Single-molecule quantum sequencing method for detecting Anti-Cancer drug incorporation into DNA

DNA is small. Really, really, small. So, when researchers want to study the structure of a single-stranded DNA, they can’t just pull out their microscopes: they have to get creative.

In a study published this week in Scientific Reports, researchers from Japan’s Osaka University explain how they came up with a really small solution to the challenge of studying anti-cancer drugs incorporated into single strands of DNA.

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Next-next generation tool for improving traditional chemotherapies

Direct Analysis of Incorporation of an Anticancer Drug into DNA at Single-Molecule Resolution

Identifying positions at which anticancer drug molecules incorporate into DNA is essential to define mechanisms underlying their activity, but current methodologies cannot yet achieve this. The thymidine fluorine substitution product trifluridine (FTD) is a DNA-damaging anticancer agent thought to incorporate into thymine positions in DNA. This mechanism, however, has not been directly confirmed. Here, we report a means to detect FTD in a single-stranded oligonucleotide using a method to distinguish single molecules by differences in electrical conductance. Entire sequences of 21-base single-stranded DNAs with and without incorporated drug were determined based on single-molecule conductances of the drug and four deoxynucleosides, the first direct observation of its kind. This methodology may foster rapid development of more effective anticancer drugs.

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More than four possible bases, more coverage

Scientists Have Created Synthetic DNA with 4 Extra Letters

A couple billion years ago, four molecules danced into the elegant double-helix structure of DNA, which provides the codes for life on our planet. But were these four players really fundamental to the appearance of life — or could others have also given rise to our genetic code?

A new study, published today (Feb. 20) in the journal Science, supports the latter proposition: Scientists have recently molded a new kind of DNA into its elegant double-helix structure and found it had properties that could support life.

But if natural DNA is a short story, this synthetic DNA is a Tolstoy novel.

The researchers crafted the synthetic DNA using four additional molecules, so that the resulting product had a code made up from eight letters rather than four. 

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Increased CRISPR specificity by limiting expression

Scientists sharpen their molecular scissors and expand the gene editing toolbox

Wake Forest Institute for Regenerative Medicine (WFIRM) scientists have figured out a better way to deliver a DNA editing tool to shorten the presence of the editor proteins in the cells in what they describe as a "hit and run" approach.

CRISPR (clustered regularly interspaced short palindromic repeats) technology is used to alter DNA sequences and modify gene function. CRISPR/Cas9 is an enzyme that is used like a pair of scissors to cut two strands of DNA at a specific location to add, remove or repair bits of DNA. But CRISPR/Cas9 is not 100 percent accurate and could potentially cut unexpected locations, causing unwanted results.

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Cancer mutation characterization with machine learning (original article -- very cool)

Integrated structural variation and point mutation signatures in cancer genomes using correlated topic models

Loss of DNA repair mechanisms can leave specific mutation signatures in the genomes of cancer cells. To identify cancers with broken DNA-repair processes, accurate methods are needed for detecting mutation signatures and, in particular, their activities or probabilities within individual cancers. In this paper, we introduce a class of statistical modeling methods used for natural language processing, known as “topic models”, that outperform standard methods for signature analysis. We show that topic models that incorporate signature probability correlations across cancers perform best, while jointly analyzing multiple mutation types improves robustness to low mutation counts.

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Synthetic DNA suggests other bases might be out there

Synthetic DNA could help with search for alien life

Scientists have long suggested that if life exists beyond Earth, the processes behind it may be entirely different from everything we know.

On Thursday, researchers announced that they were able to create a DNA-like molecular system that can store and transmit information. It's not a life form, but the genetic system represents what an alternative to DNA-based life may resemble.

It could also help scientists keep a different picture in mind when searching for life elsewhere in the universe.

