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1.
Annu Rev Immunol ; 38: 249-287, 2020 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-32340579

RESUMO

Since the birth of biotechnology, hundreds of biotherapeutics have been developed and approved by the US Food and Drug Administration (FDA) for human use. These novel medicines not only bring significant benefit to patients but also represent precision tools to interrogate human disease biology. Accordingly, much has been learned from the successes and failures of hundreds of high-quality clinical trials. In this review, we discuss general and broadly applicable themes that have emerged from this collective experience. We base our discussion on insights gained from exploring some of the most important target classes, including interleukin-1 (IL-1), tumor necrosis factor α (TNF-α), IL-6, IL-12/23, IL-17, IL-4/13, IL-5, immunoglobulin E (IgE), integrins and B cells. We also describe current challenges and speculate about how emerging technological capabilities may enable the discovery and development of the next generation of biotherapeutics.


Assuntos
Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Terapia Biológica , Desenvolvimento de Medicamentos , Animais , Produtos Biológicos/história , Terapia Biológica/história , Terapia Biológica/métodos , Biotecnologia/história , Biotecnologia/métodos , Ensaios Clínicos como Assunto , Desenvolvimento de Medicamentos/história , Descoberta de Drogas/história , Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos , História do Século XX , História do Século XXI , Humanos
2.
Cell ; 185(15): 2613-2616, 2022 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-35868263

RESUMO

Dr. Michelle McMurry-Heath brings a wide-ranging background in medicine, immunology, research, and policy coordination to her current role as the chief executive officer for the Biotechnology Innovation Organization (BIO). She had a chat with Cell editor Cheri Sirois about how biotech differs from basic science and about the opportunities it offers. A lightly edited transcript of their conversation is shared here.


Assuntos
Biotecnologia , Pesquisadores , Humanos
3.
Cell ; 184(21): 5271-5274, 2021 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-34562362

RESUMO

This year's Lasker∼Debakey Clinical Research Award honors Katalin Karikó and Drew Weissman for the development of a therapeutic technology based on nucleoside-modification of messenger RNA, enabling the rapid development of the highly effective COVID-19 vaccines.


Assuntos
Biotecnologia/métodos , Vacinas contra COVID-19/administração & dosagem , COVID-19/prevenção & controle , RNA Mensageiro/administração & dosagem , SARS-CoV-2/imunologia , Vacinas Sintéticas/administração & dosagem , COVID-19/epidemiologia , COVID-19/imunologia , COVID-19/virologia , Humanos , RNA Mensageiro/química , Vacinas de mRNA
4.
Cell ; 184(21): 5293-5296, 2021 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-34562365

RESUMO

The highly effective and safe mRNA-based severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines draw on decades of painstaking research to overcome the many hurdles for delivering, expressing, and avoiding toxicity of therapeutic mRNA. Cell editor Nicole Neuman talked with Dr. Katalin Karikó and Dr. Drew Weissman, recipients of the 2021 Lasker∼DeBakey Clinical Medical Research Award, to learn more about their quest to develop mRNA-based therapeutics, which led them to the crucial discovery that modification of mRNA could prevent toxicity and increase expression. This conversation has been adapted for print below, with editing for clarity, accuracy, and length.


Assuntos
Biotecnologia/métodos , Vacinas contra COVID-19/administração & dosagem , COVID-19/prevenção & controle , RNA Mensageiro/administração & dosagem , SARS-CoV-2/imunologia , Vacinas Sintéticas/administração & dosagem , COVID-19/epidemiologia , COVID-19/imunologia , COVID-19/virologia , Descoberta de Drogas , Humanos , Entrevistas como Assunto , RNA Mensageiro/química , Vacinas de mRNA
5.
Annu Rev Biochem ; 87: 533-553, 2018 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-29925257

