Introduction to organioids

What you need to know about organoids

By Chloe Reichel

Paola Arlotta, chair of and professor in the stem cell and regenerative biology department at Harvard University, is growing brain tissue in her lab. In recent years, scientists have developed new techniques that add another level to the two-dimensional tissue culture of yore (e.g., growing cells in a single layer in a petri dish). These cells grow and divide in three dimensions, ultimately giving rise to samples of tissue that resemble the organ itself. They’re called organoids, but many news headlines have described them as if they are real, live organs.

Take these headlines for example: “Scientists grow human brains in a dish” and “Scientists brew up the creepiest batches of brain balls yet.” While science is in its infancy, the headlines don’t reflect that, taking liberties in describing what organoids are and overstating their form and function.

“You imagine a mini brain in a dish — that’s not what these things are,” Arlotta stresses. That bears repeating: They’re not mini brains; they’re not brains in a dish. They’re brain organoids, simplified replicas with some of the features of the organ they model.

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Important reminder that your genome is your property

Your invaluable genome

Genomic data is the currency of a new era of medicine that promises incredible advances. Here, bioinformatician Nana Mensah explains why…

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In the race for greatest medical revolution of the 21st century, genomics is undoubtedly a frontrunner. Those outside of the field, however, might still find themselves wondering: 'what's all the fuss about?' There are many reasons why genomics is revolutionary, but data is at the root of it all. As genomics is used more and more in mainstream care, it becomes ever more important to understand the great power and value of this new kind of data, writes Nana Mensah.

From cell to computer

While the word ‘genome’ refers to the entire sequence of DNA of an individual organism, the term ‘genomic data’ refers to its digital representation – a large data file resulting from the sequencing process.

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Cabozantinib added to the kidney cancer treatment arsenal

Cabozantinib Approval Expands Initial Treatment Options for Advanced Kidney Cancer

Cabozantinib added to the kidney cancer treatment arsenal. Genome Media.

For patients with the most common type of kidney cancer, there is now a new approved use of the targeted therapy cabozantinib (Cabometyx®). In December 2017, the Food and Drug Administration (FDA) approved use of the drug as an initial, or first-line, treatment for patients with advanced renal cell carcinoma (RCC).






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Connecting chromatin states (Epigenetics) to structural variation in human genomes

Chromatin organization modulates the origin of heritable structural variations in human genome 

Tanmoy Roychowdhury and Alexej Abyzov

Nucleic Acids Research (Article)

Abstract

Connecting chromatin states (Epigenetics) to structural variation in human genomes. Genome Media.

“Structural variations (SVs) in the human genome originate from different mechanisms related to DNA repair, replication errors, and retrotransposition. Our analyses of 26 927 SVs from the 1000 Genomes Project revealed differential distributions and consequences of SVs of different origin, e.g. deletions from non-allelic homologous recombination (NAHR) are more prone to disrupt chromatin organization while processed pseudogenes can create accessible chromatin. Spontaneous double stranded breaks (DSBs) are the best predictor of enrichment of NAHR deletions in open chromatin. This evidence, along with strong physical interaction of NAHR breakpoints belonging to the same deletion suggests that majority of NAHR deletions are non-meiotic i.e. originate from errors during homology directed repair (HDR) of spontaneous DSBs. In turn, the origin of the spontaneous DSBs is associated with transcription factor binding in accessible chromatin revealing the vulnerability of functional, open chromatin. The chromatin itself is enriched with repeats, particularly fixed Alu elements that provide the homology required to maintain stability via HDR. Through co-localization of fixed Alus and NAHR deletions in open chromatin we hypothesize that old Alu expansion had a stabilizing role on the human genome.”

Pediatric cancer mutation review

The genomic landscape of pediatric cancers: Implications for diagnosis and treatment

E. Alejandro Sweet-Cordero1 and Jaclyn A. Biegel

Science (Review Artice)

Pediatric cancer mutation review. Genome Media.

Abstract-The past decade has witnessed a major increase in our understanding of the genetic underpinnings of childhood cancer. Genomic sequencing studies have highlighted key differences between pediatric and adult cancers. Whereas many adult cancers are characterized by a high number of somatic mutations, pediatric cancers typically have few somatic mutations but a higher prevalence of germline alterations in cancer predisposition genes. Also noteworthy is the remarkable heterogeneity in the types of genetic alterations that likely drive the growth of pediatric cancers, including copy number alterations, gene fusions, enhancer hijacking events, and chromoplexy. Because most studies have genetically profiled pediatric cancers only at diagnosis, the mechanisms underlying tumor progression, therapy resistance, and metastasis remain poorly understood. We discuss evidence that points to a need for more integrative approaches aimed at identifying driver events in pediatric cancers at both diagnosis and relapse. We also provide an overview of key aspects of germline predisposition for cancer in this age group.


