Selected Grantee Publications
Collective Behavior Emerges from Genetically Controlled Simple Behavioral Motifs in Zebrafish
Harpaz et al., Science Advances. 2021.
https://www.science.org/doi/10.1126/sciadv.abi7460
Harpaz et al. report that zebrafish regulate their proximity and alignment with each other at early larval stages. Two visual responses (one measuring relative visual field occupancy and one accounting for global visual motion), account for emerging group behavior. Mutations in genes known to affect social behavior in humans perturb these reflexes in individual larval zebrafish and change their emergent collective behaviors. Model simulations show that changes in these two responses in individual mutant animals predict well the distinctive collective patterns that emerge in a group. Hence, group behaviors reflect in part genetically defined primitive sensorimotor “motifs” evident in young larvae. Supported by ORIP (R43OD024879, R44OD024879) and NINDS.
Limited Expansion of Human Hepatocytes in FAH/RAG2-Deficient Swine
Nelson et al., Tissue Engineering – Part A. 2021.
https://pubmed.ncbi.nlm.nih.gov/34309416/
The mammalian liver's regenerative ability has led researchers to engineer animals as incubators for expansion of human hepatocytes. Nelson et al. engineered immunodeficient swine to support expansion of human hepatocytes and identify barriers to their clinical application. Immunodeficient swine were engineered by knockout of the recombinase-activating gene 2 (RAG2) and fumarylacetoacetate hydrolase (FAH). Immature human hepatocytes (ihHCs) were injected into fetal swine by intrauterine cell transplantation (IUCT) at day 40 of gestation. They identified the mechanism of the eventual graft rejection by the intact NK cell population. They confirmed the presence of residual adaptive immunity in this model of immunodeficiency. Supported by ORIP (U42OD011140).
Comparative Cellular Analysis of Motor Cortex in Human, Marmoset and Mouse
Bakken et al., Nature. 2021.
https://pubmed.ncbi.nlm.nih.gov/34616062/
Investigators used high-throughput transcriptomic and epigenomic profiling of more than 450,000 single nuclei in humans, marmosets, and mice, to characterize the cellular makeup of the primary motor cortex (M1), which exhibits similarities that mirror evolutionary distance and are consistent between the transcriptome and epigenome. Despite the overall conservation, many species-dependent specializations are apparent. These results demonstrate the robust molecular foundations of cell-type diversity in M1 across mammals and point to the genes and regulatory pathways responsible for the functional identity of cell types and their species-specific adaptations. Supported by ORIP (P51OD010425), NIMH, NCATS, NINDS, and NIDA.
Safety, Pharmacokinetics and Antiviral Activity of PGT121, a Broadly Neutralizing Monoclonal Antibody Against HIV-1: A Randomized, Placebo-Controlled, Phase 1 Clinical Trial
Stephenson et al., Nature Medicine. 2021.
https://doi.org/10.1038/s41591-021-01509-0
Researchers carried out a double-blind trial of one administration of the HIV-1 V3-glycan-specific antibody (Ab) PGT121 in HIV-uninfected and HIV-infected adults on antiretroviral therapy (ART), as well as an open-label trial of one infusion of PGT121 in viremic HIV-infected adults not on ART. The investigators observed no treatment-related serious adverse events among the 48 participants, and neutralizing anti-drug Abs were not elicited. PGT121 reduced plasma HIV RNA by a median of 1.77 log in viremic participants. Two individuals experienced ART-free viral suppression for ≥168 days following Ab infusion. These findings motivate further investigation of Ab-based therapeutic strategies for long-term HIV suppression. Supported by ORIP (R01OD024917, R01OD011095), NIAID, and NCATS.
A Novel Non-Human Primate Model of Pelizaeus-Merzbacher Disease
Sherman et al., Neurobiology of Disease. 2021.
https://www.sciencedirect.com/science/article/pii/S096999612100214X
Pelizaeus-Merzbacher disease (PMD) in humans is a severe hypomyelinating disorder of the central nervous system (CNS) linked to mutations in the proteolipid protein-1 (PLP1) gene. Investigators report on three spontaneous cases of male neonatal rhesus macaques (RMs) with clinical symptoms of hypomyelinating disease. Genetic analysis revealed that the parents of these related RMs carried a rare, hemizygous missense variant in exon 5 of the PLP1 gene. These RMs represent the first reported NHP model of PMD, providing an opportunity for studies to promote myelination in pediatric hypomyelinating diseases, as other animal models for PMD do not fully mimic the human disorder. Supported by ORIP (R24OD021324, P51OD011092, and S10OD025002) and NINDS.
