Wnt Signaling And TB

Here is an interesting paper from several years ago discussing a potential link between a signaling pathway more commonly associated with (colorectal) cancer and the immune response to tuberculosis. Abstract:

Mycobacterium tuberculosis (M. tuberculosis), an intracellular pathogenic Gram-positive bacterium, is the cause of tuberculosis (TB), a major worldwide human infectious disease. The innate immune system is the first host defense against M. tuberculosis. The recognition of this pathogen is mediated by several classes of pattern recognition receptors expressed on the host innate immune cells, including Toll-like receptors, Nod-like receptors, and C-type lectin receptors like Dectin-1, the Mannose receptor, and DC-SIGN. M. tuberculosis interaction with any of these receptors activates multiple signaling pathways among which the protein kinase C, the MAPK, and the NFκB pathways have been widely studied. These pathways have been implicated in macrophage invasion, M. tuberculosis survival, and impaired immune response, thus promoting a successful infection and disease. Interestingly, the Wnt signaling pathway, classically regarded as a pathway involved in the control of cell proliferation, migration, and differentiation in embryonic development, has recently been involved in immunoregulatory mechanisms in infectious and inflammatory diseases, such as TB, sepsis, psoriasis, rheumatoid arthritis, and atherosclerosis. In this review, we present the current knowledge supporting a role for the Wnt signaling pathway during macrophage infection by M. tuberculosis and the regulation of the immune response against M. tuberculosis. Understanding the cross talk between different signaling pathways activated by M. tuberculosis will impact on the search for new therapeutic targets to fuel the rational design of drugs aimed to restore the immunological response against M. tuberculosis.

Once again, the importance of basic science research is seen.  First, the Wnt pathway was studied as a model of cell signaling, including in the fruit fly model.  Then, the absolute importance of this pathway in cancer, particularly colorectal cancer, was determined.  Next, Wnt signaling was identified as important in many other disorders, including neurodegenerative, and now has important implications in infectious disease.

Gene Editing For Muscular Dystrophy

Here is a paper from several years ago discussing promising results with gene therapy in a mouse model of muscular dystrophy.  Abstract:

Gene replacement therapies utilizing adeno-associated viral (AAV) vectors hold great promise for treating Duchenne muscular dystrophy (DMD). A related approach uses AAV vectors to edit specific regions of the DMD gene using CRISPR/Cas9. Here we develop multiple approaches for editing the mutation in dystrophic mdx4cv mice using single and dual AAV vector delivery of a muscle-specific Cas9 cassette together with single-guide RNA cassettes and, in one approach, a dystrophin homology region to fully correct the mutation. Muscle-restricted Cas9 expression enables direct editing of the mutation, multi-exon deletion or complete gene correction via homologous recombination in myogenic cells. Treated muscles express dystrophin in up to 70% of the myogenic area and increased force generation following intramuscular delivery. Furthermore, systemic administration of the vectors results in widespread expression of dystrophin in both skeletal and cardiac muscles. Our results demonstrate that AAV-mediated muscle-specific gene editing has significant potential for therapy of neuromuscular disorders.

That's very promising.  What's going on more recently? Future posts here will explore the progress in this and other similar projects using gene therapy tested in mouse models. This is why basic science research is so important, as the methods utilized are ultimately derived from such research.

Lessons From Mice And Flies

On Wnt signaling, abstract:

Adult stem cells play critical roles in the basal maintenance of tissue integrity, also known as homeostasis, and in tissue regeneration following damage. The highly conserved Wnt signalling pathway is a key regulator of stem cell fate. In the gastrointestinal tract, Wnt signalling activation drives homeostasis and damage-induced repair. Additionally, deregulated Wnt signalling is a common hallmark of age-associated tissue dysfunction and cancer. Studies using mouse and fruit fly models have greatly improved our understanding of the functional contribution of the Wnt signalling pathway in adult intestinal biology. Here, we summarize the latest knowledge acquired from mouse and Drosophila research regarding canonical Wnt signalling and its key functions during stem cell driven intestinal homeostasis, regeneration, ageing and cancer.

