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Joe Biden Announced Science Team Nominations for the New Administration

Posted in and Bioethics, Biological Engineering, Evidence-based decision-making, Foundations for supporting Science and Education, Funding Opportunities for Cancer Research, Health Law & Patient Safety, Health Law Policy, HealthCare IT, Interviews with Key Opinion Leaders (KOLs), Leadership, Power, Social Interlocking Connections, National Academy of Sciences AWARDS, Nobel Prize Winners, Personalized and Precision Medicine & Genomic Research, Precision Cancer Medicine, Women in Life Sciences, women in science, tagged aerospace, bioengineering, Broad Institute, Eric Lander, genomics, global warming, Human Genome Project, Joe Biden, MIT, nobel leureates, precision medicine, Princeton University, Science Advisory Panel, science policy, US science on January 17, 2021| Leave a Comment »

Joe Biden Announced Science Team Nominations for the New Administration

Reporter: Stephen J. Williams, PhD

WordCloud Image Produced by Adam Tubman

In an announcement televised on C-Span, President Elect Joseph Biden announced his new Science Team to advise on science policy matters, as part of the White House Advisory Committee on Science and Technology. Below is a video clip and the transcript, also available at

https://www.c-span.org/video/?508044-1/president-elect-biden-introduces-white-house-science-team

 

 

