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The Nobel Prize in Chemistry 2020: Emmanuelle Charpentier & Jennifer A. Doudna

Reporters: Stephen J. Williams, Ph.D. and Aviva Lev-Ari, PhD, RN

 

UPDATED on 11/12/2020

Harvard’s Jack Szostak congratulates former advisee Jennifer Doudna

It was a toast from one Nobel laureate to another, sweetened by the pride of a mentor to a prized student.

When Jennifer Doudna Ph.D. ’89 was honored on Wednesday with the Nobel Prize in chemistry for her work on the CRISPR gene-editing technique, she became the second person to gain such an honor from the lab of Jack Szostak, a genetics professor at Harvard Medical School and Massachusetts General Hospital, and professor of chemistry and chemical biology at Harvard’s Faculty of Arts and Sciences.

Szostak, who won the Nobel Prize in physiology or medicine in 2009 for work on how telomere caps keep the body’s chromosomes from breaking down, advised Doudna’s doctoral work on RNA and on Wednesday raised a glass in honor of Doudna, now at the University of California, Berkeley. In a tweet, Szostak expressed his delight at seeing someone he once guided through her early scientific steps soar to science’s highest reaches:

Doudna received the prize together with Emmanuelle Charpentier, for their work discovering and developing CRISPR as a precise gene-editing tool. In just the eight years since the pair announced their discovery the use of the technique has rapidly spread to a host of fields, allowing researchers to alter the code of life and develop resistant crops, new medical therapies, and even anticipate curing inherited diseases.

 

UPDADTED on 11/2/2020

 

Announcement of the Nobel Prize in Chemistry 2020

Live webcast from the press conference where the Royal Swedish Academy of Sciences will announce the Nobel Prize in Chemistry 2020.

 

 

The Royal Swedish Academy of Sciences has decided to award the Nobel Prize in Chemistry 2020 to

Emmanuelle Charpentier
Max Planck Unit for the Science of Pathogens, Berlin, Germany

Jennifer A. Doudna
University of California, Berkeley, USA

“for the development of a method for genome editing”

Genetic scissors: a tool for rewriting the code of life

Emmanuelle Charpentier and Jennifer A. Doudna have discovered one of gene technology’s sharpest tools: the CRISPR/Cas9 genetic scissors. Using these, researchers can change the DNA of animals, plants and microorganisms with extremely high precision. This technology has had a revolutionary impact on the life sciences, is contributing to new cancer therapies and may make the dream of curing inherited diseases come true.

Researchers need to modify genes in cells if they are to find out about life’s inner workings. This used to be time-consuming, difficult and sometimes impossible work. Using the CRISPR/Cas9 genetic scissors, it is now possible to change the code of life over the course of a few weeks.

“There is enormous power in this genetic tool, which affects us all. It has not only revolutionised basic science, but also resulted in innovative crops and will lead to ground-breaking new medical treatments,” says Claes Gustafsson, chair of the Nobel Committee for Chemistry.

As so often in science, the discovery of these genetic scissors was unexpected. During Emmanuelle Charpentier’s studies of Streptococcus pyogenes, one of the bacteria that cause the most harm to humanity, she discovered a previously unknown molecule, tracrRNA. Her work showed that tracrRNA is part of bacteria’s ancient immune system, CRISPR/Cas, that disarms viruses by cleaving their DNA.

Charpentier published her discovery in 2011. The same year, she initiated a collaboration with Jennifer Doudna, an experienced biochemist with vast knowledge of RNA. Together, they succeeded in recreating the bacteria’s genetic scissors in a test tube and simplifying the scissors’ molecular components so they were easier to use.

In an epoch-making experiment, they then reprogrammed the genetic scissors. In their natural form, the scissors recognise DNA from viruses, but Charpentier and Doudna proved that they could be controlled so that they can cut any DNA molecule at a predetermined site. Where the DNA is cut it is then easy to rewrite the code of life.

Since Charpentier and Doudna discovered the CRISPR/Cas9 genetic scissors in 2012 their use has exploded. This tool has contributed to many important discoveries in basic research, and plant researchers have been able to develop crops that withstand mould, pests and drought. In medicine, clinical trials of new cancer therapies are underway, and the dream of being able to cure inherited diseases is about to come true. These genetic scissors have taken the life sciences into a new epoch and, in many ways, are bringing the greatest benefit to humankind.

Illustrations

The illustrations are free to use for non-commercial purposes. Attribute ”© Johan Jarnestad/The Royal Swedish Academy of Sciences”

Illustration: Using the genetic scissors (pdf)
Illustration: Streptococcus’ natural immune system against viruses:CRISPR/Cas9 pdf)
Illustration: CRISPR/Cas9 genetic scissors (pdf)

Read more about this year’s prize

Popular information: Genetic scissors: a tool for rewriting the code of life (pdf)
Scientific Background: A tool for genome editing (pdf)

Emmanuelle Charpentier, born 1968 in Juvisy-sur-Orge, France. Ph.D. 1995 from Institut Pasteur, Paris, France. Director of the Max Planck Unit for the Science of Pathogens, Berlin, Germany.

Jennifer A. Doudna, born 1964 in Washington, D.C, USA. Ph.D. 1989 from Harvard Medical School, Boston, USA. Professor at the University of California, Berkeley, USA and Investigator, Howard Hughes Medical Institute.

SOURCE

https://www.nobelprize.org/prizes/chemistry/2020/press-release/

 

Nobel Prize in Chemistry awarded to scientists who discovered CRISPR gene editing tool for ‘rewriting the code of life’

(CNN)The Nobel Prize in Chemistry has been awarded to Emmanuelle Charpentier and Jennifer A. Doudna for the development of a method for genome editing.