RESUMO

The formation of ordered nanostructures by molecular self-assembly of proteins and peptides represents one of the principal directions in nanotechnology. Indeed, polyamides provide superior features as materials with diverse physical properties. A reductionist approach allowed the identification of extremely short peptide sequences, as short as dipeptides, which could form well-ordered amyloid-like ß-sheet-rich assemblies comparable to supramolecular structures made of much larger proteins. Some of the peptide assemblies show remarkable mechanical, optical, and electrical characteristics. Another direction of reductionism utilized a natural noncoded amino acid, α-aminoisobutryic acid, to form short superhelical assemblies. The use of this exceptional helix inducer motif allowed the fabrication of single heptad repeats used in various biointerfaces, including their use as surfactants and DNA-binding agents. Two additional directions of the reductionist approach include the use of peptide nucleic acids (PNAs) and coassembly techniques. The diversified accomplishments of the reductionist approach, as well as the exciting future advances it bears, are discussed.


Assuntos
Nanoestruturas/química , Peptídeos/química , Proteínas Amiloidogênicas/química , Animais , Biotecnologia , Humanos , Modelos Moleculares , Nanotecnologia/métodos , Oligopeptídeos/química , Ácidos Nucleicos Peptídicos/química , Engenharia de Proteínas
6.
Nat Rev Mol Cell Biol ; 22(8): 563-579, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34089013

RESUMO

CRISPR loci and Cas proteins provide adaptive immunity in prokaryotes against invading bacteriophages and plasmids. In response, bacteriophages have evolved a broad spectrum of anti-CRISPR proteins (anti-CRISPRs) to counteract and overcome this immunity pathway. Numerous anti-CRISPRs have been identified to date, which suppress single-subunit Cas effectors (in CRISPR class 2, type II, V and VI systems) and multisubunit Cascade effectors (in CRISPR class 1, type I and III systems). Crystallography and cryo-electron microscopy structural studies of anti-CRISPRs bound to effector complexes, complemented by functional experiments in vitro and in vivo, have identified four major CRISPR-Cas suppression mechanisms: inhibition of CRISPR-Cas complex assembly, blocking of target binding, prevention of target cleavage, and degradation of cyclic oligonucleotide signalling molecules. In this Review, we discuss novel mechanistic insights into anti-CRISPR function that have emerged from X-ray crystallography and cryo-electron microscopy studies, and how these structures in combination with function studies provide valuable tools for the ever-growing CRISPR-Cas biotechnology toolbox, to be used for precise and robust genome editing and other applications.


Assuntos
Biotecnologia , Proteínas Associadas a CRISPR/antagonistas & inibidores , Sistemas CRISPR-Cas/imunologia , Proteínas Virais/química , Proteínas Virais/metabolismo , Bacteriófagos/metabolismo , Proteínas Associadas a CRISPR/química , Proteínas Associadas a CRISPR/metabolismo , Edição de Genes , Ligação Proteica
7.
Mol Cell ; 84(5): 816-818, 2024 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-38458171

RESUMO

In this issue of Molecular Cell, Vaisvila et al.1 report a tour de force functional characterization of a large and highly diverse set of polynucleotide cytosine deaminase (PCD) enzymes, which is already propelling new biotechnology applications.


Assuntos
Biotecnologia , Citosina Desaminase
8.
Nat Rev Mol Cell Biol ; 25(3): 157-158, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38081974
9.
Immunity ; 54(8): 1636-1651, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34348117