Smart stats make use of large-scale health insurance claims

Repurposing large health insurance claims data to estimate genetic and environmental contributions in 560 phenotypes

We analysed a large health insurance dataset to assess the genetic and environmental contributions of 560 disease-related phenotypes in 56,396 twin pairs and 724,513 sibling pairs out of 44,859,462 individuals that live in the United States. We estimated the contribution of environmental risk factors (socioeconomic status (SES), air pollution and climate) in each phenotype. Mean heritability (h2 = 0.311) and shared environmental variance (c2 = 0.088) were higher than variance attributed to specific environmental factors such as zip-code-level SES (varSES = 0.002), daily air quality (varAQI = 0.0004), and average temperature (vartemp = 0.001) overall, as well as for individual phenotypes. We found significant heritability and shared environment for a number of comorbidities (h2 = 0.433, c2 = 0.241) and average monthly cost (h2 = 0.290, c2 = 0.302). All results are available using our Claims Analysis of Twin Correlation and Heritability (CaTCH) web application.

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Extended genetic alphabet covered in New York Times

DNA Gets a New — and Bigger — Genetic Alphabet

DNA is spelled out with four letters, or bases. Researchers have now built a system with eight. It may hold clues to the potential for life elsewhere in the universe and could also expand our capacity to store digital data on Earth.

In 1985, the chemist Steven A. Benner sat down with some colleagues and a notebook and sketched out a way to expand the alphabet of DNA. He has been trying to make those sketches real ever since.

On Thursday, Dr. Benner and a team of scientists reported success: in a paper, published in Science, they said they have in effect doubled the genetic alphabet.

Natural DNA is spelled out with four different letters known as bases — A, C, G and T. Dr. Benner and his colleagues have built DNA with eight bases — four natural, and four unnatural. They named their new system Hachimoji DNA (hachi is Japanese for eight, moji for letter).

Crafting the four new bases that don't exist in nature was a chemical tour-de-force. They fit neatly into DNA’s double helix, and enzymes can read them as easily as natural bases, in order to make molecules.

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Autism GWAS finds common risk variants

Identification of common genetic risk variants for autism spectrum disorder

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci.

Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.

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Insomnia GWAS with 1.3 million individuals yields results

Genome-wide analysis of insomnia in 1,331,010 individuals identifies new risk loci and functional pathways

Insomnia is the second most prevalent mental disorder, with no sufficient treatment available. Despite substantial heritability, insight into the associated genes and neurobiological pathways remains limited.

Here, we use a large genetic association sample (n = 1,331,010) to detect novel loci and gain insight into the pathways, tissue and cell types involved in insomnia complaints.

We identify 202 loci implicating 956 genes through positional, expression quantitative trait loci, and chromatin mapping. The meta-analysis explained 2.6% of the variance. We show gene set enrichments for the axonal part of neurons, cortical and subcortical tissues, and specific cell types, including striatal, hypothalamic, and claustrum neurons. We found considerable genetic correlations with psychiatric traits and sleep duration, and modest correlations with other sleep-related traits. Mendelian randomization identified the causal effects of insomnia on depression, diabetes, and cardiovascular disease, and the protective effects of educational attainment and intracranial volume. Our findings highlight key brain areas and cell types implicated in insomnia, and provide new treatment targets.

Crispr Therapeutics AG has treated its first human

Crispr Infuses First Human in Landmark Gene-Editing Study

Crispr Therapeutics AG  shares surged after the company said it has treated the first human with the same genetic technology that shares its name in an early-stage study.

Crispr Therapeutics and partner Vertex Pharmaceuticals Inc. said on Monday morning that the first patient in a trial using CTX001, a therapy created using Crispr technology, as a treatment for the rare blood disease, beta thalassemia, received the one-time medicine. The pair also announced the enrollment of the first patient has started in a parallel study for the medicine in sickle-cell disease with the first dosing on track for mid-year.

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New DNA repair mechanism identified

Novel DNA repair mechanism preserves genome integrity

"I'm just astounded," said Cortez, Ingram Professor of Cancer Research and professor of Biochemistry. The investigators, led by postdoctoral fellow Kareem Mohni, Ph.D., have discovered a new DNA repair mechanism.

"DNA repair is a very mature field. The Nobel Prize was given a few years ago to three scientists who studied DNA repair in the 1970s and 80s," Cortez said.

"People are still very interested in DNA repair, and there are important questions that we're asking, but the idea of finding a whole new repair mechanism … nobody would have thought this is possible."

