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  • richardmitnick 11:24 am on September 16, 2021 Permalink | Reply
    Tags: "New programmable gene editing proteins found outside of CRISPR systems", , , , CRISPR, , IscB; IsrB; and TnpB are found in mobile genetic elements called transposons., IscBs and TnpBs appear to be predecessors of Cas9 and Cas12 CRISPR systems., , Programmable DNA modifying systems called OMEGAs (Obligate Mobile Element Guided Activity), Programmable enzymes-particularly those that use an RNA guide-can be rapidly adapted for different uses., , The first hints that OMEGA proteins might be directed by RNA came from the genes for proteins called IscBs., Two other classes of small proteins known as IsrBs and TnpBs-one of the most abundant genes in bacteria-also use ωRNAs that act as guides to direct the cleavage of DNA.   

    From Massachusetts Institute of Technology (US) : “New programmable gene editing proteins found outside of CRISPR systems” 

    MIT News

    From Massachusetts Institute of Technology (US)

    September 15, 2021
    Jennifer Michalowski | McGovern Institute for Brain Research

    Soumya Kannan is a 2021-22 Yang-Tan Center for Molecular Therapeutics Graduate Student Fellow in the lab of MIT Professor Feng Zhang and co-first author with Han Altae-Tran of a study reporting a new class of programmable DNA modifying systems known as OMEGAs. Credit: Caitlin Cunningham.

    Within the last decade, scientists have adapted CRISPR systems from microbes into gene editing technology, a precise and programmable system for modifying DNA. Now, scientists at MIT’s McGovern Institute for Brain Research and the Broad Institute of MIT and Harvard have discovered a new class of programmable DNA modifying systems called OMEGAs (Obligate Mobile Element Guided Activity), which may naturally be involved in shuffling small bits of DNA throughout bacterial genomes.

    These ancient DNA-cutting enzymes are guided to their targets by small pieces of RNA. While they originated in bacteria, they have now been engineered to work in human cells, suggesting they could be useful in the development of gene editing therapies, particularly as they are small (about 30 percent of the size of Cas9), making them easier to deliver to cells than bulkier enzymes. The discovery, reported Sept. 9 in the journal Science, provides evidence that natural RNA-guided enzymes are among the most abundant proteins on Earth, pointing toward a vast new area of biology that is poised to drive the next revolution in genome editing technology.

    The research was led by McGovern Investigator Feng Zhang, who is the James and Patricia Poitras Professor of Neuroscience at MIT, a Howard Hughes Medical Institute (US) investigator, and a Core Institute Member of the Broad Institute. Zhang’s team has been exploring natural diversity in search of new molecular systems that can be rationally programmed.

    “We are super excited about the discovery of these widespread programmable enzymes, which have been hiding under our noses all along,” says Zhang. “These results suggest the tantalizing possibility that there are many more programmable systems that await discovery and development as useful technologies.”

    Natural adaptation

    Programmable enzymes-particularly those that use an RNA guide-can be rapidly adapted for different uses. For example, CRISPR enzymes naturally use an RNA guide to target viral invaders, but biologists can direct Cas9 to any target by generating their own RNA guide. “It’s so easy to just change a guide sequence and set a new target,” says Soumya Kannan, MIT graduate student in biological engineering and co-first author of the paper. “So one of the broad questions that we’re interested in is trying to see if other natural systems use that same kind of mechanism.”

    The first hints that OMEGA proteins might be directed by RNA came from the genes for proteins called IscBs. The IscBs are not involved in CRISPR immunity and were not known to associate with RNA, but they looked like small, DNA-cutting enzymes. The team discovered that each IscB had a small RNA encoded nearby and it directed IscB enzymes to cut specific DNA sequences. They named these RNAs “ωRNAs.”

    The team’s experiments showed that two other classes of small proteins known as IsrBs and TnpBs-one of the most abundant genes in bacteria-also use ωRNAs that act as guides to direct the cleavage of DNA.

    IscB; IsrB; and TnpB are found in mobile genetic elements called transposons. Han Altae-Tran, MIT graduate student in biological engineering and co-first author on the paper, explains that each time these transposons move, they create a new guide RNA, allowing the enzyme they encode to cut somewhere else.

    It’s not clear how bacteria benefit from this genomic shuffling — or whether they do at all. Transposons are often thought of as selfish bits of DNA, concerned only with their own mobility and preservation, Kannan says. But if hosts can “co-opt” these systems and repurpose them, hosts may gain new abilities, as with CRISPR systems that confer adaptive immunity.

    IscBs and TnpBs appear to be predecessors of Cas9 and Cas12 CRISPR systems. The team suspects they, along with IsrB, likely gave rise to other RNA-guided enzymes, too — and they are eager to find them. They are curious about the range of functions that might be carried out in nature by RNA-guided enzymes, Kannan says, and suspect evolution likely already took advantage of OMEGA enzymes like IscBs and TnpBs to solve problems that biologists are keen to tackle.

    “A lot of the things that we have been thinking about may already exist naturally in some capacity,” says Altae-Tran. “Natural versions of these types of systems might be a good starting point to adapt for that particular task.”

    The team is also interested in tracing the evolution of RNA-guided systems further into the past. “Finding all these new systems sheds light on how RNA-guided systems have evolved, but we don’t know where RNA-guided activity itself comes from,” Altae-Tran says. Understanding those origins, he says, could pave the way to developing even more classes of programmable tools.

    This work was made possible with support from the Simons Center for the Social Brain at MIT, the National Institutes of Health and its Intramural Research Program, Howard Hughes Medical Institute, Open Philanthropy, G. Harold and Leila Y. Mathers Charitable Foundation, Edward Mallinckrodt, Jr. Foundation, Poitras Center for Psychiatric Disorders Research at MIT, Hock E. Tan and K. Lisa Yang Center for Autism Research at MIT, Yang-Tan Center for Molecular Therapeutics at MIT, Lisa Yang, Phillips family, R. Metcalfe, and J. and P. Poitras.

    See the full article here .

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    Massachusetts Institute of Technology (US) is a private land-grant research university in Cambridge, Massachusetts. The institute has an urban campus that extends more than a mile (1.6 km) alongside the Charles River. The institute also encompasses a number of major off-campus facilities such as the MIT Lincoln Laboratory (US), the MIT Bates Research and Engineering Center (US), and the Haystack Observatory (US), as well as affiliated laboratories such as the Broad Institute of MIT and Harvard(US) and Whitehead Institute (US).

    Founded in 1861 in response to the increasing industrialization of the United States, Massachusetts Institute of Technology (US) adopted a European polytechnic university model and stressed laboratory instruction in applied science and engineering. It has since played a key role in the development of many aspects of modern science, engineering, mathematics, and technology, and is widely known for its innovation and academic strength. It is frequently regarded as one of the most prestigious universities in the world.

    As of December 2020, 97 Nobel laureates, 26 Turing Award winners, and 8 Fields Medalists have been affiliated with MIT as alumni, faculty members, or researchers. In addition, 58 National Medal of Science recipients, 29 National Medals of Technology and Innovation recipients, 50 MacArthur Fellows, 80 Marshall Scholars, 3 Mitchell Scholars, 22 Schwarzman Scholars, 41 astronauts, and 16 Chief Scientists of the U.S. Air Force have been affiliated with Massachusetts Institute of Technology (US) . The university also has a strong entrepreneurial culture and MIT alumni have founded or co-founded many notable companies. Massachusetts Institute of Technology (US) is a member of the Association of American Universities (AAU).

    Foundation and vision

    In 1859, a proposal was submitted to the Massachusetts General Court to use newly filled lands in Back Bay, Boston for a “Conservatory of Art and Science”, but the proposal failed. A charter for the incorporation of the Massachusetts Institute of Technology, proposed by William Barton Rogers, was signed by John Albion Andrew, the governor of Massachusetts, on April 10, 1861.

    Rogers, a professor from the University of Virginia (US), wanted to establish an institution to address rapid scientific and technological advances. He did not wish to found a professional school, but a combination with elements of both professional and liberal education, proposing that:

    “The true and only practicable object of a polytechnic school is, as I conceive, the teaching, not of the minute details and manipulations of the arts, which can be done only in the workshop, but the inculcation of those scientific principles which form the basis and explanation of them, and along with this, a full and methodical review of all their leading processes and operations in connection with physical laws.”

    The Rogers Plan reflected the German research university model, emphasizing an independent faculty engaged in research, as well as instruction oriented around seminars and laboratories.

    Early developments

    Two days after Massachusetts Institute of Technology (US) was chartered, the first battle of the Civil War broke out. After a long delay through the war years, MIT’s first classes were held in the Mercantile Building in Boston in 1865. The new institute was founded as part of the Morrill Land-Grant Colleges Act to fund institutions “to promote the liberal and practical education of the industrial classes” and was a land-grant school. In 1863 under the same act, the Commonwealth of Massachusetts founded the Massachusetts Agricultural College, which developed as the University of Massachusetts Amherst (US)). In 1866, the proceeds from land sales went toward new buildings in the Back Bay.

    Massachusetts Institute of Technology (US) was informally called “Boston Tech”. The institute adopted the European polytechnic university model and emphasized laboratory instruction from an early date. Despite chronic financial problems, the institute saw growth in the last two decades of the 19th century under President Francis Amasa Walker. Programs in electrical, chemical, marine, and sanitary engineering were introduced, new buildings were built, and the size of the student body increased to more than one thousand.

