Archive for the ‘Crispr’ Category

The potential of genome-editing techniques, such as CRISPR/Cas9, to alleviate disease burden has ignited the imagination for thousands of researchers looking for new therapeutic strategies.

Now, a group of investigators led by scientists at Emory University is hoping to open up new avenues of neurodegenerative research and rapidly move toward human trials after the release of their new findings. The research team showed that the CRISPR/Cas9 system could snip part of a gene that produces toxic protein aggregates in the brains of 9-month-old mice used as a model for Huntingtons disease. Moreover, the scientists noted that when they looked at the brain region where the vector was applied, some weeks later, the aggregated proteins had almost disappeared. Amazingly, the motor abilities of the mice had improved, although not to the level of control mice.

The study revealed the capacity of brain cells to heal themselves if the genetic source of the toxic proteins is removed. Moreover, in comparison with control Huntingtons mice, CRISPR/Cas9-injected mice showed significant improvements on tests of motor control, balance, and grip strength, although they did not recover to the point where they performed as well as control mice.

[Read the full study here]

The GLP aggregated and excerpted this blog/article to reflect the diversity of news, opinion, and analysis. Read full, original post:CRISPR Reverses Huntingtons Disease in Mice

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Reversing Huntington's? Brain shown to heal itself after disease source edited out in mice - Genetic Literacy Project

Off Target Effects

But almost as soon as the technology was introduced, scientists raised concerns about off target effects. Said Xiao-Hui Zhanget al.of the College of Veterinary Medicine, South China Agricultural University and coauthors at MIT in a 2015Molecular TherapyNucleic Acidsarticle, The high frequency of off-target activity (50%)RGEN (RNA-guided endonuclease)-induced mutations at sites other than the intended on-target site is one major concern, especially for CRISPR technology therapeutic and clinical applications.

The growth of any new technology, the authors note, including CRISPR/Cas9, demands progressive enhancement. And while research in CRISPR/Cas9 has made huge strides in the evolution of gene editing, it and other RGENs, which include ZFNs and TALENs, have more severe off-target effects than other nucleases due to their inherent structure and mechanism.

At an American Society of Hematology workshop on genome editing, CRISPR pioneer J. Keith Joung, M.D., Ph.D., of Massachusetts General Hospitalsaid, In the early days of this field, algorithms were generated to predict off-target effects and [made] available on the web miss a fair number of off-target effects. He added, These tools are used in a lot of papers, but they really arent very good at predicting where there will be off-target effects, according toSTAT.

Observations in the recent literature have raised more alarms among CRISPR cognoscenti, all of whom would agree than technical improvements are needed. In one of the most blogged-about papers on CRISPR, Unexpected mutations after CRISPRCas9 editingin vivo, Kellie A. Schaefer and colleagues at Stanford concluded that More work may be needed to increase the fidelity of CRISPR/Cas9 with regard to off-target mutation generation before the CRISPR platform can be used without risk, especially in the clinical setting.

The authors had, they reported in a 2016 study by W.H. Wuet al.inMolecular Therapy,used CRISPR/Cas9 for sight restoration in blindrd1mice by correcting a mutation in thePde6bgene. Mice homozygous for the rd mutation have hereditary retinal degeneration and have been considered a model for human retinitis pigmentosa.

Citing persistent concerns about secondary mutations in regions not targeted by a single guide RNA (sgRNA)concerns also expressed by a number of other scientistsKellie A. Schaefer, Ph.D., at Stanford University and colleagues at Howard Hughes and Massachusetts General Hospital performed whole genome sequencing (WGS) on DNA isolated from two CRISPR-repaired mice (F03 and F05) and one uncorrected control.

CRISPR/Cas9-treated mice were sequenced at an average depth of 50, and the control to 30 to identify all off target mutations. The sequencing the authors said identified an unexpectedly high number of single nucleotide variations (SNVs), contrary to the widely accepted assumption that CRISPR causes mutations mostly at regions homologous to the sgRNA.

CRISPRs penchant for promiscuous behavior has spawned an entirely new research field focused on fixing it. Patents have already been filed on the fixes and the developers believe that these advances will incrementally enable more reliable CRISPER performance. Most efforts have concentrated on modifying CRISPR nuclease Cas9 using structure-design based changes in the enzyme, chemical modifications, and amino acid substitutions at critical sights to better predict and control its function.

Writing inNaturein 2015,Benjamin P. Kleinstiver, Ph.D., of the Molecular Pathology Unit and Center for Cancer Research at the Massachusetts General Hospital and colleagues noted that although CRISPR/Cas9 nucleases are widely used for genome editing, the range of sequences that Cas9 can recognize is constrained by the need for a specific PAM.

The investigators reported that they could modify Cas9 to recognize alternative PAM sequences using structural information, bacterial selection-based directed evolution, and combinatorial design. The altered PAM specificity variants, they said, could edit endogenous gene sites in zebrafish and human cells that are not targetable by wild-type SpCas9. Further, they said, the variants genome-wide specificities are comparable to wild-type SpCas9 as judged by GUIDE-seq analysis and establish the feasibility of engineering a wide range of Cas9s with altered and improved PAM specificities.

Kleinstiver and other investigators working in Joungs also developed the unique endonuclease SpCas9-HF1, which they describe as a high-fidelity enzyme variant with alterations designed to reduce non-specific DNA contacts. The scientists hypothesized that reducing iCas9 and the target DNA interactions might help eliminate off-target effects while still retaining the desired on-target interaction.

Since certain portions of the Cas9 nuclease can itself interact with the backbone of the target DNA molecule, the team altered four of these Cas9-mediated contacts by replacing the long amino acid side-chains that bind to the DNA backbone with shorter ones that could not bind.

SpCas9-HF1 retained on-target activities comparable to wild-type SpCas9 with >85% of single-guide RNAs (sgRNAs) tested in human cells. Notably, with sgRNAs targeted to standard nonrepetitive sequences, SpCas9-HF1 rendered all or nearly all off-target events undetectable by genome-wide break capture and targeted sequencing methods.