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CRISPR Gene Editing advances

Gene Editing is trickier THAN expected—BUT fixes are in sight

Of all the big, world-remaking bets on the genome-editing tool known as Crispr, perhaps none is more tantalizing than its potential to edit some of humanity’s worst diseases right out of the history books. Just this week, Crispr Therapeutics announced it had begun treating patients with an inherited blood disorder called beta thalassemia, in the Western drug industry’s first test of the technology for genetic disease. But despite the progress, there remain a host of unknowns standing in the way of Crispr-based medicines going mainstream, chief among them safety.

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World Health Organization might make some human genome editing rules

Human genome editing is here – now we have to decide who is in charge

The World Health Organization (WHO) will convene a meeting this month to develop global standards of governance for human genome editing. This is a welcome move. Although the committee has no powers to enforce compliance – it is still a matter for individual nations to decide on regulations, with China reportedly updating its rules earlier this week – the WHO committee’s recommendations will be influential and far-reaching in their ambition. But I hope committee members will bear a few points in mind in their discussions.

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Synthetic DNA is a new technology and probably needs some new rules

Opinion: Ethical Boundaries Needed on the Uses of Synthetic DNA

A newly expanded genetic alphabet that includes four synthetic nucleotides highlights the need for strict boundaries on their use.

A study published last week expands the redesign of the 4-billion-year-old genetic code from a four-nucleotide base-pair alphabet to an eight-base-pair alphabet by incorporating artificial nucleotides. The scientists, led by Steven Benner of the Foundation for Applied Molecular Evolution and Firebird Biomolecular Sciences in Florida, have also identified a bacteriophage RNA polymerase variant that transcribes the synthetic DNA into synthetic RNA.  

Previously, a scientific team led by Floyd Romesberg at The Scripps Research Institute used its own synthetic base pairs to create bacteria that replicate the artificial DNA, translate the DNA into mRNA, and create new types of amino acids. 

These are technologically impressive accomplishments and the translational applications of these discoveries could be revolutionary.

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Four new bases available for synthetic biology (original article)

Hachimoji DNA and RNA: A genetic system with eight building blocks

Expanding the genetic code

DNA and RNA are naturally composed of four nucleotide bases that form hydrogen bonds in order to pair. Hoshika et al. added an additional four synthetic nucleotides to produce an eight-letter genetic code and generate so-called hachimoji DNA. Coupled with an engineered T7 RNA polymerase, this expanded DNA alphabet could be transcribed into RNA. Thus, new forms of DNA that add information density to genetic biopolymers can be generated that may be useful for future synthetic biological applications.

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A European take on CRISPR corn

Boosting corn yields with CRISPR-carrying pollen

Scientists have developed a single-step gene editing process that can increase corn yields.
The new technique uses pollen to transfer the components of CRISPR-Cas9 into another plant allowing them to produce gene edited corn, a process previously hindered by the thick cell walls of many plants, such as corn and wheat. Results of the first set of experiments were published on 4 March in Nature Biotechnology.

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CRISPR quality improvement tested

CRISPR Base Editor Takes Diagnostic and Remedial Exams

Whether a CRISPR-based editing tool makes the grade or needs remedial work isn’t clear until it is subjected to testing, thorough and systematic testing. Consequently, scientists based at South Korea’s Institute for Basic Science (IBS) are administering the CRISPR equivalent of standardized tests. Rather than present CRISPR tools with a #2 pencil and a fill-in-the-oval sheet, the scientists provide different guide RNAs. Then the scientists use genome sequencing to check for errors such as off-target effects.

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What will human cloning be like, when we eventually start doing it...

#Science #Biology #Medicine #HumanCloning #Future

It had looked impossible, but, in the end it was surprisingly easy. So, though few knew of their creation at the time, the first human clones were born in 2020 in Taiwan. Now, as those clones celebrate their 30th C-days, it seems a good moment to review the history of cloning…

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CRISPR off-target errors

A CRISPR spin-off causes unintended typos in DNA

Even the best editor sometimes introduces typos. That’s true whether the editor is human or a version of the much-heralded gene-editing tool CRISPR.

One type of CRISPR gene editor that changes individual DNA bases, rather than cutting DNA, introduces more unwanted mutations than expected in mouse embryos and rice plants, researchers report. Those mistakes occurred in places where the tool wasn’t supposed to make changes. Another tested base editor, however, didn’t make the undesirable edits. The results were described in two studies published online February 28 in Science.

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