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Protein engineering has yielded a new, potent tool — in the form of a chimeric enzyme — for correcting genetic mutations. Proof of principle that this enzyme can correct different types of mutation, and even combinations of mutations, has been obtained in different types of mammalian cells.

Genome editing with CRISPR–Cas9 is beginning to be used clinically; promising results to date inspire hope for broad medical impact and mindfulness about safety. A new study shows that when Cas9 cuts its target, a fraction of the time, the target chromosome experiences a breakage process known as chromothripsis, thus prompting efforts to understand the potential negative consequences of this phenomenon and ways to mitigate them.

[...]some 3,000 varieties of crops produced through chemical and irradiation mutagenesis are widely grown and consumed in the United States, Europe, and Asia (https://doi.org/mvd.iaea.org/ and ref. 3). [...]the use of Bt crops over the past 20 years has dramatically decreased global spraying of chemical insecticides on corn, soy, eggplant, cotton, and other crops6,7. [...]genome editing leaves no foreign DNA in the targeted genome (a major difference from transgenesis). Fourth, the same modification can be easily introduced into multiple genetic backgrounds in crops adapted and/or selected for other characteristics (for example, climate adaptation, flavor, and disease resistance), thus facilitating the planting of genetically diverse varieties. Since the initial description of gene editing in crops in 2009 (refs 9,10), modern genome editing has been applied to more than 50 plant species (Supplementary Table 1), including not only all the major crop species (for example, maize, rice, and wheat) but also crops as varied as oranges, lettuce, and cassava.

Signaling by the tumor-suppressor protein p53 antagonizes CRISPR–Cas9 gene editing of human pluripotent stem cells and immortalized human retinal pigment epithelial cells.

Parasitic genetic elements called transposons carry CRISPR machinery that is normally used against them by bacterial cells. This paradox has now been explained, with implications for gene-therapy research. RNA-guided transposition of DNA.

Twenty genetic therapies have been approved by the US Food and Drug Administration to date, a number that now includes the first CRISPR genome-editing therapy for sickle cell disease—CASGEVY (exagamglogene autotemcel, Vertex Pharmaceuticals). This extraordinary milestone is widely celebrated owing to the promise for future genome-editing treatments of previously intractable genetic disorders and cancers. At the same time, such genetic therapies are the most expensive drugs on the market, with list prices exceeding US$4 million per patient. Although all approved cell and gene therapies trace their origins to academic or government research institutions, reliance on for-profit pharmaceutical companies for subsequent development and commercialization results in prices that prioritize recouping investments, paying for candidate product failures and meeting investor and shareholder expectations. To increase affordability and access, sustainable discovery-to-market alternatives are needed that address system-wide deficiencies. Here we present recommendations of a multidisciplinary task force assembled to chart such a path. We describe a pricing structure that, once implemented, could reduce per-patient cost tenfold and propose a business model that distributes responsibilities while leveraging diverse funding sources. We also outline how academic licensing provisions, manufacturing innovation and supportive regulations can reduce cost and enable broader patient treatment. Implementation of new pricing and business structures and improved licensing and manufacturing processes could reduce the per-patient cost of gene therapy tenfold.