RESUMO

The development of effective vaccines to combat infectious diseases is a complex multi-year and multi-stakeholder process. To accelerate the development of vaccines for coronavirus disease 2019 (COVID-19), a novel pathogen emerging in late 2019 and spreading globally by early 2020, the United States government (USG) mounted an operation bridging public and private sector expertise and infrastructure. The success of the endeavor can be seen in the rapid advanced development of multiple vaccine candidates, with several demonstrating efficacy and now being administered around the globe. Here, we review the milestones enabling the USG-led effort, the methods utilized, and ensuing outcomes. We discuss the current status of COVID-19 vaccine development and provide a perspective for how partnership and preparedness can be better utilized in response to future public-health pandemic emergencies.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/epidemiologia , COVID-19/prevenção & controle , Pesquisa , SARS-CoV-2/imunologia , Bioengenharia , Biotecnologia , Vacinas contra COVID-19/administração & dosagem , Humanos , Modelos Moleculares , Avaliação de Resultados em Cuidados de Saúde , Vigilância em Saúde Pública , Pesquisa/estatística & dados numéricos , Pesquisa/tendências , Estados Unidos/epidemiologia , Cobertura Vacinal/estatística & dados numéricos , Vacinologia
10.
Nat Rev Mol Cell Biol ; 19(8): 507-525, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29858606

RESUMO

Synthetic biology is the discipline of engineering application-driven biological functionalities that were not evolved by nature. Early breakthroughs of cell engineering, which were based on ectopic (over)expression of single sets of transgenes, have already had a revolutionary impact on the biotechnology industry, regenerative medicine and blood transfusion therapies. Now, we require larger-scale, rationally assembled genetic circuits engineered to programme and control various human cell functions with high spatiotemporal precision in order to solve more complex problems in applied life sciences, biomedicine and environmental sciences. This will open new possibilities for employing synthetic biology to advance personalized medicine by converting cells into living therapeutics to combat hitherto intractable diseases.


Assuntos
Engenharia Celular/métodos , Redes Reguladoras de Genes/genética , Genes Sintéticos/genética , Engenharia Genética/métodos , Biologia Sintética/métodos , Animais , Biotecnologia/métodos , Comunicação Celular/genética , Regulação da Expressão Gênica/genética , Humanos
11.
Nature ; 628(8009): 804-810, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38538783

RESUMO

Sugarcane, the world's most harvested crop by tonnage, has shaped global history, trade and geopolitics, and is currently responsible for 80% of sugar production worldwide1. While traditional sugarcane breeding methods have effectively generated cultivars adapted to new environments and pathogens, sugar yield improvements have recently plateaued2. The cessation of yield gains may be due to limited genetic diversity within breeding populations, long breeding cycles and the complexity of its genome, the latter preventing breeders from taking advantage of the recent explosion of whole-genome sequencing that has benefited many other crops. Thus, modern sugarcane hybrids are the last remaining major crop without a reference-quality genome. Here we take a major step towards advancing sugarcane biotechnology by generating a polyploid reference genome for R570, a typical modern cultivar derived from interspecific hybridization between the domesticated species (Saccharum officinarum) and the wild species (Saccharum spontaneum). In contrast to the existing single haplotype ('monoploid') representation of R570, our 8.7 billion base assembly contains a complete representation of unique DNA sequences across the approximately 12 chromosome copies in this polyploid genome. Using this highly contiguous genome assembly, we filled a previously unsized gap within an R570 physical genetic map to describe the likely causal genes underlying the single-copy Bru1 brown rust resistance locus. This polyploid genome assembly with fine-grain descriptions of genome architecture and molecular targets for biotechnology will help accelerate molecular and transgenic breeding and adaptation of sugarcane to future environmental conditions.


Assuntos
Genoma de Planta , Poliploidia , Saccharum , Cromossomos de Plantas/genética , Genoma de Planta/genética , Haplótipos/genética , Hibridização Genética/genética , Melhoramento Vegetal , Saccharum/classificação , Saccharum/genética , Biotecnologia , Padrões de Referência , DNA de Plantas/genética
12.
Nature ; 632(8024): 375-382, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38961300