They discovered one of gene technology’s sharpest tools: the CRISPR/Cas9 genetic scissors. Using these, researchers can change the DNA of animals, plants and micro-organisms with extremely high precision.
Before announcing the winners on Wednesday, Göran K. Hansson, secretary-general for the Royal Swedish Academy of Sciences, said that this year’s prize was about “rewriting the code of life.”
The American biochemist Jennifer A. Doudna (left) and French microbiologist Emmanuelle Charpentier, pictured together in 2016.
 
The CRISPR/Cas9 gene editing tools have revolutionized the molecular life sciences, brought new opportunities for plant breeding, are contributing to innovative cancer therapies and may make the dream of curing inherited diseases come true, according to a press release from the Nobel committee.
 
 
There have also been some ethical concerns around the CRISPR technology, however.
Charpentier, a French microbiologist, and Doudna, an American biochemist, are the first women to jointly win the Nobel Prize in Chemistry, and the sixth and seventh women to win the chemistry prize.
close dialog

 

Jennifer Doudna wins 2020 Nobel Prize in chemistry

 

First Day in a Nobel Life: Jennifer Doudna

12,365 views
Oct 7, 2020
 
Scenes from day that UC Berkeley Professor Jennifer Doudna won the Nobel Prize For the full story, visit: https://news.berkeley.edu/2020/10/07/… University of California, Berkeley, biochemist Jennifer Doudna today won the 2020 Nobel Prize in Chemistry, sharing it with colleague Emmanuelle Charpentier for the co-development of CRISPR-Cas9, a genome editing breakthrough that has revolutionized biomedicine. CRISPR-Cas9 allows scientists to rewrite DNA — the code of life — in any organism, including human cells, with unprecedented efficiency and precision. The groundbreaking power and versatility of CRISPR-Cas9 has opened up new and wide-ranging possibilities across biology, agriculture and medicine, including the treatment of thousands of intractable diseases. Doudna and Charpentier, director of the Max Planck Institute for Infection Biology, will share the 10 million Swedish krona (more than $1 million) prize. “This great honor recognizes the history of CRISPR and the collaborative story of harnessing it into a profoundly powerful engineering technology that gives new hope and possibility to our society,” said Doudna. “What started as a curiosity‐driven, fundamental discovery project has now become the breakthrough strategy used by countless researchers working to help improve the human condition. I encourage continued support of fundamental science as well as public discourse about the ethical uses and responsible regulation of CRISPR technology.” Video by Clare Major & Roxanne Makasdjian
SOURCE

 

Jennifer Doudna wins 2020 Nobel Prize in chemistry

 

Jennifer Doudna in the PBS Movie CRISPR

Our critically-acclaimed documentary HUMAN NATURE is now streaming on NETFLIX. #HumanNatureFilm. Find out more about the film on our website.

 

Other Articles on the Nobel Prize in this Open Access Journal Include:

2020 Nobel Prize for Physiology and Medicine for Hepatitis C Discovery goes to British scientist Michael Houghton and US researchers Harvey Alter and Charles Rice

CONTAGIOUS – About Viruses, Pandemics and Nobel Prizes at the Nobel Prize Museum, Stockholm, Sweden 

AACR Congratulates Dr. William G. Kaelin Jr., Sir Peter J. Ratcliffe, and Dr. Gregg L. Semenza on 2019 Nobel Prize in Physiology or Medicine

2018 Nobel Prize in Physiology or Medicine for contributions to Cancer Immunotherapy to James P. Allison, Ph.D., of the University of Texas, M.D. Anderson Cancer Center, Houston, Texas. Dr. Allison shares the prize with Tasuku Honjo, M.D., Ph.D., of Kyoto University Institute, Japan

2017 Nobel prize in chemistry given to Jacques Dubochet, Joachim Frank, and Richard Henderson  for developing cryo-electron microscopy

2016 Nobel Prize in Chemistry awarded for development of molecular machines, the world’s smallest mechanical devices, the winners: Jean-Pierre Sauvage, J. Fraser Stoddart and Bernard L. Feringa

Correspondence on Leadership in Genomics and other Gene Curations: Dr. Williams with Dr. Lev-Ari

Programming life: An interview with Jennifer Doudna by Michael Chui, a partner of the McKinsey Global Institute

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CRISPR-Cas9 and the Power of Butterfly Gene Editing

Reporter: Madison Davis

Genome editing is a relatively new branch of genetic engineering that utilizes modern technologies in altering, inserting, or deleting selective DNA sequences within cells.  CRISPR-Cas9, otherwise known as “Clustered Regularly Interspaced Short Palindromic Repeat”, is a groundbreaking genome editing technique for scientists, as it is more efficient and allows for more precise genome changes at less of a cost in comparison to other editing methods.  The CRISPR-Cas9 procedure chiefly involves two biological molecules: an enzyme known as “Cas9” whose role is to cut the DNA during transcription, and a guide RNA molecule located within the Cas9 enzyme.  

The process of extracting and editing certain segments of DNA begins with identifying the respective segment of DNA to edit, typically around twenty nucleotides in length but can vary depending on the goal of the scientists.  This selection process can be based on prior knowledge of gene mapping sequences or random experimentation.  Upon identifying the segment, scientists will manually formulate a guide RNA molecule that matches the sequence of nucleotides found in the DNA sequence.  This gRNA molecule will then be placed in empty Cas9 enzymes.  Through the process of transcription, Cas9 enzymes will find and cut out the designated DNA sequence, where scientists are then able to insert, delete, or modify certain sequences by hand under high-definition microscopes.  