Jiang and Doudna pointed out in a 2017 piece inAnnual Review of Biophysicshow Cas9 locates specific 20-base-pair (bp) target sequences within the genomes that are millions to billions of base pairs long and, subsequently, how it induces sequence-specific double-stranded DNA (dsDNA) cleavage remain critical questions, not just in CRISPR biology, but in the efforts to develop more precise and efficient Cas9-based tools.

Molecular insights from biochemical and structural studies such as those describe above will provide a framework for rational engineering aimed at altering catalytic function, guide RNA specificity and PAM requirements, and reducing off-target activity for the development of Cas9-based therapies against genetic diseases.

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Fixing CRISPR - Genetic Engineering & Biotechnology News (blog)

Posted 21 June 2017 By Zachary Brennan

Although the US market is likely more than a year or two away from seeing any commercialized medical products that rely on CRISPR-Cas9 technology, the rapidly developing field has already grabbed the attention of the US Food and Drug Administration (FDA) and other drug regulators.

According to the Broad Institute, CRISPR (pronounced "crisper") stands for Clustered Regularly Interspaced Short Palindromic Repeats, which form the basis for a genome editing technology known as CRISPR-Cas9, which can be programmed to target specific segments of genetic code and edit DNA precisely.

Unlike other genome editing technologies that have entered the clinic, like what Sangamo Therapeutics has been developing, experts say CRISPR-Cas9 is easier.

The potential for such technology to help treat or even cure genetic or other diseases has spurred the creation of a number of different companies, though none of the developing products have begun clinical trials in the US yet.

FDA senior policy adviser Ritu Nalubola explained to attendees at the DIA annual conference in Chicago on Wednesday that the agency is in the early stages of building capacity to regulate treatments that use CRISPR-Cas9 technology, and though they are collaborating with other regulators and working with the National Academies of Science, the cross-border regulation of such treatments seems unlikely.

"Harmonization is not always possible because of the statute," Nalubola said.

And although there is a gene therapy working group within the International Pharmaceutical Regulators Forum that addresses transnational issues, Nalubola said that there's a "lot of research that we cant oversee," and that there's "a role for further public engagement and addressing best practices."

Kurt von Emster, managing partner of the investment firm Abingworth, which made early investments in the Switzerland-based company CRISPR Therapeutics that he said is now worth about $650 million, noted European regulators have so far been more receptive than FDA.

The European Medicines Agency's Committee for Advanced Therapies has discussed the prospects for CRISPR-Cas9 products. And FDA's Office of Pharmaceutical Quality has an Emerging Technology Team that Nalubola mentioned could help companies with early discussions.

And though the initial hope was that CRISPR-based treatments "would cure one or two diseases, I think that's moved up quite a bit," von Emster said, noting that CRISPR Therapeutics has invested more than $80 million in pre-clinical models and still has its sights on entering clinical trials in the US for the first time before the end of 2017. Massachusetts-based Editas Medicine, which was co-founded by the Broad Institute's Feng Zhang, recently delayed the filing of its IND for its lead CRISPR program.

"This is a technology, not a product," von Emster added, noting that CRISPR Therapeutics decided early to partner with companies like Vertex Pharmaceuticals and Bayer on some projects, though "we decided to keep oncology to ourselves."

He also said the next six months will clarify a lot in the CRISPR space, especially as intellectual property (IP) issues get further ironed out. The US Patent and Trademark Office recently upheld a series of patents granted to the Broad Institute for theCRISPR-Cas9technology, which will likely be a win for Editas and the Broad Institute.

But Editas, CRISPR Therapeutics and Intellia Therapeutics, among other companies in the CRISPR-Cas9 space, are moving in different directions, von Emster said.

He also told DIA attendees that "no one should think were pushing Editas aside," as it's "in our common interests to work together to overcome the IP situation to get to the task of curing disease."

But in terms of how to approach regulators with what many believe could be breakthrough treatments, companies are just beginning to test the waters.

"We haven't spent a lot of time approaching FDA because we don't know what our product is yet," von Emster said.

Eva Essig, VP of regulatory affairs at Intellia, noted the importance of early technology platform discussions with FDA as such discussions can help with determining which indications are more plausible to bring forward in development.

And both he and Essig said they had their doubts about a small study in mice that made headlines recently on off-target issues with CRISPR, though they think it's important that different approaches are being undertaken.

For now, a lot of the discussion on which treatments will win approval is still hypothetical.

When asked what news headlines will look like a year from now on CRISPR and gene editing, Essig pointed to human trials conducted in China that will probably start seeing early results.

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Regulating CRISPR: FDA and Industry Offer Perspective | RAPS - Regulatory Focus

Versant Venture and MPM Capital co-led a $68-million Series A fundraising round to establish Repare Therapeutics, a Canada-based cancer drug company exploiting a high-throughput, CRISPR-based screening platform to identify synthetic lethality cancer targets and develop precision anticancer therapies.

For the last 18 months, Repare has been working in stealth mode under Versant incubation to develop its synthetic lethality platform and identify initial oncology targets. The firm says a number of programs have now been moved into preclinical development, and clinical trials with an initial candidate could start in 2019.

Additional investors in Repares Series A fundraising included Fonds de solidarit FTQ, Celgene Switzerland, and BDC Capitals Healthcare Venture Fund.

Versants commitment to and confidence in Repares distinct science has enabled the company to build the team, operations and initial programs away from the spotlight, said Repare CEO Lloyd M. Segal. With the added leadership of MPM and this syndicate, we are financed to achieve our goal of testing our multiple new, precision oncology therapeutics in a clinical setting.

Synthetic lethality occurs when the presence of mutations in two specific genes cause cell death, whereas the presence of one of the mutations alone does not. The concept of using synthetic lethality to target cancers is already being exploited through the development of PARP inhibitors for treating cancers with BRCA1 or BRCA1 mutations.

Repares discovery engine exploits CRISPR/Cas9 gene editing, in combination with protein crystallography, computational biology, and clinical informatics, in a high-throughput screening platform that is designed to identify new drug targets that, when blocked, induce synthetic lethality in cancer cells exhibiting commonly found tumor-related mutations.

