scispace - formally typeset
Search or ask a question

Showing papers by "David Baltimore published in 2015"


Journal ArticleDOI
03 Apr 2015-Science
TL;DR: The meeting identified immediate steps to take toward ensuring that the application of genome engineering technology is performed safely and ethically, and identified those areas where action is essential to prepare for future developments.
Abstract: A framework for open discourse on the use of CRISPR-Cas9 technology to manipulate the human genome is urgently needed

527 citations


Journal ArticleDOI
TL;DR: A proof-of-concept that gene transfer of anti-HIV antibody genes can protect against infection by viruses that cause AIDS in primates when host immune responses are controlled is shown.
Abstract: Broadly neutralizing antibodies (bnAbs) can prevent lentiviral infection in nonhuman primates and may slow the spread of human immunodeficiency virus type 1 (HIV-1). Although protection by passive transfer of human bnAbs has been demonstrated in monkeys, durable expression is essential for its broader use in humans. Gene-based expression of bnAbs provides a potential solution to this problem, although immune responses to the viral vector or to the antibody may limit its durability and efficacy. Here, we delivered an adeno-associated viral vector encoding a simianized form of a CD4bs bnAb, VRC07, and evaluated its immunogenicity and protective efficacy. The expressed antibody circulated in macaques for 16 weeks at levels up to 66 μg/ml, although immune suppression with cyclosporine (CsA) was needed to sustain expression. Gene-delivered simian VRC07 protected against simian-human immunodeficiency virus (SHIV) infection in monkeys 5.5 weeks after treatment. Gene transfer of an anti-HIV antibody can therefore protect against infection by viruses that cause AIDS in primates when the host immune responses are controlled.

97 citations


Journal ArticleDOI
16 Jun 2015-Immunity
TL;DR: In this paper, the microRNA212/132 cluster (Mirc19) is enriched in HSCs and is upregulated during aging, leading to inappropriate hematopoietic cell-fate decisions.

81 citations


Journal ArticleDOI
TL;DR: These exciting new findings will shape the fundamental understanding of how inflammatory signaling regulates hematopoiesis in health and disease, and facilitate the development of potential interventions to treat hematologic diseases associated with altered inflammatory signaling.
Abstract: Purpose of review: Hematopoietic stem cells can self-renew and also give rise to the entire repertoire of hematopoietic cells. During acute infectious and inflammatory stresses, the hematopoietic system can quickly adapt to demand by increasing output of innate immune cells many-fold, often at the expense of lymphopoiesis and erythropoiesis. We review recent advances in understanding the regulation of stress-induced hematopoiesis with a specific focus on the direct effects of inflammatory signaling on hematopoietic stem and progenitor cells (HSPCs). Recent findings: Recent studies have highlighted several areas of exciting new developments in the field, including the complex interaction and crosstalk within HSPCs and between bone marrow mesenchymal stem cells and endothelial cells needed to achieve regulated myelopoiesis, identification of increased number of inflammatory and infectious molecules with direct effects on HSPCs, the critical role of inflammatory signaling on embryonic specification of hematopoietic stem cells, and the ability of cytokines to instruct lineage choice at the HSPC level. Summary: These exciting new findings will shape our fundamental understanding of how inflammatory signaling regulates hematopoiesis in health and disease, and facilitate the development of potential interventions to treat hematologic diseases associated with altered inflammatory signaling.

79 citations


Journal ArticleDOI
TL;DR: A novel role for miR-212/132 as a regulator of early B cell development is uncovered and this work contributes to the understanding of B cell reprograming and its role in wound healing.
Abstract: MicroRNAs have emerged as key regulators of B cell fate decisions and immune function. Deregulation of several microRNAs in B cells leads to the development of autoimmune disease and cancer in mice. We demonstrate that the microRNA-212/132 cluster (miR-212/132) is induced in B cells in response to B cell receptor signaling. Enforced expression of miR-132 results in a block in early B cell development at the prepro–B cell to pro–B cell transition and induces apoptosis in primary bone marrow B cells. Importantly, loss of miR-212/132 results in accelerated B cell recovery after antibody-mediated B cell depletion. We find that Sox4 is a target of miR-132 in B cells. Co-expression of SOX4 with miR-132 rescues the defect in B cell development from overexpression of miR-132 alone, thus suggesting that miR-132 may regulate B lymphopoiesis through Sox4. In addition, we show that the expression of miR-132 can inhibit cancer development in cells that are prone to B cell cancers, such as B cells expressing the c-Myc oncogene. We have thus uncovered miR-132 as a novel contributor to B cell development.