The usage of CRISPR can range from identifying tumor suppressor genes to gene mapping for species.  In recent years, it has been used more specifically to understand the evolutionary genetics behind butterfly wing patterns.  Butterfly wings are constructed from two separate layers that contain thousands of individual scales made of a hard protein called chitin.  Each individual scale contains embedded structures and pigments that reflect or absorb certain colors of light depending on their wavelengths.  Their unique structures allows certain butterfly species to exhibit wide ranges of color variation.  All together, these scales can act as identification, insulation, and camouflage. 

Through selective processing, scientists were able to identify how a loss in a certain genetic sequence labeled WntA results in a reduction in CSS (Central Symmetry Systems) and pattern boundaries, resulting in more abstract wing patterns.  A research expedition led by Anyi Mazo-Vargas experimented on two species, Heliconius erato demophoon and Heliconius sara sara.  Each butterfly wing pair composed of mainly black pigment with two main stripe patterns consisting of red and yellow and blue and white for each species, respectively.  When the WntA gene was removed in offspring, there was an increase in color pigment in areas that were previously black scales.   For instance, in Heliconius erato demophoon, there appeared to be more blurred red and yellow pigment rather than distinct colored stripe patterns.  The WntA gene was also experimented in monarch butterflies, where an absence in WnTA genes caused the initially black tipped-scales of the monarch wings to become a whiter, “bleached” pigment.

While efficient in scale, CRISPR-Cas9 editing system is often riddled with mosaic mutations, which can be a challenge in making valid conclusions in gene editing.  Mosaicism is a process of gene editing that results in an individual having multiple cells with different DNA sequences.  Not all cells of a singular individual contain the same genetic code.  When editing genetic sequences during the larva stage, not all subsequent cells are affected by such a change, and thus changes in butterfly wings can only be partially identified.  As CRISPR and other gene editing technologies continue to evolve, scientists should try to increase the accuracy of their experiments, such as editing genes in earlier germline cells or varying their experiments on more subspecies for more data analysis. 

 

SOURCES

“What Are Genome Editing and CRISPR-Cas9? – Genetics Home Reference – NIH.” U.S. National Library of Medicine, National Institutes of Health, 17 Aug. 2020, ghr.nlm.nih.gov/primer/genomicresearch/genomeediting.

Pak, Ekaterina. “CRISPR: A Game-Changing Genetic Engineering Technique.” Science in the News, 31 July 2014, sitn.hms.harvard.edu/flash/2014/crispr-a-game-changing-genetic-engineering-technique/.

Mazo-Vargas, A., Concha, C., Livraghi, L., Massardo, D., Wallbank, R., Zhang, L., Papador, J., Martinez-Najera, D., Jiggins, C., Kronforst, M., Breuker, C., Reed, R., Patel, N., McMillan, W. and Martin, A., 2020. Macroevolutionary Shifts Of Wnta Function Potentiate Butterfly Wing-Pattern Diversity. [online] PNAS. Available at: https://www.pnas.org/content/114/40/10701 [Accessed 20 August 2020].

Mehravar, Maryam, et al. “Mosaicism in CRISPR/Cas9-Mediated Genome Editing.” Developmental Biology, Academic Press, 22 Oct. 2018, www.sciencedirect.com/science/article/pii/S0012160618302513.

https://pharmaceuticalintelligence.com/2020/08/29/prime-editing-as-a-new-crispr-tool-to-enhance-precision-and-versatility/

 

 

CAST – Alternative to CRISPR/Cas9 3
Select CRISPR alternative for editing genes without cuttingCRISPR alternative for editing genes without cutting3
Select CRISPR applied to Human Germ LineCRISPR applied to Human Germ Line66
Select CRISPR/Cas9 & Gene EditingCRISPR/Cas9 & Gene Editing5
Select Transposon-encoded CRISPR–Cas systems direct RNA-guided DNA integrationTransposon-encoded CRISPR–Cas systems direct RNA-guided DNA integration
3

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Live Conference Coverage AACR 2020 in Real Time: Monday June 22, 2020 Mid Day Sessions

Reporter: Stephen J. Williams, PhD

This post will be UPDATED during the next two days with notes from recordings from other talks

Follow Live in Real Time using

#AACR20

@pharma_BI

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Register for FREE at https://www.aacr.org/

 

AACR VIRTUAL ANNUAL MEETING II

 

June 22-24: Free Registration for AACR Members, the Cancer Community, and the Public
This virtual meeting will feature more than 120 sessions and 4,000 e-posters, including sessions on cancer health disparities and the impact of COVID-19 on clinical trials

 

This Virtual Meeting is Part II of the AACR Annual Meeting.  Part I was held online in April and was centered only on clinical findings.  This Part II of the virtual meeting will contain all the Sessions and Abstracts pertaining to basic and translational cancer research as well as clinical trial findings.

 

REGISTER NOW

 

Pezcoller Foundation-AACR International Award for Extraordinary Achievement in Cancer Research

The prestigious Pezcoller Foundation-AACR International Award for Extraordinary Achievement in Cancer Research was established in 1997 to annually recognize a scientist of international renown who has made a major scientific discovery in basic cancer research OR who has made significant contributions to translational cancer research; who continues to be active in cancer research and has a record of recent, noteworthy publications; and whose ongoing work holds promise for continued substantive contributions to progress in the field of cancer. For more information regarding the 2020 award recipient go to aacr.org/awards.

