeshrew, Ptilocercus lowii, and extinct plesiadapiforms for which tali are known. However, it differs from P. lowii and is more like other early euprimates in exhibiting an expanded posterior trochlear shelf and deep talar body. In overall form, the bone approximates more leaping reliant euprimates. The phylogenetically basal signal from the new fossil is confirmed with cladistic analyses of two different character matrices, which place D. provincialis as the most basal strepsirrhine when the new tarsal data are included. Interpreting our results in the context of other recent discoveries, we conclude that the lineage leading to the ancestral euprimate had already become somewhat leaping specialized, while certain specializations for the small branch niche came after crown primates began to radiate.

Oldest skeleton of a plesiadapiform provides additional evidence for an exclusively arboreal radiation of stem primates in the Palaeocene.

Palaechthonid plesiadapiforms from the Palaeocene of western North America have long been recognized as among the oldest and most primitive euarchontan mammals, a group that includes extant primates, colugos and treeshrews. Despite their relatively sparse fossil record, palaechthonids have played an important role in discussions surrounding adaptive scenarios for primate origins for nearly a half-century. Likewise, palaechthonids have been considered important for understanding relationships among plesiadapiforms, with members of the group proposed as plausible ancestors of Paromomyidae and Microsyopidae. Here, we describe a dentally associated partial skeleton of Torrejonia wilsoni from the early Palaeocene (approx. 62 Ma) of New Mexico, which is the oldest known plesiadapiform skeleton and the first postcranial elements recovered for a palaechthonid. Results from a cladistic analysis that includes new data from this skeleton suggest that palaechthonids are a paraphyletic group of stem primates, and that T. wilsoni is most closely related to paromomyids. New evidence from the appendicular skeleton of T. wilsoni fails to support an influential hypothesis based on inferences from craniodental morphology that palaechthonids were terrestrial. Instead, the postcranium of T. wilsoni indicates that it was similar to that of all other plesiadapiforms for which skeletons have been recovered in having distinct specializations consistent with arboreality.

Search for Primate Origins of Phonological Uniqueness in Human Languages

Search for Primate Origins of Phonological Uniqueness in Human Languages

Coupling Therapeutics to Human Erythrocytes Demonstrates Target-Dependent Effects on Red Cell Physiology While Preserving Efficacy

Delivery of bio-therapeutics by red blood cells (RBCs) can greatly enhance pharmacokinetics and pharmacodynamics of the appended or loaded agents, and may even potentiate induction of immunologic tolerance. Our group and others have successfully used fusion proteins, antibodies, and peptides to couple therapeutics to murine, but not human, RBCs. It is known that extracellular ligands have the potential to induce marked, epitope-dependent changes in red cell physiology, including changes in deformability, phosphatidyl-serine (PS) exposure, and reactive oxygen species (ROS) production, particularly for agents targeted to glycophorin A and Band 3, two highly-expressed membrane proteins. To produce clinically translatable strategies for human RBCs, it is critical to identify optimal red cell target epitopes, understand their effects on red cell physiology, and create humanized or human-like ligands to minimize immunogenicity.We constructed single chain antibodies (scFv) against antigenic determinants on Band 3 protein (Wrb) and RHCE protein (Rh17/Hr0) on human erythrocytes using phage display libraries prepared from immunized cynamolgous macaques (Macaca fascicularis). Both these antigens are present on essentially 100% of the human population. Unfused scFvs were produced in E.coli while fusions of scFv with the extracellular domain of human thrombomodulin (TM-scFv) were produced in Drosophila S2 cells. Binding of recombinant proteins to human RBCs was measured by radioimmunoassay and flow cytometry. Generation of activated protein (APC) by RBCs loaded with TM-scFv fusions was measured by colorimetric assay. RBCs pre-incubated with varying concentrations of anti-Band3 and anti-RHCE fusions were assessed for osmotic resistance and mechanical integrity by exposure to hypo-osmolar medium and rotation in the presence of glass beads, respectively. PS exposure was measured by annexin V binding, and ROS generation was measured by dihydrorhodamine-associated fluorescence. Effects on RBC rheology were measured by flowing through microfluidic channels under controlled shear rates. Efficacy of TM-scFv fusions in diseased micro-vessels was assessed using a TNF-alpha stimulated, endothelialized microfluidic model.Single-chain antibody fragments and TM fusion proteins targeted to conserved epitopes on Band 3 protein and RHCE protein bound to human, but not murine or porcine, RBCs with high specificity and affinity (~50 nM), and in numbers consistent with the expected level of target expression (105 and 106 copies/RBC for RHCE and Band3, respectively). Coating RBCs with proteins targeted to Band 3 lessened RBC hypo-osmolar hemolysis (20% reduction) but increased hemolysis (2-fold) under mechanical stress, changes compatible with decreased red cell deformability. Proteins targeted to RHCE did not induce significant changes in hemolysis of RBCs under either osmotic or mechanical stress. Targeting neither Band 3 nor RHCE induced significant exposure of PS or production of ROS. Target-dependent effects on RBC rheology were observed under varying shear stresses in a microfluidic system. Fusion proteins of TM targeted to both epitopes demonstrated dose- and surface-copy-number-dependent generation of APC in the presence of PC and thrombin. Both TM-scFv fusion proteins were efficacious in a microfluidic model of disseminated intravascular coagulation using whole human blood by demonstrating near complete abrogation of fibrin generation in response to endothelial activation with TNF-alpha.In summary, we designed human RBC-specific non-human primate single chain antibody fragments capable of fusion to therapeutic cargoes. The TM-scFv fusions maintained therapeutic activity when bound to human RBCs and showed effective thromboprophylaxis in a whole-blood model of vasculitic injury. These antibodies and fusion proteins bound to erythroid-specific epitopes, and demonstrated target-dependent effects on several aspects of red cell physiology. The non-human primate origin of the antibodies should minimize their potential immunogenicity and the findings provide a platform to translate red cell targeted drug delivery into the clinical realm. DisclosuresNo relevant conflicts of interest to declare.