Repares first disclosed program targets PolQ, which codes for enzyme DNA-directed DNA polymerase theta, a polymerase enzyme that plays a key role in repairing double stranded DNA breaks. Polymerase theta is highly expressed in ovarian, breast and other cancers. The PolQ program is based on drug discovery work carried out by Agnel Sfeir, Ph.D., at NYU School of Medicine, to which Repare has an exclusive license.

Based on Quebec, Canada, and in Boston, MA, Repare is headed by Lloyd M. Segal, who is a Versant entrepreneur-in-residence, who has previously headed Caprion Pharmaceuticals, Advanced Bioconcept, and Thallion Pharmaceuticals. The Repare management team also includes Executive Vice President and Head of R&D Michael Zinda, Ph.D., who previously led the oncology bioscience operation at AstraZeneca in Boston. Repares vice president of discovery, Cameron Black, Ph.D., led Merck Frossts medicinal chemistry efforts for 18 years.

Jerel Davis, Ph.D., managing director at Versant, and Todd Foley, managing director at MPM Capital, will join Repares board of directors. We are impressed by the speed and precision with which Repare, in collaboration with its founders and scientific advisors, generated impressive insights and multiple novel targets, Dr. Davis commented. We evaluated nearly every opportunity in the synthetic lethality space and have complete conviction that Repare, its founders and its SAB members represent the leaders in the field, added Foley.

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Repare Raises $68M in Series A to Develop CRISPR-Based Synthetic Lethality Platform - Genetic Engineering & Biotechnology News (blog)

If DNA were an essay and genes individual words, CRISPR would be the keyboard: adding, deleting and editing to create, for instance, drought-resistant crops.

PANAMA CITY Imagine a world where scientists could manipulate an organisms DNA with enough precision to reliably edit a single gene, creating drought-resistant crops or eliminating mosquitoes that carry malaria.

You actually dont have to imagine that hard. The technology already exists and this fall, it will be taught in lab courses at Gulf Coast State College (GCSC).

Biology professors and science teachers from Bay District Schools spent their day Tuesday learning about a cutting-edge gene manipulation called CRISPR clustered regularly interspaced short palindromic repeats which essentially uses a particular bacterias immune system to edit DNA on the singular gene level. If DNA were an essay and genes individual words, CRISPR would be the keyboard: adding, deleting and editing.

Understandably, it has everyone in the biotechnology field talking.

CRISPR itself is causing a revolution in molecular biology, said Ben Stephenson, a former Arnold High graduate who, after graduating from GCSC and the University of Florida, returned to help teach his former professors this new method. There are medicines and all types of technologies with different applications that are coming about just because the system is so amenable to innovation.

In fact, the possibilities are so mind-boggling that even scientists like Stephenson havent considered them all. Almost any time Stephenson talks to someone about CRISPR, they inevitably come up with an idea or application he hasnt thought of.

Its a technology that gets people excited, he said. It will get kids excited.

Carrie Fioramonti, a natural sciences teacher at Gulf Coast who was participating in the workshop, said the faculty at the college already is brainstorming how they can incorporate CRISPR into their classes. Similar to when smartphones became more accessible and people became more interested in learning how to code, CRISPR, which is in a sense biological coding, has the potential to draw in people who arent trained in biology but are interested in the application. Do-it-yourself CRISPR starter kits already are available on Amazon for about $165, and Stephenson said bio-hacker clubs have sprung up in several major cities.

This is one of the hottest, fastest-growing fields of technology, Fioramonti said.

But as with many scientific fields that have exploded suddenly, regulations havent quite kept up. Gene editing comes with serious ethical implications, and while their samples were in the centrifuge, several of the participants in Tuesdays workshop chatted about experiments on embryos in Sweden and China using CRISPR to edit human genes. The experimentsdidnt go well, and CRISPR isnt quite understood well enough to use on humans yet, but the ethical implications are there.

Beyond the human question, there also is the question of whether such a precise gene-editing tool should be so widely available. According to the 2015 NY Magazine article The Crispr Quandary, the methods co-inventor, Jennifer Doudna, has questioned whether the technology should be available to students, as a minor mistake could have major implications, or a mutation might be accidentally introduced into the wild and affect a whole ecosystem.

While that concern is valid, Stephenson said the CRISPR kits, and anything being taught in a lab, would be fairly self-contained and largely harmless. The kits usually use an innocuous bacteria to test on, and on Tuesday, participants experimented with sea anemone DNA, adding a gene for fluorescence.

Many of the teachers at the workshop said they were amazed at how far biotechnology had come since they were in school, remembering when gene manipulation was a cumbersome, imprecise process. Even Stephenson, who just finished grad school, has to work to keep up, and he said most students now are starting college with a better understanding of CRISPR than he had after he graduated.

This is what our students are going to be going to school for, so we need to give them what they need, Fioramonti said of future labs using CRISPR.

Original post:

Gulf Coast State College looks to incorporate CRISPR into labs - The News Herald

Two major biotech companies have criticised a recent study that claimed CRISPR may cause hundreds of unwanted mutations.

Scientists from the CRISPR-based firms Intellia TherapeuticsandEditas Medicinehave written open lettersto the journal Nature Methods, stating that the conclusions of the study are 'unsubstantiated'.

'Our opinion is that the authors failed to sufficiently control the reported study in such a way that one could conclude that CRISPR induces the observed mutations,' said Editas'letter, co-signedby 13 of the company's scientists. 'In our view, the genetic differences seen in this comparative analysis were likely present prior to editing with CRISPR.'

DrNessan Bermingham, CEO of Intellia, has called for the paper to be retractedon grounds offlawed design and interpretation. Both firms' share prices have been negatively impacted by the study, andsome companies saw afall of up to 15 percent.

The study reported the discovery of over 100 large deletionsorinsertions in the genome of two mice which had previously undergone CRISPR genome editing. These had not been anticipated by other widely used methods to detect the accuracy of the technique, the authors claimed (see BioNews 903).

The studyhas gathered a lot of attention since its publication last month. A number of scientists have highlighted flaws within the research, including the small number of animals and misidentification of off-targets effects. Many have offered alternative explanations for the findings.