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Cancers are tissue-specific, truly important perspective

Tissue-specificity in cancer: The rule, not the exception

Kevin M. Haigis, Karen Cichowski, and Stephen J. Elledge

Science (article)

Cancers are tissue-specific, truly important perspective. Genome Media.

“Abstract—We are in the midst of a renaissance in cancer genetics. Over the past several decades, candidate-based targeted sequencing efforts provided a steady stream of information on the genetic drivers for certain cancer types. However, with recent technological advances in DNA sequencing, this stream has become a torrent of unbiased genetic information revealing the frequencies and patterns of point mutations and copy number variations (CNVs) across the entire spectrum of cancers. One of the most important observations from this work is that genetic alterations in bona fide cancer drivers (those genes that, when mutated, promote tumorigenesis) show a remarkable spectrum of tissue specificity”


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A boozy view of the human genome project, where it's been and might go

Human Genome Project: new alcohol abuse study could help us finally unlock secrets to beating genetic diseases

A boozy view of the human genome project, where it's been and might go. Genome Media

“Geneticists tried to exploit the revelations about the genome with studiesthat combed through thousands of tiny genetic changes in hundreds of thousands of patients with different diseases to see how they compared to healthy people. This enabled them to correlate genetic changes in diseased DNA in a manner unimaginable before June 2000. The “genetic architecture” of a wide number of conditions from cancers to schizophrenia to addiction became much better understood as a result.

Yet after the first few thousand studies were published, geneticists were horrified to discover that 98% of the disease-associated changes they’d identified in the genome do not occur in the genes. Instead, the vast majority of changes related to disease occur in the 98% of the genome that is not made up of genes – known as the “junk genome”, since few had the foggiest notion of what it was or how to study it.”


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Positive results for Epic prostate cancer testing

Blood Test Study Meets Goal, Validates Epic’s Prostate Cancer Target

Positive results for Epic prostate cancer testing. Genome Media.

Epic Sciences has commercialized a blood test that can predict how likely a patient with late-stage prostate cancer treated with hormones is likely to respond to an additional course of such therapy. Now, the San Diego-based company has additional data that it says supports use of its tests to determine when not to use hormone therapy



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Insights into the bugs in your guts, their diversity and associations with disease

Novel insights from uncultivated genomes of the global human gut microbiome

Insights into the bugs in your guts, their diversity and associations with disease. Genome Media

“Largely due to challenges cultivating microbes under laboratory conditions, the genome sequence of many species in the human gut microbiome remains unknown. To address this problem, we reconstructed 60,664 prokaryotic draft genomes from 3,810 faecal metagenomes from geographically and phenotypically diverse human subjects. These genomes provide reference points for 2,058 previously unknown species-level operational taxonomic units (OTUs), representing a 50% increase in the phylogenetic diversity of sequenced gut bacteria. On average, new OTUs comprise 33% of richness and 28% of species abundance per individual and are enriched in humans from rural populations. A meta-analysis of clinical gut microbiome studies pinpointed numerous disease associations for new OTUs, which have the potential to improve predictive models. Finally, our analysis revealed that uncultured gut species have undergone genome reduction with loss of certain biosynthetic pathways, which may offer clues for improving cultivation strategies in the future.”


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Gene expression used for leukemia diagnostics

Gene expression patterns identify high-risk chronic lymphocytic leukemia

Gene expression used for leukemia diagnostics. Genome Media.

A 290-gene expression signature and IGHV mutation status stratified patients with chronic lymphocytic leukemia to identify those with high-risk disease who might benefit from prompt initiation of therapy, according to a study published in Frontiers in Oncology.

Although CLL treatment is typically delayed until disease progression, it is uncertain whether patients would benefit from treatment immediately following diagnosis, when they have a smaller tumor mass and are in better physical condition.


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The origins of an important cancer causing virus

Origin and evolution of papillomavirus (onco)genes and genomes

Anouk Willemsen and Ignacio G. Bravo

biorxiv (Research Article)

Abstract—Papillomaviruses (PVs) are ancient viruses infecting vertebrates, from fish to mammals. Although the genomes of PVs are small and show conserved synteny, PVs display large genotypic diversity and ample variation in the phenotypic presentation of the infection. Most PVs genomes contain two small early genes E6 and E7. In a bunch of closely related human PVs, the E6 and E7 proteins provide the viruses with oncogenic potential. The recent discoveries of PVs without E6 and E7 in different fish species place a new root on the PV tree, and suggest that the ancestral PV consisted of the minimal PV backbone E1-E2-L2-L1. Bayesian phylogenetic analyses date the most recent common ancestor of the PV backbone to 424 million years ago (Ma). Common ancestry tests on extant E6 and E7 genes indicate that they share respectively a common ancestor dating back to at least 184 Ma. In AlphaPVs infecting primates, the appearance of the E5 oncogene 53-58 Ma concurred with i) a significant increase in substitution rate, ii) a basal radiation, and iii) key gain of functions in E6 and E7. This series of events was instrumental to build the extant phenotype of oncogenic human PVs. Our results assemble the current knowledge on PV diversity and present an ancient evolutionary timeline punctuated by evolutionary innovations in the history of this successful viral family.