COMING UP TONIGHT ON C-SPAN, NEXT, PRESIDENT-ELECT JOE BIDEN AND VICE PRESIDENT-ELECT KAMALA HARRIS ANNOUNCE SEVERAL MEMBERS OF THEIR WHITE HOUSE SCIENCE TEAM. AND THEN SENATE MINORITY LEADER CHUCK SCHUMER TALKS ABOUT THE IMPEACHMENT OF PRESIDENT TRUMP IN THE WEEKLY DEMOCRATIC ADDRESS. AND AFTER THAT, TODAY’S SPEECH BY VICE PRESIDENT MIKE PENCE TO SAILORS AT NAVAL AIR STATION LAMORE IN CALIFORNIA. NEXT, PRESIDENT-ELECT JOE BIDEN AND VICE PRESIDENT-ELECT KAMALA HARRIS ANNOUNCE SEVERAL MEMBERS OF THEIR WHITE HOUSE SCIENCE TEAM. FROM WILMINGTON, DELAWARE, THIS IS ABOUT 40 MINUTES. PRESIDENT-ELECT BIDEN: GOOD AFTERNOON, FOLKS. I WAS TELLING THESE FOUR BRILLIANT SCIENTISTS AS I STOOD IN THE BACK, IN A WAY, THEY — THIS IS THE MOST EXCITING ANNOUNCEMENT THAT I’VE GOTTEN TO MAKE IN THE ENTIRE CABINET RAISED TO A CABINET LEVEL POSITION IN ONE CASE. THESE ARE AMONG THE BRIGHTEST MOST DEDICATED PEOPLE NOT ONLY IN THE COUNTRY BUT THE WORLD. THEY’RE COMPOSED OF SOME OF THE MOST SCIENTIFIC BRILLIANT MINDS IN THE WORLD. WHEN I WAS VICE PRESIDENT AS — I I HAD INTENSE INTEREST IN EVERYTHING THEY WERE DOING AND I PAID ENORMOUS ATTENTION. AND I WOULD — LIKE A KID GOING BACK TO SCHOOL. SIT DOWN AND CAN YOU EXPLAIN TO ME AND THEY WERE — VERY PATIENT WITH ME. AND — BUT AS PRESIDENT, I WANTED YOU TO KNOW I’M GOING TO PAY A GREAT DEAL OF ATTENTION. WHEN I TRAVEL THE WORLD AS VICE PRESIDENT, I WAS OFTEN ASKED TO EXPLAIN TO WORLD LEADERS, THEY ASKED ME THINGS LIKE DEFINE AMERICA. TELL ME HOW CAN YOU DEFINE AMERICA? WHAT’S AMERICA? AND I WAS ON A TIBETAN PLATEAU WITH AT THE TIME WITH XI ZIN PING AND WE HAD AN INTERPRETER CAN I DEFINE AMERICA FOR HIM? I SAID YES, I CAN. IN ONE WORD. POSSIBILITIES. POSSIBILITIES. I THINK IT’S ONE OF THE REASONS WHY WE’VE OCCASIONALLY BEEN REFERRED TO AS UGLY AMERICANS. WE THINK ANYTHING’S POSSIBLE GIVEN THE CHANCE, WE CAN DO ANYTHING. AND THAT’S PART OF I THINK THE AMERICAN SPIRIT. AND WHAT THE PEOPLE ON THIS STAGE AND THE DEPARTMENTS THEY WILL LEAD REPRESENT ENORMOUS POSSIBILITIES. THEY’RE THE ONES ASKING THE MOST AMERICAN OF QUESTIONS, WHAT NEXT? WHAT NEXT? NEVER SATISFIED, WHAT’S NEXT? AND WHAT’S NEXT IS BIG AND BREATHTAKING. HOW CAN — HOW CAN WE MAKE THE IMPOSSIBLE POSSIBLE? AND THEY WERE JUST ASKING QUESTIONS FOR THE SAKE OF QUESTIONS, THEY’RE ASKING THESE QUESTIONS AS CALL TO ACTION. , TO INSPIRE, TO HELP US IMAGINE THE FUTURE AND FIGURE OUT HOW TO MAKE IT REAL AND IMPROVE THE LIVES OF THE AMERICAN PEOPLE AND PEOPLE AROUND THE WORLD. THIS IS A TEAM THAT ASKED US TO IMAGINE EVERY HOME IN AMERICA BEING POWERED BY RENEWABLE ENERGY WITHIN THE NEXT 10 YEARS. OR 3-D IMAGE PRINTERS RESTORING TISSUE AFTER TRAUMATIC INJURIES AND HOSPITALS PRINTING ORGANS FOR ORGAN TRANSPLANTS. IMAGINE, IMAGINE. AND THEY REALLY — AND, YOU KNOW, THEN RALLY, THE SCIENTIFIC COMMUNITY TO GO ABOUT DOING WHAT WE’RE IMAGINING. YOU NEED SCIENCE, DATA AND DISCOVERY WAS A GOVERNING PHILOSOPHY IN THE OBAMA-BIDEN ADMINISTRATION. AND EVERYTHING FROM THE ECONOMY TO THE ENVIRONMENT TO CRIMINAL JUSTICE REFORM AND TO NATIONAL SECURITY. AND ON HEALTH CARE. FOR EXAMPLE, A BELIEF IN SCIENCE LED OUR EFFORTS TO MAP THE HUMAN BRAIN AND TO DEVELOP MORE PRECISE INDIVIDUALIZED MEDICINES. IT LED TO OUR ONGOING MISSION TO END CANCER AS WE KNOW IT, SOMETHING THAT IS DEEPLY PERSONAL TO BOTH MY FAMILY AND KAMALA’S FAMILY AND COUNTLESS FAMILIES IN AMERICA. WHEN PRESIDENT OBAMA ASKED ME TO LEAD THE CANCER MOON SHOT, I KNEW WE HAD TO INJECT A SENSE OF URGENCY INTO THE FIGHT. WE BELIEVED WE COULD DOUBLE THE RATE OF PROGRESS AND DO IN FIVE YEARS WHAT OTHERWISE WOULD TAKE 10. MY WIFE, JILL, AND I TRAVELED AROUND THE COUNTRY AND THE WORLD MEETING WITH THOUSANDS OF CANCER PATIENTS AND THEIR FAMILIES, PHYSICIANS, RESEARCHERS, PHILANTHROPISTS, TECHNOLOGY LEADERS AND HEADS OF STATE. WE SOUGHT TO BETTER UNDERSTAND AND BREAK DOWN THE SILOS AND STOVE PIPES THAT PREVENT THE SHARING OF INFORMATION AND IMPEDE ADVANCES IN CANCER RESEARCH AND TREATMENT WHILE BUILDING A FOCUSED AND COORDINATED EFFORT HERE AT HOME AND ABROAD. WE MADE PROGRESS. BUT THERE’S SO MUCH MORE THAT WE CAN DO. WHEN I ANNOUNCED THAT I WOULD NOT RUN IN 2015 AT THE TIME, I SAID I ONLY HAD ONE REGRET IN THE ROSE GARDEN AND IF I HAD ANY REGRETS THAT I HAD WON, THAT I WOULDN’T GET TO BE THE PRESIDENT TO PRESIDE OVER CANCER AS WE KNOW IT. WELL, AS GOD WILLING, AND ON THE 20TH OF THIS MONTH IN A COUPLE OF DAYS AS PRESIDENT I’M GOING TO DO EVERYTHING I CAN TO GET THAT DONE. I’M GOING TO — GOING TO BE A PRIORITY FOR ME AND FOR KAMALA AND IT’S A SIGNATURE ISSUE FOR JILL AS FIRST LADY. WE KNOW THE SCIENCE IS DISCOVERY AND NOT FICTION. AND IT’S ALSO ABOUT HOPE. AND THAT’S AMERICA. IT’S IN THE D.N.A. OF THIS COUNTRY, HOPE. WE’RE ON THE CUSP OF SOME OF THE MOST REMARKABLE BREAKTHROUGHS THAT WILL FUNDAMENTALLY CHANGE THE WAY OF LIFE FOR ALL LIFE ON THIS PLANET. WE CAN MAKE MORE PROGRESS IN THE NEXT 10 YEARS, I PREDICT, THAN WE’VE MADE IN THE LAST 50 YEARS. AND EXPONENTIAL MOVEMENT. WE CAN ALSO FACE SOME OF THE MOST DIRE CRISES IN A GENERATION WHERE SCIENCE IS CRITICAL TO WHETHER OR NOT WE MEET THE MOMENT OF PERIL AND PROMISE THAT WE KNOW IS WITHIN OUR REACH. IN 1944, FRANKLIN ROOSEVELT ASKED HIS SCIENCE ADVISOR HOW COULD THE UNITED STATES FURTHER ADVANCE SCIENTIFIC RESEARCH IN THE CRITICAL YEARS FOLLOWING THE SECOND WORLD WAR? THE RESPONSE LED TO SOME OF THE MOST GROUND BREAKING DISCOVERIES IN THE LAST 75 YEARS. AND WE CAN DO THAT AGAIN. AND WE CAN DO MORE. SO TODAY, I’M PROUD TO ANNOUNCE A TEAM OF SOME OF THE COUNTRY’S MOST BRILLIANT AND ACCOMPLISHED SCIENTISTS TO LEAD THE WAY. AND I’M ASKING THEM TO FOCUS ON FIVE KEY AREAS. FIRST THE PANDEMIC AND WHAT WE CAN LEARN ABOUT WHAT IS POSSIBLE OR WHAT SHOULD BE POSSIBLE TO ADDRESS THE WIDEST RANGE OF PUBLIC HEALTH NEEDS. SECONDLY, THE ECONOMY, HOW CAN WE BUILD BACK BETTER TO ENSURE PROSPERITY IS FULLY SHARED ALL ACROSS AMERICA? AMONG ALL AMERICANS? AND THIRDLY, HOW SCIENCE HELPS US CONFRONT THIS CLIMATE CRISIS WE FACE IN AMERICA AND THE WORLD BUT IN AMERICA HOW IT HELPS US CONFRONT THE CLIMATE CRISIS WITH AMERICAN JOBS AND INGENUITY. AND FOURTH, HOW CAN WE ENSURE THE UNITED STATES LEADS THE WORLD IN TECHNOLOGIES AND THE INDUSTRIES THAT THE FUTURE THAT WILL BE CRITICAL FOR OUR ECONOMIC PROSPERITY AND NATIONAL SECURITY? ESPECIALLY WITH THE INTENSE INCREASED COMPETITION AROUND THE WORLD FROM CHINA ON? AND FIFTH, HOW CAN WE ASSURE THE LONG-TERM HEALTH AND TRUST IN SCIENCE AND TECHNOLOGY IN OUR NATION? YOU KNOW, THESE ARE EACH QUESTIONS THAT CALL FOR ACTION. AND I’M HONORED TO ANNOUNCE A TEAM THAT IS ANSWERING THE CALL TO SERVE. AS THE PRESIDENTIAL SCIENCE ADVISOR AND DIRECTOR OF THE OFFICE OF SCIENCE AND TECHNOLOGY POLICY, I NOMINATE ONE OF THE MOST BRILLIANT GUYS I KNOW, PERSONS I KNOW, DR. ERIC LANDER. AND THANK YOU, DOC, FOR COMING BACK. THE PIONEER — HE’S A PIONEER IN THE STIFFING COMMUNITY. PRINCIPAL LEADER IN THE HUMAN GENOME PROJECT. AND NOT HYPERBOLE TO SUGGEST THAT DR. LANDER’S WORK HAS CHANGED THE COURSE OF HUMAN HISTORY. HIS ROLE IN HELPING US MAP THE GENOME PULLED BACK THE CURTAIN ON HUMAN DISEASE, ALLOWING SCIENTISTS, EVER SINCE, AND FOR GENERATIONS TO COME TO EXPLORE THE MOLECULAR BASIS FOR SOME OF THE MOST DEVASTATING ILLNESSES AFFECTING OUR WORLD. AND THE APPLICATION OF HIS PIONEERING WORK AS — ARE POISED TO LEAD TO INCREDIBLE CURES AND BREAKTHROUGHS IN THE YEARS TO COME. DR. LANDER NOW SERVES AS THE PRESIDENT AND FOUNDING DIRECTOR OF THE BRODE INSTITUTE AT M.I.T. AND HARVARD, THE WORLD’S FOREMOST NONPROFIT GENETIC RESEARCH ORGANIZATION. AND I CAME TO APPRECIATE DR. LANDER’S EXTRAORDINARY MIND WHEN HE SERVED AS THE CO-CHAIR OF THE PRESIDENT’S COUNCIL ON ADVISORS AND SCIENCE AND TECHNOLOGY DURING THE OBAMA-BIDEN ADMINISTRATION. AND I’M GRATEFUL, I’M GRATEFUL THAT WE CAN WORK TOGETHER AGAIN. I’VE ALWAYS SAID THAT BIDEN-HARRIS ADMINISTRATION WILL ALSO LEAD AND WE’RE GOING TO LEAD WITH SCIENCE AND TRUTH. WE BELIEVE IN BOTH. [LAUGHTER] GOD WILLING OVERCOME THE PANDEMIC AND BUILD OUR COUNTRY BETTER THAN IT WAS BEFORE. AND THAT’S WHY FOR THE FIRST TIME IN HISTORY, I’M GOING TO BE ELEVATING THE PRESIDENTIAL SCIENCE ADVISOR TO A CABINET RANK BECAUSE WE THINK IT’S THAT IMPORTANT. AS DEPUTY DIRECTOR OF THE OFFICE OF SCIENCE AND TECHNOLOGY POLICY AND SCIENCE AND — SCIENCE AND SOCIETY, I APPOINT DR. NELSON. SHE’S A PROFESSOR AT THE INSTITUTE OF ADVANCED STUDIES AT PRINCETON UNIVERSITY. THE PRESIDENT OF THE SOCIAL SCIENCE RESEARCH COUNCIL. AND ONE OF AMERICA’S LEADING SCHOLARS IN THE — AN AWARD-WINNING AUTHOR AND RESEARCHER AND EXPLORING THE CONNECTIONS BETWEEN SCIENCE AND OUR SOCIETY. THE DAUGHTER OF A MILITARY FAMILY, HER DAD SERVED IN THE UNITED STATES NAVY AND HER MOM WAS AN ARMY CRIPPING TO RAFFER. DR. NELSON DEVELOPED A LOVE OF TECHNOLOGY AT A VERY YOUNG AGE PARTICULARLY WITH THE EARLY COMPUTER PRODUCTS. COMPUTING PRODUCTS AND CODE-BREAKING EQUIPMENT THAT EVERY KID HAS AROUND THEIR HOUSE. AND SHE GREW UP WITHIN HER HOME. WHEN I WROTE THAT DOWN, I THOUGHT TO MYSELF, I MEAN, HOW MANY KIDS — ANY WAY, THAT PASSION WAS A PASSION FORGED A LIFELONG CURIOSITY ABOUT THE INEQUITIES AND THE POWER DIAMONDICS THAT SIT BENEATH THE SURFACE OF SCIENTIFIC RESEARCH AND THE TECHNOLOGY WE BUILD. DR. NELSON IS FOCUSED ON THOSE INSIGHTS. AND THE SCIENCE, TECHNOLOGY AND SOCIETY, LIKE FEW BEFORE HER EVER HAVE IN AMERICAN HISTORY. BREAKING NEW GROUND ON OUR UNDERSTANDING OF THE ROLE SCIENCE PLAYS IN AMERICAN LIFE AND OPENING THE DOOR TO — TO A FUTURE WHICH SCIENCE BETTER SERVES ALL PEOPLE. AS CO-CHAIR OF THE PRESIDENT’S COUNCIL ON ADVISORS OF SCIENCE AND TECHNOLOGY, I APPOINT DR. FRANCIS ARNOLD, DIRECTOR OF THE ROSE BIOENGINEERING CENTER AT CALTECH AND ONE OF THE WORLD’S LEADING EXPERTS IN PROTEIN ENGINEERING, A LIFE-LONG CHAMPION OF RENEWABLE ENERGY SOLUTIONS WHO HAS BEEN INDUCTED INTO THE NATIONAL INVENTORS’ HALL OF FAME. THAT AIN’T A BAD PLACE TO BE. NOT ONLY IS SHE THE FIRST WOMAN TO BE ELECTED TO ALL THREE NATIONAL ACADEMIES OF SCIENCE, MEDICINE AND ENGINEERING AND ALSO THE FIRST WOMAN, AMERICAN WOMAN, TO WIN A NOBEL PRIZE IN CHEMISTRY. A VERY SLOW LEARNER, SLOW STARTER, THE DAUGHTER OF PITTSBURGH, SHE WORKED AS A CAB DRIVER, A JAZZ CLUB SERVER, BEFORE MAKING HER WAY TO BERKELEY AND A CAREER ON THE LEADING EDGE OF HUMAN DISCOVERY. AND I WANT TO MAKE THAT POINT AGAIN. I WANT — IF ANY OF YOUR CHILDREN ARE WATCHING, LET THEM KNOW YOU CAN DO ANYTHING. THIS COUNTRY CAN DO ANYTHING. ANYTHING AT ALL. AND SO SHE SURVIVED BREAST CANCER, OVERCAME A TRAGIC LOSS IN HER FAMILY WHILE RISING TO THE TOP OF HER FIELD, STILL OVERWHELMINGLY DOMINATED BY MEN. HER PASSION HAS BEEN A STEADFAST COMMITMENT TO RENEWABLE ENERGY FOR THE BETTERMENT OF OUR PLANET AND HUMANKIND. SHE IS AN INSPIRING FIGURE TO SCIENTISTS ACROSS THE FIELD AND ACROSS NATIONS. AND I WANT TO THANK DR. ARNOLD FOR AGREEING TO CO-CHAIR A FIRST ALL WOMAN TEAM TO LEAD THE PRESIDENT’S COUNCIL OF ADVISORS ON SCIENCE AND TECHNOLOGY WHICH LEADS ME TO THE NEXT MEMBER OF THE TEAM. AS CO-CHAIR, THE PRESIDENT’S COUNCIL OF ADVISORS ON SCIENCE AND TECHNOLOGY, I APPOINT DR. MARIE ZUBER. A TRAIL BLAZER BRAISING GEO PHYSICIST AND PLANETARY SCIENTIST A. FORMER CHAIR OF THE NATIONAL SCIENCE BOARD. FIRST WOMAN TO LEAD THE SCIENCE DEPARTMENT AT M.I.T. AND THE FIRST WOMAN TO LEAD NASA’S ROBOTIC PLANETARY MISSION. GROWING UP IN COLE COUNTRY NOT FAR FROM HEAVEN, SCRANTON, PENNSYLVANIA, IN CARBON COUNTY, PENNSYLVANIA, ABOUT 50 MILES SOUTH OF WHERE I WAS A KID, SHE DREAMED OF EXPLORING OUTER SPACE. COULD HAVE TOLD HER SHE WOULD JUST GO TO GREEN REACH IN SCRANTON AND FIND WHERE IT WAS. AND I SHOULDN’T BE SO FLIPPANT. BUT I’M SO EXCITED ABOUT THESE FOLKS. YOU KNOW, READING EVERY BOOK SHE COULD FIND AND LISTENING TO HER MOM’S STORIES ABOUT WATCHING THE EARLIEST ROCKET LAUNCH ON TELEVISION, MARIE BECAME THE FIRST PERSON IN HER FAMILY TO GO TO COLLEGE AND NEVER LET GO OF HER DREAM. TODAY SHE OVERSEES THE LINCOLN LABORATORY AT M.I.T. AND LEADS THE INSTITUTION’S CLIMATE ACTION PLAN. GROWING UP IN COLD COUNTRY, NOT AND FINALLY, COULD NOT BE HERE TODAY, BUT I’M PLEASED TO ANNOUNCE THAT I’VE HAD A LONG CONVERSATION WITH DR. FRANCIS COLLINS AND COULD NOT BE HERE TODAY. AND I’VE ASKED THEM TO STAY ON AS DIRECTOR OF THE INSTITUTE OF HEALTH AND — AT THIS CRITICAL MOMENT. I’VE KNOWN DR. COLLINS FOR MANY YEARS. I WORKED WITH HIM CLOSELY. HE’S BRILLIANT. A PIONEER. A TRUE LEADER. AND ABOVE ALL, HE’S A MODEL OF PUBLIC SERVICE AND I’M HONORED TO BE WORKING WITH HIM AGAIN. AND IT IS — IN HIS ABSENCE I WANT TO THANK HIM AGAIN FOR BEING WILLING TO STAY ON. I KNOW THAT WASN’T HIS ORIGINAL PLAN. BUT WE WORKED AN AWFUL LOT ON THE MOON SHOT AND DEALING WITH CANCER AND I JUST WANT TO THANK HIM AGAIN. AND TO EACH OF YOU AND YOUR FAMILIES, AND I SAY YOUR FAMILIES, THANK YOU FOR THE WILLINGNESS TO SERVE. AND NOT THAT YOU HAVEN’T BEEN SERVING ALREADY BUT TO SERVE IN THE ADMINISTRATION. AND THE AMERICAN PEOPLE, TO ALL THE AMERICAN PEOPLE, THIS IS A TEAM THAT’S GOING TO HELP RESTORE YOUR FAITH IN AMERICA’S PLACE IN THE FRONTIER OF SCIENCE AND DISCOVER AND HOPE. I’M NOW GOING TO TURN THIS OVER STARTING WITH DR. LANDER, TO EACH OF OUR NOMINEES AND THEN WITH — HEAR FROM THE VICE PRESIDENT. BUT AGAIN, JUST CAN’T THANK YOU ENOUGH AND I REALLY MEAN IT. THANK YOU, THANK YOU, THANK YOU FOR WILLING TO DO THIS. DOCTOR, IT’S ALL YOURS. I BETTER PUT MY MASK ON OR I’M GOING TO GET IN TROUBLE.