Talking to The Scientist, Dr Gatan Burgio,a geneticistfrom the Australian National University, Canberra, points out that the use of published sequence data rather than non-edited control animals kept in the same laboratory conditions may mean that the study was unable to 'tease out which variants are due to the natural genetic variation and which ones are CRISPR-related.'

In response to the criticism, a spokesperson at Springer Nature, which publishesNature Methods, told MIT Technology Review, 'We are carefully considering all concerns that have been raised with us and are discussing them with the authors.'

Scientists are aware that using CRISPR will sometimes result in unintended genomic changes. 'Getting people to talk about the need for controls is a good outcome of this whole thing. I think the data is perfectly fine. It's just the interpretation of it that to me seems odd,' saidDr Matthew Taliaferro,who studies genome editing at Massachusetts Institute of Technology.

Co-author of the study in question,Dr Vinit MahajanofStanford University, told The Scientistheremains 'very excited' about the potential of CRISPR, though admits that they cannot be completely certain that it caused all of the observedmutations. However, 'if you make an observation that's important enough to share with your community, you're obligated to do that right away,'hetold WIRED.

Link:

Biotech companies criticise CRISPR mutation study - BioNews

TechCrunch

China sides with Emmanulle Charpentier and Jennifer Doudna in ... TechCrunch Continuing the patent dispute internationally, China has now given the Charpentier/Doudna side a patent to edit genes in the country. CRISPR pioneers.. and more »

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China sides with Emmanulle Charpentier and Jennifer Doudna in ... - TechCrunch

The gene-editing technique CRISPR is often touted as an eventual cure-all for all that ails us, from fatal genetic diseases to food shortages. But when it comes to disease, its likely that it will have the most impact on disorders caused by mutations in one single gene. New research published this week in the Journal of Clinical Investigation suggests that Huntingtons Disease may be a good candidate for a CRISPR cure.

Huntingtons Disease is a fatal, inherited disorder that gradually causes the breakdown of nerve cells in the brain. Its caused by a gene that encodes a toxic protein that causes brain cells to die, with symptoms that usually show up around mid life.

In the new study from scientists at Emory University, researchers used mice engineered to possess the same human gene that causes Huntingtons. In such mice, the motor problems associated with Huntingtons show up at about 9 months of age. They then used CRISPR-Cas9 to snip the part of the gene that produces the toxic protein. Weeks later, the researchers found that those proteins had almost fully disappeared from the brain, and the motor abilities of the mice had improved (though they still had some motor impairment). Longer term effects of the treatment are not yet clear, although the researchers think the genetic alteration will be permanent.

Their findings, the researchers wrote, suggested a permanent therapeutic treatment for Huntingtons, and potentially other neurodegenerative diseases, too.

This research, of course, is preliminary, though other scientists have said it is encouraging.

Importantly, in their paper the scientists reported finding no off-target effects, a major concern associated with using CRISPR in humans. Still, they write, it will have to be tested for long-term safety and efficacy before being ready to try out in people.

Already, there are two clinical trials using CRISPR in humans underfoot in China, and a US trial is slated to begin sometime in the next year. But those trials are aimed at cancer. While scientists have had success treating other single-mutation conditions like sickle-cell anaemia and blindness in mice, so far, human trials for such diseases have not begun.

[Journal of Clinical Investigation]

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Scientists Used CRISPR to Reverse Huntington's Disease in Mice - Gizmodo

If there was one misstep that doomed thelong and bitter fightby the University of California to wrest key CRISPR patents from the Broad Institute, it was star UC Berkeley scientistJennifer Doudnas habit of being scientifically cautious, realistic, and averse to overpromising.

A biochemist who co-led a breakthrough2012 studyof CRISPR-Cas9, Doudna repeatedly emphasized in interviews the challenges of repurposing the molecular system, which bacteria use to fend off viruses, to edit human genomes. The U.S. patent office, in a Februaryrulingthat let the Broad keep its CRISPR patents (for now), relied heavily on those statements We werent sure if CRISPR/Cas9 would work in animal cells, for example to conclude that when scientists at the BroadCRISPRd human cellsin 2013, it was a non-obvious advance and therefore deserving of patents.

So its striking that the careful, measured Doudna who said CRISPRing human cells and thereby curing devastating diseases would be a challenge is hardly in evidence in A Crack in Creation: Gene Editing and the Unthinkable Power to Control Evolution, the new book she co-authored with her former student Samuel Sternberg. Itwent on sale last week.

This Doudna doesnt hold back. We are on the cusp of a new age in genetic engineering and biological mastery, she and Sternberg write, dangling the prospect of life-changing treatments and lifesaving cures. She says she is not kidding that CRISPR could bring about woolly mammoths, winged lizards, and unicorns. It wont be long before CRISPR allows us to bend nature to our will.

The hyperbole contrasts with CRISPRs stumbles, including altering parts of genomes (in lab studies, not patients yet) it wasnt supposed to. I dont think well have a version of CRISPR thats 100 percent perfect, so it comes down to a risk-benefit analysis, Sternberg, a biochemist atCaribou Biosciences(which Doudna co-founded), said in an interview. There has been phenomenal progress in understanding off-target effects; I think its a solvable problem. We have every reason to be optimistic but I hope we avoided overhyping and didnt give the impression that there would be windfall of cures in the next couple of years.

This is not a tell-all. The farthest Doudna goes in addressing the patent fight a disheartening twist is to say that because of such rivalries she experienced the gamut of human relationships, from deep friendships to disturbing betrayals. She doesnt name the betrayers.

An earlyreviewchastised Doudna for presenting herself as so flawless the book seems more concealing than revealing, not insightful [and] candid.

So what she does choose to reveal is fascinating, especially about her collaboration with Emmanuelle Charpentier. The two are so closely linked that all the prizes theyve won for CRISPR, theyve won together; among CRISPR watchers Doudna and Charpentier is virtually a macro.

But the books account of their breakthrough experiment showing that CRISPR could be programmed to edit a precise spot in a genomeleaves a different impression. We read that Martin [Jinek, Doudnas postdoctoral fellow] showed and Martin labored tirelessly, Martin and I brainstormed and designed an experiment, and when Martin walked me through the data, Doudnaknew wed done it.