    The curriculum drifted to a vocational emphasis, with less focus on theoretical science. The fledgling school still suffered from chronic financial shortages which diverted the attention of the MIT leadership. During these “Boston Tech” years, Massachusetts Institute of Technology (US) faculty and alumni rebuffed Harvard University (US) president (and former MIT faculty) Charles W. Eliot’s repeated attempts to merge MIT with Harvard College’s Lawrence Scientific School. There would be at least six attempts to absorb MIT into Harvard. In its cramped Back Bay location, MIT could not afford to expand its overcrowded facilities, driving a desperate search for a new campus and funding. Eventually, the MIT Corporation approved a formal agreement to merge with Harvard, over the vehement objections of MIT faculty, students, and alumni. However, a 1917 decision by the Massachusetts Supreme Judicial Court effectively put an end to the merger scheme.

    In 1916, the Massachusetts Institute of Technology (US) administration and the MIT charter crossed the Charles River on the ceremonial barge Bucentaur built for the occasion, to signify MIT’s move to a spacious new campus largely consisting of filled land on a one-mile-long (1.6 km) tract along the Cambridge side of the Charles River. The neoclassical “New Technology” campus was designed by William W. Bosworth and had been funded largely by anonymous donations from a mysterious “Mr. Smith”, starting in 1912. In January 1920, the donor was revealed to be the industrialist George Eastman of Rochester, New York, who had invented methods of film production and processing, and founded Eastman Kodak. Between 1912 and 1920, Eastman donated $20 million ($236.6 million in 2015 dollars) in cash and Kodak stock to MIT.

    Curricular reforms

    In the 1930s, President Karl Taylor Compton and Vice-President (effectively Provost) Vannevar Bush emphasized the importance of pure sciences like physics and chemistry and reduced the vocational practice required in shops and drafting studios. The Compton reforms “renewed confidence in the ability of the Institute to develop leadership in science as well as in engineering”. Unlike Ivy League schools, Massachusetts Institute of Technology (US) catered more to middle-class families, and depended more on tuition than on endowments or grants for its funding. The school was elected to the Association of American Universities (US)in 1934.

    Still, as late as 1949, the Lewis Committee lamented in its report on the state of education at Massachusetts Institute of Technology (US) that “the Institute is widely conceived as basically a vocational school”, a “partly unjustified” perception the committee sought to change. The report comprehensively reviewed the undergraduate curriculum, recommended offering a broader education, and warned against letting engineering and government-sponsored research detract from the sciences and humanities. The School of Humanities, Arts, and Social Sciences and the MIT Sloan School of Management were formed in 1950 to compete with the powerful Schools of Science and Engineering. Previously marginalized faculties in the areas of economics, management, political science, and linguistics emerged into cohesive and assertive departments by attracting respected professors and launching competitive graduate programs. The School of Humanities, Arts, and Social Sciences continued to develop under the successive terms of the more humanistically oriented presidents Howard W. Johnson and Jerome Wiesner between 1966 and 1980.

    Massachusetts Institute of Technology (US)‘s involvement in military science surged during World War II. In 1941, Vannevar Bush was appointed head of the federal Office of Scientific Research and Development and directed funding to only a select group of universities, including MIT. Engineers and scientists from across the country gathered at Massachusetts Institute of Technology (US)’s Radiation Laboratory, established in 1940 to assist the British military in developing microwave radar. The work done there significantly affected both the war and subsequent research in the area. Other defense projects included gyroscope-based and other complex control systems for gunsight, bombsight, and inertial navigation under Charles Stark Draper’s Instrumentation Laboratory; the development of a digital computer for flight simulations under Project Whirlwind; and high-speed and high-altitude photography under Harold Edgerton. By the end of the war, Massachusetts Institute of Technology (US) became the nation’s largest wartime R&D contractor (attracting some criticism of Bush), employing nearly 4000 in the Radiation Laboratory alone and receiving in excess of $100 million ($1.2 billion in 2015 dollars) before 1946. Work on defense projects continued even after then. Post-war government-sponsored research at MIT included SAGE and guidance systems for ballistic missiles and Project Apollo.

    These activities affected Massachusetts Institute of Technology (US) profoundly. A 1949 report noted the lack of “any great slackening in the pace of life at the Institute” to match the return to peacetime, remembering the “academic tranquility of the prewar years”, though acknowledging the significant contributions of military research to the increased emphasis on graduate education and rapid growth of personnel and facilities. The faculty doubled and the graduate student body quintupled during the terms of Karl Taylor Compton, president of Massachusetts Institute of Technology (US) between 1930 and 1948; James Rhyne Killian, president from 1948 to 1957; and Julius Adams Stratton, chancellor from 1952 to 1957, whose institution-building strategies shaped the expanding university. By the 1950s, Massachusetts Institute of Technology (US) no longer simply benefited the industries with which it had worked for three decades, and it had developed closer working relationships with new patrons, philanthropic foundations and the federal government.

    In late 1960s and early 1970s, student and faculty activists protested against the Vietnam War and Massachusetts Institute of Technology (US)’s defense research. In this period Massachusetts Institute of Technology (US)’s various departments were researching helicopters, smart bombs and counterinsurgency techniques for the war in Vietnam as well as guidance systems for nuclear missiles. The Union of Concerned Scientists was founded on March 4, 1969 during a meeting of faculty members and students seeking to shift the emphasis on military research toward environmental and social problems. Massachusetts Institute of Technology (US) ultimately divested itself from the Instrumentation Laboratory and moved all classified research off-campus to the MIT (US) Lincoln Laboratory facility in 1973 in response to the protests. The student body, faculty, and administration remained comparatively unpolarized during what was a tumultuous time for many other universities. Johnson was seen to be highly successful in leading his institution to “greater strength and unity” after these times of turmoil. However six Massachusetts Institute of Technology (US) students were sentenced to prison terms at this time and some former student leaders, such as Michael Albert and George Katsiaficas, are still indignant about MIT’s role in military research and its suppression of these protests. (Richard Leacock’s film, November Actions, records some of these tumultuous events.)

    In the 1980s, there was more controversy at Massachusetts Institute of Technology (US) over its involvement in SDI (space weaponry) and CBW (chemical and biological warfare) research. More recently, Massachusetts Institute of Technology (US)’s research for the military has included work on robots, drones and ‘battle suits’.

    Recent history

    Massachusetts Institute of Technology (US) has kept pace with and helped to advance the digital age. In addition to developing the predecessors to modern computing and networking technologies, students, staff, and faculty members at Project MAC, the Artificial Intelligence Laboratory, and the Tech Model Railroad Club wrote some of the earliest interactive computer video games like Spacewar! and created much of modern hacker slang and culture. Several major computer-related organizations have originated at MIT since the 1980s: Richard Stallman’s GNU Project and the subsequent Free Software Foundation were founded in the mid-1980s at the AI Lab; the MIT Media Lab was founded in 1985 by Nicholas Negroponte and Jerome Wiesner to promote research into novel uses of computer technology; the World Wide Web Consortium standards organization was founded at the Laboratory for Computer Science in 1994 by Tim Berners-Lee; the MIT OpenCourseWare project has made course materials for over 2,000 Massachusetts Institute of Technology (US) classes available online free of charge since 2002; and the One Laptop per Child initiative to expand computer education and connectivity to children worldwide was launched in 2005.

    Massachusetts Institute of Technology (US) was named a sea-grant college in 1976 to support its programs in oceanography and marine sciences and was named a space-grant college in 1989 to support its aeronautics and astronautics programs. Despite diminishing government financial support over the past quarter century, MIT launched several successful development campaigns to significantly expand the campus: new dormitories and athletics buildings on west campus; the Tang Center for Management Education; several buildings in the northeast corner of campus supporting research into biology, brain and cognitive sciences, genomics, biotechnology, and cancer research; and a number of new “backlot” buildings on Vassar Street including the Stata Center. Construction on campus in the 2000s included expansions of the Media Lab, the Sloan School’s eastern campus, and graduate residences in the northwest. In 2006, President Hockfield launched the MIT Energy Research Council to investigate the interdisciplinary challenges posed by increasing global energy consumption.

    In 2001, inspired by the open source and open access movements, Massachusetts Institute of Technology (US) launched OpenCourseWare to make the lecture notes, problem sets, syllabi, exams, and lectures from the great majority of its courses available online for no charge, though without any formal accreditation for coursework completed. While the cost of supporting and hosting the project is high, OCW expanded in 2005 to include other universities as a part of the OpenCourseWare Consortium, which currently includes more than 250 academic institutions with content available in at least six languages. In 2011, Massachusetts Institute of Technology (US) announced it would offer formal certification (but not credits or degrees) to online participants completing coursework in its “MITx” program, for a modest fee. The “edX” online platform supporting MITx was initially developed in partnership with Harvard and its analogous “Harvardx” initiative. The courseware platform is open source, and other universities have already joined and added their own course content. In March 2009 the Massachusetts Institute of Technology (US) faculty adopted an open-access policy to make its scholarship publicly accessible online.