Low Oxygen And Osteogenic Differentiation

Low oxygen conditions can affect the differentiation of bone precursor cells.  Abstract:

This study examined the effects of low oxygen tension on the osteogenic differentiation of embryonic stem cells (ESCs) in a three-dimensional culture system. The high expression levels of hypoxia-related proteins hypoxia-inducible factor-1α and vascular endothelial growth factor were first validated in ESCs subjected to hypoxic conditions compared with normoxic controls. The osteogenic differentiation of hypoxic ESCs with either osteogenic or osteogenic factor-free media was subsequently evaluated by measuring alkaline phosphatase activity, intracellular calcium levels, matrix mineralization, and the protein levels of osteogenic markers Runt-related transcription factor 2 and osterix. We confirmed that hypoxia significantly stimulated ESC osteogenic activity; the strongest stimulation of ESC osteogenesis was exerted when cells were grown in osteogenic media. To identify differentially expressed genes associated with hypoxia-induced ESC differentiation, we performed microarray analysis of ESCs cultured in osteogenic media under normoxic and hypoxic conditions. This study demonstrated that differences in oxygen tension induced the differential expression of genes known to play roles in such processes as skeletal system development and signaling pathways for bone morphogenetic protein, Wnt, Notch, mitogen-activated protein kinase, and integrin. These findings reveal the effects of low oxygen tension on osteogenic progression in ESCs and provide insight into the molecular pathways that regulate ESC differentiation following exposure to hypoxia.

Tea Genetics

Understanding the tea genome; abstract

Tea, one of the world's most important beverage crops, provides numerous secondary metabolites that account for its rich taste and health benefits. Here we present a high-quality sequence of the genome of tea, Camellia sinensis var. sinensis (CSS), using both Illumina and PacBio sequencing technologies. At least 64% of the 3.1-Gb genome assembly consists of repetitive sequences, and the rest yields 33,932 high-confidence predictions of encoded proteins. Divergence between two major lineages, CSS and Camellia sinensis var. assamica (CSA), is calculated to ∼0.38 to 1.54 million years ago (Mya). Analysis of genic collinearity reveals that the tea genome is the product of two rounds of whole-genome duplications (WGDs) that occurred ∼30 to 40 and ∼90 to 100 Mya. We provide evidence that these WGD events, and subsequent paralogous duplications, had major impacts on the copy numbers of secondary metabolite genes, particularly genes critical to producing three key quality compounds: catechins, theanine, and caffeine. Analyses of transcriptome and phytochemistry data show that amplification and transcriptional divergence of genes encoding a large acyltransferase family and leucoanthocyanidin reductases are associated with the characteristic young leaf accumulation of monomeric galloylated catechins in tea, while functional divergence of a single member of the glutamine synthetase gene family yielded theanine synthetase. This genome sequence will facilitate understanding of tea genome evolution and tea metabolite pathways, and will promote germplasm utilization for breeding improved tea varieties.

Prognostic Genes For Colon Cancer

Determining prognostic genes for colon cancer; abstract:

PROPOSE:

We aimed to explore the potential molecular mechanism and independent prognostic genes for colon cancer (CC).

METHODS:

Microarray datasets GSE17536 and GSE39582 were downloaded from Gene Expression Omnibus. Meanwhile, the whole CC-related dataset were downloaded from The Cancer Genome Atlas (TCGA) database. Differentially expressed mRNA (DEMs) were identified between cancer tissue samples and para-carcinoma tissue samples in TCGA dataset, followed by the KEGG pathway and GO function analyses. Furthermore, the clinical prognostic analysis including overall survival (OS) and disease-free survival (DFS) were performed in all three datasets.

RESULTS:

A total of 633 up- and 321 down-regulated mRNAs were revealed in TCGA dataset. The up-regulated mRNAs were mainly assembled in functions including extracellular matrix and pathways including Wnt signaling. The down-regulated mRNAs were mainly assembled in functions like Digestion and pathways like Drug metabolism. Furthermore, up-regulation of UL16-binding protein 2 (ULBP2) was associated with OS in CC patients. A total of 12 DEMs including Surfactant Associated 2 (SFTA2) were potential DFS prognostic genes in CC patients. Meanwhile, the GRP and Transmembrane Protein 37 (TMEM37) were two outstanding independent DFS prognostic genes in CC.