That work was described in the 2012 paper, which is widely recognized by prize committees, the European Patent Office, and many scientists as the Bastille moment for the CRISPR revolution. It identified the three crucial molecules in the CRISPR system one to cut, one to guide the cutting enzyme to its target DNA, one to activate the cutting enzyme that produced a programmable DNA-cutting machine. We had built the means to rewrite the code of life, Doudnaand Sternberg write. Nothing after that would ever be the same.

Although Doudna and her collaborators didnt actually change genomes in cells their CRISPR molecules altered cell-free DNA in test tubes that was an obvious next step. How difficult a next step was the core dispute in the patent fight and one that she repeatedly cautioned was no slam dunk. But Crack in Creation says that doing so was immediately clear to us, and there were good reasons to expect success.

That contrasts with her cautious statements, cited by the patent office, at the time. WhenFeng Zhangof the Broad Institute andGeorge Churchof Harvard used CRISPR to edit genes, it was just as we had proposed in 2012, according to the book. She waselated that her 2012 work inspired others to pursue a line of experimentation similar to our own.

Doudna became a public scientist shes given aTED talkand will appear on Sunday Night with Megyn Kelly because of her research, but also because she was instrumental in getting the scientific community to focus on ethical issues it raises, especially about editing embryos in a way that would be inherited by future generations (germline editing). She writes that she had nightmares that a man asking her about this was Hitler and that she began to feel a bit like Dr. Frankenstein.

Her own moral journey is intriguing. She feels germline editing can be safe, and the its unnatural! argument doesnt carry much weight with me anymore, she writes. It seems to me that wed be justified in using CRISPR to eliminate genes that cause untold suffering, such as those for Huntingtons disease. When I think about the pain that genetic diseases cause families, the stakes are simply too high to exclude the possibility of eventually using germline editing, as an expert panel alsoconcluded.

Doudnaacknowledges, however, that its difficult to see how wed do it equitably, especially when the line between therapy and enhancement is paper thin: Some families might purchase a genetic legacy that gives them less need for sleep, greater endurance, extra-strong bones, leaner or larger muscles, lower risk of diabetes and Alzheimers, even less armpit odor while other families muddle through with the genes nature gave them.

That threatens to transcribe our societies financial inequality into our genetic code, Doudna writes.

Her solution? Redoubl[ing] our commitment to building a society in which all humans are respected and treated equally, regardless of their genetic makeup.

Update, June 14: Doudna, whose office cancelled an interview with STAT before this story ran, said in an email that positioning Martin Jineksrole to your readers as above the work of Emmanuelle Charpentier is incorrect and unfair.Our work was conducted closely with Emmanuelle, whose contributions and insights includingthe role of tracrRNA in the DNA targeting complex were a key aspect of the development ofCRISPR-Cas as a gene editing technology.

This story was originally published by STAT, an online publication of Boston Globe Media that covers health, medicine, and scientific discovery.

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CRISPR Pioneer Doudna: Humans on Cusp of 'New Age in ... - KQED - KQED

Intellia Therapeutics said today it received notice from Chinas State Intellectual Property Office (SIPO) that it will grant the company a broad patent covering CRISPR/Cas9 single-guide gene-editing methods and compositions.

CRISPR stands for clustered regularly interspaced short palindromic repeats. The CRISPR patent to be issued by SIPO includes claims covering methods for editing DNA in noncellular and cellular settings, including in eukaryotic cells such as human and mammalian cells, Intellia said.

Also included in the patent, the company added, are CRISPR/Cas9 composition of matter and system claims for use in any setting, including claims covering the use of CRISPR/Cas9 in producing medicines for treating disease.

Intellia holds rights to CRISPR intellectual property developed by the Regents of the University of California (UC), the University of Vienna, and Emmanuelle Charpentier, Ph.D., a director at the Max-Planck Institute in Berlin, through a 2014 license agreement with Caribou Biosciences, the exclusive licensee of the UC and University of Vienna. Those rights include human therapeutic, prophylactic, and palliative uses (including companion diagnostics), excluding antifungal and antimicrobial applications.

CRISPR ownership has been at the heart of a bitter legal battle royal with the Broad Institute of MIT and Harvard. A researcher based at the Institute, Feng Zhang, Ph.D., is listed an inventor on 12 patents related to CRISPR technology awarded in the U.S.

In February, the U.S. Patent Trial and Appeal Board (PTAB) sided with the Broad Institute by finding no interference in fact between the 12 patents, and a patent application by Dr. Charpentier and Jennifer Doudna, Ph.D., of UC Berkeley. UC, University of Vienna, and Dr. Charpentier are appealing the PTAB decision to the U.S. Court of Appeals for the Federal Circuit.

Chinas plans to grant a patent for CRISPR come less than a year after the nation has seen two clinical trials involving the technology. On October 29, You Lu, M.D., and colleagues at Sichuan Universitys West China Hospital in Chengdu launched the worlds first CRISPR trial in humans by using the technology to knock out a gene encoding the programmed cell death protein 1 (PD-1) in patients with non-small-cell lung cancer (NSCLC).

The second trial was initiated in April in patients with late-stage nasopharyngeal carcinoma,by researchers led by Jia Wei, M.D., Ph.D., vice director of the Clinical Cancer Institute of Nanjing University. The first U.S. trial is expected to be started later this year by a team led by Carl June, M.D. of the University of Pennsylvania.

SIPOs decision further expands our IP portfolio and is further global recognition that Jennifer Doudna, Emmanuelle Charpentier, and their team are the pioneers in the application of CRISPR/Cas9 in all cell types, Nessan Bermingham, Ph.D., Intellias CEO and president, said in a statement.

In March, Intellia and Caribouco-founded by one of the original CRISPR researchers, Dr. Doudna, of UC Berkeleyjoined ERS Genomics and CRISPR Therapeutics in signing a global cross-consent and invention management agreement for the foundational intellectual property covering CRISPR/Cas9 with the Regents of UC, the University of Vienna, and Dr. Charpentier.

That intellectual property underlies patents awarded by the European Patent Office and the United Kingdoms Intellectual Property Office earlier this year. Those patents were issued from an international patent application based on the same U.S. priority applications filed by UC, University of Vienna, and Dr. Doudna on May 25, 2012.