    Massachusetts Institute of Technology (US) has its own police force. Three days after the Boston Marathon bombing of April 2013, MIT Police patrol officer Sean Collier was fatally shot by the suspects Dzhokhar and Tamerlan Tsarnaev, setting off a violent manhunt that shut down the campus and much of the Boston metropolitan area for a day. One week later, Collier’s memorial service was attended by more than 10,000 people, in a ceremony hosted by the Massachusetts Institute of Technology (US) community with thousands of police officers from the New England region and Canada. On November 25, 2013, Massachusetts Institute of Technology (US) announced the creation of the Collier Medal, to be awarded annually to “an individual or group that embodies the character and qualities that Officer Collier exhibited as a member of the Massachusetts Institute of Technology (US) community and in all aspects of his life”. The announcement further stated that “Future recipients of the award will include those whose contributions exceed the boundaries of their profession, those who have contributed to building bridges across the community, and those who consistently and selflessly perform acts of kindness”.

    In September 2017, the school announced the creation of an artificial intelligence research lab called the MIT-IBM Watson AI Lab. IBM will spend $240 million over the next decade, and the lab will be staffed by MIT and IBM scientists. In October 2018 MIT announced that it would open a new Schwarzman College of Computing dedicated to the study of artificial intelligence, named after lead donor and The Blackstone Group CEO Stephen Schwarzman. The focus of the new college is to study not just AI, but interdisciplinary AI education, and how AI can be used in fields as diverse as history and biology. The cost of buildings and new faculty for the new college is expected to be $1 billion upon completion.

    The Caltech/MIT Advanced aLIGO (US) was designed and constructed by a team of scientists from California Institute of Technology (US), Massachusetts Institute of Technology (US), and industrial contractors, and funded by the National Science Foundation (US) .

    MIT/Caltech Advanced aLigo .

    It was designed to open the field of gravitational-wave astronomy through the detection of gravitational waves predicted by general relativity. Gravitational waves were detected for the first time by the LIGO detector in 2015. For contributions to the LIGO detector and the observation of gravitational waves, two Caltech physicists, Kip Thorne and Barry Barish, and Massachusetts Institute of Technology (US) physicist Rainer Weiss won the Nobel Prize in physics in 2017. Weiss, who is also an Massachusetts Institute of Technology (US) graduate, designed the laser interferometric technique, which served as the essential blueprint for the LIGO.

    The mission of Massachusetts Institute of Technology (US) is to advance knowledge and educate students in science, technology, and other areas of scholarship that will best serve the nation and the world in the twenty-first century. We seek to develop in each member of the Massachusetts Institute of Technology (US) community the ability and passion to work wisely, creatively, and effectively for the betterment of humankind.

  • richardmitnick 10:21 am on July 3, 2017 Permalink | Reply
    Tags: , CRISPR, , , ,   

    From HMS: “Bringing CRISPR into Focus” 

    Harvard University

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    Harvard Medical School

    Harvard Medical School

    June 29, 2017

    CRISPR-Cas3 is a subtype of the CRISPR-Cas system, a widely adopted molecular tool for precision gene editing in biomedical research. Aspects of its mechanism of action, however, particularly how it searches for its DNA targets, were unclear, and concerns about unintended off-target effects have raised questions about the safety of CRISPR-Cas for treating human diseases.

    Harvard Medical School and Cornell University scientists have now generated near-atomic resolution snapshots of CRISPR that reveal key steps in its mechanism of action. The findings, published in Cell on June 29, provide the structural data necessary for efforts to improve the efficiency and accuracy of CRISPR for biomedical applications.

    Through cryo-electron microscopy, the researchers describe for the first time the exact chain of events as the CRISPR complex loads target DNA and prepares it for cutting by the Cas3 enzyme. These structures reveal a process with multiple layers of error detection—a molecular redundancy that prevents unintended genomic damage, the researchers say.

    High-resolution details of these structures shed light on ways to ensure accuracy and avert off-target effects when using CRISPR for gene editing.

    “To solve problems of specificity, we need to understand every step of CRISPR complex formation,” said Maofu Liao, assistant professor of cell biology at Harvard Medical School and co-senior author of the study. “Our study now shows the precise mechanism for how invading DNA is captured by CRISPR, from initial recognition of target DNA and through a process of conformational changes that make DNA accessible for final cleavage by Cas3.”

    Target search

    Discovered less than a decade ago, CRISPR-Cas is an adaptive defense mechanism that bacteria use to fend off viral invaders. This process involves bacteria capturing snippets of viral DNA, which are then integrated into its genome and which produce short RNA sequences known as crRNA (CRISPR RNA). These crRNA snippets are used to spot “enemy” presence.

    Acting like a barcode, crRNA is loaded onto members of the CRISPR family of enzymes, which perform the function of sentries that roam the bacteria and monitor for foreign code. If these riboprotein complexes encounter genetic material that matches its crRNA, they chop up that DNA to render it harmless. CRISPR-Cas subtypes, notably Cas9, can be programmed with synthetic RNA in order to cut genomes at precise locations, allowing researchers to edit genes with unprecedented ease.

    To better understand how CRISPR-Cas functions, Liao partnered with Ailong Ke of Cornell University. Their teams focused on type 1 CRISPR, the most common subtype in bacteria, which utilizes a riboprotein complex known as CRISPR Cascade for DNA capture and the enzyme Cas3 for cutting foreign DNA.

    Through a combination of biochemical techniques and cryo-electron microscopy, they reconstituted stable Cascade in different functional states, and further generated snapshots of Cascade as it captured and processed DNA at a resolution of up to 3.3 angstroms—or roughly three times the diameter of a carbon atom.

    A sample cryo-electron microscope image of CRISPR molecules(left). The research team combined hundreds of thousands of particles into 2D averages (right), before turning them into 3D projections. Image: Xiao et al.

    Seeing is believing

    In CRISPR-Cas3, crRNA is loaded onto CRISPR Cascade, which searches for a very short DNA sequence known as PAM that indicates the presence of foreign viral DNA.

    Liao, Ke and their colleagues discovered that as Cascade detects PAM, it bends DNA at a sharp angle, forcing a small portion of the DNA to unwind. This allows an 11-nucleotide stretch of crRNA to bind with one strand of target DNA, forming a “seed bubble.”

    The seed bubble acts as a fail-safe mechanism to check whether the target DNA matches the crRNA. If they match correctly, the bubble is enlarged and the remainder of the crRNA binds with its corresponding target DNA, forming what is known as an “R-loop” structure.

    Once the R-loop is completely formed, the CRISPR Cascade complex undergoes a conformational change that locks the DNA into place. It also creates a bulge in the second, non-target strand of DNA, which is run through a separate location on the Cascade complex.

    Only when a full R-loop state is formed does the Cas3 enzyme bind and cut the DNA at the bulge created in the non-target DNA strand.

    The findings reveal an elaborate redundancy to ensure precision and avoid mistakenly chopping up the bacteria’s own DNA.

    CRISPR forms a “seed bubble” state, which acts as an initial fail-safe mechanism to ensure that CRISPR RNA matches its target DNA. Image: Liao Lab/HMS

    “To apply CRISPR in human medicine, we must be sure the system is accurate and that it does not target the wrong genes,” said Ke, who is co-senior author of the study. “Our argument is that the CRISPR-Cas3 subtype has evolved to be a precise system that carries the potential to be a more accurate system to use for gene editing. If there is mistargeting, we know how to manipulate the system because we know the steps involved and where we might need to intervene.”

    Setting the sights

    Structures of CRISPR Cascade without target DNA and in its post-R-loop conformational states have been described, but this study is the first to reveal the full sequence of events from seed bubble formation to R-loop formation at high resolution.

    In contrast to the scalpel-like Cas9, CRISPR-Cas3 acts like a shredder that chews DNA up beyond repair. While CRISPR-Cas3 has, thus far, limited utility for precision gene editing, it is being developed as a tool to combat antibiotic-resistant strains of bacteria. A better understanding of its mechanisms may broaden the range of potential applications for CRISPR-Cas3.

    In addition, all CRISPR-Cas subtypes utilize some version of an R-loop formation to detect and prepare target DNA for cleavage. The improved structural understanding of this process can now enable researchers to work toward modifying multiple types of CRISPR-Cas systems to improve their accuracy and reduce the chance of off-target effects in biomedical applications.

    “Scientists hypothesized that these states existed but they were lacking the visual proof of their existence,” said co-first author Min Luo, postdoctoral fellow in the Liao lab at HMS. “The main obstacles came from stable biochemical reconstitution of these states and high-resolution structural visualization. Now, seeing really is believing.”

    “We’ve found that these steps must occur in a precise order,” Luo said. “Evolutionarily, this mechanism is very stringent and has triple redundancy, to ensure that this complex degrades only invading DNA.”

    Additional authors on the study include Yibei Xiao, Robert P. Hayes, Jonathan Kim, Sherwin Ng, and Fang Ding.

    This work is supported by National Institutes of Health

    See the full article here .

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    HMS campus

    Established in 1782, Harvard Medical School began with a handful of students and a faculty of three. The first classes were held in Harvard Hall in Cambridge, long before the school’s iconic quadrangle was built in Boston. With each passing decade, the school’s faculty and trainees amassed knowledge and influence, shaping medicine in the United States and beyond. Some community members—and their accomplishments—have assumed the status of legend. We invite you to access the following resources to explore Harvard Medical School’s rich history.