Key Points Targeted genetic engineering in many important model systems and in human tissue culture cells has historically been challenging. This has changed dramatically over the past 5 years with the development of zinc finger nuclease (ZFN) technology. A ZFN is an artificial endonuclease that consists of a designed zinc finger protein (ZFP) fused to the cleavage domain of the Fok I restriction enzyme. A ZFN may be redesigned to cleave new targets by developing ZFPs with new sequence specificities. For genome engineering, a ZFN is targeted to cleave a chosen genomic sequence. The cleavage event induced by the ZFN provokes cellular repair processes that in turn mediate efficient modification of the targeted locus. If the ZFN-induced cleavage event is resolved via non-homologous end joining, this can result in small deletions or insertions, effectively leading to gene knockout. This approach has now been used to establish facile and efficient reverse genetics (that is, reverse genetics that does not require selection) in Drosophila melanogaster , zebrafish, rats, Arabidopsis thaliana and mammalian somatic cells. If the break is resolved via a homology-based process in the presence of an investigator-provided donor, small changes or entire transgenes can be transferred, often without selection, into the chromosome; this is referred to as 'gene correction' and 'gene addition', respectively. This approach has been used to make novel alleles in D. melanogaster , mammalian cells and tobacco, and has been used to drive targeted integration in maize, tobacco and human embryonic stem and induced pluripotent stem cells. Therapeutic application of ZFN technology requires the engineering of ZFNs that are highly specific in their action. Three clinical trials with ZFNs are underway, including one in which T cells are isolated from a patient infected with HIV, treated with ZFNs that disrupt the chemokine (C-C motif) receptor type 5 ( CCR5 ) gene to make them resistant to virus infection, and transferred back to the patient. Zinc finger nucleases (ZFNs) are versatile tools for making precise modifications to genomes, and their use is now established in a range of model systems. ZFNs are also showing potential in human gene therapy, and several clinical trials are underway. Reverse genetics in model organisms such as Drosophila melanogaster , Arabidopsis thaliana , zebrafish and rats, efficient genome engineering in human embryonic stem and induced pluripotent stem cells, targeted integration in crop plants, and HIV resistance in immune cells — this broad range of outcomes has resulted from the application of the same core technology: targeted genome cleavage by engineered, sequence-specific zinc finger nucleases followed by gene modification during subsequent repair. Such 'genome editing' is now established in human cells and a number of model organisms, thus opening the door to a range of new experimental and therapeutic possibilities.

Engineered nucleases target specific DNA sequences for gene disruption in nonmodel organisms. Evolutionary studies necessary to dissect diverse biological processes have been limited by the lack of reverse genetic approaches in most organisms with sequenced genomes. We established a broadly applicable strategy using zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs) for targeted disruption of endogenous genes and cis-acting regulatory elements in diverged nematode species.

The emergence of artemisinin resistance in Southeast Asia imperils efforts to reduce the global malaria burden. We genetically modified the Plasmodium falciparum K13 locus using zinc-finger nucleases and measured ring-stage survival rates after drug exposure in vitro; these rates correlate with parasite clearance half-lives in artemisinin-treated patients. With isolates from Cambodia, where resistance first emerged, survival rates decreased from 13 to 49% to 0.3 to 2.4% after the removal of K13 mutations. Conversely, survival rates in wild-type parasites increased from ≤0.6% to 2 to 29% after the insertion of K13 mutations. These mutations conferred elevated resistance to recent Cambodian isolates compared with that of reference lines, suggesting a contemporary contribution of additional genetic factors. Our data provide a conclusive rationale for worldwide K13-propeller sequencing to identify and eliminate artemisinin-resistant parasites.

Colleges and universities across the country are struggling to develop strategies for effective control of COVID-19 transmission as students return to campus. We conducted a prospective cohort study with students living on or near the UC Berkeley campus from June 1st through August 18th, 2020 with the goal of providing guidance for campus reopening in the safest possible manner. In this cohort, we piloted an alternative testing model to provide access to low-barrier, high-touch testing and augment student-driven testing with data-driven adaptive surveillance that targets higher-risk students and triggers testing notifications based on reported symptoms, exposures, or other relevant information. A total of 2,180 students enrolled in the study, 51% of them undergraduates. Overall, 6,247 PCR tests were administered to 2,178 students over the two-month period. Overall test positivity rate was 0.9%; 2.6% of students tested positive. Uptake and acceptability of regular symptom and exposure surveys was high; 98% of students completed at least one survey, and average completion rate was 67% (Median: 74%, IQR: 39%) for daily reporting of symptoms and 68% (Median: 75%, IQR: 40%) for weekly reporting of exposures. Of symptom-triggered tests, 5% were PCR-positive; of exposure-triggered tests, 10% were PCR-positive. The integrated study database augmented traditional contact tracing during an outbreak; 17 potentially exposed students were contacted the following day and sent testing notifications. At study end, 81% of students selected their desire \"to contribute to UC Berkeley's response to COVID-19\" as a reason for their participation in the Safe Campus study. Our results illustrate the synergy created by bringing together a student-friendly, harm reduction approach to COVID-19 testing with an integrated data system and analytics. We recommend the use of a confidential, consequence-free, incentive-based daily symptom and exposure reporting system, coupled with low-barrier, easy access, no stigma testing. Testing should be implemented alongside a system that integrates multiple data sources to effectively trigger testing notifications to those at higher risk of infection and encourages students to come in for low-barrier testing when needed.