RESUMO

In biological systems, the activities of macromolecular complexes must sometimes be turned off. Thus, a wide variety of protein inhibitors has evolved for this purpose. These inhibitors function through diverse mechanisms, including steric blocking of crucial interactions, enzymatic modification of key residues or substrates, and perturbation of post-translational modifications1. Anti-CRISPRs-proteins that block the activity of CRISPR-Cas systems-are one of the largest groups of inhibitors described, with more than 90 families that function through diverse mechanisms2-4. Here, we characterize the anti-CRISPR AcrIF25, and we show that it inhibits the type I-F CRISPR-Cas system by pulling apart the fully assembled effector complex. AcrIF25 binds to the predominant CRISPR RNA-binding components of this complex, comprising six Cas7 subunits, and strips them from the RNA. Structural and biochemical studies indicate that AcrIF25 removes one Cas7 subunit at a time, starting at one end of the complex. Notably, this feat is achieved with no apparent enzymatic activity. To our knowledge, AcrIF25 is the first example of a protein that disassembles a large and stable macromolecular complex in the absence of an external energy source. As such, AcrIF25 establishes a paradigm for macromolecular complex inhibitors that may be used for biotechnological applications.


Assuntos
Proteínas Associadas a CRISPR , Sistemas CRISPR-Cas , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Substâncias Macromoleculares , Proteínas Virais , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Proteínas Associadas a CRISPR/metabolismo , Proteínas Associadas a CRISPR/química , Modelos Moleculares , Ligação Proteica , Subunidades Proteicas/metabolismo , Subunidades Proteicas/química , Substâncias Macromoleculares/química , Substâncias Macromoleculares/metabolismo , Biotecnologia/tendências , Bacteriófagos , Proteínas Virais/metabolismo
13.
Nature ; 633(8029): 371-379, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39232160

RESUMO

The past two decades has witnessed a remarkable increase in the number of microbial genomes retrieved from marine systems1,2. However, it has remained challenging to translate this marine genomic diversity into biotechnological and biomedical applications3,4. Here we recovered 43,191 bacterial and archaeal genomes from publicly available marine metagenomes, encompassing a wide range of diversity with 138 distinct phyla, redefining the upper limit of marine bacterial genome size and revealing complex trade-offs between the occurrence of CRISPR-Cas systems and antibiotic resistance genes. In silico bioprospecting of these marine genomes led to the discovery of a novel CRISPR-Cas9 system, ten antimicrobial peptides, and three enzymes that degrade polyethylene terephthalate. In vitro experiments confirmed their effectiveness and efficacy. This work provides evidence that global-scale sequencing initiatives advance our understanding of how microbial diversity has evolved in the oceans and is maintained, and demonstrates how such initiatives can be sustainably exploited to advance biotechnology and biomedicine.


Assuntos
Organismos Aquáticos , Biodiversidade , Bioprospecção , Mapeamento Geográfico , Metagenoma , Peptídeos Catiônicos Antimicrobianos/genética , Peptídeos Catiônicos Antimicrobianos/isolamento & purificação , Organismos Aquáticos/classificação , Organismos Aquáticos/genética , Organismos Aquáticos/isolamento & purificação , Archaea/genética , Archaea/classificação , Bactérias/genética , Bactérias/classificação , Tecnologia Biomédica , Bioprospecção/tendências , Biotecnologia , Proteína 9 Associada à CRISPR/genética , Proteína 9 Associada à CRISPR/isolamento & purificação , Sistemas CRISPR-Cas/genética , Farmacorresistência Bacteriana/genética , Genoma Arqueal/genética , Genoma Bacteriano/genética , Metagenoma/genética , Oceanos e Mares , Filogenia , Água do Mar/microbiologia , Microbiologia da Água
14.
Mol Cell ; 82(2): 227-228, 2022 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-35063088

RESUMO

Scientists often contemplate careers in academia versus the biotech industry. We spoke with Dr. Rachel Haurwitz about her career trajectory, being a female scientist in the biotech world, how research in academia compares to industry, and career advice for young scientists thinking about venturing outside of academia into this area.