    Harvard University campus

    Harvard is the oldest institution of higher education in the United States, established in 1636 by vote of the Great and General Court of the Massachusetts Bay Colony. It was named after the College’s first benefactor, the young minister John Harvard of Charlestown, who upon his death in 1638 left his library and half his estate to the institution. A statue of John Harvard stands today in front of University Hall in Harvard Yard, and is perhaps the University’s best known landmark.

    Harvard University has 12 degree-granting Schools in addition to the Radcliffe Institute for Advanced Study. The University has grown from nine students with a single master to an enrollment of more than 20,000 degree candidates including undergraduate, graduate, and professional students. There are more than 360,000 living alumni in the U.S. and over 190 other countries.

  • richardmitnick 1:15 pm on June 25, 2017 Permalink | Reply
    Tags: , , Bacteriophages, CRISPR, Genetically modified viruses,   

    From Nature: “Modified viruses deliver death to antibiotic-resistant bacteria” 

    Nature Mag

    21 June 2017
    Sara Reardon

    Engineered microbes turn a bacterium’s immune response against itself using CRISPR.

    Phages (green) attack a bacterium (orange). Researchers are hoping to use engineered versions of these viruses to fight antibiotic resistance. AMI Images/SPL

    Genetically modified viruses that cause bacteria to kill themselves could be the next step in combating antibiotic-resistant infections [Nature].

    Several companies have engineered such viruses, called bacteriophages, to use the CRISPR gene-editing system to kill specific bacteria, according to a presentation at the CRISPR 2017 conference in Big Sky, Montana, last week. These companies could begin clinical trials of therapies as soon as next year.

    Initial tests have saved mice from antibiotic-resistant infections that would otherwise have killed them, said Rodolphe Barrangou, chief scientific officer of Locus Biosciences in Research Triangle Park, North Carolina, at the conference.

    Bacteriophages isolated and purified from the wild have long been used to treat infections in people, particularly in Eastern Europe. These viruses infect only specific species or strains of bacteria, so they have less of an impact on the human body’s natural microbial community, or microbiome, than antibiotics do. They are also generally thought to be very safe for use in people.

    But the development of phage therapy has been slow, in part because these viruses are naturally occurring and so cannot be patented. Bacteria can also quickly evolve resistance to natural phages, meaning researchers would have to constantly isolate new ones capable of defeating the same bacterial strain or species. And it would be difficult for regulatory agencies to continually approve each new treatment.

    CRISPR-fuelled death

    To avoid these issues, Locus and several other companies are developing phages that turn the bacterial immune system known as CRISPR against itself. In Locus’ phages, which target bacteria resistant to antibiotics, the CRISPR system includes DNA with instructions for modified guide RNAs that home in on part of an antibiotic-resistance gene. Once the phage infects a bacterium, the guide RNA latches on to the resistance gene. That prompts an enzyme called Cas3, which the bacterium normally produces to kill phages, to destroy that genetic sequence instead. Cas3 eventually destroys all the DNA, killing the bacterium. “I see some irony now in using phages to kill bacteria,” says Barrangou.

    Another company, Eligo Bioscience in Paris, uses a similar approach. It has removed all the genetic instructions that allow phages to replicate, and inserted DNA that encodes guide RNAs and the bacterial enzyme Cas9. Cas9 cuts the bacterium’s DNA at a designated spot, and the break triggers the bacterium to self-destruct. The system will target human gut pathogens, says Eligo chief executive Xavier Duportet, although he declined to specify which ones.

    The two companies hope to start clinical trials in 18–24 months. Their first goal is to treat bacterial infections that cause severe disease. But eventually, they want to develop phages that let them precisely engineer the human microbiome by removing naturally occurring bacteria associated with conditions such as obesity, autism and some cancers.

    Both Barrangou and Duportet acknowledge that for now, causal links between the human microbiome and these conditions are tenuous at best. But they hope that by the time their therapies have been proved safe and effective in humans, the links will be better understood. Phages could also allow researchers to manipulate the microbiomes of experimental animals, which could help them to untangle how certain bacteria influence conditions such as autism, says Timothy Lu, a synthetic biologist at the Massachusetts Institute of Technology in Cambridge and a co-founder of Eligo.

    An engineered solution

    Other companies are working to get phages to perform different tasks. ‘Supercharged’ phages, created by a group at Synthetic Genomics in La Jolla, California, could contain dozens of special features, including enzymes that break down biofilms or proteins that help to hide the phages from the human immune system.

    But engineered phages still have to overcome some hurdles. Treating an infection might require a large volume of phages, says Elizabeth Kutter, a microbiologist at Evergreen State College in Olympia, Washington, and it’s unclear whether this would trigger immune reactions, some of which could interfere with the treatment. Phages could also potentially transfer antibiotic-resistance genes to non-resistant bacteria, she notes.

    Lu adds that bacteria may still develop resistance even to the engineered phages. So researchers might have to frequently modify their phages to keep up with bacterial mutations.

    But as antibiotic resistance spreads, Kutter says, there will be plenty of space for both engineered phages and natural phage therapies, which are also growing in popularity. “I think they’ll complement the things that can be done by natural phages that have been engineered for hundreds of thousands of years,” she says.

    Related stories and links
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  • richardmitnick 5:23 pm on June 2, 2016 Permalink | Reply
    Tags: , , CRISPR, Researchers unlock new CRISPR system for targeting RNA   

    From Broad Institute: “Researchers unlock new CRISPR system for targeting RNA” 

    Broad Institute

    Broad Institute

    June 2nd, 2016
    Broad Institute of MIT and Harvard
    Paul Goldsmith

    Discovered in bacteria as viral defense mechanism, researchers program C2c2 to manipulate cellular RNA using CRISPR

    Researchers from the Broad Institute of MIT and Harvard, Massachusetts Institute of Technology, the National Institutes of Health, Rutgers University-New Brunswick and the Skolkovo Institute of Science and Technology have characterized a new CRISPR system that targets RNA, rather than DNA.

    The new approach has the potential to open a powerful avenue in cellular manipulation. Whereas DNA editing makes permanent changes to the genome of a cell, the CRISPR-based RNA-targeting approach may allow researchers to make temporary changes that can be adjusted up or down, and with greater specificity and functionality than existing methods for RNA interference.

    A team led by Feng Zhang of the Broad and MIT and Eugene Koonin of the NIH has revealed that C2c2 helps protect bacteria against viral
    infection by targeting RNA. Photo composite by Lauren Solomon, Broad communications. Images courtesy of Broad communications and NIH.

    In a study* published today in Science, Feng Zhang and colleagues at the Broad Institute and the McGovern Institute for Brain Research at MIT, along with co-authors Eugene Koonin and his colleagues at the NIH, and Konstantin Severinov of Rutgers University-New Brunswick and Skoltech, report the identification and functional characterization of C2c2, an RNA-guided enzyme capable of targeting and degrading RNA.

    The findings reveal that C2c2—the first naturally-occurring CRISPR system that targets only RNA to have been identified, discovered by this collaborative group in October 2015—helps protect bacteria against viral infection. They demonstrate that C2c2 can be programmed to cleave particular RNA sequences in bacterial cells, which would make it an important addition to the molecular biology toolbox.

    The RNA-focused action of C2c2 complements the CRISPR-Cas9 system, which targets DNA, the genomic blueprint for cellular identity and function. The ability to target only RNA, which helps carry out the genomic instructions, offers the ability to specifically manipulate RNA in a high-throughput manner—and manipulate gene function more broadly. This has the potential to accelerate progress to understand, treat and prevent disease.

    “C2c2 opens the door to an entirely new frontier of powerful CRISPR tools,” said Feng Zhang, senior author, and Core Institute Member of the Broad Institute. “There are an immense number of possibilities for C2c2 and we are excited to develop it into a platform for life science research and medicine.”

    “The study of C2c2 uncovers a fundamentally novel biological mechanism that bacteria seem to use in their defense against viruses,” said Eugene Koonin, senior author, and leader of the Evolutionary Genomics Group at the NIH’s National Center for Biotechnology Information. “Applications of this strategy could be quite striking.”

    Currently, the most common technique for performing gene knockdown is small interfering RNA (siRNA). According to the researchers, C2c2 RNA-editing methods suggest greater specificity and hold the potential for a wider range of applications, such as:

    Adding modules to specific RNA sequences to alter their function—how they are translated into proteins—which would make them valuable tools for large-scale screens and constructing synthetic regulatory networks, and
    Harnessing C2c2 to fluorescently tag RNAs as a means to study their trafficking and subcellular localization.

    In this work, the team was able to precisely target and remove specific RNA sequences using C2c2 – lowering the expression level of the corresponding protein. This suggests C2c2 could represent an alternate approach to siRNA, complementing the specificity and simplicity of CRISPR-based DNA editing and offering researchers adjustable gene “knockdown” capability using RNA.

    C2c2 has advantages that make it suitable for tool development:

    C2c2 is a two-component system, requiring only a single guide RNA to function, and
    C2c2 is genetically encodable—meaning the necessary components can be synthesized as DNA for delivery into tissue and cells.

    “C2c2’s greatest impact may be made on our understanding the role of RNA in disease and cellular function,” said co-first author Omar Abudayyeh, a graduate student in the Zhang Lab.

    *Science paper:
    C2c2 is a single-component programmable RNA-guided RNA-targeting CRISPR effector

    See the full article here .