 

Director’s Page

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The world’s most innovative intersection

Posted in BioIT: BioInformatics, NGS, Clinical & Translational, Pharmaceutical R&D Informatics, Clinical Genomics, Cancer Informatics, tagged gene biology, gene sequencing, genetics, genomics, Harvard, MIT on January 2, 2016| Leave a Comment »

The world’s most innovative intersection

Reported by: Irina Robu

The world’s most innovative crossroads in history is the intersection of

Vassar Street and Main Street, in the new world’s Cambridge, Massachusetts, would be a leading candidate.

According to the article published in Wired Magazine in November 2015 “when the Whitehead got too small for genomicist Eric Lander’s ambitions, he launched a flashier and brasher newcomer next door. The Broad Institute’s gargantuan gleaming glass lobby is filled with early gene-sequencing instruments. Its multimedia screens boast that this is one of the world’s largest gene-sequencing and research factories. The Broad’s strategy is different from that of the Whitehead; instead of concentrating a few in an ultra-exclusive bioclub, Broad bridges MIT, Harvard and most of the hospitals in Boston. Its 2,000 members extend outwards, partnering with tens of thousands of others globally. Those working at the Broad are not averse to commerce; its director alone helped to build Foundation Medicine, Verastem, Millennium, Fidelity Biosciences, Courtagen and Aclara among many other leading companies.

The sixth building on this extraordinary corner, Novartis, focuses on private research, and represents a huge migration from Basel in Switzerland towards the MIT campus, becoming Cambridge’s largest employer. Pfizer, Sanofi, Amgen, Biogen-Idec and hundreds of others cluster nearby. “

Attracting the best and the brightest, one can change not just a city but the world.

 

Source

http://www.wired.co.uk/magazine/archive/2015/11/ideas-bank/vassar-main-cambridge-massachusetts-innovaton

 

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CRISPR/Cas9 Finds Its Way As an Important Tool For Drug Discovery & Development

Posted in Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Cell Biology, Signaling & Cell Circuits, Conference Coverage with Social Media, CRISPR/Cas9 & Gene Editing, Disease Biology, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Drug Delivery Platform Technology, Drug Toxicity, Gene Regulation, Gene Regulation and Evolution, Genetics & Innovations in Treatment, Genetics & Pharmaceutical, Metabolism, Metabolomics, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Drug Discovery, Pharmacodynamics and Pharmacokinetics, Pharmacogenomics, Signaling & Cell Circuits, Small Molecules in Development of Therapeutic Drugs, tagged anti-cancer drugs, Cancer - General, CRISPR-Cas9, Duodna, FDA, gene editing, gene expression, genetics, genome, Genome engineering, health, MIT, mouse model, research, science, tumor model on September 2, 2015| Leave a Comment »

CRISPR/Cas9 Finds Its Way As an Important Tool For Drug Discovery & Development

  UPDATED 6/11/2021

CRISPR Diagnostics: CRISPR-dx Comes of Age: Tool in Drug Development

The past five years has seen a rapid expansion of the ability of CRISPR based tools toward diagnostic testing. Recently, CRISPR has been used to detect SARS-CoV-2 in patients. An article in the journal Science describes the different classes of CRISPR diagnostics in use today .

Update near end of post

UPDATED 8/08/2020

Association to Causation: Using GWAS to Identify Druggable Targets

A Gen Webinar Thursday, August 6, 2020; 11:00am – 12:30pm EST

See at end of post

Curator: Stephen J. Williams, Ph.D.

• 

 

CRISPR/Cas9 Finds Its Way As an Important Tool For Drug Discovery & Development, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 2: CRISPR for Gene Editing and DNA Repair

The RNA-guided Cas9 nuclease from the microbial clustered regularly interspaced short palindromic repeats (CRISPR) adaptive immune system can be used to facilitate efficient genome engineering in eukaryotic cells by simply specifying a 20-nt targeting sequence within its guide RNA.

CRISPR/Cas systems are part of the adaptive immune system of bacteria and archaea, protecting them against invading nucleic acids such as viruses by cleaving the foreign DNA in a sequence-dependent manner. Although CRISPR arrays were first identified in the Escherichia coli genome in 1987 (Ishino et al., 1987), their biological function was not understood until 2005, when it was shown that the spacers were homologous to viral and plasmid sequences suggesting a role in adaptive immunity (Bolotin et al., 2005; Mojica et al., 2005; Pourcel et al., 2005). Two years later, CRISPR arrays were confirmed to provide protection against invading viruses when combined with Cas genes (Barrangou et al., 2007). The mechanism of this immune system based on RNA-mediated DNA targeting was demonstrated shortly thereafter (Brouns et al., 2008; Deltcheva et al., 2011; Garneau et al., 2010; Marraffini and Sontheimer, 2008).

Jennifer Doudna, PhD Professor of Molecular and Cell Biology and Chemistry, University of California, Berkeley Investigator, Howard Hughes Medical Institute has recently received numerous awards and accolades for the discovery of CRISPR/Cas9 as a tool for mammalian genetic manipulation as well as her primary intended research target to understand bacterial resistance to viral infection.

A good post on the matter and Dr. Doudna can be seen below:

http://pharmaceuticalintelligence.com/2014/06/13/215-245-6132014-jennifer-doudna-the-biology-of-crisprs-from-genome-defense-to-genetic-engineering/

In Delineating a Role for CRISPR-Cas9 in Pharmaceutical Targeting inheritable metabolic disorders in which may benefit from a CRISPR-Cas9 mediated therapy is discussed. However this curation is meant to focus on CRISPR/CAS9 AS A TOOL IN PRECLINICAL DRUG DEVELOPMENT.

 

Three Areas of Importance of CRISPR/Cas9 as a TOOL in Preclinical Drug Discovery Include:

1. Gene-Function Studies: CRISPR/CAS9 ability to DEFINE GENETIC LESION and INSERTION SITE
2. CRISPR/CAS9 Use in Developing Models of Disease
3. CRISPR/CAS9 Use as a Diagnostic Tool

• Using CRISPR/Cas9 in PRECLINICAL TOXICOLOGY STUDIES

I.     Gene-Function Studies: CRISPR/CAS9 ability to DEFINE GENETIC LESION and INSERTION SITE

The advent of the first tools for manipulating genetic material (cloning, PCR, transgenic technology, and before microarray and other’omic methods) allowed scientists to probe novel, individual gene functions as well as their variants and mutants in a “one-gene-at-a time” process. In essence, a gene (or mutant gene) was sequenced, cloned into expression vectors and transfected into recipient cells where function was evaluated.

However, some of the experimental issues with this methodology involved

• Lack of knowledge of insertion site of the transgene – this leads to off-target effects usually due to insertion of a transgene in front of unwanted promoters or insertion at a site resulting in gene disruption or even mutagenesis. In an extreme case, such as transposon-induced mutagenesis may lead to transformation as described in an earlier post on this site How Mobile Elements in “Junk” DNA Promote Cancer – Part 1: Transposon-mediated Tumorigenesis

• Most transfections experiments result in NON ISOGENIC cell lines – by definition the insertion of a transgene alters the genetic makeup of a cell line. Simple transfection experiments with one transgene compared to a “null” transfectant compares non-isogenic lines, possibly confusing the interpretation of gene-function studies. Therefore a common technique is to develop cell lines with inducible gene expression, thereby allowing the investigator to compare a gene’s effect in ISOGENIC cell lines.

1. Use of CRSPR in Highthrough-put Screening of Genetic Function

A very nice presentation and summary of CRSPR’s use in determining gene function in a high-throughput manner can be found below

www.rna.uzh.ch/events/journalclub/20140429JCCaihong.pdf

1. Determining Off-target Effects of Gene Therapy Simplified with CRSPR

In GUIDE-seq: First genome-wide method of detecting off-target DNA breaks induced by CRISPR-Cas nucleases (from This Journal’s series on Live Meeting Coverage) at a 2014 Koch lecture

Shengdar Q Tsai and J Keith Joung describe

“

an approach for global detection of DNA double-stranded breaks (DSBs) introduced by RGNs and potentially other nucleases. This method, called genome-wide, unbiased identification of DSBs enabled by sequencing (GUIDE-seq), relies on capture of double-stranded oligodeoxynucleotides into DSBs. Application of GUIDE-seq to 13 RGNs in two human cell lines revealed wide variability in RGN off-target activities and unappreciated characteristics of off-target sequences. The majority of identified sites were not detected by existing computational methods or chromatin immunoprecipitation sequencing (ChIP-seq). GUIDE-seq also identified RGN-independent genomic breakpoint ‘hotspots’.

SOURCE http://www.nature.com/nbt/journal/vaop/ncurrent/full/nbt.3117.html

“

II. CRISPR/Cas9 Use in Developing Models of Disease

 

1. Developing Animal Tumor Models

In a post this year I discussed a talk at the recent 2015 AACR National Meeting on a laboratories ability to use CRISPR gene editing in-vivo to produce a hepatocarcinoma using viral delivery. The post can be seen here: Notes from Opening Plenary Session – The Genome and Beyond from the 2015 AACR Meeting in Philadelphia PA; Sunday April 19, 2015

1) In this talk Dr. Tyler Jacks discussed his use of CRSPR to generate a mouse model of liver tumor in an immunocompetent mouse. Some notes from this talk are given below

1. B) Engineering Cancer Genomes: Tyler Jacks, Ph.D.; Director, Koch Institute for Integrative Cancer Research

• Cancer GEM’s (genetically engineered mouse models of cancer) had moved from transgenics to defined oncogenes
• Observation that p53 -/- mice develop spontaneous tumors (lymphomas)
• then GEMs moved to Cre/Lox systems to generate mice with deletions however these tumor models require lots of animals, much time to create, expensive to keep;
• figured can use CRSPR/Cas9 as rapid, inexpensive way to generate engineered mice and tumor models
• he used CRSPR/Cas9 vectors targeting PTEN to introduce PTEN mutations in-vivo to hepatocytes; when they also introduced p53 mutations produced hemangiosarcomas; took ONLY THREE months to produce detectable tumors
• also produced liver tumors by using CRSPR/Cas9 to introduce gain of function mutation in β-catenin

See an article describing this study by MIT News “A New Way To Model Cancer: New gene-editing technique allows scientists to more rapidly study the role of mutations in tumor development.”