John E. Dick, Enzo Galligioni, David A Tuveson

DETAILS

Awardee: John E. Dick
Princess Anne Margaret Cancer Center, Toronto, Ontario
For determining how stem cells contribute to normal and leukemic hematopoeisis
  • not every cancer cell equal in their Cancer Hallmarks
  • how do we monitor and measure clonal dynamics
  • Barnie Clarkson did pivotal work on this
  • most cancer cells are post mitotic but minor populations of cells were dormant and survive chemotherapy
  •  only one cell is 1 in a million can regenerate and transplantable in mice and experiments with flow cytometry resolved the question of potency and repopulation of only small percentage of cells and undergo long term clonal population
  • so instead of going to cell lines and using thousands of shRNA looked at clinical data and deconvoluted the genetic information (RNASeq data) to determine progenitor and mature populations (how much is stem and how much is mature populations)
  • in leukemic patients they have seen massive expansion of a single stem cell population so only need one cell in AML if the stem cells have the mutational hits early on in their development
  • finding the “seeds of relapse”: finding the small subpopulation of stem cells that will relapse
  • they looked in BALL;;  there are cells resistant to l-aspariginase, dexamethasone, and vincristine
  • a lot of OXPHOS related genes (in DRIs) that may be the genes involved in this resistance
  • it a wonderful note of acknowledgement he dedicated this award to all of his past and present trainees who were the ones, as he said, made this field into what it is and for taking it into directions none of them could forsee

Monday, June 22

1:30 PM – 3:30 PM EDT

Virtual Educational Session

Experimental and Molecular Therapeutics, Drug Development, Cancer Chemistry

Chemistry to the Clinic: Part 1: Lead Optimization Case Studies in Cancer Drug Discovery

How can one continue to deliver innovative medicines to patients when biological targets are becoming ever scarcer and less amenable to therapeutic intervention? Are there sound strategies in place that can clear the path to targets previously considered “undruggable”? Recent advances in lead finding methods and novel technologies such as covalent screening and targeted protein degradation have enriched the toolbox at the disposal of drug discovery scientists to expand the druggable ta

Stefan N Gradl, Elena S Koltun, Scott D Edmondson, Matthew A. Marx, Joachim Rudolph

DETAILS

Monday, June 22

1:30 PM – 3:30 PM EDT

Virtual Educational Session

Bioinformatics and Systems Biology, Molecular and Cellular Biology/Genetics

Informatics Technologies for Cancer Research

Cancer researchers are faced with a deluge of high-throughput data. Using these data to advance understanding of cancer biology and improve clinical outcomes increasingly requires effective use of computational and informatics tools. This session will introduce informatics resources that support the data management, analysis, visualization, and interpretation. The primary focus will be on high-throughput genomic data and imaging data. Participants will be introduced to fundamental concepts

Rachel Karchin, Daniel Marcus, Andriy Fedorov, Obi Lee Griffith

DETAILS

  • Variant analysis is the big bottleneck, especially interpretation of variants
  • CIVIC resource is a network for curation, interpretation of genetic variants
  • CIVIC curators go through multiple rounds of editors review
  • gene summaries, variant summaries
  • curation follows ACSME guidelines
  • evidences are accumulated, categories by various ontologies and is the heart of the reports
  • as this is a network of curators the knowledgebase expands
  • CIVIC is linked to multiple external informatic, clinical, and genetic databases
  • they have curated 7017 clinical interpretations, 2527 variants, using 2578 papers, and over 1000 curators
  • they are currently integrating with COSMIC ClinVar, and UniProt
  • they are partnering with ClinGen to expand network of curators and their curation effort
  • CIVIC uses a Python interface; available on website

https://civicdb.org/home

The Precision Medicine Revolution

Precision medicine refers to the use of prevention and treatment strategies that are tailored to the unique features of each individual and their disease. In the context of cancer this might involve the identification of specific mutations shown to predict response to a targeted therapy. The biomedical literature describing these associations is large and growing rapidly. Currently these interpretations exist largely in private or encumbered databases resulting in extensive repetition of effort.

CIViC’s Role in Precision Medicine

Realizing precision medicine will require this information to be centralized, debated and interpreted for application in the clinic. CIViC is an open access, open source, community-driven web resource for Clinical Interpretation of Variants in Cancer. Our goal is to enable precision medicine by providing an educational forum for dissemination of knowledge and active discussion of the clinical significance of cancer genome alterations. For more details refer to the 2017 CIViC publication in Nature Genetics.

U24 funding announced: We are excited to announce that the Informatics Technology for Cancer Research (ICTR) program of the National Cancer Institute (NCI) has awarded funding to the CIViC team! Starting this year, a five-year, $3.7 million U24 award (CA237719), will support CIViC to develop Standardized and Genome-Wide Clinical Interpretation of Complex Genotypes for Cancer Precision Medicine.

Informatics tools for high-throughput analysis of cancer mutations

Rachel Karchin
  • CRAVAT is a platform to determine, categorize, and curate cancer mutations and cancer related variants
  • adding new tools used to be hard but having an open architecture allows for modular growth and easy integration of other tools
  • so they are actively making an open network using social media

Towards FAIR data in cancer imaging research

Andriy Fedorov, PhD

Towards the FAIR principles

While LOD has had some uptake across the web, the number of databases using this protocol compared to the other technologies is still modest. But whether or not we use LOD, we do need to ensure that databases are designed specifically for the web and for reuse by humans and machines. To provide guidance for creating such databases independent of the technology used, the FAIR principles were issued through FORCE11: the Future of Research Communications and e-Scholarship. The FAIR principles put forth characteristics that contemporary data resources, tools, vocabularies and infrastructures should exhibit to assist discovery and reuse by third-parties through the web. Wilkinson et al.,2016. FAIR stands for: Findable, Accessible, Interoperable and Re-usable. The definition of FAIR is provided in Table 1:

Number Principle
F Findable
F1 (meta)data are assigned a globally unique and persistent identifier
F2 data are described with rich metadata
F3 metadata clearly and explicitly include the identifier of the data it describes
F4 (meta)data are registered or indexed in a searchable resource
A Accessible
A1 (meta)data are retrievable by their identifier using a standardized communications protocol
A1.1 the protocol is open, free, and universally implementable
A1.2 the protocol allows for an authentication and authorization procedure, where necessary
A2 metadata are accessible, even when the data are no longer available
I Interoperable
I1 (meta)data use a formal, accessible, shared, and broadly applicable language for knowledge representation.
I2 (meta)data use vocabularies that follow FAIR principles
I3 (meta)data include qualified references to other (meta)data
R Reusable
R1 meta(data) are richly described with a plurality of accurate and relevant attributes
R1.1 (meta)data are released with a clear and accessible data usage license
R1.2 (meta)data are associated with detailed provenance
R1.3 (meta)data meet domain-relevant community standards

A detailed explanation of each of these is included in the Wilkinson et al., 2016 article, and the Dutch Techcenter for Life Sciences has a set of excellent tutorials, so we won’t go into too much detail here.

  • for outside vendors to access their data, vendors would need a signed Material Transfer Agreement but NCI had formulated a framework to facilitate sharing of data using a DIACOM standard for imaging data

Monday, June 22

1:30 PM – 3:01 PM EDT

Virtual Educational Session

Experimental and Molecular Therapeutics, Cancer Chemistry, Drug Development, Immunology

Engineering and Physical Sciences Approaches in Cancer Research, Diagnosis, and Therapy

The engineering and physical science disciplines have been increasingly involved in the development of new approaches to investigate, diagnose, and treat cancer. This session will address many of these efforts, including therapeutic methods such as improvements in drug delivery/targeting, new drugs and devices to effect immunomodulation and to synergize with immunotherapies, and intraoperative probes to improve surgical interventions. Imaging technologies and probes, sensors, and bioma

Claudia Fischbach, Ronit Satchi-Fainaro, Daniel A Heller

DETAILS

Monday, June 22

1:30 PM – 3:30 PM EDT

Virtual Educational Session

Survivorship

Exceptional Responders and Long-Term Survivors

How should we think about exceptional and super responders to cancer therapy? What biologic insights might ensue from considering these cases? What are ways in which considering super responders may lead to misleading conclusions? What are the pros and cons of the quest to locate exceptional and super responders?

Alice P Chen, Vinay K Prasad, Celeste Leigh Pearce

DETAILS

Monday, June 22

1:30 PM – 3:30 PM EDT

Virtual Educational Session

Tumor Biology, Immunology

Exploiting Metabolic Vulnerabilities in Cancer

The reprogramming of cellular metabolism is a hallmark feature observed across cancers. Contemporary research in this area has led to the discovery of tumor-specific metabolic mechanisms and illustrated ways that these can serve as selective, exploitable vulnerabilities. In this session, four international experts in tumor metabolism will discuss new findings concerning the rewiring of metabolic programs in cancer that support metabolic fitness, biosynthesis, redox balance, and the reg

Costas Andreas Lyssiotis, Gina M DeNicola, Ayelet Erez, Oliver Maddocks

DETAILS

Monday, June 22

1:30 PM – 3:30 PM EDT

Virtual Educational Session

Other Articles on this Open Access  Online Journal on Cancer Conferences and Conference Coverage in Real Time Include

Press Coverage

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Symposium: New Drugs on the Horizon Part 3 12:30-1:25 PM

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on NCI Activities: COVID-19 and Cancer Research 5:20 PM

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on Evaluating Cancer Genomics from Normal Tissues Through Metastatic Disease 3:50 PM

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on Novel Targets and Therapies 2:35 PM

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Bioinformatic Tools for RNASeq: A Curation

Curator: Stephen J. Williams, Ph.D. 

 

Note:  This will be an ongoing curation as new information and tools become available.

RNASeq is a powerful tool for the analysis of the transcriptome profile and has been used to determine the transcriptional changes occurring upon stimuli such as drug treatment or detecting transcript differences between biological sample cohorts such as tumor versus normal tissue.  Unlike its genomic companion, whole genome and whole exome sequencing, which analyzes the primary sequence of the genomic DNA, RNASeq analyzes the mRNA transcripts, thereby more closely resembling the ultimate translated proteome. In addition, RNASeq and transcriptome profiling can determine if splicing variants occur as well as determining the nonexomic sequences, such as miRNA and lncRNA species, all of which have shown pertinence in the etiology of many diseases, including cancer.

However, RNASeq, like other omic technologies, generates enormous big data sets, which requires multiple types of bioinformatic tools in order to correctly analyze the sequence reads, and to visualize and interpret the output data.  This post represents a curation by the RNA-Seq blog of such tools useful for RNASeq studies and lists and reviews published literature using these curated tools.

 

From the RNA-Seq Blog

List of RNA-Seq bioinformatics tools

Posted by: RNA-Seq Blog in Data Analysis, Web Tools September 16, 2015 6,251 Views

from: https://en.wiki2.org/wiki/List_of_RNA-Seq_bioinformatics_tools

A review of some of the literature using some of the aforementioned curated tools are discussed below:

 

A.   Tools Useful for Single Cell RNA-Seq Analysis

 

B.  Tools for RNA-Seq Analysis of the Sliceasome

 

C.  Tools Useful for RNA-Seq read assembly visualization

 

Other articles on RNA and Transcriptomics in this Open Access Journal Include:

NIH to Award Up to $12M to Fund DNA, RNA Sequencing Research: single-cell genomics, sample preparation, transcriptomics and epigenomics, and genome-wide functional analysis.