Assuntos
Pesquisa Biomédica/história , Biotecnologia/história , Escolha da Profissão , Técnicas Genéticas/história , Indústrias/história , Pesquisa Biomédica/tendências , Biotecnologia/tendências , Mobilidade Ocupacional , Difusão de Inovações , Técnicas Genéticas/tendências , História do Século XXI , Humanos , Indústrias/tendências , Pesquisadores
15.
Nature ; 620(7972): 122-127, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37407813

RESUMO

Possessing only essential genes, a minimal cell can reveal mechanisms and processes that are critical for the persistence and stability of life1,2. Here we report on how an engineered minimal cell3,4 contends with the forces of evolution compared with the Mycoplasma mycoides non-minimal cell from which it was synthetically derived. Mutation rates were the highest among all reported bacteria, but were not affected by genome minimization. Genome streamlining was costly, leading to a decrease in fitness of greater than 50%, but this deficit was regained during 2,000 generations of evolution. Despite selection acting on distinct genetic targets, increases in the maximum growth rate of the synthetic cells were comparable. Moreover, when performance was assessed by relative fitness, the minimal cell evolved 39% faster than the non-minimal cell. The only apparent constraint involved the evolution of cell size. The size of the non-minimal cell increased by 80%, whereas the minimal cell remained the same. This pattern reflected epistatic effects of mutations in ftsZ, which encodes a tubulin-homologue protein that regulates cell division and morphology5,6. Our findings demonstrate that natural selection can rapidly increase the fitness of one of the simplest autonomously growing organisms. Understanding how species with small genomes overcome evolutionary challenges provides critical insights into the persistence of host-associated endosymbionts, the stability of streamlined chassis for biotechnology and the targeted refinement of synthetically engineered cells2,7-9.


Assuntos
Evolução Molecular , Genes Essenciais , Genoma Bacteriano , Mycoplasma mycoides , Biologia Sintética , Biotecnologia/métodos , Biotecnologia/tendências , Divisão Celular , Genoma Bacteriano/genética , Mutação , Mycoplasma mycoides/citologia , Mycoplasma mycoides/genética , Mycoplasma mycoides/crescimento & desenvolvimento , Biologia Sintética/métodos , Tamanho Celular , Epistasia Genética , Seleção Genética , Aptidão Genética , Simbiose , Tubulina (Proteína)/química
16.
Nature ; 623(7987): 601-607, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37853129

RESUMO

Many bacteria use CRISPR-Cas systems to combat mobile genetic elements, such as bacteriophages and plasmids1. In turn, these invasive elements have evolved anti-CRISPR proteins to block host immunity2,3. Here we unveil a distinct type of CRISPR-Cas Inhibition strategy that is based on small non-coding RNA anti-CRISPRs (Racrs). Racrs mimic the repeats found in CRISPR arrays and are encoded in viral genomes as solitary repeat units4. We show that a prophage-encoded Racr strongly inhibits the type I-F CRISPR-Cas system by interacting specifically with Cas6f and Cas7f, resulting in the formation of an aberrant Cas subcomplex. We identified Racr candidates for almost all CRISPR-Cas types encoded by a diverse range of viruses and plasmids, often in the genetic context of other anti-CRISPR genes5. Functional testing of nine candidates spanning the two CRISPR-Cas classes confirmed their strong immune inhibitory function. Our results demonstrate that molecular mimicry of CRISPR repeats is a widespread anti-CRISPR strategy, which opens the door to potential biotechnological applications6.


Assuntos
Bactérias , Bacteriófagos , Sistemas CRISPR-Cas , Mimetismo Molecular , RNA Viral , Bactérias/genética , Bactérias/imunologia , Bactérias/virologia , Bacteriófagos/genética , Bacteriófagos/imunologia , Biotecnologia/métodos , Biotecnologia/tendências , Proteínas Associadas a CRISPR/metabolismo , Sistemas CRISPR-Cas/genética , Sistemas CRISPR-Cas/imunologia , Plasmídeos/genética , Prófagos/genética , Prófagos/imunologia , RNA Viral/genética
17.
Nature ; 620(7973): 381-385, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37532933