63 citations


Journal ArticleDOI
TL;DR: The role of intracellular and extracellular miRNAs in nutritional control of various (patho)physiological processes is discussed.
Abstract: MicroRNAs (miRNAs) are one of a growing class of noncoding RNAs that are involved in the regulation of a wide range of metabolic processes including cellular differentiation, cell proliferation and apoptosis. The generation of miRNA is regulated in complex ways, for example by small interfering RNAs (small nucleolar and nuclear RNAs) and various other metabolites. This complexity of control is likely to explain how a relatively small part of the DNA that codes for proteins has enabled the evolution of such complex organisms as mammals. Non-protein-coding DNA is therefore thought to carry the memory of early evolutionary steps that led to progressively complex metabolic controls. Clinically, miRNAs are becoming increasingly important following the recognition that some congenital abnormalities can be traced to defects in miRNA processing. The potential for manipulating metabolism and affecting disease processes by the pharmaceutical or biological targeting of specific miRNA pathways is now being tested. miRNAs are also released into the extracellular milieu after packaging by cells into nano-sized extracellular vesicles. Such vesicles can be taken up by adjacent and possibly more distant cells, thereby allowing coordinated intercellular communication in specific tissues. Extracellular miRNAs found in the blood stream may also serve as novel biomarkers for both diagnosing specific forms of cancer and assessing the likelihood of metastasis, and as powerful prognostic indices for various cancers. Here, we discuss the role of intracellular and extracellular miRNAs in nutritional control of various (patho)physiological processes. In this review, we provide an update of the presentations from the 25th Marabou Symposium (Stockholm, 14–16 June 2013) entitled ‘Role of miRNA in health and nutrition’, attended by 50 international experts.

34 citations


Journal ArticleDOI
TL;DR: It is found that RAG–RSS binding is reversible, with measurable dwell times before release, and that the synaptic complex has a mean lifetime of roughly 400 s and that its formation is readily reversible,With only ∼40% of observed synapses resulting in cleavage at consensus RSS binding sites.
Abstract: The recombination-activating gene products, RAG1 and RAG2, initiate V(D)J recombination during lymphocyte development by cleaving DNA adjacent to conserved recombination signal sequences (RSSs). The reaction involves DNA binding, synapsis, and cleavage at two RSSs located on the same DNA molecule and results in the assembly of antigen receptor genes. We have developed single-molecule assays to examine RSS binding by RAG1/2 and their cofactor high-mobility group-box protein 1 (HMGB1) as they proceed through the steps of this reaction. These assays allowed us to observe in real time the individual molecular events of RAG-mediated cleavage. As a result, we are able to measure the binding statistics (dwell times) and binding energies of the initial RAG binding events and characterize synapse formation at the single-molecule level, yielding insights into the distribution of dwell times in the paired complex and the propensity for cleavage on forming the synapse. Interestingly, we find that the synaptic complex has a mean lifetime of roughly 400 s and that its formation is readily reversible, with only ∼40% of observed synapses resulting in cleavage at consensus RSS binding sites.

22 citations


01 May 2015
TL;DR: It is found that the microRNA-212/132 cluster (Mirc19) is enriched in HSCs and is upregulated during aging, and plays a role in maintaining balanced hematopoietic output by buffering FOXO3 expression.
Abstract: MicroRNAs are critical post-transcriptional regulators of hematopoietic cell-fate decisions, though little remains known about their role in aging hematopoietic stem cells (HSCs). We found that the microRNA-212/132 cluster (Mirc19) is enriched in HSCs and is upregulated during aging. Both overexpression and deletion of microRNAs in this cluster leads to inappropriate hematopoiesis with age. Enforced expression of miR-132 in the bone marrow of mice led to rapid HSC cycling and depletion. A genetic deletion of Mirc19 in mice resulted in HSCs that had altered cycling, function, and survival in response to growth factor starvation. We found that miR-132 exerted its effect on aging HSCs by targeting the transcription factor FOXO3, a known aging associated gene. Our data demonstrate that Mirc19 plays a role in maintaining balanced hematopoietic output by buffering FOXO3 expression. We have thus identified it as a potential target that might play a role in age-related hematopoietic defects.

12 citations


Patent
03 Apr 2015
TL;DR: In this paper, compositions and methods are provided for the identification of peptide sequences that are ligands for a T cell receptor (TCR) of interest, in a given MHC context.
Abstract: Compositions and methods are provided for the identification of peptide sequences that are ligands for a T cell receptor (TCR) of interest, in a given MHC context.

6 citations


Patent
15 Jan 2015
TL;DR: In this paper, the authors describe methods, vectors, and genetically engineered T cells related to genetically engineered t cell receptors, and describe their application in the field of T cell immunology.
Abstract: Disclosed herein are genetically engineered T cell receptors, and methods, vectors, and genetically engineered T cells related to genetically engineered T cell receptors.

3 citations