Single-cell Genomics: Directions in Computational and Systems Biology – Contributions of Prof. Aviv Regev @Broad Institute of MIT and Harvard, Cochair, the Human Cell Atlas Organizing Committee with Sarah Teichmann of the Wellcome Trust Sanger Institute

Complex rearrangements and oncogene amplification revealed by long-read DNA and RNA sequencing of a breast cancer cell line

Single-cell RNA-seq helps in finding intra-tumoral heterogeneity in pancreatic cancer

First challenge to make use of the new NCI Cloud Pilots – Somatic Mutation Challenge – RNA: Best algorithms for detecting all of the abnormal RNA molecules in a cancer cell

Evolution of the Human Cell Genome Biology Field of Gene Expression, Gene Regulation, Gene Regulatory Networks and Application of Machine Learning Algorithms in Large-Scale Biological Data Analysis

 

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Medicine in 2045 – Perspectives by World Thought Leaders in the Life Sciences & Medicine

Reporter: Aviva Lev-Ari, PhD, RN

 

This report is based on an article in Nature Medicine | VOL 25 | December 2019 | 1800–1809 | http://www.nature.com/naturemedicine

Looking forward 25 years: the future of medicine.

Nat Med 25, 1804–1807 (2019) doi:10.1038/s41591-019-0693-y

 

Aviv Regev, PhD

Core member and chair of the faculty, Broad Institute of MIT and Harvard; director, Klarman Cell Observatory, Broad Institute of MIT and Harvard; professor of biology, MIT; investigator, Howard Hughes Medical Institute; founding co-chair, Human Cell Atlas.

  • millions of genome variants, tens of thousands of disease-associated genes, thousands of cell types and an almost unimaginable number of ways they can combine, we had to approximate a best starting point—choose one target, guess the cell, simplify the experiment.
  • In 2020, advances in polygenic risk scores, in understanding the cell and modules of action of genes through genome-wide association studies (GWAS), and in predicting the impact of combinations of interventions.
  • we need algorithms to make better computational predictions of experiments we have never performed in the lab or in clinical trials.
  • Human Cell Atlas and the International Common Disease Alliance—and in new experimental platforms: data platforms and algorithms. But we also need a broader ecosystem of partnerships in medicine that engages interaction between clinical experts and mathematicians, computer scientists and engineers

Feng Zhang, PhD

investigator, Howard Hughes Medical Institute; core member, Broad Institute of MIT and Harvard; James and Patricia Poitras Professor of Neuroscience, McGovern Institute for Brain Research, MIT.

  • fundamental shift in medicine away from treating symptoms of disease and toward treating disease at its genetic roots.
  • Gene therapy with clinical feasibility, improved delivery methods and the development of robust molecular technologies for gene editing in human cells, affordable genome sequencing has accelerated our ability to identify the genetic causes of disease.
  • 1,000 clinical trials testing gene therapies are ongoing, and the pace of clinical development is likely to accelerate.
  • refine molecular technologies for gene editing, to push our understanding of gene function in health and disease forward, and to engage with all members of society

Elizabeth Jaffee, PhD

Dana and Albert “Cubby” Broccoli Professor of Oncology, Johns Hopkins School of Medicine; deputy director, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins.

  • a single blood test could inform individuals of the diseases they are at risk of (diabetes, cancer, heart disease, etc.) and that safe interventions will be available.
  • developing cancer vaccines. Vaccines targeting the causative agents of cervical and hepatocellular cancers have already proven to be effective. With these technologies and the wealth of data that will become available as precision medicine becomes more routine, new discoveries identifying the earliest genetic and inflammatory changes occurring within a cell as it transitions into a pre-cancer can be expected. With these discoveries, the opportunities to develop vaccine approaches preventing cancers development will grow.

Jeremy Farrar, OBE FRCP FRS FMedSci

Director, Wellcome Trust.

  • shape how the culture of research will develop over the next 25 years, a culture that cares more about what is achieved than how it is achieved.
  • building a creative, inclusive and open research culture will unleash greater discoveries with greater impact.

John Nkengasong, PhD

Director, Africa Centres for Disease Control and Prevention.

  • To meet its health challenges by 2050, the continent will have to be innovative in order to leapfrog toward solutions in public health.
  • Precision medicine will need to take center stage in a new public health order— whereby a more precise and targeted approach to screening, diagnosis, treatment and, potentially, cure is based on each patient’s unique genetic and biologic make-up.

Eric Topol, MD

Executive vice-president, Scripps Research Institute; founder and director, Scripps Research Translational Institute.

  • In 2045, a planetary health infrastructure based on deep, longitudinal, multimodal human data, ideally collected from and accessible to as many as possible of the 9+ billion people projected to then inhabit the Earth.
  • enhanced capabilities to perform functions that are not feasible now.
  • AI machines’ ability to ingest and process biomedical text at scale—such as the corpus of the up-to-date medical literature—will be used routinely by physicians and patients.
  • the concept of a learning health system will be redefined by AI.

Linda Partridge, PhD

Professor, Max Planck Institute for Biology of Ageing.

  • Geroprotective drugs, which target the underlying molecular mechanisms of ageing, are coming over the scientific and clinical horizons, and may help to prevent the most intractable age-related disease, dementia.

Trevor Mundel, MD

President of Global Health, Bill & Melinda Gates Foundation.

  • finding new ways to share clinical data that are as open as possible and as closed as necessary.
  • moving beyond drug donations toward a new era of corporate social responsibility that encourages biotechnology and pharmaceutical companies to offer their best minds and their most promising platforms.
  • working with governments and multilateral organizations much earlier in the product life cycle to finance the introduction of new interventions and to ensure the sustainable development of the health systems that will deliver them.
  • deliver on the promise of global health equity.