RESUMO

The human gut microbiota has gained interest as an environmental factor that may contribute to health or disease1. The development of next-generation probiotics is a promising strategy to modulate the gut microbiota and improve human health; however, several key candidate next-generation probiotics are strictly anaerobic2 and may require synergy with other bacteria for optimal growth. Faecalibacterium prausnitzii is a highly prevalent and abundant human gut bacterium associated with human health, but it has not yet been developed into probiotic formulations2. Here we describe the co-isolation of F. prausnitzii and Desulfovibrio piger, a sulfate-reducing bacterium, and their cross-feeding for growth and butyrate production. To produce a next-generation probiotic formulation, we adapted F. prausnitzii to tolerate oxygen exposure, and, in proof-of-concept studies, we demonstrate that the symbiotic product is tolerated by mice and humans (ClinicalTrials.gov identifier: NCT03728868 ) and is detected in the human gut in a subset of study participants. Our study describes a technology for the production of next-generation probiotics based on the adaptation of strictly anaerobic bacteria to tolerate oxygen exposures without a reduction in potential beneficial properties. Our technology may be used for the development of other strictly anaerobic strains as next-generation probiotics.


Assuntos
Biotecnologia , Microbioma Gastrointestinal , Probióticos , Animais , Humanos , Camundongos , Butiratos/metabolismo , Oxigênio/metabolismo , Oxigênio/farmacologia , Probióticos/metabolismo , Aerobiose , Faecalibacterium prausnitzii/efeitos dos fármacos , Faecalibacterium prausnitzii/metabolismo , Simbiose , Biotecnologia/métodos
18.
Annu Rev Biochem ; 82: 775-97, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23495938

RESUMO

Sera of camelids contain both conventional heterotetrameric antibodies and unique functional heavy (H)-chain antibodies (HCAbs). The H chain of these homodimeric antibodies consists of one antigen-binding domain, the VHH, and two constant domains. HCAbs fail to incorporate light (L) chains owing to the deletion of the first constant domain and a reshaped surface at the VHH side, which normally associates with L chains in conventional antibodies. The genetic elements composing HCAbs have been identified, but the in vivo generation of these antibodies from their dedicated genes into antigen-specific and affinity-matured bona fide antibodies remains largely underinvestigated. However, the facile identification of antigen-specific VHHs and their beneficial biochemical and economic properties (size, affinity, specificity, stability, production cost) supported by multiple crystal structures have encouraged antibody engineering of these single-domain antibodies for use as a research tool and in biotechnology and medicine.


Assuntos
Anticorpos/química , Camelus/imunologia , Cadeias Pesadas de Imunoglobulinas/química , Anticorpos de Domínio Único/química , Animais , Anticorpos/genética , Anticorpos/imunologia , Afinidade de Anticorpos , Biotecnologia , Camelídeos Americanos , Camelus/genética , Cadeias Pesadas de Imunoglobulinas/genética , Cadeias Pesadas de Imunoglobulinas/imunologia , Anticorpos de Domínio Único/imunologia
19.
Annu Rev Microbiol ; 77: 89-109, 2023 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-37001148

RESUMO

Hypersaline waters and glacial ice are inhospitable environments that have low water activity and high concentrations of osmolytes. They are inhabited by diverse microbial communities, of which extremotolerant and extremophilic fungi are essential components. Some fungi are specialized in only one of these two environments and can thrive in conditions that are lethal to most other life-forms. Others are generalists, highly adaptable species that occur in both environments and tolerate a wide range of extremes. Both groups efficiently balance cellular osmotic pressure and ion concentration, stabilize cell membranes, remodel cell walls, and neutralize intracellular oxidative stress. Some species use unusual reproductive strategies. Further investigation of these adaptations with new methods and carefully designed experiments under ecologically relevant conditions will help predict the role of fungi in hypersaline and glacial environments affected by climate change, decipher their stress resistance mechanisms and exploit their biotechnological potential.


Assuntos
Biotecnologia , Microbiota , Membrana Celular , Parede Celular , Fungos
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