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  • richardmitnick 3:18 pm on May 3, 2016 Permalink | Reply
    Tags: , , CRISPR,   

    From AAAS: “The gene editor CRISPR won’t fully fix sick people anytime soon. Here’s why” 



    May. 3, 2016
    Jocelyn Kaiser

    Researchers still have a ways to go before using CRISPR to repair genes in patients. iStock

    This week, scientists will gather in Washington, D.C., for an annual meeting devoted to gene therapy—a long-struggling field that has clawed its way back to respectability with a string of promising results in small clinical trials. Now, many believe the powerful new gene-editing technology known as CRISPR will add to gene therapy’s newfound momentum. But is CRISPR really ready for prime time? Science explores the promise—and peril—of the new technology.

    How does CRISPR work?

    Traditional gene therapy works via a relatively brute-force method of gene transfer. A harmless virus, or some other form of so-called vector, ferries a good copy of a gene into cells that can compensate for a defective gene that is causing disease. But CRISPR can fix the flawed gene directly, by snipping out bad DNA and replacing it with the correct sequence. In principle, that should work much better than adding a new gene because it eliminates the risk that a foreign gene will land in the wrong place and turn on a cancer gene. And a CRISPR-repaired gene will be under the control of that gene’s natural promoter, so the cell won’t make too much or too little of its protein product.

    What has CRISPR accomplished so far?

    Researchers have published successes with using CRISPR to treat animals with an inherited liver disease and muscular dystrophy, and there will be more such preclinical reports at this week’s annual meeting of the American Society of Gene and Cell Therapy (ASGCT). The buzz around CRISPR is growing. This year’s meeting includes 93 abstracts on CRISPR (of 768 total), compared with only 33 last year. What’s more, investors are flocking to CRISPR. Three startups, Editas Medicine, Intellia Therapeutics, and CRISPR Therapeutics, have already attracted hundreds of millions of dollars.

    So why isn’t CRISPR ready for prime time?

    CRISPR still has a long way to go before it can be used safely and effectively to repair—not just disrupt—genes in people. That is particularly true for most diseases, such as muscular dystrophy and cystic fibrosis, which require correcting genes in a living person because if the cells were first removed and repaired then put back, too few would survive. And the need to treat cells inside the body means gene editing faces many of the same delivery challenges as gene transfer—researchers must devise efficient ways to get a working CRISPR into specific tissues in a person, for example.

    CRISPR also poses its own safety risks. Most often mentioned is that the Cas9 enzyme that CRISPR uses to cleave DNA at a specific location could also make cuts where it’s not intended to, potentially causing cancer.

    With these caveats, do you even need CRISPR?

    Conventional gene addition treatments for some diseases are so far along that it may not make sense to start over with CRISPR. In Europe, where one gene therapy is already approved for use for a rare metabolic disorder, regulators are poised to approve a second for an immune disorder known as adenosine deaminase–severe combined immunodeficiency (SCID). And in the United States, a company this year expects to seek approval for a gene transfer treatment for a childhood blindness disease called Leber congenital amaurosis (LCA).

    At the ASCGT meeting, researchers working with the company Bluebird Bio will present interim data for a late-stage trial showing that gene addition can halt the progression of cerebral adrenoleukodystrophy, a devastating childhood neurological disease. Final results could help pave the way for regulatory approval. Bluebird will also report on trials using gene transfer for two blood disorders, sickle cell disease and β-thalassemia, bringing these treatments closer to the clinic.

    Except for LCA, in which gene-carrying viruses are injected directly into eyes, these diseases are treated by removing bone marrow cells from patients, adding a gene to the cells, and reinfusing the cells back into the patient. New, safer viral vectors have reduced risks of leukemia seen in a few patients in some early trials for immunodeficiency diseases. Researchers are seeing “excellent clinical responses,” says Donald Kohn of the University of California, Los Angeles.

    Although Kohn and other researchers have used an older gene-editing tool known as zinc finger nucleases to repair defective genes causing sickle cell disease and a type of SCID in cells in a dish, only a tiny fraction of immature blood cells needed for the therapy to work end up with the gene corrected—far below the fraction altered by now standard gene transfer methods. One reason is because the primitive blood cells aren’t dividing much (more on this below). Because gene-editing methods such as CRISPR are so much less efficient than gene addition, for several diseases, “I don’t think there will be a strong rationale for switching to editing,” says Luigi Naldini of the San Raffaele Telethon Institute for Gene Therapy in Milan, Italy.

    CRISPR also has other issues

    Using CRISPR to cut out part of a gene—not correct the sequence—is relatively easy to do. In fact, this strategy is already being tested with zinc finger nucleases in a clinical effort to stop HIV infection. In this treatment, the nucleases are used to knock out a gene for a receptor called CCR5 in blood cells that HIV uses to get into cells.

    But when CRISPR is used to correct a gene using a strand of DNA that scientists supply to cells, not just to snip out some DNA, it doesn’t work very well. That’s because the cells must edit the DNA using a process called homology-directed repair, or HDR, that is only active in dividing cells. And unfortunately, most cells in the body—liver, neuron, muscle, eye, blood stem cells—are not normally dividing. For this reason, “knocking out a gene is a lot simpler than knocking in a gene and correcting a mutation,” says Cynthia Dunbar, president-elect of ASGCT and a gene therapy researcher at the National Heart, Lung, and Blood Institute in Bethesda, Maryland.

    Researchers are working on ways to get around this limitation. The genes for HDR are present in all cells, and it’s a matter of turning them on, perhaps by adding certain drugs to the cells, says CRISPR researcher Feng Zhang of the Broad Institute in Cambridge, Massachusetts. Another avenue is to find alternatives to the Cas9 system that don’t rely on the HDR process, Zhang says.

    But the low rate of HDR in most cells is one reason why the first use of CRISPR in the clinic will likely involve disrupting genes, not fixing them. For example, several labs have shown in mice that CRISPR can remove a portion of the defective gene that causes Duchenne muscular dystrophy, so that the remaining portion will produce a functional, albeit truncated protein. Editas hopes to start a clinical trial next year to treat a form of LCA blindness by chopping out part of the defective gene. One proposed gene-editing treatment for sickle cell disease would similarly snip out some DNA, so that blood cells produce a fetal form of the oxygen-carrying protein hemoglobin.

    And CRISPR still has big safety risks

    The most-discussed safety risk with CRISPR is that the Cas9 enzyme, which is supposed to slice a specific DNA sequence, will also make cuts in other parts of the genome that could result in mutations that raise cancer risk. Researchers are moving quickly to make CRISPR more specific. For example, in January, one lab described a tweak to Cas9 that dramatically reduces off-target effects. And in April in Nature, another team showed how to make the enzyme more efficient at swapping out single DNA bases.

    But immediate off-target cuts aren’t the only worry. Although it’s possible to deliver CRISPR’s components into cells in a dish as proteins or RNA, so far researchers can usually only get it working in tissue inside the body by using a viral vector to deliver the DNA for Cas9 into cells. This means that even after Cas9 has made the desired cuts, cells will keep cranking it out. “The enzyme will still hang around over 10, 20 years,” Zhang says. That raises the chances that even a very specific Cas9 will still make off-target cuts and that the body will mount an immune response to the enzyme.

    This may not truly be a problem, Zhang suggests. His team created a mouse strain that is born with the gene for Cas9 turned on all the time, so it expresses the enzyme in all cells for the animal’s entire life. Even after interbreeding these mice for about 20 generations, the mice “seem to be fine” with no obvious abnormal health effects, Zhang says. All the same, “the most ideal case is, we want to shut off the enzyme.” And that may mean finding nonviral methods for getting Cas9 into cells, such as ferrying the protein with lipids or nanoparticles—delivery methods that biologists have long struggled to make work in living animals.

    Other long-standing obstacles to gene therapy will confront efforts using CRISPR, too. Depending on the disease, any gene-edited cells may eventually die and patients could have to be treated multiple times. Researchers using gene transfer and editing approaches are also both hindered by limits on how much DNA a viral vector can carry. Right now CRISPR researchers often must use two different viruses to get CRISPR’s components into cells, which is less efficient than a single vector.

    So what’s the bottom line?

    Gene therapists remain excited by CRISPR, in part because it could tackle many more inherited diseases than can be treated with gene transfer. Among them are certain immune diseases where the amount of the repaired protein must be precisely controlled. In other cases, such as sickle cell disease, patients won’t get completely well unless a defective protein is no longer made by their cells, so just adding a gene isn’t enough. “It opens up a lot of diseases to gene therapy because gene addition wasn’t going to work,” Dunbar says.

    After more than 2 decades of seeing their field through ups and downs, veterans of the gene therapy field are wary of raising expectations about CRISPR for treating diseases. “Whenever there’s a new technology, there’s a huge amount of excitement and everybody thinks it will be ready tomorrow to cure patients,” says gene therapy researcher Mark Kay of Stanford University in Palo Alto, California. “It’s going to take some time.”

    See the full article here .

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  • richardmitnick 2:12 pm on March 22, 2016 Permalink | Reply
    Tags: , , CRISPR,   

    From MIT: “Toward a better understanding of the brain” 

    MIT News
    MIT News

    March 22, 2016
    Anne Trafton | MIT News Office

    “I was always interested in biology but I felt that it’s important to get a solid training in chemistry and physics,” Feng Zhang says. Photo: Bryce Vickmark


    In 2011, about a month after joining the MIT faculty, Feng Zhang attended a talk by Harvard Medical School Professor Michael Gilmore, who studies the pathogenic bacterium Enteroccocus. The scientist mentioned that these bacteria protect themselves from viruses with DNA-cutting enzymes known as nucleases, which are part of a defense system known as CRISPR.