The EPO acted on European patent application No. 13793997, which had been challenged by parties that include the Broad Institute.

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Intellia, Holder of Rights to UC's CRISPR Technology, to Win China Patent - Genetic Engineering & Biotechnology News

Stock researchfirms currently have a positive stance on shares of athenahealth, Inc. (NASDAQ:ATHN). Analysts are projecting that the stock will reach $133.65 on a short term (1 year) basis.

The majority of analysts covering the equity have either a Buy or Strong Buy recommendation on the stock, yielding a consensus score of 2.30. This is based on the research brokerage reports taken into consideration by Thomson Reuters.

athenahealth, Inc. (NASDAQ:ATHN)s shares may have a significant upside to the consensus target of133.65, but how has it been performing relative to the market? The stocks price is 145.36 and their relative strength index (RSI) stands at 69.85. RSI is a technical oscillator that shows price strength by comparing upward and downward movements. It indicates oversold and overbought price levels for a stock.

athenahealth, Inc. (NASDAQ:ATHN) shares are moving2.64% trading at $145.36 today.

Brokerage firms currently have a positive stance on shares of CRISPR Therapeutics AG (:CRSP). The majority of analysts covering the equity have either a Buy or Strong Buy recommendation on the stock, yielding a consensus score of 2.00. Those same analysts are projecting that the stock will reach $23.70 on a short term basis.

Performance At the time of writing, the stock was trading at $14.81. This represents a change from most recent open price of 2.63%. In terms of performance, year to date, the stock is -26.90%. The monthly stock performance comes in at -4.51%. For the quarter, shares are performing at -28.63%. Weekly performance analysis shows the equity at 1.44%.

Technicals In taking a look at technical levels, shares are trading -9.95% away from the 50 day simple moving average and -19.49% away from the 200 day simple moving average. Based on a recent bid, the stock is trading -40.76% away from its 52- week high and 27.34% away from its 52 week low. After the recent moves, investors may also look to see if the stock has entered oversold or overbought territory and could be ripe for a bounce. As of writing, CRISPR Therapeutics AGs RSI stands at 45.44. In looking at volatility levels, the shares saw weekly volatility of 4.16% and 4.84% over the past month.

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June 19, 2017 Professor Michael Farzan, co-chair of TSRI's Department of Immunology and Microbiology. Credit: The Scripps Research Institute

Scientists on the Florida campus of The Scripps Research Institute (TSRI) have improved a state-of-the-art gene-editing technology to advance the system's ability to target, cut and paste genes within human and animal cellsand broadening the ways the CRISPR-Cpf1 editing system may be used to study and fight human diseases.

Professor Michael Farzan, co-chair of TSRI's Department of Immunology and Microbiology, and TSRI Research Associate Guocai Zhong improved the efficiency of the CRISPR-Cpf1 gene editing system by incorporating guide RNAs with "multiplexing" capability.

Guide RNAs are short nucleic acid strings that lead the CRISPR molecular scissors to their intended gene targets. The TSRI discovery means multiple genetic targets in a cell may be hit by each CRISPR-Cpf1 complex.

"This system simplifies and significantly improves the efficiency of simultaneous editing of multiple genes, or multiple sites of a single gene," Zhong said. "This could be very useful when multiple disease-related genes or multiple sites of a disease-related gene need to be targeted."

"This approach improves gene editing for a number of applications," Farzan added. "The system makes some applications more efficient and other applications possible."

This study was published as an advanced online paper in the journal Nature Chemical Biology on June 19, 2017.

TSRI Advance Makes CRISPR More Efficient

Short for "Clustered Regularly Interspaced Short Palindromic Repeat," the CRISPR gene editing system exploits an ancient bacterial immune defense process. Some microbes thwart viral infection by sequestering a piece of a virus' foreign genetic material within its own DNA, to serve as a template. The next time the viral sequence is encountered by the microbe, it's recognized immediately and cut up for disposal with the help of two types of RNA. Molecules called guide RNAs provide the map to the invader, and CRISPR effector proteins act as the scissors that cut it apart.

Over the last five years, the CRISPR gene editing system has revolutionized microbiology and renewed hopes that genetic engineering might eventually become a useful treatment for disease.

But time has revealed the technology's limitations. For one, gene therapy currently requires using a viral shell to serve as the delivery package for the therapeutic genetic material. The CRISPR molecule is simply too large to fit with multiple guide RNAs into the most popular and useful viral packaging system.

The new study from Farzan and colleagues helps solve this problem by letting scientists package multiple guide RNAs.

This advance could be important if gene therapy is to treat diseases such as hepatitis B, Farzan said. After infection, hepatitis B DNA sits in liver cells, slowly directing the production of new viruses, ultimately leading to liver damage, cirrhosis and even cancer. The improved CRISPR-Cpf1 system, with its ability to 'multiplex,' could more efficiently digest the viral DNA, before the liver is irrevocably damaged, he said.

"Efficiency is important. If you modify 25 cells in the liver, it is meaningless. But if you modify half the cells in the liver, that is powerful," Farzan said. "There are other good casessay muscular dystrophywhere if you can repair the gene in enough muscle cells, you can restore the muscle function."

Two types of these molecular scissors are now being widely used for gene editing purposes: Cas9 and Cpf1. Farzan said he focused on Cpf1 because it is more precise in mammalian cells. The Cpf1 molecule they studied was sourced from two types of bacteria, Lachnospiraceae bacterium and Acidaminococus sp., whose activity has been previously studied in E. coli. A key property of these molecules is they are able to grab their guide RNAs out of a long string of such RNA; but it was not clear that it would work with RNA produced from mammalian cells. Guocai tested this idea by editing a firefly bioluminescence gene into the cell's chromosome. The modified CRISPR-Cpf1 system worked as anticipated.

"This means we can use simpler delivery systems for directing the CRISPR effector protein plus guide RNAs," Farzan said. "It's going to make the CRISPR process more efficient for a variety of applications."

Looking forward, Farzan said the Cpf1 protein needs to be more broadly understood so that its utility in delivering gene therapy vectors can be further expanded.