Josep Tabernero, MD, PhD

Vall d’Hebron Institute of Oncology (VHIO); president, European Society for Medical Oncology (2018–2019).

  • genomic-driven analysis will continue to broaden the impact of personalized medicine in healthcare globally.
  • Precision medicine will continue to deliver its new paradigm in cancer care and reach more patients.
  • Immunotherapy will deliver on its promise to dismantle cancer’s armory across tumor types.
  • AI will help guide the development of individually matched
  • genetic patient screenings
  • the promise of liquid biopsy policing of disease?

Pardis Sabeti, PhD

Professor, Harvard University & Harvard T.H. Chan School of Public Health and Broad Institute of MIT and Harvard; investigator, Howard Hughes Medical Institute.

  • the development and integration of tools into an early-warning system embedded into healthcare systems around the world could revolutionize infectious disease detection and response.
  • But this will only happen with a commitment from the global community.

Els Toreele, PhD

Executive director, Médecins Sans Frontières Access Campaign

  • we need a paradigm shift such that medicines are no longer lucrative market commodities but are global public health goods—available to all those who need them.
  • This will require members of the scientific community to go beyond their role as researchers and actively engage in R&D policy reform mandating health research in the public interest and ensuring that the results of their work benefit many more people.
  • The global research community can lead the way toward public-interest driven health innovation, by undertaking collaborative open science and piloting not-for-profit R&D strategies that positively impact people’s lives globally.

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@BroadInstitute a shift from Permanently editing DNA to Temporarily revising RNA – An approach with promise for addressing the risk of developing Alzheimer’s by deactivating APOE4 – RESCUE: RNA Editing for Specific C to U Exchange, the platform builds on REPAIR: RNA Editing for Programmable A to I

Reporter: Aviva Lev-Ari, PhD, RN

 

  • The RNA editors converted “the nucleotide base adenine to inosine, or letters A to I. Zhang and colleagues took the REPAIR fusion and evolved it in the lab until it could change cytosine to uridine, or C to U.”
  • Using Cas13, Zhang’s team was able to take the APOE4 gene — believed to carry the added risk of spurring Alzheimer’s — and changed it to a benign APOE2.

RNA-guided DNA insertion with CRISPR-associated transposases

Science  05 Jul 2019:
Vol. 365, Issue 6448, pp. 48-53
DOI: 10.1126/science.aax9181
SOURCE

Other related articles on CRISPR derived Gene Editing for Gene Therapy published in this Open Access on Online Scientific Journal include the following:

 

Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS & BioInformatics, Simulations and the Genome Ontology

Forthcoming 12/2019, Volume Two

by

Prof. Marcus W. Feldman, PhD, Editor, Stanford University

Prof. Stephen J. Williams, PhD, Editor, Temple University

and Aviva Lev-Ari, PhD, RN, Editor, LPBI Group 

 

Part 2: CRISPR for Gene Editing and DNA Repair

2.1 The Science – 77 articles

2.2 Technologies and Methodologies – 27 articles

2.3 Clinical Aspects – 9 articles

2.4 Business and Legal – 18 articles

 

Series B: Frontiers in Genomics Research

 

  • VOLUME 1: Genomics Orientations for Personalized Medicine. On Amazon.com since 11/23/2015

http://www.amazon.com/dp/B018DHBUO6

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Breakthrough in Gene Editing CRISPR–Cas systems: First example of a fully programmable, RNA-guided integrase and lays the foundation for genomic manipulations that obviate the requirements for double-strand breaks and homology-directed repair.

 

Reporter: Aviva Lev-Ari, PhD, RN

 

CRISPR alternatives for editing genes without cutting: CRISPR 12, 12a, 13, 14 – Alternative Techniques to CRISPR/Cas9

 

  • Alternative to CRISPR/Cas9 – CAST (CRISPR-associated transposase) – A New Gene-editing Approach for Insertion of Large DNA Sequences into a Genome developed @BroadInstitute @MIT @Harvard

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2019/06/11/alternative-to-crispr-cas9-cast-crispr-associated-transposase-a-new-gene-editing-approach-for-insertion-of-large-dna-sequences-into-a-genome-developed-broadinstitute-mit-harvard/

 

  • Vertex Pharmaceuticals agreed to pay $420 million to acquire Exonics and to expand its partnership with CRISPR Therapeutics. The deal sets in motion a planto use CRISPR to treat Duchenne muscular dystrophy and myotonic dystrophy type 1.

 

  • In May, a team at the Fred Hutchinson Cancer Research Center described a method developed there to use gold nanoparticles to carry CRISPR components into cells and to use the Cas12a enzyme to make cleaner cuts than Cas9 typically does.

 

  • A UC Berkeley spinoff, GenEdit, is also developing a gold-based CRISPR system.

 

  • Other recently proposed ideas for improving CRISPR include attaching a hairpin-like guide to RNA to improve the accuracy of DNA cuts and adding an on-off switch to Cas9 enzymes to ensure they can’t make edits anywhere other than the targeted sites.

 

  • The next step for Sternberg’s team at Columbia is to test the INTEGRATE technology in mammalian cells. They believe the technique could eventually be applied to a variety of products, such as gene therapies and engineered crops.