CONCLUSIONS:

ULBP2 might be a potential novel OS prognostic biomarker in CC, while GRP and TMEM37 could be served as the independent DFS prognostic genes in CC. Furthermore, functions including extracellular matrix and digestion, as well as pathways including Wnt signaling and drug metabolism might play important roles in the process of CC.

Human Embryo Epigenetics: Methylation

Epigenetic programming during human embryonic development.  Abstract:

DNA methylation is a crucial layer of epigenetic regulation during mammalian embryonic development 1-3 . Although the DNA methylome of early human embryos has been analyzed 4-6 , some of the key features have not been addressed thus far. Here we performed single-cell DNA methylome sequencing for human preimplantation embryos and found that tens of thousands of genomic loci exhibited de novo DNA methylation. This finding indicates that genome-wide DNA methylation reprogramming during preimplantation development is a dynamic balance between strong global demethylation and drastic focused remethylation. Furthermore, demethylation of the paternal genome is much faster and thorough than that of the maternal genome. From the two-cell to the postimplantation stage, methylation of the paternal genome is consistently lower than that of the maternal genome. We also show that the genetic lineage of early blastomeres can be traced by DNA methylation analysis. Our work paves the way for deciphering the secrets of DNA methylation reprogramming in early human embryo.

Clock And Cycle: Wnt Signaling

The circadian clock controls daily life activities; the cell cycle is what allows cells to proliferate.  The two are linked via cell signaling, and in the intestines Wnt signaling is, unsurprisingly, important.  This has applications for modulation of the cell cycle for therapeutics.  Abstract:

Like two dancers, the circadian clock and cell cycle are biological oscillators engaged in bidirectional communication, resulting in circadian clock-gated cell division cycles in species ranging from cyanobacteria to mammals. The identified mechanisms for this phenomenon have expanded beyond intracellular molecular coupling components to include intercellular connections. However, detailed molecular mechanisms, dynamics, and physiological functions of the circadian clock and cell cycle as coupled oscillators remain largely unknown. In this review, we discuss current understanding of this connection in light of recent findings that have uncovered intercellular coupling between the circadian clock in Paneth cells and the cell cycle in intestinal stem cells via WNT signaling. This extends the impact of circadian rhythms regulating the timing of cell divisions beyond the intracellular domain of homogenous cell populations into dynamic, multicellular systems. In-depth understanding of the molecular links and dynamics of these two oscillators will identify potential targets and temporal regimens for effective chronotherapy.

Modeling Chemical Communication

Metabolite-protein interactions can be used to model chemical communication in the body. Abstract:

Metabolite-protein interactions control a variety of cellular processes, thereby playing a major role in maintaining cellular homeostasis. Metabolites comprise the largest fraction of molecules in cells, but our knowledge of the metabolite-protein interactome lags behind our understanding of protein-protein or protein-DNA interactomes. Here, we present a chemoproteomic workflow for the systematic identification of metabolite-protein interactions directly in their native environment. The approach identified a network of known and novel interactions and binding sites in Escherichia coli, and we demonstrated the functional relevance of a number of newly identified interactions. Our data enabled identification of new enzyme-substrate relationships and cases of metabolite-induced remodeling of protein complexes. Our metabolite-protein interactome consists of 1,678 interactions and 7,345 putative binding sites. Our data reveal functional and structural principles of chemical communication, shed light on the prevalence and mechanisms of enzyme promiscuity, and enable extraction of quantitative parameters of metabolite binding on a proteome-wide scale.