The original research article can be found in the August 6, 2014 issue of Nature[1]

And see also on the Jacks Lab site under Research

2)     In the Upcoming Meeting New Frontiers in Gene Editing multiple uses of CRISPR technology is discussed in relation to gene knockout/function studies, tumor model development and

New Frontiers in Gene Editing

Session Spotlight:
BUILDING IN VIVO MODELS FOR DRUG DISCOVERY

Genome Editing Animal Models in Drug Discovery
Myung Shin, Ph.D., Senior Principal Scientist, Biology-Discovery, Genetics and Pharmacogenomics, Merck Research Laboratories

Recent advances in genome editing have greatly accelerated and expanded the ability to generate animal models. These tools allow generating mouse models in condensed timeline compared to that of conventional gene-targeting knock-out/knock-in strategies. Moreover, the genome editing methods have expanded the ability to generate animal models beyond mice. In this talk, we will discuss the application of ZFN and CRISPR to generate various animal models for drug discovery programs.

In vivo Cancer Modeling and Genetic Screening Using CRISPR/Cas9
Sidi Chen, Ph.D., Postdoctoral Fellow, Laboratories of Dr. Phillip A. Sharp and Dr. Feng Zhang, Koch Institute for Integrative Cancer Research at MIT and Broad Institute of Harvard and MIT

Here we describe a genome-wide CRISPR-Cas9-mediated loss-of-function screen in tumor growth and metastasis. We mutagenized a non-metastatic mouse cancer cell line using a genome-scale library. The mutant cell pool rapidly generates metastases when transplanted into immunocompromised mice. Enriched sgRNAs in lung metastases and late stage primary tumors were found to target a small set of genes, suggesting specific loss-of-function mutations drive tumor growth and metastasis.

FEATURED PRESENTATION: In vivo Chromosome Engineering Using CRISPR-Cas9
Andrea Ventura, M.D., Ph.D., Assistant Member, Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center

We will discuss our experience using somatic genome editing to engineer oncogenic chromosomal rearrangements in vivo. More specifically, we will present the results of our ongoing efforts aimed at modeling cancers driven by chromosomal rearrangements using viral mediated delivery of Crispr-Cas9 to adult animals.

RNAi and CRISPR/Cas9-Based in vivo Models for Drug Discovery
Christof Fellmann, Ph.D., Postdoctoral Fellow, Laboratory of Dr. Jennifer Doudna, Department of Molecular and Cell Biology, The University of California, Berkeley

Genetically engineered mouse models (GEMMs) are a powerful tool to study disease initiation, treatment response and relapse. By combining CRISPR/Cas9 and “Sensor” validated, tetracycline-regulated “miR-E” shRNA technology, we have developed a fast and scalable platform to generate RNAi GEMMs with reversible gene silencing capability. The synergy of CRISPR/Cas9 and RNAi enabled us to not only model disease pathogenesis, but also mimic drug therapy in mice, providing us capability to perform preclinical studies in vivo.

In vivo Genome Editing Using Staphylococcus aureus Cas9
Fei Ann Ran, Ph.D., Post-doctoral Fellow, Laboratory of Dr. Feng Zhang, Broad Institute and Junior Fellow, Harvard Society of Fellows

The RNA-guided Cas9 nuclease from the bacterial CRISPR/Cas system has been adapted as a powerful tool for facilitating targeted genome editing in eukaryotes. Recently, we have identified an additional small Cas9 nuclease from Staphylococcus aureus that can be packaged with its guide RNA into a single adeno-associated virus (AAV) vector for in vivo applications. We demonstrate the use of this system for effective gene modification in adult animals and further expand the Cas9 toolbox for in vivo genome editing.

OriGene, Making the Right Tools for CRISPR Research
Xuan Liu, Ph.D., Senior Director, Marketing, OriGene

CRISPR technology has quickly revolutionized the scientific community. Its simplicity has democratized the genome editing technology and enabled every lab to consider its utility in gene function research. As the largest tool box for gene functional research, OriGene created a large collection of CRISPR-related tools, including various all-in-one vectors for gRNA cloning, donor vector backbones, genome-wide knockout kits, AAVS1 insertion vectors, etc. OriGene’s high quality products will accelerate CRISPR research.

1. Transgenic Animals : Custom Mouse and Rat Model Generation Service Using CRISPR/Cas9 by AppliedStem Cell Inc. (http://www.appliedstemcell.com/)

A critical component of producing transgenic animals is the ability of each successive generations to pass on the transgene. In her post on this site, A NEW ERA OF GENETIC MANIPULATION  Dr. Demet Sag discusses the molecular biology of Cas9 systems and their efficiency to cause point mutations which can be passed on to subsequent generations

“

This group developed a new technology for editing genes that can be transferable change to the next generation by combining microbial immune defense mechanism, CRISPR/Cas9 that is the latest ground breaking technology for translational genomics with gene therapy-like approach.

• In short, this so-called “mutagenic chain reaction” (MCR) introduces a recessive mutation defined by CRISPR/Cas9 that lead into a high rate of transferable information to the next generation. They reported that when they crossed the female MCR offspring to wild type flies, the yellow phenotype observed more than 95 percent efficiency.

“

The advantage of CRISPR/Cas9 over ZFNs or TALENs is its scalability and multiplexibility in that multiple sites within the mammalian genome can be simultaneously modified, providing a robust, high-throughput approach for gene editing in mammalian cells.

Applied StemCell, Inc. offers various services related to animal models including conventional transgenic rats, and phenotype analysis using knock-in, knock-out strategies.

Further explanation of their use of CRSPR can be found at the site below:

http://pharmaceuticalintelligence.com/2014/10/29/gene-editing-at-crispr-speed-services-and-tools/

In addition, ReproCELL Inc., a Tokyo based stem cell company, uses CRSPR to develop

· Tailored disease model cells (hiPSC-Disease Model Cells)

• 2 types of services

• ReproUNUS™-g：human iPS cell derived functional cells involving gene editing by CRISPR/Cas9 system
• eproUNUS™-p：patient derived iPS cell derived functional cells

III. Using CRISPR/Cas9 in PRECLINICAL TOXICOLOGY STUDIES

As of now it is unclear as to the strategy of pharma in how to use this technology for toxicology testing however a few companies have licensed the technology to use across their R&D platforms including

• AstraZeneca
• Thermo
• Novartis
• GE Healthcare

A recent paper used a sister technique TALEN to generate knock-in pigs which suggest that it would be possible to generate pigs with human transgenes, especially in human liver isozymes in orer to study hepatotoxicity of drugs.

Efficient bi-allelic gene knockout and site-specific knock-in mediated by TALENs in pigs

Jing Yao, Jiaojiao Huang, Tang Hai, Xianlong Wang, Guosong Qin, Hongyong Zhang, Rong Wu, Chunwei Cao, Jianzhong Jeff Xi, Zengqiang Yuan, Jianguo Zhao

Sci Rep. 2014; 4: 6926. Published online 2014 November 5. doi: 10.1038/srep06926

UPDATED 8/08/2020

Association to Causation: Using GWAS to Identify Druggable Targets

A Gen Webinar Thursday, August 6⋅11:00am – 12:30pm

This webinar is available at https://www.genengnews.com/resources/webinars/association-to-causation-using-gwas-to-identify-druggable-target/

Speakers:

Martin Kampmann, PhD

Associate Professor
UCSF
Investigator
Chan Zuckerberg Biohub

Kevin Holden, PhD

Head of Science
Synthego

Abhi Saharia, PhD

VP, Commercial Development
Synthego

Human genetics provides perhaps the single best opportunity to innovate and improve clinical success rates, through the identification of novel drug targets for complex disease. Even as correlation identifies multiple genetic variants associated with disease, it is challenging to conduct requisite functional studies to identify the causal variants, especially since most association signals map to non-coding regions of the genome.

Genetic editing technologies, such as CRISPR, have enabled the modeling of associated variants at their native loci, including non-coding loci, empowering the identification of underlying biological mechanisms of disease with potential causal genes. However, genome editing is largely manual today severely limiting scale, and forcing the use of rational filters to prioritize which variants to investigate functionally.

In this GEN webinar, we will discuss several strategies enabling large-scale functional investigation of disease-associated variants in a cost- and time-effective manner, including different types of pooled CRISPR-based screens and the development of a fully automated genome engineering platform. We will also review how optimization of genome engineering on this platform enables the engineering of disease-associated variants at scale in pluripotent cells.

• They will be presenting on use of wide scale CRSPR screens to validate druggable targets
• The presenters will also discuss new platforms for these wide scale screens

Martin Kampmann, PhD UCSF

• Multiple genetic variants associated with disease
• Big gap between accumulation of genetic variant information and functions of these variants
• CRSPRi or CRSPa (siRNA coupled or enhancer coupled CRSPR guides)
• Arrayed screens: multiplate guide RNAs and phenotype measured (phenotype can be morphology, complex biological systems like organoids or non autonomous functions
• Using pooled screens and use of suitable cell model critical for this strategy
• For example in iPSC vs. neurons has different expression patterns upon same CRSPR of UBA1
• Advantage is using CRSPR to take iPSC from diseased variant patient to make a corrected isogenic control then introduce gRNAs and use modifier screens to determine phenotypes
• Generated a platform called CRISPRbrain.org to do bioinformatics on various experiments with different guide RNAs (CRSPRs)

Abhi Saharia, PhD Syntheco

• Target identification with CSRSPR at Scale
• Nature medicine paper did GWAS and found 27 SNV associated with high risk disease and a rational filter focused on 1 SNV in noncoding region but why study a single variant and if studied all 27 would they have been able to identify a more representative druggable set?
• Goal is to reduce or eliminate these rational filters
• HALO (scalable RNA guide), ECLIPSE platform (automated generation of modified cell lines, BIOINFORMATIC platform (integrated informatics)
• Syntheco uses an electroporation with ribonucleic proteins (RNP) to give highest efficiency and minimizes off target as complex is only in cells for a short period of time
• They confirm they are doing single cell cloning by using automated microscopy to confirm single cell growth in each cloning well

Kevin Holden, Head of Science at Syntheco

• Engineering iPSc genetically modified cells at scale
• The closer you get to your target site the more efficient your CRSPR so a big factor when making guides, especially for knock-in CRSPR
• Adding a small molecule non homologous end joining inhibitor increases efficiency to 95%
• Cold shocking the cells also assists in homologous repair
• Use cleavage resistant templates

III. CRISPR/CAS9 AS A DIAGNOSTIC TOOL

     In the journal Science, Omar Abudayyeh and Jonathan Gootenberg discuss how CRISPR-based diagnostic (CRISPR-dx) tools offer a solution, and multiple CRISPR-dx products for detection of the SARS-CoV-2 RNA genome have been authorized by the US Food and Drug Administration (FDA).  In addition they discuss the work by Jiao et al. in combining this technique to develop a rapid and sensitive SARS-CoV2 diagnostic test.