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Viral coinfection increases variation, fitness

Beneficial coinfection can promote within-host viral diversity 

Asher Leeks, Ernesto A. Segredo-Otero, Rafael Sanjuán, and Stuart A. West

Virus Evolution (Research Article)

Viral coinfection increases variation, fitness. Genome Media.

Abstract—In many viral infections, a large number of different genetic variants can coexist within a host, leading to more virulent infections that are better able to evolve antiviral resistance and adapt to new hosts. But how is this diversity maintained? Why do faster-growing variants not outcompete slower-growing variants, and erode this diversity? One hypothesis is if there are mutually beneficial interactions between variants, with host cells infected by multiple different viral genomes producing more, or more effective, virions. We modelled this hypothesis with both mathematical models and simulations, and found that moderate levels of beneficial coinfection can maintain high levels of coexistence, even when coinfection is relatively rare, and when there are significant fitness differences between competing variants. Rare variants are more likely to be coinfecting with a different variant, and hence beneficial coinfection increases the relative fitness of rare variants through negative frequency dependence, and maintains diversity. We further find that coexisting variants sometimes reach unequal frequencies, depending on the extent to which different variants benefit from coinfection, and the ratio of variants which leads to the most productive infected cells. These factors could help drive the evolution of defective interfering particles, and help to explain why the different segments of multipartite viruses persist at different equilibrium frequencies.


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Lucence improving personalized liver cancer treatment with AI

Lucence Diagnostics to Develop AI Tools for Liver Cancer Treatment

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Lucence Diagnostics, a genomic medicine company focused on personalizing cancer care, today announced a new project to develop AI algorithms for improving diagnosis and treatment of liver cancer. The goal is to combine the imaging and molecular data from liver cancer patients into smarter software tools that help physicians make better treatment decisions.

Lucence will be working with Olivier Gevaert, PhD, Assistant Professor of Medicine (Biomedical Informatics) and of Biomedical Data Science at the Stanford University School of Medicine. Having developed LiquidHALLMARK®, the world's first liquid biopsy next-generation sequencing test that analyzes the DNA of cancer-causing mutations and viruses, Lucence will contribute its genomics expertise and proprietary sequencing technology to this project.


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Insights into how cancers escape an important class of treatments

Genome-wide screening identifies novel genes and biological processes implicated in cisplatin resistance

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Abstract

Cisplatin-based chemotherapeutic regimens are frequently used for treatments of solid tumors. However, tumor cells may have inherent or acquired cisplatin resistance, and the underlying mechanisms are largely unknown. We performed genome-wide screening of genes implicated in cisplatin resistance in A375 human melanoma cells. A substantial fraction of genes whose disruptions cause cisplatin sensitivity or resistance overlap with those whose disruptions lead to increased or decreased cell growth, respectively. Protein translation, mitochondrial respiratory chain complex assembly, signal recognition particle–dependent cotranslational protein targeting to membrane, and mRNA catabolic processes are the top biologic processes responsible for cisplatin sensitivity. In contrast, proteasome-mediated ubiquitin-dependent protein catabolic process, negative regulations of cellular catabolic process, and regulation of cellular protein localization are the top biologic processes responsible for cisplatin resistance. ZNRF3, a ubiquitin ligase known to be a target and negative feedback regulator of Wnt–β-catenin signaling, enhances cisplatin resistance in normal and melanoma cells independently of β-catenin. Ariadne-1 homolog (ARIH1), another ubiquitin ligase, also enhances cisplatin resistance in normal and melanoma cells. By regulating ARIH1, neurofibromin 2, a tumor suppressor, enhances cisplatin resistance in melanoma but not normal cells. Our results shed new lights on cisplatin resistance mechanisms and may be useful for development of cisplatin-related treatment strategies.—Ko, T., Li, S. Genome-wide screening identifies novel genes and biological processes implicated in cisplatin resistance.


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Cloud-based access to the fully sequenced genomes of 10,000 pediatric patients with cancer

Genomics Data Could Lead to New Treatments for Children

BY BETH FAND INCOLLINGO

PUBLISHED MARCH 12, 2019

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St. Jude Children’s Research Hospital is offering cloud-based access to the fully sequenced genomes of 10,000 pediatric patients with cancer, in the hopes that sharing the information will lead to the highest possible number of treatment breakthroughs.