Explore further: Modifying fat content in soybean oil with the molecular scissors Cpf1

More information: Cpf1 proteins excise CRISPR RNAs from mRNA transcripts in mammalian cells, Nature Chemical Biology (2017). nature.com/articles/doi:10.1038/nchembio.2410

A team from the Center for Genome Engineering, within the Institute for Basic Research (IBS), succeeded in editing two genes that contribute to the fat contents of soybean oil using the new CRISPR-Cpf1 technology: an alternative ...

Using the new gene-editing enzyme CRISPR-Cpf1, researchers at UT Southwestern Medical Center have successfully corrected Duchenne muscular dystrophy in human cells and mice in the lab.

Researchers at the Institute of Basic Science (IBS) proved the accuracy of a recently developed gene editing method. This works as "DNA scissors" designed to identify and substitute just one nucleotide among the 3 billion. ...

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Picture bacteria and viruses locked in an arms race. For many bacteria, one line of defense against viral infection is a sophisticated RNA-guided "immune system" called CRISPR-Cas. At the center of this system is a surveillance ...

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Firefly gene illuminates ability of optimized CRISPR-Cpf1 to efficiently edit human genome - Phys.Org

ByMolly Wood and Paulina Velasco

June 16, 2017 | 3:00 PM

In 2012, Jennifer Doudna, along with a small group of scientists, invented a ground-breaking technology to edit DNA known as Crispr. Scientists are still experimenting with it.

Crispr has been in the news recently because a group of scientists released a much-debated study arguing that editing genes can lead to many unintended, unpredictable consequences. In the controversial case, the scientists edited genetic blindness out of a group of mice and said they found two thousand unintended consequences. The scientific community is split on the results, and Doudna said it's hard to conclude anything from the study. But she knows the possible dangers of gene editing, and she warned about them in aWired article in May.

Marketplace's senior tech correspondent Molly Wood spoke withDoudna at the Wired Business Conference in New York earlier this month and asked Doudna whatconcerns her the most about her revolutionary new technology?

The following is an edited transcript of their conversation.

Jennifer Doudna: I guess I worry about a couple of things. I think there's sort of the potential for unintended consequences of gene editing in people for clinical use. How would you ever do the kinds of experiments that you might want to do to ensure safety? And then there's another application of gene editing called gene drive that involves moving a genetic trait very quickly through a population. And there's been discussion about this in the media around the use of gene drives in insects like mosquitoes to control the spread of disease. On one hand, that sounds like a desirable thing, and on the other hand, I think one, again, has to think about potential for unintended consequences of releasing a system like that into an environmental setting where you can't predict what might happen.

Molly Wood: How important is the accessibility? You know, you could buy a Crispr kit online for $150. What does that kind of accessibility lead to, either in terms of opportunity or problems?

Doudna: I think it's mostly a really good thing in the sense that it makes the science more tangible. I honestly feel that things that break down the barriers between scientists and technologists and everybody else, in a way, is a good thing. Although it's easy to use this technology for those that have some training in molecular biology, its actually not going to be very easy to do anything that would be particularly dangerous in my opinion.

Wood: How do you think this technology could change the way we practice medicine? I mean, if we're really talking about potentially curing genetic diseases, it seems like a whole industry will be affected by that.

Doudna: I think it's a fascinating question, and I've been thinking about this a lot and having a number of discussions with folks that work in the pharmaceutical industry to think about really changing the paradigm for how we do human therapeutics, at least for certain types of disease. Imagine that you had a technology or a treatment that allowed, rather than having someone take a pill every day for the rest of their life, that you had a treatment that you could do once and cure them. It also brings along a lot of other issues. Who pays for that? How do you price such a thing? How do you get insurance companies to cover it? Even if there won't be easy answers, I think the first step is really just to realize that that's the moment that we're in right now.

Wood: One of the things I find fascinating is the intellectual property part of the conversation to what extent people might try to patent genetically modified versions of organisms or plants or even human genes?

Doudna: It's very difficult to patent genes. But I think youre touching on an important point. I think the real value of a technology like this that really allows research to move at a much faster pace than it has in the past, is that it opens up opportunities for applications that I think will lead to incredible commercial opportunities and creative things to make products that couldn't have been generated in the past. And along with that, of course, goes all of the issues regarding regulation and pricing and things like that.

Wood: Jennifer, on that question of regulation and pricing, do you have a sense of what body might end up being in charge of that? Because it's really a global issue on some level, right?

Doudna: It is. But I think a lot of it will come down to initial regulatory approval. If we're talking about agricultural products in the U.S. we're talking about the U.S. Department of Agriculture. We might be talking about the Food and Drug Administration, certainly for therapeutics. Of course that affects pricing and valuations, because if there is an onerous regulatory pathway for things, then that adds to the cost of developing them. So this is why I think it's actually very important that scientists be engaging right now with these agencies to set up appropriate regulations, but also not ones that are so onerous that it really prevents development of important products.

Originally posted here:

Crispr inventor worries about the unintended consequences of gene ... - Marketplace.org

Scientific zeal Jennifer Doudna. Photograph: The Washington Post/Getty Images

It began with the kind of research the Trump administration wants to unfund: fiddling about with tiny obscure creatures. And there had been US Republican hostility to science before Trump, of course, when Sarah Palin objected to federal funding of fruit fly research (Fruit flies I kid you not, she said). The fruit fly has been a vital workhorse of genetics for 100 years. Jennifer Doudnas work began with organisms even further out on the Palin scale: bacteriophages, tiny viruses that prey on bacteria.

Yoghurt manufacturers knew they were important, not least because bacteriophages can destroy yoghurt cultures. Research on the mechanism of this process began in the labs of Danisco (now part of the giant DuPont) in the early 2000s, before spreading through the university biotech labs. In 2012 Doudna and Samuel Sternbergs team at Berkeley (they are co-authors of the book but its written solely in Doudnas voice) came up with probably the greatest biological breakthrough since that of Francis Crick, James Watson and Rosalind Franklin.

Biologists had become intrigued by a curiosity in the genome of some bacteria: they had repeat patterns interspersed always by 20 bases of DNA, which turned out to match sequences found in the phages (as bacteriophages are always known) that prey on them. They had stumbled on a bacterial immune system, now known as Crispr (Clustered regularly interspaced short palindromic repeats) a sequence reading the same forwards and backwards.