Omar O. Abudayyeh, Jonathan S. Gootenberg. Science  28 May 2021: CRISPR Diagnostics
Vol. 372, Issue 6545, pp. 914-915; DOI: 10.1126/science.abi9335

Summary

Although clinical diagnostics take many forms, nucleic acid–based testing has become the gold standard for sensitive detection of many diseases, including pathogenic infections. Quantitative polymerase chain reaction (qPCR) has been widely adopted for its ability to detect only a few DNA or RNA molecules that can unambiguously specify a particular disease. However, the complexity of this technique restricts application to laboratory settings. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has underscored the need for the development and deployment of nucleic acid tests that are economical, easily scaled, and capable of being run in low-resource settings, without sacrifices in speed, sensitivity or specificity. CRISPR-based diagnostic (CRISPR-dx) tools offer a solution, and multiple CRISPR-dx products for detection of the SARS-CoV-2 RNA genome have been authorized by the US Food and Drug Administration (FDA). On page 941 of this issue, Jiao et al. (1) describe a new CRISPR-based tool to distinguish several SARS-CoV-2 variants in a single reaction.

Although clinical diagnostics take many forms, nucleic acid–based testing has become the gold standard for sensitive detection of many diseases, including pathogenic infections. Quantitative polymerase chain reaction (qPCR) has been widely adopted for its ability to detect only a few DNA or RNA molecules that can unambiguously specify a particular disease. However, the complexity of this technique restricts application to laboratory settings. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has underscored the need for the development and deployment of nucleic acid tests that are economical, easily scaled, and capable of being run in low-resource settings, without sacrifices in speed, sensitivity or specificity. CRISPR-based diagnostic (CRISPR-dx) tools offer a solution, and multiple CRISPR-dx products for detection of the SARS-CoV-2 RNA genome have been authorized by the US Food and Drug Administration (FDA). On page 941 of this issue, Jiao et al. (1) describe a new CRISPR-based tool to distinguish several SARS-CoV-2 variants in a single reaction.

There are multiple types of CRISPR systems comprising basic components of a single protein or protein complex, which cuts a specific DNA or RNA target programmed by a complementary guide sequence in a CRISPR-associated RNA (crRNA). The type V and VI systems and the CRISPR-associated endonucleases Cas12 (2, 3) and Cas13 (4, 5) bind and cut DNA or RNA, respectively. Furthermore, upon recognizing a target DNA or RNA sequence, Cas12 and Cas13 proteins exhibit “collateral activity” whereby any DNA or RNA, respectively, in the sample is cleaved regardless of its nucleic acid sequence (4, 6). Thus, reporter DNAs or RNAs, which allow for visual or fluorescent detection upon cleavage, can be added to a sample to infer the presence or absence of specific DNA or RNA species (4–8).

Initial versions of CRISPR-dx utilizing Cas13 alone were sensitive to the low picomolar range, corresponding to a limit of detection of millions of molecules in a microliter sample. To improve sensitivity, preamplification methods, such as recombinase polymerase amplification (RPA), PCR, loop-mediated isothermal amplification (LAMP), or nucleic acid sequence–based amplification (NASBA), can be used with Cas12 or Cas13 to enable a limit of detection down to a single molecule (8). This preamplification approach, applicable to both Cas12 and Cas13 (6, 7), enabled a suite of detection methods and multiplexing up to four orthogonal targets (7). Additional developments expanded CRISPR-dx readouts beyond fluorescence, including lateral flow (7), colorimetric (9), and electronic or material responsive readouts (10), allowing for instrument-free approaches. In addition, post–collateral-cleavage amplification methods, such as the use of the CRISPR-associated enzyme Csm6, have been combined with Cas13 to further increase the speed of CRISPR-dx tests (7). As an alternative to collateral-cleavage–based detection, type III CRISPR systems, which involve large multiprotein complexes capable of targeting both DNA and RNA, have been used for SARS-CoV-2 detection through production of colorimetric or fluorometric readouts (11).

FDA-authorized CRISPR-dx tests are currently only for use in centralized labs, because the most common CRISPR detection protocols require fluid handling steps and two different incubations, precluding their immediate use at the point of care. Single-step formulations have been developed to overcome this limitation, and these “one-pot” versions of CRISPR-dx are simple to run, operate at a single temperature, and run without complex equipment, producing either fluorescence or lateral flow readouts. The programmability of CRISPR makes new diagnostic tests easier to develop, and within months of the release of the SARS-CoV-2 genome, many COVID-19–specific CRISPR tests were reported and distributed around the world.

The broader capability for Cas enzyme–enhanced nucleic acid binding or cleavage has led to several other detection modalities. Cas9-based methods for cleaving nucleic acids in solution for diagnostic purposes have been combined with other detection platforms, such as destruction of undesired amplicons for preparation of next-generation sequencing libraries (12), or selective removal of alleles for nucleotide-specific detection (13). Alternatively, the programmable cleavage event from the Cas nuclease can be used to initiate an amplification reaction (14). Cas9-based DNA targeting has also been used for nucleotide detection in combination with solid-state electronics, promising an amplification-free platform for detection. In this platform, called CRISPR-Chip, the Cas9 protein binds nucleotide targets of interest (often in the context of the native genome) to graphene transistors, where the presence of these targets alters either current or voltage (15). By utilizing additional Cas9 orthologs and specific guide designs, CRISPR-Chip approaches have been tuned for single–base-pair sensitivity (15). Because they are integrated with electronic readers, CRISPR-Chip platforms may allow facile point-of-care detection with handheld devices.

 

Other related articles on CRISPR/Cas9 were published in this Open Access Online Scientific Journal, include the following:

Search Results for ‘CRISPR’

Where is the most promising avenue to success in Pharmaceuticals with CRISPR-Cas9?

CRISPR/Cas9 genome editing tool for Staphylococcus aureus Cas9 complex (SaCas9) @ MIT’s Broad Institute

Delineating a Role for CRISPR-Cas9 in Pharmaceutical Targeting

Using CRISPR to investigate pancreatic cancer

Simple technology makes CRISPR gene editing cheaper

RNAi, CRISPR, and Gene Editing: Discussions on How To’s and Best Practices @14th Annual World Preclinical Congress June 10-12, 2015 | Westin Boston Waterfront | Boston, MA

CRISPR/Cas9: Contributions on Endoribonuclease Structure and Function, Role in Immunity and Applications in Genome Engineering

CRISPR-CAS editing brings cloning of woolly mammoth one step closer to reality

GUIDE-seq: First genome-wide method of detecting off-target DNA breaks induced by CRISPR-Cas nucleases

The Patents for CRISPR, the DNA editing technology as the Biggest Biotech Discovery of the Century

CRISPR: Applications for Autoimmune Diseases @UCSF

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Geneticist George Church: A Future Without Limits

Posted in BioIT: BioInformatics, BioIT: BioInformatics, NGS, Clinical & Translational, Pharmaceutical R&D Informatics, Clinical Genomics, Cancer Informatics, BioTechnology - Venture Creation, Genomic Testing: Methodology for Diagnosis, Interviews with Key Opinion Leaders (KOLs), Investment in Technological Breakthrough, Massachusetts Academy of Sciences (MAS)  , Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Personalized Medicine Coalition, Precision Cancer Medicine, RNA Biology, Cancer and Therapeutics, Scoop.it, Transcriptomics, Translational Science, tagged biotech, Exome sequencing, gene, George Church, MIT, Personalized medicine, precision medicine, variants, Venture capital, WES on October 24, 2014| Leave a Comment »

Geneticist George Church: A Future Without Limits

Reporter: Aviva Lev-Ari, PhD, RN

WordCloud Image Produced by Adam Tubman

UPDATED 12/05/2020

 

In the future, George Church believes, almost everything will be better because of genetics. If you have a medical problem, your doctor will be able to customize a treatment based on your specific DNA pattern. When you fill up your car, you won’t be draining the world’s dwindling supply of crude oil, because the fuel will come from microbes that have been genetically altered to produce biofuel. When you visit the zoo, you’ll be able to take your children to the woolly mammoth or passenger pigeon exhibits, because these animals will no longer be extinct. You’ll be able to do these things, that is, if the future turns out the way Church envisions it—and he’s doing everything he can to see that it does.

UPDATED 12/05/2020

George Church backs a startup solution to the massive gene therapy manufacturing bottleneck

Source: https://endpts.com/george-church-backs-a-startup-solution-to-the-massive-gene-therapy-manufacturing-bottleneck/
Jason Mast: Associate Editor
George Church and his graduate students have spent the last decade seeding startups on the razor’s edge between biology and science fiction: gene therapy to prevent aging, CRISPRed pigs that can be used to harvest organs for transplant, and home kits to test your poop for healthy or unhealthy bacteria. (OK, maybe they’re not all on that razor’s edge.)

But now a new spinout from the Department of Genetics’ second floor is tackling a far humbler problem — one that major company after major company has stumbled over as they tried to get cures for rare diseases and other gene therapies into the clinic and past regulators: How the hell do you build these?

CEO Lex Vovner of 64x Bio

“There’s a lot happening for new therapies but not enough attention around this problem,” Lex Rovner, who was a post-doc at Church’s lab from 2015 to 2018, told Endpoints News. “And if we don’t figure out how to fix this, many of these therapies won’t even reach patients.”

This week, with Church and a couple other prominent scientists as co-founders, Rovner launched 64x Bio to tackle one key part of the manufacturing bottleneck. They won’t be looking to retrofit plants or build gene therapy factories, as Big Pharma and big biotech are now spending billions to do. Instead, with $4.5 million in seed cash, they will try to engineer the individual cells that churn out a critical component of the therapies.

George Church
The goal is to build cells that are fine-tuned to do nothing but spit out the viral vectors that researchers and drug developers use to shuttle gene therapies into the body. Different vectors have different demands; 64x Bio will look to make efficient cellular factories for each.

“While a few general ways to increase vector production may exist, each unique vector serotype and payload poses a specific challenge,” Church said in an emailed statement. “Our platform enables us to fine tune custom solutions for these distinct combinations that are particularly hard to overcome.”

Before joining Church’s lab, Rovner did her graduate work at Yale, where she studied how to engineer bacteria to produce new kinds of protein for drugs or other purposes. And after leaving Church’s lab in 2018, she initially set out to build a manufacturing startup with a broad focus.