Called the Pediatric Cancer Genome Project (PCGP), the growing set of data, categorized by cancer type, is meant to help researchers at the Memphis facility and beyond understand the genetic mutations that drive pediatric cancers and find new drugs to treat the diseases.

In whole-genome sequencing, a child’s normal and tumor genes are sequenced and then compared. Mutations that are present in a child’s tumor but not his or her normal genes may be driving the disease, and could be good candidates to target with drugs, said Jinghui Zang, Ph.D., chair of the Department of Computational Biology at St. Jude.


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Population-specific structural variation

Genome maps across 26 human populations reveal population-specific patterns of structural variation

Abstract—Large structural variants (SVs) in the human genome are difficult to detect and study by conventional sequencing technologies. With long-range genome analysis platforms, such as optical mapping, one can identify large SVs (>2 kb) across the genome in one experiment. Analyzing optical genome maps of 154 individuals from the 26 populations sequenced in the 1000 Genomes Project, we find that phylogenetic population patterns of large SVs are similar to those of single nucleotide variations in 86% of the human genome, while ~2% of the genome has high structural complexity. We are able to characterize SVs in many intractable regions of the genome, including segmental duplications and subtelomeric, pericentromeric, and acrocentric areas. In addition, we discover ~60 Mb of non-redundant genome content missing in the reference genome sequence assembly. Our results highlight the need for a comprehensive set of alternate haplotypes from different populations to represent SV patterns in the genome.

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A discussion of the limitations of a single, static reference genome

Buffalo gave us spicy wings and the ‘book of life.’ Here’s why that’s undermining personalized medicine

“The human reference genome, largely completed in 2001, has achieved near-mythic status. It is “the book of life,” the “operating manual for Homo sapiens.” But the reference genome falls short in ways that have become embarrassing, misleading, and, in the worst cases, emblematic of the white European dominance of science — shortcomings that are threatening the dream of genetically based personalized medicine.“

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Disease risk estimates need more samples from more populations (Genome Biology)

Genetic disease risks can be misestimated across global populations

Michelle S. Kim, Kane P. Patel, Andrew K. Teng, Ali J. Berens, and Joseph Lachance

Genome Biology (Research article)

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Accurate assessment of health disparities requires unbiased knowledge of genetic risks in different populations. Unfortunately, most genome-wide association studies use genotyping arrays and European samples. Here, we integrate whole genome sequence data from global populations, results from thousands of genome-wide association studies (GWAS), and extensive computer simulations to identify how genetic disease risks can be misestimated. In contrast to null expectations, we find that risk allele frequencies at known disease loci are significantly different for African populations compared to other continents. 


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Alzheimers insights from the desk of the NIH Director, Dr. Francis Collins

Largest-Ever Alzheimer’s Gene Study Brings New Answers

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Predicting whether someone will get Alzheimer’s disease (AD) late in life, and how to use that information for prevention, has been an intense focus of biomedical research. The goal of this work is to learn not only about the genes involved in AD, but how they work together and with other complex biological, environmental, and lifestyle factors to drive this devastating neurological disease.

It’s good news to be able to report that an international team of researchers, partly funded by NIH, has made more progress in explaining the genetic component of AD. Their analysis, involving data from more than 35,000 individuals with late-onset AD, has identified variants in five new genes that put people at greater risk of AD [1]. It also points to molecular pathways involved in AD as possible avenues for prevention, and offers further confirmation of 20 other genes that had been implicated previously in AD.

The results of this largest-ever genomic study of AD suggests key roles for genes involved in the processing of beta-amyloid peptides, which form plaques in the brain recognized as an important early indicator of AD. They also offer the first evidence for a genetic link to proteins that bind tau, the protein responsible for telltale tangles in the AD brain that track closely with a person’s cognitive decline.


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50,000 Human Exomes at the UK Biobank

New genetic data on 50,000 UK Biobank participants made available to the global health research community

A vast tranche of new UK Biobank genetic data becomes available to health researchers today, offering an unprecedented resource to enhance understanding of human biology and aid in therapeutic discovery.

The exome sequence data of 50,000 UK Biobank participants were generated at the Regeneron Genetics Center through a collaboration between UK Biobank, Regeneron (US) and GSK (UK) and are linked to detailed health records, imaging and other health-related data. Regeneron is also leading a consortium of biopharma companies (including Abbvie, Alnylam, AstraZeneca, Bristol-Myers Squibb, Biogen, Pfizer and Takeda) to complete exome sequencing of the remaining 450,000 UK Biobank participants by 2020. In addition, GSK has committed a £40 million investment to initiatives, such as UK Biobank, that harness advances in genetic research in the development of new medicines

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