    “I had no idea what CRISPR was but I was interested in nucleases,” Zhang says. “I went to look up CRISPR, and that’s when I realized you might be able to engineer it for use for genome editing.”

    Zhang devoted himself to adapting the system to edit genes in mammalian cells and recruited new members to his nascent lab at the Broad Institute of MIT and Harvard to work with him on this project. In January 2013, they reported their success in the journal Science.

    Since then, scientists in fields from medicine to plant biology have begun using CRISPR to study gene function and investigate the possibility of correcting faulty genes that cause disease. Zhang now heads a lab of 19 scientists who continue to develop the system and pursue applications of genome editing, especially in neuroscience.

    “The goal is to try to make our lives better by developing new technologies and using them to understand biological systems so that we can improve our treatment of disease and our quality of life,” says Zhang, W. M. Keck Career Development Associate Professor in Biomedical Engineering and a member of MIT’s McGovern Institute for Brain Research. Zhang recently earned tenure in MIT’s Departments of Biological Engineering and Brain and Cognitive Sciences.

    Understanding the brain

    Growing up in Des Moines, Iowa, where his parents moved from China when he was 11, Zhang had plenty of opportunities to feed his interest in science. He participated in Science Bowl competitions and took special Saturday science classes, where he got his first introduction to molecular biology. Experiments such as extracting DNA from strawberries and transforming bacteria with genes for drug resistance whetted his appetite for genetic engineering, which was further stimulated by a showing of “Jurassic Park.”

    “That really caught my attention,” he recalls. “It didn’t seem that far-fetched. I guess that’s what makes it good science fiction. It kind of tantalizes your imagination.”

    As a sophomore in high school, Zhang began working with Dr. John Levy in a gene therapy lab at the Iowa Methodist Medical Center in Des Moines, where he studied green fluorescent protein (GFP). Scientists had recently figured out how to adapt this naturally occurring protein to tag and image proteins inside living cells. Zhang used it to track viral proteins within infected cells to determine how the proteins assemble to form new viruses. He also worked on a project to adapt GFP for a different purpose — protecting DNA from damage induced by ultraviolet light.

    At Harvard University, where he earned his undergraduate degree, Zhang majored in chemistry and physics and did research under the mentorship of Xiaowei Zhuang, a professor of chemistry and chemical biology. “I was always interested in biology but I felt that it’s important to get a solid training in chemistry and physics,” he says.

    While Zhang was at Harvard, a close friend was severely affected by a psychiatric disorder. That experience made Zhang think about whether such disorders could be approached just like cancer or heart disease, if only scientists knew more about their underlying causes.

    “The difference is we’re at a much earlier stage of understanding psychiatric diseases. That got me really interested in trying to understand more about how the brain works,” he says.

    At Stanford University, where Zhang earned his PhD in chemistry, he worked with Karl Deisseroth, who was just starting his lab with a focus on developing new technology for studying the brain. Zhang was the second student to join the lab, and he began working on a protein called channelrhodopsin, which he and Deisseroth believed held potential for engineering mammalian cells to respond to light.

    The resulting technique, known as optogenetics, has transformed biological research. Collaborating with Edward Boyden, a member of the Deisseroth lab who is now a professor at MIT, Zhang adapted channelrhodopsin so that it could be inserted into neurons and make them light-sensitive. Using this approach, neuroscientists can now selectively activate and de-activate specific neurons in the brain, allowing them to map brain circuits and investigate how disruption of those circuits causes disease.

    Better gene editing

    After leaving Stanford, Zhang spent a year as a junior fellow at the Harvard Society of Fellows, studying brain development with Professor Paola Arlotta and collaborating with Professor George Church. That’s when he began to focus on gene editing — a type of genetic engineering that allows researchers to selectively delete a gene or replace it with a new one.

    He began with zinc finger nucleases — enzymes that can be designed to target and cut specific DNA sequences. However, these proteins turned out to be challenging to work with, in part because it is so time-consuming to design a new protein for each possible DNA target.

    That led Zhang to experiment with a different type of nucleases known as transcription activator-like effector nucleases (TALENs), but these also proved laborious to work with. “Learning how to use them is a project on its own,” Zhang says.

    When he heard about CRISPR in early 2011, Zhang sensed that harnessing the natural bacterial process held the potential to solve many of the challenges associated with those earlier gene-editing techniques. CRISPR includes a nuclease called Cas9, which can be guided to the correct genetic target by RNA molecules known as guide strands. For each target, scientists need only design and synthesize a new RNA guide, which is much simpler than creating new TALEN and zinc finger proteins.

    Since his first CRISPR paper in 2013, Zhang’s lab has devised many enhancements to the original system, such as making the targeting more precise and preventing unintended cuts in the wrong locations. They also recently reported another type of CRISPR system based on a different nuclease called Cpf1, which is simpler and has unique features that further expand the genome editing toolbox.

    Zhang’s lab has become a hub for CRISPR research worldwide. It has shared CRISPR-Cas9 components in response to nearly 30,000 requests from academic laboratories around the world and has trained thousands of researchers in the use of CRISPR-Cas9 genome-editing technology through in-person events and online opportunities.

    His team is now working on creating animal models of autism, Alzheimer’s, and other neurological disorders, and in the long term, they hope to develop CRISPR for use in humans to potentially cure diseases caused by defective genes.

    “There are many genetic diseases that we don’t have any way of treating and this could be one way, but we still have to do a lot of work,” Zhang says.

    See the full article here .

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  • richardmitnick 5:31 pm on February 5, 2016 Permalink | Reply
    Tags: , CRISPR,   

    From SA: “The Embarrassing, Destructive Fight over Biotech’s Big Breakthrough” 

    Scientific American

    Scientific American

    February 4, 2016
    Stephen S. Hall

    The gene-editing technology known as CRISPR has spawned an increasingly unseemly brawl over who will reap the rewards.

    A defining moment in modern biology occurred on July 24, 1978, when biotechnology pioneer Robert Swanson, who had recently co-founded Genentech, brought two young scientists to dinner with Thomas Perkins, the legendary venture capitalist. As they stood outside Perkins’s magnificent mansion in Marin County, with its swimming pool and garden and a view of the Golden Gate Bridge, Swanson turned to his two young colleagues and said, “This is what we’re all working for.”

    That scene came to mind as I sorted through the tawdry verbal wreckage on social media and in print of the “debate” over CRISPR, the revolutionary new gene-editing technology. The current brouhaha, triggered by Eric Lander’s now-infamous essay in Cell called The Heroes of CRISPR, is the most entertaining food fight in science in years.

    The stakes are exceedingly high. CRISPR is the most important new technology to hit biology since recombinant DNA, which launched Genentech, made Swanson, along with his colleagues and investors, rich and brought molecular biology, long the province of academia, into the realm of celebrity and big money. In this context, the Cell essay has huge patent and prize implications. Lander has been accused of writing an incomplete and inaccurate history of the CRISPR story, burnishing the patent claims of the Broad Institute in Cambridge, Mass., (he is its director) and minimizing the contributions of rival scientists. A blogger has referred to him as “an evil genius at the height of his craft.” And George Church, a colleague at the Broad Institute, likens Lander to a figure out of a Greek tragedy. “The only person that could hurt him was himself,” he says. “He was invulnerable to anybody else’s sword.” And you thought scientists couldn’t talk smack.

    Spectators, scientific and otherwise, have followed this bitter dispute with fascination but the fight is destructive–and far from over. In waging a nasty public battle over CRISPR, the protagonists have given science a black eye for the reason Swanson suggested on that long-ago night in Marin County: money and glory. In waging a nasty public fight over CRISPR, they have already attracted the scrutiny of the mainstream press (The Washington Post and the Boston Globe Media’s STAT, to name two avid voyeurs), the scientific press and, oh boy, the Internet. The trash talking has undermined the public image of science, raised unflattering questions about the motives of scientists and institutions and, less obviously, fueled doubts about the judgment of leading scientific journals, which act as unofficial auditors of the billions of taxpayer dollars spent on biological research. The spat is like an escalating and increasingly ugly domestic dispute: no one wants outsiders to get involved but the screaming has gotten so loud that somebody has to call the cops. The fight over CRISPR is getting to that point. Woe be it to science if the politicians step in and use the fight as an excuse to rethink funding or the rules of technology transfer.

    The scientific story has deep roots. Scientists glimpsed the first hint of CRISPR biology in the 1980s and primitive forms of gene-editing arose in the 1990s. But a crucial leap occurred in 2012 when a group led by Jennifer Doudna of the University of California, Berkeley, and Emmanuelle Charpentier, now at the Max Planck Institute for Infection Biology in Berlin, demonstrated the possibility of simple CRISPR-based gene-editing to a broad audience of scientists with a paper in Science. The University of California and the University of Vienna filed for a patent, listing Doudna, Charpentier and other individuals. But the U.S. Patent and Trademark Office issued a patent in 2014 to Feng Zhang of the Broad Institute, which filed its application after Berkeley but requested expedited consideration. The University of California has challenged the validity of all the Broad patents (now numbering about a dozen) and the ensuing “interference” proceedings may allow another year of trash talking by scientists and bloggers alike. Meanwhile the protagonists—and their institutional proxies—continue to jockey for priority, prizes and reputation.