Yet as she spoke with hundreds of biotech executives on LinkedIn and in coffee shops around Cambridge, the same issue kept popping up: They liked their gene therapy technology in the lab but they didn’t know how to scale it up.

“Everyone kept saying the same thing,” Rovner said. “We basically realized there’s this huge problem.”

The issue would soon make headlines in industry publications: bluebird delaying the launch of Zynteglo, Novartis delaying the launch of Zolgensma in the EU, Axovant delaying the start of their Parkinson’s trial.

Part of the problem, Rovner said, is that gene therapies are delivered on viral vectors. You can build these vectors in mammalian cell lines by feeding them a small circular strand of DNA called a plasmid. The problem is that mammalian cells have, over billions of years, evolved tools and defenses precisely to avoid making viruses. (Lest the mammal they live in die of infection).

There are genetic mutations that can turn off some of the internal defenses and unleash a cell’s ability to produce virus, but they’re rare and hard to find. Other platforms, Rovner said, try to find these mutations by using CRISPR to knock out genes in different cells and then screening each of them individually, a process that can require hundreds of thousands of different 100-well plates, with each well containing a different group of mutant cells.

“It’s just not practical, and so these platforms never find the cells,” Rovner said.

64x Bio will try to find them by building a library of millions of mutant mammalian cells and then using a molecular “barcoding” technique to screen those cells in a single pool. The technique, Rovner said, lets them trace how much vector any given cell produces, allowing researchers to quickly identify super-producing cells and their mutations.

The technology was developed partially in-house but draws from IP at Harvard and the Wyss Institute. Harvard’s Pam Silver and Wyss’s Jeffrey Way are co-founders.

The company is now based in SoMa in San Francisco. With the seed cash from Fifty Years, Refactor and First Round Capital, Rovner is recruiting and looking to raise a Series A soon. They’re in talks with pharma and biotech partners, while they try to validate the first preclinical and clinical applications.

Gene therapy is one focus, but Rovner said the platform works for anything that involves viral vector, including vaccines and oncolytic viruses. You just have to find the right mutation.

“It’s the rare cell you’re looking for,” she said.

AUTHOR
Jason Mast
Associate Editor
jason@endpointsnews.com
@JasonMMast
Jason Mas

In 2005 he launched the Personal Genome Project, with the goal of sequencing and sharing the DNA of 100,000 volunteers. With an open-source database of that size, he believes, researchers everywhere will be able to meaningfully pursue the critical task of correlating genetic patterns with physical traits, illnesses, and exposure to environmental factors to find new cures for diseases and to gain basic insights into what makes each of us the way we are. Church, tagged as subject hu43860C, was first in line for testing. Since then, more than 13,000 people in the U.S., Canada, and the U.K. have volunteered to join him, helping to establish what he playfully calls the Facebook of DNA.

Church has made a career of defying the impossible. Propelled by the dizzying speed of technological advancement since then, the Personal Genome Project is just one of Church’s many attempts to overcome obstacles standing between him and the future.

“It’s not for everyone,” he says. “But I see a trend here. Openness has changed since many of us were young. People didn’t use to talk about sexuality or cancer in polite society. This is the Facebook generation.” If individuals were told which diseases or medical conditions they were genetically predisposed to, they could adjust their behavior accordingly, he reasoned. Although universal testing still isn’t practical today, the cost of sequencing an individual genome has dropped dramatically in recent years, from about $7 million in 2007 to as little as $1,000 today.

“It’s all too easy to dismiss the future,” he says. “People confuse what’s impossible today with what’s impossible tomorrow.”, especially through the emerging discipline of “synthetic” biology. The basic idea behind synthetic biology, he explained, was that natural organisms could be reprogrammed to do things they wouldn’t normally do, things that might be useful to people. In pursuit of this, researchers had learned not only how to read the genetic code of organisms but also how to write new code and insert it into organisms. Besides making plastic, microbes altered in this way had produced carpet fibers, treated wastewater, generated electricity, manufactured jet fuel, created hemoglobin, and fabricated new drugs. But this was only the tip of the iceberg, Church wrote. The same technique could also be used on people.

“Every cell in our body, whether it’s a bacterial cell or a human cell, has a genome,” he says. “You can extract that genome—it’s kind of like a linear tape—and you can read it by a variety of methods. Similarly, like a string of letters that you can read, you can also change it. You can write, you can edit it, and then you can put it back in the cell.”

This April, the Broad Institute, where Church holds a faculty appointment, was awarded a patent for a new method of genome editing called CRISPR (clustered regularly interspersed short palindromic repeats), which Church says is one of the most effective tools ever developed for synthetic biology. By studying the way that certain bacteria defend themselves against viruses, researchers figured out how to precisely cut DNA at any location on the genome and insert new material there to alter its function. Last month, researchers at MIT announced they had used CRISPR to cure mice of a rare liver disease that also afflicts humans. At the same time, researchers at Virginia Tech said they were experimenting on plants with CRISPR to control salt tolerance, improve crop yield, and create resistance to pathogens.

The possibilities for CRISPR technology seem almost limitless, Church says. If researchers have stored a genetic sequence in a computer, they can order a robot to produce a piece of DNA from the data. That piece can then be put into a cell to change the genome. Church believes that CRISPR is so promising that last year he co-founded a genome-editing company, Editas, to develop drugs for currently incurable diseases.

Source: news.nationalgeographic.com

See on Scoop.it – Cardiovascular and vascular imaging

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Diagnosing Diseases & Gene Therapy: Precision Genome Editing and Cost-effective microRNA Profiling

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Genome Biology, Medical and Population Genetics, Patient Experience: Personal Memories of Invasive Medical Intervantion, Personalized and Precision Medicine & Genomic Research, Pharmacogenomics, Population Health Management, Genetics & Pharmaceutical, Proteomics, Uncategorized, tagged Chief technology officer, Firefly, Messenger RNA, MicroRNA, MIT, national cancer institute, Small Business Innovation Research on March 28, 2013| 4 Comments »

Curator: Aviva Lev-Ari, PhD, RN

On 3/13/2013 Forbes Science Writer, Metthew Herper, presented a curated article about the protein Cas9. With a compelling title like 

This Protein Could Change Biotech Forever, we drew over 40 comments. 

A tiny molecular machine used by bacteria to kill attacking viruses could change the way that scientists edit the DNA of plants, animals and fungi, revolutionizing genetic engineering. The protein, called Cas9, is quite simply a way to more accurately cut a piece of DNA.

“This could significantly accelerate the rate of discovery in all areas of biology, including gene therapy in medicine, the generation of improved agricultural goods, and the engineering of energy-producing microbes,” says Luciano Marraffini of Rockefeller University.

The ability to make modular changes in the DNA of bacteria and primitive algae has resulted in drug and biofuel companies such as Amyris and LS9. But figuring out how to make changes in the genomes of more complicated organisms has been tough.

http://www.forbes.com/sites/matthewherper/2013/03/19/the-protein-that-could-change-biotech-forever/?goback=.gde_48920_member_227143277

In this article we bring all the pieces to one place, telling the evolution of a series of discoveries, which together may have the Protein, Cas9,  changing the Biotech Industry forever with its contributions to Diagnosing Diseases and Gene Therapy by Precision Genome Editing and Cost-effective microRNA Profiling. 

MicroRNA detection on the cheap

MIT alumni’s startup provides rapid, cost-effective microRNA profiling, which is beneficial for diagnosing diseases.

Rob Matheson, MIT News Office

March 28, 2013

Current methods of detecting microRNA (miRNA) — gene-regulating molecules implicated in the onset of various diseases — can be time-consuming and costly: The custom equipment used in such tests costs more than $100,000, and the limited throughput of these systems further hinders progress.

Two MIT alumni are helping to rectify these issues through their fast-growing, Cambridge-headquartered startup, Firefly BioWorks Inc., which provides technology that allows for rapid miRNA detection in a large number of samples using standard lab equipment. This technology has helped the company thrive — and also has the potential to increase the body of research on miRNA, which could help lead to better disease diagnosis and screening.The company’s core technology, called Optical Liquid Stamping (OLS) — which was invented at MIT by Firefly co-founder and Chief Technical Officer Daniel C. Pregibon PhD ’08 — works by imprinting (or stamping) microparticle structures onto photosensitive fluids. The resulting three-dimensional hydrogel particles, encoded with unique “barcodes,” can be used for the detection of miRNAs across large numbers of samples. These particles are custom-designed for readout in virtually any flow cytometer, a cost-effective device that’s accessible to most scientists.“Our manufacturing process allows us to make very sophisticated particles that can be read on the most basic instruments,” says co-founder and CEO Davide Marini PhD ’03.The company’s first commercial product, FirePlex miRSelect, an miRNA-detection kit that uses an assay based on OLS-manufactured particles and custom software, began selling about a year ago. Since then, the company has drawn a steady influx of customers (primarily academic and clinical scientists) while seeing rapid revenue growth.

To date, most of the company’s revenue has come from backers who see value in Firefly’s novel technology. In addition to a cumulative $2.5 million awarded through Small Business Innovation Research grants — primarily from the National Cancer Institute — the company has attracted $3 million from roughly 20 independent investors. Its most recent funding came from a $500,000 grant from the Massachusetts Life Sciences Center.

Pregibon developed the technology in the lab of MIT chemical engineering professorPatrick Doyle, a Firefly co-founder who serves on the company’s scientific advisory board. Firefly’s intellectual property is partially licensed through the Technology Licensing Office at MIT, along with several other Firefly patents. Firefly’s technology, from OLS to miRNA detection, has been described in papers published in several leading journals, including Science, Nature Materials, Nature Protocols and Analytical Chemistry.

Shifting complexity from equipment to particle

The success of the technology, Marini says, derives from an early business decision to focus attention on the development of the hydrogel particle instead of the equipment needed. Essentially, this allowed the co-founders to focus on developing a high-quality miRNA assay and hit the market quickly with particles that are universally readable on basic lab instrumentation.

“Imagine sticking a microscopic barcode on a microscopic product,” Marini says. “How do you scan it? At the beginning we thought we would have to build our own scanner. This would have been an expensive proposition. Instead, by using a few clever tricks, we redesigned the barcode to make it readable by existing instruments. You can write these ‘barcodes,’ and all you need is one scanner to read different codes. To quote an investor: ‘It shifts the complexity from the equipment to the particle.’”

Firefly’s particles appear to a standard flow cytometer as a series of closely spaced cells; these data are recorded and the company’s FireCode software then regroups them into particle information, including miRNA target identification and quantity.

But why, specifically, did the company choose a flow cytometer as its primary “scanner”? Pregibon answers: “To start, there are nearly 100,000 cytometers worldwide. In addition, we are now seeing a trend where flow cytometers are getting smaller and closer to the bench — closer to the actual researcher. We’re finding that people are tight for money because of the economy and are trying to conserve capital as much as possible. In order to use our products, they can either buy a very inexpensive bench-top flow cytometer or use one that already exists in their core facility.”