Genetic Basis For an Evolutionary Shift From Ancestral Preaxial to Postaxial Limb Polarity in Non-urodele Vertebrates
Trofka et al., Current Biology. 2021.
https://www.sciencedirect.com/science/article/pii/S0960982221012501
In most tetrapod vertebrates, limb skeletal progenitors condense with postaxial dominance. Posterior elements (ulna and fibula) appear prior to their anterior counterparts (radius and tibia), followed by digit-appearance order with continuing postaxial polarity. Recent fossil evidence suggests that preaxial polarity represents an ancestral rather than derived state. These authors report that 5'Hoxd (Hoxd11-d13) gene deletion in mouse is atavistic and uncovers an underlying preaxial polarity in mammalian limb formation. Evolutionary changes in Gli3R activity level, key in the fin-to-limb transition, appear to be fundamental to the shift from preaxial to postaxial polarity in formation of the tetrapod limb skeleton. Supported by ORIP (P40OD01979) and NCI.
Prior Infection With SARS-CoV-2 WA1/2020 Partially Protects Rhesus Macaques Against Re-Infection With B.1.1.7 and B.1.351 Variants
Chandrashekar et al., Science Translational Medicine. 2021.
https://doi.org/10.1126/scitranslmed.abj2641
Using the rhesus macaque model, researchers addressed whether natural immunity induced by the original SARS-CoV-2 WA1/2020 strain protects against re-challenge with B.1.1.7 and B.1.351, known as the alpha and beta variants of concern, respectively. The investigators infected rhesus macaques with WA1/2020 and re-challenged them on day 35 with WA1/2020 or with the alpha or beta variants. Natural immunity to WA1/2020 led to robust protection against re-challenge with WA1/2020, partial protection against beta, and an intermediate degree of protection against alpha. These findings have important implications for vaccination and public health strategies in the context of emerging SARS-CoV-2 variants of concern. Supported by ORIP (P51OD011106) and NCI.
Improving Rigor and Reproducibility in Nonhuman Primate Research
Bliss-Moreau et al., American Journal of Primatology. 2021.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8629848/
Investigators across interdisciplinary fields consider approaches to enhance rigor and producibility in nonhuman primate (NHP) research. Given their similarity to humans, NHPs are often the animal model of choice for translational/preclinical biomedical research. However, availability of NHPs is limited. Hence, increased rigor is required to maximize the information gained from NHP studies. The co-authors consider approaches, such as, normative protocols, preregistration, data sharing, and how more extensive training in biostatics can enhance rigorous research in NHPs across biomedical disciplines. Supported by ORIP (P51OD011107, P51OD011106, P51OD011132, P51OD010425, P51OD011104, P51OD011092, and P51OD011133).
Whole-Organism 3D Quantitative Characterization of Zebrafish Melanin by Silver Deposition Micro-CT
Katz et al., eLife. 2021.
https://www.biorxiv.org/content/10.1101/2021.03.11.434673v1
This research team combined micro-computed tomography (CT) with a novel application of ionic silver staining to characterize melanin distribution in whole zebrafish larvae. The resulting images enabled whole-body, computational analyses of regional melanin content and morphology. Normalized micro-CT reconstructions of silver-stained fish consistently reproduced pigment patterns seen by light microscopy and allowed direct quantitative comparisons of melanin content. Silver staining of melanin for micro-CT provides proof-of-principle for whole-body, 3D computational phenomic analysis of a specific cell type at cellular resolution. Advances such as this in whole-organism, high-resolution phenotyping provide superior context for studying the phenotypic effects of genetic, disease, and environmental variables. Supported by ORIP (R24OD018559).
A Large Repertoire of B Cell Lineages Targeting One Cluster of Epitopes in a Vaccinated Rhesus Macaque
Li et al., Vaccine. 2021.
https://www.sciencedirect.com/science/article/pii/S0264410X21010355?via%3Dihub=
A rhesus macaque that was serially immunized six times with the 8-mer epitope for human monoclonal antibody (mAb) 447-52D—specific to the V3 region of gp120 HIV-1—provided a rare opportunity to study the repertoire of antibodies produced upon vaccination against a particular antigenic site. From a blood sample taken 3 weeks after the last immunization, researchers produced 41 V3-specific recombinant mAbs by single B cell isolation and cloning. Sequence analysis revealed 21 B cell lineages (single and clonally related). The broad repertoire of Abs directed to a small antigenic site shows the targeting potency of a vaccine-elicited immune response in rhesus macaques. Supported by ORIP (P51OD011092, U42OD010246) and NIAID.