    Against this backdrop, Lander’s piece came as a shock. Lander is director of the Broad Institute and therefore someone with a very big dog in the patent fight. Maybe by calling it a “Perspective” the editors of Cell were signaling Lander’s obvious conflict of interest; nothing else in the article did.

    Let me note, first, that The Heroes of CRISPR is beautifully written. In addition to being a fabulous scientist and truly visionary thinker, Lander is a terrific communicator. His history reads at times like high-end magazine journalism (the story begins in Spain’s Costa Blanca, “where the beautiful coast and vast salt marshes have for centuries attracted vacationers, flamingoes and commercial salt producers”) with almost novelistic detail (Zhang, born in China and reared in Des Moines, has his eureka moment while “holed up” in a Miami hotel)—not your average journal prose. Lander’s account of the early work on CRISPR, often overlooked, is thorough, accurate and generous, according to people who know the history well. And it’s written as a feel-good story with an inspirational take-home message: People who work off the beaten track, in both the geographic and biological sense, often make dramatic contributions to the “remarkable ecosystem underlying scientific discovery,” he notes. Scientific breakthroughs are “ensemble acts” that unfold over many years. “It’s a wonderful lesson for the general public,” Lander concludes, “as well as for a young person contemplating a life in science.”

    Beautifully put. So why did the Twitterverse go radioactive on Lander within hours of the article’s publication on January 14?

    As I often suggest to students in my science journalism classes, just because a story is beautifully written doesn’t mean that it is true—in whole or in part. Judging from the firestorm of criticism, “The Heroes of CRISPR” falls short on a number of issues, beginning with this awkward money-tinged paradox: If the CRISPR story (and science in general) is such a beautiful ensemble activity, why is there only one name on the Broad Institute’s patent? Well, patents have to do with money, and money turns a lot of beautiful scientific stories into ugly legal narratives.

    Case in point: in 1979, a year after Bob Swanson’s pep talk to his Genentech biologists, a biologist then at Columbia University named Michael Wigler published a very clever method (called “co-transformation”) for smuggling genes into eukaryotic cells; the university filed a patent application in 1980, with Wigler and two colleagues as inventors, and received the first of several patents in 1983. Like CRISPR, the technique may sound esoteric but biologists (and companies) quickly recognized its value, and Columbia ultimately reaped nearly $800 million from those patents. (Other, unofficial estimates run between $1 billion and $1.5 billion.) Columbia became so enamored of the revenue stream that it resorted to several controversial tactics, including having a U.S. senator try to extend the patent by slipping language into an agricultural bill. These maneuvers prompted an uproar and were later characterized, by historians of genomics Robert Cook-Deegan and Alessandra Colaianni, both then at Duke University, as “behavior unbecoming a nonprofit academic institution.”

    Wigler, who now runs a lab at Cold Spring Harbor Laboratory, says of the Columbia patent: “Of course it’s had an impact on institutions, because institutions are desperate for money.” That’s why the University of California and the Broad Institute (a joint venture of Harvard University and Massachusetts Institute of Technology) will fight fiercely—“red in tooth and claw,” you might say—to claim intellectual property on CRISPR.

    Many readers (including me) interpreted Lander’s elegant history of CRISPR as a calculated attempt to elevate the intellectual contribution of Zhang (the Broad Institute scientist who is recognized, for the moment, by the patent office as the lone “inventor” of CRISPR) as it minimizes the contributions of Doudna and Charpentier. (Zhang’s discovery narrative is long, detailed and colorful; Doudna’s appearance comes in the middle of a paragraph, and her work doesn’t get nearly the same star treatment.) In other words, this beautifully crafted history can also be read as a patent brief in disguise. (A blog by science historian Nathaniel Comfort shrewdly deconstructs the rhetoric used by Lander to advance Broad’s interests. Inexplicably, Cell didn’t even mention Lander’s flagrant conflict of interest (an instance of editorial neglect to which we’ll return later).

    Both Doudna and Charpentier quickly posted frostily brief comments to PubMed Commons; Doudna claimed the description of her lab’s work was “factually incorrect,” and Charpentier characterized her part of the story as “incomplete and inaccurate.” Church, whose Harvard lab published on the utility of CRISPR gene-editing in mammalian cells at the same time as Zhang’s, disputed Lander’s history as well in press accounts. When I spoke with Church about a week after the Cell article came out, he was not shy about itemizing. “Normally I’m not so nitpicky about all these errors,” he said. “But as soon as I saw that they [Lander and Cell] were not giving the young people, the people who actually did the work, and Jennifer and Emmanuelle, adequate credit, I just said, ‘No, I have to correct what I know to be false.’” (Lander was “delighted” to append Church’s clarifications to the Cell article). Church acknowledged that the essay was “exquisitely crafted,” but crafted, in his view, with an ulterior motive. “It was like, ‘I’m going to prove my point of view,’” he said. But according to Church, Lander may have achieved the exact opposite effect. “I think Jennifer and Emmanuelle deserve a lot of credit,” he said. “And the more you try to take it from them, the more people want to give it to them.”

    In truth, there are a lot of moving parts and proxies in this messy battle. The hostilities involve institutions (M.I.T. and Harvard versus University of California), gender (Doudna, Charpentier, Zhang), geography (east versus west coast) and what you might call über-institutions (the Broad Institute, which has become an empire of genomic research under Lander’s direction, especially after his leading role in the Human Genome Project, versus the Howard Hughes Medical Institute, whose president, Robert Tjian, is based at Berkeley and has co-authored at least one CRISPR paper with Doudna, also an HHMI investigator). Probably because of this combustible mix of interests, the debate over the Cell article has become especially nasty; whatever used to be the line of decorum in scientific debate, it was breached within 24 hours after the Cell article appeared.

    Some viewed Lander’s history as a gender diss. The title of a post on the Web site Jezebel says it all: How One Man Tried to Write Women Out of CRISPR, the Biggest Biotech Innovation in Decades. Others saw it as shameless politicking for a Nobel Prize.

    And a lot of the invective has been surprisingly personal. Michael Eisen, an HHMI researcher at Berkeley, has been particularly outspoken in his blog. The Cell essay was “an elaborate lie,” Eisen wrote on January 25, and his attack didn’t stop there.

    Lander is in Antarctica and unavailable for comment, according to a Broad Institute spokesperson. But in an e-mail to the Broad staff on January 28 he reiterated his pride in writing the essay and added: “Needless to say, ‘Perspective’ articles are personal opinions. Not everyone will fully agree with anyone else’s point of view. In the end, we come to understand science only by integrating a diverse range of thoughtfully expressed perspectives. And, when scientific discovery is also the subject of patent disputes (as is the case with U.C. Berkeley and Broad–M.I.T.), intellectual disagreements can, as here, give rise to vigorous online discussion.” As for the conflict-of-interest issue, Broad spokesperson Lee McGuire noted that Lander had previously “disclosed the fact that he has no personal financial interest and that the institute he represents does license CRISPR technologies.”

    The dirty truth is that long before Lander’s Cell article the scientific community has been watching this food fight—for patent dollars, for credit, for prizes—with increasing dismay. Both Zhang and Doudna have been subtly lobbying for recognition in what one scientist characterized to me, dismissively, as “their little Nobel talks—they don’t give seminars anymore.” Doudna, Charpentier and Zhang are all outstanding researchers and very likable people but they appear caught up in the vortex of scientific politics and recognition spin. If it were your work and someone was trying to devalue it, you’d defend it to the hilt, too. But the ongoing drama is not a good look for science, and some of the “heroes of CRISPR” are wearing out their welcome on the public stage. “This is not David versus Goliath,” one disgusted scientist told me recently. “This is Goliath against Goliath. These two camps deserve each other, and they can bully each other into oblivion.”

    Why would such a shrewd and strategic thinker like Lander tempt such a public backlash by writing such a cleverly slanted history? Perhaps his ultimate audience was not Cell’s readers nor even the scientific community at large but rather a very small (and select) group of readers in Alexandria, Va. A gifted writer, Lander set out to produce a seemingly neutral and magnanimous history of CRISPR that even an examiner at the U.S. Patent and Trade Office could understand. (If this sounds condescending, consider how Wigler summarizes 35-plus years of dealing with the patent system: “My general experience with the patent office is that they don’t get it. They don’t understand this stuff.”)

    The Lander article has inflicted some surprising collateral damage, notably to scientific publishing itself. Cell’s decision to publish the article, despite the Broad’s clear financial interest in the patent dispute, invited withering criticism. (The journal stated that it “regularly” evaluates its policies, and “will include” in that process the role of institutional conflicts of interest.) And if CRISPR is “the century’s biggest biotech innovation,” as a blogger for The Washington Post recently noted, what does it say about the quality of scientific journals that in at least 10 instances “seminal papers,” according to Lander’s Cell article, were rejected by journals like Nature, Proceedings of the National Academy of Sciences and even Cell itself? In many cases, editors at these journals did not even send out the articles for peer review. Virtually all this research is paid for at least in part by public money, which raises an inconvenient question: Is the public interest served by journals that don’t even recognize scientific excellence? Does Cell even give a hoot about public perception? Here’s what one prominent scientist told me about Cell’s handling of the entire episode: “All they care about is how many times the article is cited in their citation index.” That and the traffic on Twitter.