Genetic Variation And Immune Checkpoint Therapy

Patient response to immune checkpoint therapy is influenced by patient genotype.  It may be necessary to determine individual genetic variation before applying this therapy; alternatively, is it possible to adjust therapy to make it more effective even for patients with less optimal (for therapy) immune genotypes.  Abstract:

CD8+ T cell-dependent killing of cancer cells requires efficient presentation of tumor antigens by human leukocyte antigen class I (HLA-I) molecules. However, the extent to which patient-specific HLA-I genotype influences response to anti-PD-1 or anti-CTLA-4 is currently unknown. We determined the HLA-I genotype of 1,535 advanced cancer patients treated with immune checkpoint blockade (ICB). Maximal heterozygosity at HLA-I loci (A, B, and C) improved overall survival after ICB compared to patients who were homozygous for at least one HLA locus. In two independent melanoma cohorts, patients with the HLA-B44 supertype had extended survival, whereas the HLA-B62 supertype (including HLA-B*15:01) or somatic loss of heterozygosity at HLA-I, was associated with poor outcome. Molecular dynamics simulations of HLA-B*15:01 revealed unique elements that may impair CD8+ T cell recognition of neoantigens. Our results have important implications for predicting response to ICB and for the design of neoantigen-based therapeutic vaccines.

The Circadian Clock And Cancer Therapy

The circadian clock, that controls many cellular activities in a ‘timed” fashion, affects cancer and tumor development; hence targeting the clock can be a novel cancer therapeutic approach.  Some nuclear hormone receptors are important components of the circadian clock; agonists (activators) of these receptors have specific anti-cancer activity, which is an important and encouraging finding and can lead to innovative therapies.  Abstract:

The circadian clock imposes daily rhythms in cell proliferation, metabolism, inflammation and DNA damage response. Perturbations of these processes are hallmarks of cancer and chronic circadian rhythm disruption predisposes individuals to tumour development. This raises the hypothesis that pharmacological modulation of the circadian machinery may be an effective therapeutic strategy for combating cancer. REV-ERBs, the nuclear hormone receptors REV-ERBα (also known as NR1D1) and REV-ERBβ (also known as NR1D2), are essential components of the circadian clock. Here we show that two agonists of REV-ERBs-SR9009 and SR9011-are specifically lethal to cancer cells and oncogene-induced senescent cells, including melanocytic naevi, and have no effect on the viability of normal cells or tissues. The anticancer activity of SR9009 and SR9011 affects a number of oncogenic drivers (such as HRAS, BRAF, PIK3CA and others) and persists in the absence of p53 and under hypoxic conditions. The regulation of autophagy and de novo lipogenesis by SR9009 and SR9011 has a critical role in evoking an apoptotic response in malignant cells. Notably, the selective anticancer properties of these REV-ERB agonists impair glioblastoma growth in vivo and improve survival without causing overt toxicity in mice. These results indicate that pharmacological modulation of circadian regulators is an effective antitumour strategy, identifying a class of anticancer agents with a wide therapeutic window. We propose that REV-ERB agonists are inhibitors of autophagy and de novo lipogenesis, with selective activity towards malignant and benign neoplasms.

Rimonabant And Colorectal Cancer

Targeted killing of neoplastic colon cells; abstract:

Colorectal cancer (CRC), like other tumor types, is a highly heterogeneous disease. Within the tumor bulk, intra-tumoral heterogeneity is also ascribable to Cancer Stem Cells (CSCs) subpopulation, characterized by high chemoresistance and the unique ability to retain tumorigenic potential, thus associated to tumor recurrence. High dynamic plasticity of CSCs, makes the development of winning therapeutic strategies even more complex to completely eradicate tumor fuel. Rimonabant, originally synthesized as antagonist/inverse agonist of Cannabinoid Receptor 1, is able to inactivate Wnt signaling, both in vitro and in vivo, in CRC models, through inhibition of p300-histone acetyltransferase activity. Since Wnt/β-Catenin pathway is the main player underlying CSCs dynamic, this finding candidates Rimonabant as potential modulator of cancer stemness, in CRC. In this work, using established 3D cultures of primary colon CSCs, taking into account the tumor heterogeneity through monitoring of Wnt activity, we demonstrated that Rimonabant was able to reduces both tumor differentiated cells and colon CSCs proliferation and to control their survival in long term cultures. Interestingly, in ex vivo model of wild type human organoids, retaining both architecture and heterogeneity of original tissue, Rimonabant showed no toxicity against cells from healthy colon epithelium, suggesting its potential selectivity toward cancer cells. Overall, results from this work provided new insights on anti-tumor efficacy of Rimonabant, strongly suggesting that it could be a novel lead compound for CRC treatment.