In turn, opting out of equipment development and manufacturing costs has helped the company stay financially sound, says Marini, who worked in London’s financial sector before coming to MIT. As an additional perk, the manufacturers of flow cytometers have begun “courting” Firefly, Marini says, because “our products help expand the capability of their systems, which are now exclusively used to analyze cells.”

The company’s FirePlex kit allows researchers to assay (or analyze) roughly 70 miRNA targets simultaneously across 96 samples of a wide variety — including serum, plasma and crude cell digests — in approximately three hours.

This is actually a “middle-ground” assaying technique, Pregibon says, and saves researchers time and money: Until now, scientists were forced to use separate techniques to look at a few miRNA targets over thousands of samples, or vice versa.

Marini adds that if a scientist suspects a number of miRNAs, perhaps 50 or so, could be involved in a pancreatic-cancer pathway, the only way to know for sure is to test those 50 targets over hundreds of samples. “There’s nowhere to do this today in a cost-effective, timely manner. Our tech now allows that,” he says.

‘Over the bridge of validation’

Because miRNAs are so important in the regulation of genes, and ultimately proteins, they have implications in a broad range of diseases, from cancer to Alzheimer’s disease. Several studies have suggested these relationships, but the field currently lacks the validation required to definitively demonstrate clinical utility.

With that in mind, Pregibon hopes that Firefly’s technology will help push miRNA-based diagnoses “over the bridge of validation,” giving scientists the means to validate miRNA signatures they discover in diagnosing diseases such as cancer. “That’s where we want to fit in,” he says. “With the help of a technology like ours, you’ll start to see more tests hitting the market and ultimately, more people benefitting from early cancer detection.”

Firefly’s aim is to strengthen preventive medicine in the United States. “In the long term, we see these products helping in the shift from reactive to preventative medicine,” Marini says. “We believe we will see a proliferation of tools for detection of diseases. We want to move away from the system we have now, which is curing before it’s too late.”

Pregibon says Firefly’s technology can be used across several molecule classes that are important in development and disease research: proteins, messenger RNA and DNA, among many others. “Essentially, the possibilities are endless,” Pregibon says.

SOURCE:

 http://web.mit.edu/newsoffice/2013/microrna-detection-on-the-cheap.html

Editing the genome with high precision

New method allows scientists to insert multiple genes in specific locations, delete defective genes.

Anne Trafton, MIT News Office

 

Researchers at MIT, the Broad Institute and Rockefeller University have developed a new technique for precisely altering the genomes of living cells by adding or deleting genes. The researchers say the technology could offer an easy-to-use, less-expensive way to engineer organisms that produce biofuels; to design animal models to study human disease; and  to develop new therapies, among other potential applications.To create their new genome-editing technique, the researchers modified a set of bacterial proteins that normally defend against viral invaders. Using this system, scientists can alter several genome sites simultaneously and can achieve much greater control over where new genes are inserted, says Feng Zhang, an assistant professor of brain and cognitive sciences at MIT and leader of the research team.“Anything that requires engineering of an organism to put in new genes or to modify what’s in the genome will be able to benefit from this,” says Zhang, who is a core member of the Broad Institute and MIT’s McGovern Institute for Brain Research.Zhang and his colleagues describe the new technique in the Jan. 3 online edition ofScience. Lead authors of the paper are graduate students Le Cong and Ann Ran.Early effortsThe first genetically altered mice were created in the 1980s by adding small pieces of DNA to mouse embryonic cells. This method is now widely used to create transgenic mice for the study of human disease, but, because it inserts DNA randomly in the genome, researchers can’t target the newly delivered genes to replace existing ones.

In recent years, scientists have sought more precise ways to edit the genome. One such method, known as homologous recombination, involves delivering a piece of DNA that includes the gene of interest flanked by sequences that match the genome region where the gene is to be inserted. However, this technique’s success rate is very low because the natural recombination process is rare in normal cells.

More recently, biologists discovered that they could improve the efficiency of this process by adding enzymes called nucleases, which can cut DNA. Zinc fingers are commonly used to deliver the nuclease to a specific location, but zinc finger arrays can’t target every possible sequence of DNA, limiting their usefulness. Furthermore, assembling the proteins is a labor-intensive and expensive process.

Complexes known as transcription activator-like effector nucleases (TALENs) can also cut the genome in specific locations, but these complexes can also be expensive and difficult to assemble.

Precise targeting

The new system is much more user-friendly, Zhang says. Making use of naturally occurring bacterial protein-RNA systems that recognize and snip viral DNA, the researchers can create DNA-editing complexes that include a nuclease called Cas9 bound to short RNA sequences. These sequences are designed to target specific locations in the genome; when they encounter a match, Cas9 cuts the DNA.

This approach can be used either to disrupt the function of a gene or to replace it with a new one. To replace the gene, the researchers must also add a DNA template for the new gene, which would be copied into the genome after the DNA is cut.

Each of the RNA segments can target a different sequence. “That’s the beauty of this — you can easily program a nuclease to target one or more positions in the genome,” Zhang says.

The method is also very precise — if there is a single base-pair difference between the RNA targeting sequence and the genome sequence, Cas9 is not activated. This is not the case for zinc fingers or TALEN. The new system also appears to be more efficient than TALEN, and much less expensive.

The new system “is a significant advancement in the field of genome editing and, in its first iteration, already appears comparable in efficiency to what zinc finger nucleases and TALENs have to offer,” says Aron Geurts, an associate professor of physiology at the Medical College of Wisconsin. “Deciphering the ever-increasing data emerging on genetic variation as it relates to human health and disease will require this type of scalable and precise genome editing in model systems.”

The research team has deposited the necessary genetic components with a nonprofit called Addgene, making the components widely available to other researchers who want to use the system. The researchers have also created a website with tips and tools for using this new technique.

Engineering new therapies

Among other possible applications, this system could be used to design new therapies for diseases such as Huntington’s disease, which appears to be caused by a single abnormal gene. Clinical trials that use zinc finger nucleases to disable genes are now under way, and the new technology could offer a more efficient alternative.

The system might also be useful for treating HIV by removing patients’ lymphocytes and mutating the CCR5 receptor, through which the virus enters cells. After being put back in the patient, such cells would resist infection.

This approach could also make it easier to study human disease by inducing specific mutations in human stem cells. “Using this genome editing system, you can very systematically put in individual mutations and differentiate the stem cells into neurons or cardiomyocytes and see how the mutations alter the biology of the cells,” Zhang says.

In the Science study, the researchers tested the system in cells grown in the lab, but they plan to apply the new technology to study brain function and diseases.

The research was funded by the National Institute of Mental Health; the W.M. Keck Foundation; the McKnight Foundation; the Bill & Melinda Gates Foundation; the Damon Runyon Cancer Research Foundation; the Searle Scholars Program; and philanthropic support from MIT alumni Mike Boylan and Bob Metcalfe, as well as the newscaster Jane Pauley.

SOURCE:

http://web.mit.edu/newsoffice/2013/editing-the-genome-with-high-precision-0103.html

Proc Natl Acad Sci U S A. 2012 September 25; 109(39): E2579–E2586.

Published online 2012 September 4. doi:  10.1073/pnas.1208507109

PMCID: PMC3465414

PNAS Plus

Cas9–crRNA ribonucleoprotein complex mediates specific DNA cleavage for adaptive immunity in bacteria

Giedrius Gasiunas,^a Rodolphe Barrangou,^b Philippe Horvath,^c and Virginijus Siksnys^a,1

Author information ► Copyright and License information ►

ABSTRACT

Clustered, regularly interspaced, short palindromic repeats (CRISPR)/CRISPR-associated (Cas) systems provide adaptive immunity against viruses and plasmids in bacteria and archaea. The silencing of invading nucleic acids is executed by ribonucleoprotein complexes preloaded with small, interfering CRISPR RNAs (crRNAs) that act as guides for targeting and degradation of foreign nucleic acid. Here, we demonstrate that the Cas9–crRNA complex of the Streptococcus thermophilus CRISPR3/Cas system introduces in vitro a double-strand break at a specific site in DNA containing a sequence complementary to crRNA. DNA cleavage is executed by Cas9, which uses two distinct active sites, RuvC and HNH, to generate site-specific nicks on opposite DNA strands. Results demonstrate that the Cas9–crRNA complex functions as an RNA-guided endonuclease with RNA-directed target sequence recognition and protein-mediated DNA cleavage. These findings pave the way for engineering of universal programmable RNA-guided DNA endonucleases.

Keywords: nuclease, site-directed mutagenesis, RNA interference, DNA interference

Comparison with Other RNAi Complexes

The mechanism proposed here for the cleavage of dsDNA by the Cas9–crRNA complex differs significantly from that for the type I-E (former “Ecoli”) system (7). In the E. coli type I-E system crRNA and Cas proteins assemble into a large ribonucleoprotein complex, Cascade, that facilitates target recognition by enhancing sequence-specific hybridization between the crRNA and complementary target sequences (7). Target recognition is dependent on the PAM and governed by the seed crRNA sequence located at the 5′ end of the spacer region (24). However, although the Cascade–crRNA complex alone is able to bind dsDNA containing a PAM and a protospacer, it requires an accessory Cas3 protein for DNA cleavage. Cas3 is an ssDNA nuclease and helicase that is able to cleave ssDNA, producing multiple cuts (10). It has been demonstrated recently that Cas3 degrades E. coli plasmid DNA in vitro in the presence of the Cascade–crRNA complex (25). Thus, current data clearly show that the mechanistic details of the interference step for the type I-E system differ from those of type II systems, both in the catalytic machinery involved and the nature of the molecular mechanisms.

In type IIIB CRISPR/Cas systems, present in many archaea and some bacteria, Cmr proteins and cRNA assemble into an effector complex that targets RNA (6, 12). In Pyrococcus furiosus the RNA-silencing complex, comprising six proteins (Cmr1–Cmr6) and crRNA, binds to the target RNA and cleaves it at fixed distance from the 3′ end. The cleavage activity depends on Mg²⁺ ions; however, individual Cmr proteins responsible for target RNA cleavage have yet to be identified. The effector complex of Sulfolobus solfataricus, comprising seven proteins (Cmr1–Cmr7) and crRNA, cuts invading RNA in an endonucleolytic reaction at UA dinucleotides (13). Importantly, these two archaeal Cmr–crRNA complexes perform RNA cleavage in a PAM-independent manner.