 

Transposon-encoded CRISPR–Cas systems direct RNA-guided DNA integration

Abstract

Conventional CRISPR–Cas systems maintain genomic integrity by leveraging guide RNAs for the nuclease-dependent degradation of mobile genetic elements, including plasmids and viruses. Here we describe a remarkable inversion of this paradigm, in which bacterial Tn7-like transposons have co-opted nuclease-deficient CRISPR–Cas systems to catalyze RNA-guided integration of mobile genetic elements into the genome. Programmable transposition of Vibrio cholerae Tn6677 in E. coli requires CRISPR- and transposon-associated molecular machineries, including a novel co-complex between Cascade and the transposition protein TniQ. Donor DNA integration occurs in one of two possible orientations at a fixed distance downstream of target DNA sequences, and can accommodate variable length genetic payloads. Deep sequencing experiments reveal highly specific, genome-wide DNA integration across dozens of unique target sites. This work provides the first example of a fully programmable, RNA-guided integrase and lays the foundation for genomic manipulations that obviate the requirements for double-strand breaks and homology-directed repair.

 SOURCE

A CRISPR alternative for editing genes without cutting

Scientists at Columbia University’s Vagelos College of Physicians and Surgeons are now proposing an alternative gene-editing system—one that sidesteps the need for DNA cutting altogether.

The researchers are using a “jumping gene,” or transposon, from a bacterium called Vibrio cholerae. The transposon is able to insert itself into different regions of the genome and can be programmed to carry any DNA sequence to any site. Therefore their technology, which they dubbed INTEGRATE, acts less like molecular scissors and more like molecular glue, they explained in the journal Nature.

“Rather than introduce DNA breaks and rely on the cell to repair the break, INTEGRATE directly inserts a user-defined DNA sequence at a precise location in the genome, a capability that molecular biologists have sought for decades,” said senior author Sam Sternberg, Ph.D., assistant professor of biochemistry and molecular biophysics at Columbia, in a statement. Sternberg recently joined Columbia after a stint working in the lab of CRISPR pioneer Jennifer Doudna at the University of California, Berkeley.

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Alternative to CRISPR/Cas9 – CAST (CRISPR-associated transposase) – A New Gene-editing Approach for Insertion of Large DNA Sequences into a Genome developed @BroadInstitute @MIT @Harvard

Reporter: Aviva Lev-Ari, PhD, RN

 

A new gene-editing CAST member

In Science, a team led by Jonathan Strecker, Alim Ladha, and core institute member Feng Zhang reports a new gene-editing approach that can precisely and efficiently insert large DNA sequences into a genome. The system, called CRISPR-associated transposase (CAST), is a completely new platform to integrate genetic sequences into cellular DNA, addressing a long-sought goal for precision gene editing. The team molecularly characterized and harnessed the natural CAST system from cyanobacteria, also unveiling a new way that some CRISPR-associated systems perform in nature: not to protect bacteria from viruses, but to facilitate the spread of transposon DNA. Check out more in coverage from STAT and New Scientist.

SOURCE

https://www.broadinstitute.org/news/research-roundup-june-7-2019

 

RNA-guided DNA insertion with CRISPR-associated transposases

Science  06 Jun 2019:
eaax9181
DOI: 10.1126/science.aax9181

Abstract

CRISPR-Cas nucleases are powerful tools to manipulate nucleic acids; however, targeted insertion of DNA remains a challenge as it requires host cell repair machinery. Here we characterize a CRISPR-associated transposase (CAST) from cyanobacteria Scytonema hofmanni which consists of Tn7-like transposase subunits and the type V-K CRISPR effector (Cas12k). ShCAST catalyzes RNA-guided DNA transposition by unidirectionally inserting segments of DNA 60-66 bp downstream of the protospacer. ShCAST integrates DNA into unique sites in the E. coli genome with frequencies of up to 80% without positive selection. This work expands our understanding of the functional diversity of CRISPR-Cas systems and establishes a paradigm for precision DNA insertion.

 

SOURCE

https://science.sciencemag.org/content/early/2019/06/05/science.aax9181

 

Other related articel published in thies Open Access Online Scientific Journal, include:

Breakthrough in Gene Editing CRISPR–Cas systems: First example of a fully programmable, RNA-guided integrase and lays the foundation for genomic manipulations that obviate the requirements for double-strand breaks and homology-directed repair.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2019/06/13/breakthrough-in-gene-editing-crispr-cas-systems-first-example-of-a-fully-programmable-rna-guided-integrase-and-lays-the-foundation-for-genomic-manipulations-that-obviate-the-requirements-for/

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New CRISPR Approach Transforms Skin Cells into Pluripotent Stem Cells

Reporter: Irina Robu, PhD

Dr. Timo Otonkoski, University of Helsinki and Dr.Juha Kere, King’s College London succeeded on reprograming skin cells into pluripotent stem cells by activating cell’s own genes using gene editing technology, CRISPR-Cas9-based gene activation (CRISPRa) that can be used to activate genes. The method uses a blunt version of Cas9 ‘gene scissors’ that does not cut DNA and can consequently be used to activate gene expression without mutating the genome. Previously, reprogramming was only possible by artificially introducing the critical transformation genes known as Yamanaka Factors into skin cells where they are normally inactive.

According to a study that is published in Nature Communication, called Human Pluripotent Reprogramming with CRISPR activators which show that CRISPRa is an attractive tool for cellular reprogramming applications due to its high multiplex capacity and direct alignment of endogenous loci. In the article, it is presented that reprogramming of primary human dermal fibroblasts to induced pluripotent stem cells with CRISPRa, the aimed at endogenous cells. The data shows that human body cells can only be reprogrammed into iPS cells with CRISPRa, and the findings reveal the involvement of EEA motif-associated mechanisms in cellular reprogramming.

The discovery also advocates that it might be likely to improve many other reprogramming tasks by addressing genetic elements that are typical of the intended target cell type. According to Jere Weltner, PhD student working on the project “the technology can find practical application in biobanking and many other applications of tissue technology.

SOURCE

https://www.sciencedaily.com/releases/2018/07/180706091723.htm

 

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