TGIF1 In Colorectal Cancer

TGIF1 is another molecular factor discovered to promote colorectal cancer, apparently by upregulating the deregulated Wnt signaling found in most cases of that disease.  This discovery may point to novel therapeutic approaches targeting this factor.  Abstract:

Colorectal cancer (CRC) is one of the most common cancers, but the mechanisms underlying its initiation and progression are largely unknown. TGIF1 (TGFB induced factor homeobox 1) is a transcriptional corepressor that belongs to the three-amino acid loop extension (TALE) superclass of atypical homeodomains. It has been reported that TGIF1 is highly expressed in mammary cancer and non-small cell lung cancer and can enhance tumor progression. However, the role of TGIF1 in colorectal cancer remains unknown. Here, we report that TGIF1 is significantly upregulated in colorectal cancers, and its high expression predicts poor prognosis. Overexpression of TGIF1 markedly promotes the proliferation of colorectal cancer cells both in vivo and in vitro. In addition, TGIF1 activates Wnt/β-catenin signaling, and the homeodomain is indispensable for Wnt activation and β-catenin interaction. Taken together, our results suggest that TGIF1 is a novel colorectal tumor promoter and indicate that TGIF1 enhances colorectal cancer tumorigenesis through activating Wnt signaling.

CDK8 Inhibitors And Cancer

CDK8 seems to have dual functions with respect to cancer, and investigating these roles, for potential therapeutic applications, will require CDK8 inhibitors.  This is how basic science intersects with the development of future therapies.  Abstract:

Cyclin-dependent kinase 8 (CDK8) plays a vital role in regulating transcription either through its association with the Mediator complex or by phosphorylating transcription factors. Myriads of genetic and biochemical studies have established CDK8 as a key oncogenic driver in many cancers. Specifically, CDK8-mediated activation of oncogenic Wnt-β-catenin signaling, transcription of estrogen-inducible genes, and suppression of super enhancer-associated genes contributes to oncogenesis in colorectal, breast, and hematological malignancies, respectively. However, while most research supports the role of CDK8 as an oncogene, other work has raised the possibility of its contrary function. The diverse biological functions of CDK8 and its seemingly context-specific roles in different types of cancers have spurred a great amount of interest and perhaps an even greater amount of controversy in the development of CDK8 inhibitors as potential cancer therapeutic agents. Herein, we review the latest landscape of CDK8 biology and its involvement in carcinogenesis. We dissect current efforts in discovering CDK8 inhibitors and attempt to provide an outlook at the future of CDK8-targeted cancer therapies.

More On CRISPR

Using new methodologies to optimize the CRISPR system.  Abstract:

CRISPR-Cas systems offer versatile technologies for genome engineering, yet their implementation has been outpaced by ongoing discoveries of new Cas nucleases and anti-CRISPR proteins. Here, we present the use of E. coli cell-free transcription-translation (TXTL) systems to vastly improve the speed and scalability of CRISPR characterization and validation. TXTL can express active CRISPR machinery from added plasmids and linear DNA, and TXTL can output quantitative dynamics of DNA cleavage and gene repression-all without protein purification or live cells. We used TXTL to measure the dynamics of DNA cleavage and gene repression for single- and multi-effector CRISPR nucleases, predict gene repression strength in E. coli, determine the specificities of 24 diverse anti-CRISPR proteins, and develop a fast and scalable screen for protospacer-adjacent motifs that was successfully applied to five uncharacterized Cpf1 nucleases. These examples underscore how TXTL can facilitate the characterization and application of CRISPR technologies across their many uses.