Overall, we have shown that the Cas9–crRNA complex in type II CRISPR/Cas systems is a functional homolog of Cascade in type I systems and represents a minimal DNAi complex. The simple modular organization of the Cas9–crRNA complex, in which specificity for DNA targets is encoded by crRNAs and the cleavage enzymatic machinery is brought by a single, multidomain Cas protein, provides a versatile platform for engineering universal RNA-guided DNA endonucleases. Indeed, by altering the RNA sequence within the Cas9–crRNA complex, programmable endonucleases can be designed both for in vitro and in vivo applications. To provide proof of principle of such a strategy, we engineered de novo into a CRISPR locus a spacer targeted to a specific sequence on a plasmid and demonstrated that such a plasmid is cleaved by the Cas9–crRNA complex at a sequence specified by the designed crRNA. Experimental demonstration that RuvC and HNH active-site mutants of Cas9 are functional as strand-specific nicking enzymes opens the possibility of generating programmed DNA single-strand breaks de novo. Taken together, these findings pave the way for the development of unique molecular tools for RNA-directed DNA surgery.

SOURCE:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3465414/

Cheap and easy technique to snip DNA could revolutionize gene therapy

By Robert Sanders, Media Relations | January 7, 2013

BERKELEY —A simple, precise and inexpensive method for cutting DNA to insert genes into human cells could transform genetic medicine, making routine what now are expensive, complicated and rare procedures for replacing defective genes in order to fix genetic disease or even cure AIDS.

The bacterial enzyme Cas9 is the engine of RNA-programmed genome engineering in human cells. Graphic by Jennifer Doudna/UC Berkeley.

IMAGE SOURCE:

http://newscenter.berkeley.edu/2013/01/07/cheap-and-easy-technique-to-snip-dna-could-revolutionize-gene-therapy/

Discovered last year by Jennifer Doudna and Martin Jinek of the Howard Hughes Medical Institute and University of California, Berkeley, and Emmanuelle Charpentier of the Laboratory for Molecular Infection Medicine-Sweden, the technique was labeled a “tour de force” in a 2012 review in the journal Nature Biotechnology.

That review was based solely on the team’s June 28, 2012, Science paper, in which the researchers described a new method of precisely targeting and cutting DNA in bacteria.

Two new papers published last week in the journal Science Express demonstrate that the technique also works in human cells. A paper by Doudna and her team reporting similarly successful results in human cells has been accepted for publication by the new open-access journal eLife.

“The ability to modify specific elements of an organism’s genes has been essential to advance our understanding of biology, including human health,” said Doudna, a professor of molecular and cell biology and of chemistry and a Howard Hughes Medical Institute Investigator at UC Berkeley. “However, the techniques for making these modifications in animals and humans have been a huge bottleneck in both research and the development of human therapeutics.

“This is going to remove a major bottleneck in the field, because it means that essentially anybody can use this kind of genome editing or reprogramming to introduce genetic changes into mammalian or, quite likely, other eukaryotic systems.”

“I think this is going to be a real hit,” said George Church, professor of genetics at Harvard Medical School and principal author of one of the Science Express papers. “There are going to be a lot of people practicing this method because it is easier and about 100 times more compact than other techniques.”

“Based on the feedback we’ve received, it’s possible that this technique will completely revolutionize genome engineering in animals and plants,” said Doudna, who also holds an appointment at Lawrence Berkeley National Laboratory. “It’s easy to program and could potentially be as powerful as the Polymerase Chain Reaction (PCR).”

The latter technique made it easy to generate millions of copies of small pieces of DNA and permanently altered biological research and medical genetics.

Cruise missiles

Two developments – zinc-finger nucleases and TALEN (Transcription Activator-Like Effector Nucleases) proteins – have gotten a lot of attention recently, including being together named one of the top 10 scientific breakthroughs of 2012 by Science magazine. The magazine labeled them “cruise missiles” because both techniques allow researchers to home in on a particular part of a genome and snip the double-stranded DNA there and there only.

Researchers can use these methods to make two precise cuts to remove a piece of DNA and, if an alternative piece of DNA is supplied, the cell will plug it into the cut instead. In this way, doctors can excise a defective or mutated gene and replace it with a normal copy. Sangamo Biosciences, a clinical stage biospharmaceutical company, has already shown that replacing one specific gene in a person infected with HIV can make him or her resistant to AIDS.

Both the zinc finger and TALEN techniques require synthesizing a large new gene encoding a specific protein for each new site in the DNA that is to be changed. By contrast, the new technique uses a single protein that requires only a short RNA molecule to program it for site-specific DNA recognition, Doudna said.

In the new Science Express paper, Church compared the new technique, which involves an enzyme called Cas9, with the TALEN method for inserting a gene into a mammalian cell and found it five times more efficient.

“It (the Cas9-RNA complex) is easier to make than TALEN proteins, and it’s smaller,” making it easier to slip into cells and even to program hundreds of snips simultaneously, he said. The complex also has lower toxicity in mammalian cells than other techniques, he added.

“It’s too early to declare total victory” over TALENs and zinc-fingers, Church said, “but it looks promising.”

Based on the immune systems of bacteria

Doudna discovered the Cas9 enzyme while working on the immune system of bacteria that have evolved enzymes that cut DNA to defend themselves against viruses. These bacteria cut up viral DNA and stick pieces of it into their own DNA, from which they make RNA that binds and inactivates the viruses.

UC Berkeley professor of earth and planetary science Jill Banfield brought this unusual viral immune system to Doudna’s attention a few years ago, and Doudna became intrigued. Her research focuses on how cells use RNA (ribonucleic acids), which are essentially the working copies that cells make of the DNA in their genes.

Doudna and her team worked out the details of how the enzyme-RNA complex cuts DNA: the Cas9 protein assembles with two short lengths of RNA, and together the complex binds a very specific area of DNA determined by the RNA sequence. The scientists then simplified the system to work with only one piece of RNA and showed in the earlier Science paper that they could target and snip specific areas of bacterial DNA.

“The beauty of this compared to any of the other systems that have come along over the past few decades for doing genome engineering is that it uses a single enzyme,” Doudna said. “The enzyme doesn’t have to change for every site that you want to target – you simply have to reprogram it with a different RNA transcript, which is easy to design and implement.”

The three new papers show this bacterial system works beautifully in human cells as well as in bacteria.

“Out of this somewhat obscure bacterial immune system comes a technology that has the potential to really transform the way that we work on and manipulate mammalian cells and other types of animal and plant cells,” Doudna said. “This is a poster child for the role of basic science in making fundamental discoveries that affect human health.”

Doudna’s coauthors include Jinek and Alexandra East, Aaron Cheng and Enbo Ma of UC Berkeley’s Department of Molecular and Cell Biology.

Doudna’s work was sponsored by the Howard Hughes Medical Institute.

RELATED INFORMATION

• RNA-programmed genome editing in human cells (accepted for publication in eLife)
• RNA-Guided Human Genome Engineering via Cas9 (Church article, Jan. 3 Science Express)
• Multiplex Genome Engineering Using CRISPR/Cas Systems (Wang article, Jan. 3 Science Express)
• Programmable RNA Complex Could Speed Genome Editing in the Lab (HHMI story, June 28, 2012)
• Jennifer Doudna’s Web page

SOURCE:
http://newscenter.berkeley.edu/2013/01/07/cheap-and-easy-technique-to-snip-dna-could-revolutionize-gene-therapy/

Matthew Herper, Forbes Staff on 3/24/2013

 A Cancer Patient’s Quest Hits DNA Pay Dirt

 

Kathy Giusti

Kathy Giusti has faced her cancer with the verve of an entrepreneur. Now her fight with multiple myeloma has moved to a new front: DNA.

Giusti was a 37-year-old marketing executive at Searle (now part of Pfizer) when she was diagnosed in 1996 with myeloma, a deadly blood and bone marrow cancer. She had a 1-year-old daughter. Sixty percent of myeloma patients die within five years, but Giusti beat the odds, living for a decade and a half through multiple rounds of drug therapy and a bone marrow transplant from her twin sister.

She has also changed the way her disease is treated. Giusti founded an advocacy group, the Multiple Myeloma Research Foundation, that works with companies like Novartis, Celgene, and Merck to develop new treatments. It played a key role in the development of Velcade and Revlimid, two of the biggest advances in treating the disease, which is diagnosed in 20,000 patients a year.

Now a new research effort, funded with $14 million of MMRF money, has revealed new hints at what causes the disease and potential avenues for treating it. “This is going to be the next wave of how health care gets changed over time,” Giusti says. The results are published in the current issue of Nature.

Working with patient samples collected by the MMRF and using DNA sequencers made by Illumina of San Diego, researchers at the Broad Institute of MIT and Harvard sequenced the genes of 38 myeloma tumors and the DNA of the patients in whom they were growing. Tumors are twisted versions of the people in which they are growing; their DNA is mutated and disfigured, turning them deadly. By comparing DNA from healthy cells with malignant ones, researchers can find genetic differences that might be what led the tumors to go bad in the first place.

This experiment would have been unthinkable just a few years ago, when sequencing a human being was so expensive that all the people whose DNA had been read out could fit in a small room. In 2005, the idea of producing 38 DNA sequences was laughable. Now it’s par for the course, and researchers expect thousands of genomes will be sequenced by the end of the year – and experiments like this are expected to become commonplace.

What’s so exciting is that sometimes the DNA changes scientists find are completely unexpected. “There were genes we found to be recurrently mutated and yet no one had any clue that they had anything to do with multiple myeloma or any other cancer,” says Todd Golub, the Broad researcher who led the study. He splits his time with the Dana-Farber Cancer Institute.

One gene, called FAM46C, was mutated in 13% of the cancers, but has never been studied in humans. “It appears no one had been working on it,” says Golub, but from studies in yeast and bacteria it appears that it has to do with how the recipes in genes are used to make proteins, the building blocks of just about everything in the body.

Another surprise gene, called BRAF, is generating excitement because it is the target of a skin cancer drug developed by Plexxikon, a small biotech firm that is partnered with Roch and is being purchased by Daiichi Sankyo. For the 4% of myeloma patients who have this mutation, this drug might be an option. The challenge will be testing it: it will be difficult to find enough of these patients to conduct a clinical trial. The MMRF says early discussions on such a study are moving forward. Giusti imagines that in the future, the MMRF may fund studies not of myeloma, but of a mix of different cancers caused by similar genetic mutations.

Several of the genes seem involved in the proteins that help guide epigenetics, a kind of molecular code written on DNA that may represent another kind of genetic code. The MMRF is already supporting some small drug companies that hope to create cancer drugs that target this second code.

Golub, the Broad scientist, says that right now it doesn’t make sense for most multiple myeloma patients to get their full DNA sequences outside of clinical trials, although he can imagine that for patients who have failed every available treatment it might make sense as a way to come up with another drug to try.

Giusti says, however, that the kinds of genetic tests that are done are changing the way that patients understand their disease. “Patients like me are starting to know, ‘I have this DNA translocation, maybe a proteasome inhibitor [a type of drug] is better for me.’ We become forerunners in the role patient can plan and the importance it has in drug development.”

Moving past old ways of thinking about inventing new medicines to a new path that is based on genetics and a flood of biological data is going to be difficult. But Giusti has never been afraid of hard — and she is sure there will be ways to drive the science forward.

SOURCE:

http://www.forbes.com/sites/matthewherper/2011/03/24/a-cancer-patients-quest-hits-dna-pay-dirt/

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3465414/

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