    That may hint at why the CRISPR dispute is so different, and so dangerous to the scientific community. Trash talking has been a part of science for centuries; Newton’s seemingly magnanimous remark that he stood “on the shoulders of giants” was, to the contrary, likely understood by his contemporaries to be a disparaging reference to the short stature of his main rival, Robert Hooke. But invective today gets amplified and disseminated so rapidly that it assumes a public life of its own, and scientific spats become a reality show complete with egos, self-promotion, greed and Machiavellian stratagems dissected in blogs, on social media and on bulletin boards.

    And then there’s the influence of money. Since the summer of 1978 biotechnology has bestowed untold riches on companies, institutions and individual biologists. It has produced thrilling science and some wonderful (albeit pricey) new medicines. But it has also slowly eroded boundaries between appropriate and inappropriate behavior. Scientific narratives used to be cast in the past tense, about what had been accomplished; now the storytelling is in the future tense to raise venture capital (or, in the case of ‘Heroes,” in what might be called the past imperfect to advance a patent claim). Hype used to be frowned on; now it is part of every business plan. Since at least the 1990s biotech companies have tried to influence university research, and it is a commonplace that the pharmaceutical industry dictates the terms of much academic clinical research. Students, already demoralized by scarce funding and no jobs, fret over whether basic research (of the sort that produced CRISPR in the first place) will be as esteemed as “patentable” work—and if their names will even be included on the patent. And the red flags that used to signal conflicts of interest are so frayed that you can essentially see right through them. It’s not that Cell should have had a stricter policy about conflicts of interest, it’s that a protagonist in the patent dispute probably shouldn’t have attempted to write a history of CRISPR in the first place. After the Lander article was published Cell posted a statement on its Web site saying Lander had indeed communicated that his institutional affiliations—Broad, M.I.T. and Harvard—had patents and patent applications related to CRISPR but that the journal only considers “personal” conflicts of interest.

    There is currently a lull in the CRISPR hostilities; no one has flamed anyone, by my count, in the last 72 hours. But that probably won’t last long. The patent interference, in which University of California lawyers will probably claim that its scientists invented CRISPR gene-editing and also applied for a patent before Broad, will be hotly contested. Maybe this little pause is an opportunity for a reset—a chance for the scientific community to acknowledge that the CRISPR system, as some have quietly suggested all along, was actually “invented” by bacteria eons ago as an ingenious immune response to viral infection, and that its rediscovery was accomplished by so many heroic (if you will) hands and with so much public coin that the technology ultimately belongs in the public commons and should not be patented and…

    …Sorry, I got a little carried away there. Yes, it would be nice if the transformative power of CRISPR remained in the public domain; maybe we could even invent a new prize—the Rashomon Prize!—that recognizes all the key players, no matter how contradictory or self-serving their stories. But in the current ecosystem of biology, where institutions are indeed desperate for money and the rules of the game create winner-take-all slugfests, that is very unlikely to happen.

    See the full article here .

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    Scientific American, the oldest continuously published magazine in the U.S., has been bringing its readers unique insights about developments in science and technology for more than 160 years.

  • richardmitnick 11:51 am on December 22, 2015 Permalink | Reply
    Tags: , CRISPR, ,   

    From New Scientist: “CRISPR will make 2016 the year of gene-edited organisms” 


    New Scientist

    15 December 2015
    Next year preview
    Michael Le Page

    Image credit: Dr Yorgos Nikas/Science Photo Library

    Will the first gene-edited baby be born in 2016? Let’s hope not. It is far from clear it can be done safely – although technically it is now possible. Gene editing with the new method known as CRISPR is so cheap, easy and effective that a few scientists with the appropriate expertise could tweak one or more genes in a human embryo before it is implanted in a woman’s womb.

    What 2016 will undoubtedly bring is a lot more gene-edited organisms. CRISPR works well in everything from butterflies to monkeys. It has already been used to create extra-muscular beagle dogs and sheep; long-haired goats; and pigs immune to common diseases. Next up could be hypoallergenic pet dogs and cats, cattle resistant to TB, or chickens that don’t get bird flu.

    But whether any of these make it out of the lab in the next 12 months depends on the regulators. Gene editing can add new pieces of DNA, as in conventional genetic engineering, so any living thing altered in this way is bound in many countries by strict regulations on genetically modified organisms. Getting approval to sell modified animals takes a lot of time and money.

    But gene editing can also be used to make changes to existing genes – tweaks that are indistinguishable from naturally occurring gene variants. The mutation that made the beagles more muscly already exists in dog breeds like the bully whippet.

    In theory, this kind of gene editing should be exempt from regulation. If the regulators agree, this could be the year that people start eating, drinking or wearing products from gene-edited farm animals and plants, or buy the first gene-edited pets.

    See the full article here .

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  • richardmitnick 7:45 am on August 10, 2015 Permalink | Reply
    Tags: , , , CRISPR,   

    From Cosmos: “Modifying human immune cells to fight cancer” 

    Cosmos Magazine bloc


    10 Aug 2015
    Viviane Richter and Elizabeth Finkel

    Coloured scanning electron micrograph of T cells (pink) attacking a cancer cell. Editing T cells’ genes could soon enhance their cancer-attacking abilities.Credit: Science Photo Library / Getty Images

    Immune cells known as T cells are formidable fighters against cancer and HIV.

    Scanning electron micrograph of a human T cell

    But they can be outsmarted by these foes. Now researchers at the University of California, San Francisco have figured out how to help T cells fight back using the latest gene editing technique called CRISPR. The method was published in Proceedings of the National Academy of Sciences in July. “This technique opens a lot of doors for the field,” says lead author Alexander Marson.

    Scientists have been tinkering with genes since the early 1970s to create faster growing pigs or herbicide-resistant crops. But the techniques had poor precision. Tens of thousands of individuals had to be tinkered with to achieve the required edits and usually those edits would be inserted on the wrong pages of the DNA text.

    To reliably manipulate specific genes to fight human disease, pinpoint precision is required.

    The CRISPR-CAS9 gene editing machinery from the Streptococcus pyogenes bacterium. RNA strands (blue) guide CRISPR to a targeted stretch of DNA, where it can snip out a specific gene. Credit: MOLEKUUL / SCIENCE PHOTO LIBRARY / Getty Images

    Which is exactly what the CRISPR gene editing technique offers. It’s no surprise that since scientists first discovered CRISPR in bacteria three years ago, it has taken the world by storm. Microbes evolved CRISPR to edit viruses out of their DNA. Now it’s been used to precisely edit everything from the DNA of crops to editing the HIV virus out of human DNA. Last April, Chinese researchers used it to edit the DNA of a human embryo – a move that created a storm of controversy. Till now tampering with the DNA of an embryo was considered out of bounds.

    But tampering with T cells is not likely to attract bad press. In particular, blood borne T cells form the major defence against viruses and cancer. Or when they misbehave, they cause auto-immune diseases such as Type 1 Diabetes. Controlling these cells by rewriting their DNA could mean a cure for incurable diseases. It’s all very doable: simply filter T cells from a person’s blood, edit their DNA and return them to the individual to do their job.

    The challenge is delivering the CRISPR machinery into T cells. Usually it’s done by packaging CRISPR into a harmless virus that ferries it into cells. CRISPR itself then acts like a guided missile, homing in on a precise stretch of the DNA code. (The guide that targets the DNA is a small piece of RNA. The missile is a shredding protein called Cas 9.) But so far, getting this guided missile inside the cells has been at the very low end of precision and efficiency. If only a tiny percentage of T cells can be engineered to resist HIV or fight cancer, it might hardly be worth the effort.

    So Marson’s team tried brute force. They zapped T cells from healthy donors with an electric current. This made temporary holes in the cells’ membrane, big enough for the intact CRISPR machinery to pop through. They managed to edit the DNA in 20 percent of T cells, a “huge” leap in efficiency according to Marco Herold, molecular biologist at Melbourne’s Walter and Eliza Hall Institute of Medical Research.

    Yet in contrast to their brute force entry, they were able to achieve very fine editing, changing individual letters of the cell’s DNA for the first time, as opposed to inserting or deleting large chunks. For instance they altered a doorway used by HIV known as CXCR4, so the deadly virus would not be able to enter and infect these T cells.

    They were also able to edit a gene called PD-1. Its role is to tell T cells to lay down their weapons so they don’t for instance attack normal cells of the body. But crafty cancer cells have learned how to give this same command to PD-1, so the T-cells lay down their arms in the vicinity of cancer cells. By editing the PD-1 gene of the T cells, the researchers should be able to turn T cells back into a fighting force against cancer. Simular approaches are successfully being trialled in cancer therapy employing antibodies to turn off the PD-1 signal.

    However the editing approach raises some concerns since T cells are long-term residents – sometimes remaining in the body for years. And if they are unleashed against cancer, one has to be sure they will not then go on to attack normal cells. “The danger is to create something you can’t control,” says Herold.

    “We have to work ahead to figure out how to ensure safety” of T cells, Marson agrees. “But it’s an exciting time for cell-based therapies.

    See the full article here.

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