Screening For Factors Influencing Neurodegenerative Diseases

Screening for factors influencing neurodegenerative diseases, such as amyotrophic lateral sclerosis and frontotemporal dementia, shows the importance of modifiers of an important mechanism of those diseases: hexanucleotide-repeat expansions in the C9ORF72 gene that result in toxic dipeptide-repeat proteins that aggregate – abnormal protein aggregation being a key feature of many nervous system-related diseases. This may have implications for treatment.  Abstract:

Hexanucleotide-repeat expansions in the C9ORF72 gene are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). The nucleotide-repeat expansions are translated into dipeptide-repeat (DPR) proteins, which are aggregation prone and may contribute to neurodegeneration. We used the CRISPR-Cas9 system to perform genome-wide gene-knockout screens for suppressors and enhancers of C9ORF72 DPR toxicity in human cells. We validated hits by performing secondary CRISPR-Cas9 screens in primary mouse neurons. We uncovered potent modifiers of DPR toxicity whose gene products function in nucleocytoplasmic transport, the endoplasmic reticulum (ER), proteasome, RNA-processing pathways, and chromatin modification. One modifier, TMX2, modulated the ER-stress signature elicited by C9ORF72 DPRs in neurons and improved survival of human induced motor neurons from patients with C9ORF72 ALS. Together, our results demonstrate the promise of CRISPR-Cas9 screens in defining mechanisms of neurodegenerative diseases.

HCMV And Cancer

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Human cytomegalovirus (HCMV) is common lifelong infection agent that usually remains latent after the initial infection and can become reactivated later in life. HCMV infection can promote the growth and metastatic potential of colorectal cancer cells.  Therefore, HCMV may contribute to the human cancer burden.  Abstract:

Increasing evidence suggests a link between persistent human cytomegalovirus (HCMV) infection and cancer. Although the role of HCMV in cancer is still elusive, recent studies revealed the presence of HCMV nucleic acids and proteins in different cancer types such as glioblastoma, colorectal, breast, and prostate cancers, and neuroblastoma. Although HCMV may not be directly associated with the neoplastic transformation, the presence of HCMV DNA in the tumorous tissue has been associated with altered clinical outcomes in cancer patients. However, the mechanisms involved in the association between colorectal cancer (CRC) and HCMV are unclear. In this study, we investigated the influence of HCMV infection on CRC or their derived cells. Proliferation and migration assays revealed a high infection efficiency in CRC-derived HT29 and SW480 'stem‑like' cells. After 24, 48 and 72 h of HCMV infection, both HT29 and SW480 parental and stem‑like cells showed a significant increase in cell proliferation and viability (p<0.0001). Moreover, HCMV infection promoted cell migration. These results demonstrate a significant phenotypic alteration in the CRC cell line upon HCMV infection. Using epithelial to mesenchymal transition (EMT) assays, we demonstrated that the EMT markers and driver genes were upregulated during the virus infection. The WNT signaling pathway, which is associated with the proliferation and migration of CRC cells, was upregulated (6-fold) in HCMV-infected cells as compared to the non‑infected cells at day 7 from infection.

Genetics Of Indian Camel Breeds

Of purely academic interest for animal lovers and those interested in genetic studies, we see this paper about the genetic history of Indian camel breeds.  The same genetic techniques can - and have been - used to discern the genetic history of human populations as well.  Abstract:

The genetic and demographic bottleneck analysis of Indian camel breeds was carried out utilizing 40 microsatellite markers. Allelic polymorphism was observed at 20 loci in the Indian dromedary breeds. A total of 66 alleles were scored. The average number of alleles, expected heterozygosity and polymorphic information content were, respectively, 3.25 ± 0.27, 0.56 ± 0.04 and 0.49 ± 0.04 in Bikaneri; 3.25 ± 0.25, 0.53 ± 0.03 and 0.46 ± 0.03 in Jaisalmeri; 3.0 ± 0.21, 0.53 ± 0.04 and 0.45 ± 0.03 in Kachchhi and 3.1 ± 0.19, 0.51 ± 0.03 and 0.44 ± 0.03 in Mewari breed. Higher genetic variation was observed in most numerous Bikaneri breed. Genetic distances were least between the breed pair Bikaneri and Jaisalmeri which was closely placed with the Kachchhi breed. The Mewari camels had relatively higher genetic distance from the other three Indian dromedary breeds. The bottleneck analysis revealed the presence of genetic bottleneck in all four breeds of Indian dromedary. However, the qualitative graphical method resulted in normal L-shaped distribution of allele frequencies in Jaisalmeri breeds and shifted mode in Bikaneri, Kachchhi and Mewari breeds. The demographic bottleneck analysis revealed minimum reduction (-9.65 %) in the population of camels in Jaisalmeri breeding tract as compared to that of Bikaneri (-14.18 %), Kachchhi (-27.78 %) and Mewari (-32 %) breeding tracts. Conclusively, the genetic bottleneck analysis could explain the demographic bottleneck in the Indian dromedary populations. Therefore, appropriate conservation and improvement efforts are needed in all four dromedary breeds with immediate attention on Mewari and Kachchhi breeds. The present study is the first report in demonstrating the genetic basis of demographic bottleneck in the Indian dromedary populations.

Multiplex Genome Editing

It is now becoming possible to perform multiple editing of genomes, a "DNA construction site" toolkit, which can enable a number of interesting applications, including, to quote the abstract: new therapeutic modalities and industrial applications, as well as 'genome writing' and de-extinction efforts.  Abstract:

Multiplex genome editing is the simultaneous introduction of multiple distinct modifications to a given genome. Though in its infancy, maturation of this field will facilitate powerful new biomedical research approaches, and will enable a host of far-reaching biological engineering applications, including new therapeutic modalities and industrial applications, as well as 'genome writing' and de-extinction efforts. In this perspective, we focus on multiplex editing of large eukaryotic genomes. We describe the current state of multiplexed genome editing, the current limits of our ability to multiplex edits, and provide perspective on the many applications that fully-realized multiplex editing technologies would enable in higher eukaryotic genomes. We offer a broad look at future directions, covering emergent CRISPR-based technologies, advances in intracellular delivery, and new DNA assembly approaches that may enable future genome editing on a massively multiplexed scale.

Down Syndrome and Alzheimer's

Down syndrome patients accumulate brain features characteristic of Alzheimer's disease by age 40, and most go on to develop dementia.  Down syndrome is trisomy 21 and the APP gene is on that chromosome, but a mouse model shows that triplication of other non-APP genes on that chromosome can also cause similar amyloid problems. This can shed new light on Alzheimer's disease, possibly with therapeutic implications.  Abstract:

Down syndrome, caused by trisomy of chromosome 21, is the single most common risk factor for early-onset Alzheimer's disease. Worldwide approximately 6 million people have Down syndrome, and all these individuals will develop the hallmark amyloid plaques and neurofibrillary tangles of Alzheimer's disease by the age of 40 and the vast majority will go on to develop dementia. Triplication of APP, a gene on chromosome 21, is sufficient to cause early-onset Alzheimer's disease in the absence of Down syndrome. However, whether triplication of other chromosome 21 genes influences disease pathogenesis in the context of Down syndrome is unclear. Here we show, in a mouse model, that triplication of chromosome 21 genes other than APP increases amyloid-β aggregation, deposition of amyloid-β plaques and worsens associated cognitive deficits. This indicates that triplication of chromosome 21 genes other than APP is likely to have an important role to play in Alzheimer's disease pathogenesis in individuals who have Down syndrome. We go on to show that the effect of trisomy of chromosome 21 on amyloid-β aggregation correlates with an unexpected shift in soluble amyloid-β 40/42 ratio. This alteration in amyloid-β isoform ratio occurs independently of a change in the carboxypeptidase activity of the γ-secretase complex, which cleaves the peptide from APP, or the rate of extracellular clearance of amyloid-β. These new mechanistic insights into the role of triplication of genes on chromosome 21, other than APP, in the development of Alzheimer's disease in individuals who have Down syndrome may have implications for the treatment of this common cause of neurodegeneration.