An astonishing story of molecular countermeasures against phage invasion was revealed; these enable the bacterium to recognise the phage next time it invades. More than that, Crispr guides a killer enzyme to cut the phages DNA at the point where the 20base sequence is found. Doudna then demonstrated that bacterial Crispr can be reprogrammed to cut any DNA from any organism. This is what has been sought for more than 30 years: an accurate (or almost accurate) way of editing DNA. And there has never been a better example of the unforeseen benefits of pure research because no one guessed that a technique of such power and universality would emerge from what appeared to be a fascinating but arcane corner of biology.

Crispr is not just a triumph for unfettered scientific curiosity, its also a reminder that the secret of life lies in tiny things. The visible world can be beautiful but we are gulled into thinking it must be more important than what we cant see. People have been making that mistake for a long time. In The Citizen of the World (1762), Oliver Goldsmith mocked the supposed pedantry of all who study the tiny creatures revealed by the microscope: Their fields of vision are too contracted to take in the whole Thus they proceed, laborious in trifles, constant in experiment, without one single abstraction, by which alone knowledge may be properly said to increase. But, of course, it is precisely being able to see small things that has unlocked the biological treasure trove.

Very soon after Doudnas paper on the technique appeared in 2012, labs all over the world tried it and found it was surpassingly easy to use; a gold rush began. Its always difficult when something like this happens to sort the hope from the hype, but anticipation is now intense. Doudna does, though, sound many notes of caution. Yes, Crispr is the most accurate form of gene editing so far, but it isnt perfect. There are 3bn bases in the human genome so there is always a chance of a stray 20-base match and a fatal cut in the wrong place. A debate is taking place on whether to allow gene edits only outside the body (with the edited cells reinserted) or to allow editing of eggs and sperm, which changes that germline forever. Doudna comes down cautiously for germline editing, pointing out that mitochondrial replacement therapy, which also leads to permanent genetic alteration, is already a reality in the UK.

Doudna recounts how, soon after her breakthrough, colleagues became rivals, papers were pored over for patent battles

For now the most exciting potential medical application is in single gene diseases, such as cystic fibrosis, sickle-cell anaemia and muscular dystrophy. This is the simplest possible task for Crispr. Just one base has to be corrected out of the 3bn and its not a needle in a haystack: Crispr can find and cut and repair it. Sickle-cell anaemia is caused by a faulty haemoglobin gene, so blood can easily be withdrawn from the body, the gene edited and returned to the body. But this approach demands extreme caution. Genes often have multiple effects and the sickle-cell gene is known to protect against malaria. So if you fixed the sickle-cell gene in the African population (where it is prevalent) there would be many new cases of malaria. But then Crispr can probably fix that, too; other researchers, with Gates Foundation funding, are urgently tackling that problem. There is hardly an area of medicine that could not benefit from Crispr, and on the fringe there is the Jurassic Park fantasy, kept tenuously alive by the work of Crisprs other great name, George Church at Harvard, who is editing the elephant genome to create a creature more like a woolly mammoth.

If medical ethics loom large in debates around Crispr, money and patents loom even larger. Now that this apparently unpromising research has blossomed, the venture capitalists are gathering. Doudna recounts how, so soon after her triumph, colleagues became rivals; papers were pored over for future patent battles. The patent battle in question came to fruition after the book was completed. Doudnas team lost this round, and its not clear what the future holds for Crisprs intellectual property rights. It is unlikely that medical progress will be delayed but there will be some bruised participants and money spent along the way.

It is unusual to have a popular account of a great scientific breakthrough written by the protagonist, so soon after its discovery. Watsons The Double Helix appeared 15 years after the work. We owe Doudna several times over for her discovery, for her zeal to take it from the lab into the clinic, for her involvement in the ethical issues raised, for her public engagement work, and now for this book. Its a fine weapon against the still far too large tribe of those who dont believe in the power of very small things.

Peter Forbess latest book, written with Tom Grimsey, is Nanoscience: Giants of the Infinitesimal. A Crack in Creation is published by Bodley Head. To order a copy for 16.59 (RRP 20) go to bookshop.theguardian.com or call 0330 333 6846. Free UK p&p over 10, online orders only. Phone orders min p&p of 1.99.

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A Crack in Creation review Jennifer Doudna, Crispr and a great ... - The Guardian

Thermo Fisher Scientific has launched a program of four-day lecture-based and hands-on CRISPR (clustered regulatory interspaced short palindromic repeats) and TALEN (transcription activator-like effector nuclease) genome-editing workshops at its global training facilities.

The workshops will provide an overview of CRISPR/Cas9 and TALEN technologies through both lecture-based sessions and laboratory practice. The focus will be on topics spanning experimental design strategies, methods for delivering guide RNAs (gRNAs) and Cas9 mRNA/Cas9 proteins into cells for generating gene knockouts, the use of TALs as genome-editing tools for gene knockins, and approaches to analyzing editing efficiency. The workshops will highlight the use of TALEN genome-editing technology for genome-editing applications, including single-nucleotide polymorphism (SNP) repair.

Workshop participants will have the opportunity to design a genome-editing experiment with experts in the field. "Our workshops are designed to equip researchers with the instruction and hands-on training they need to comfortably utilize the leading genome-editing technologies in their own labs," said Helge Bastian, Ph.D., vp and general manager of synthetic biology at Thermo Fisher Scientific. "As the practice of engineering nucleic acids in silico, in vitro, and in living cells evolves at a high-speed pace, it is increasingly important for life science professionals to learn about the basics and the newest formats of these high-precision molecular technologies. This will enable them to unravel the underlying mechanisms of normal cellular processes and disease onset or progression, support the discovery and development of new drugs, and enhance biomanufacturing and therapy solutions."

Thermo Fisher says that as a result of strong demand following workshops in the U.S., Germany, and the U.K., it has now more than doubled the number of workshops offered, and plans to hold courses throughout North America, Europe, the Middle East, and Asia.

Last month, the firm reported a deal to acquire contract development and manufacturing organization (CDMO) Patheon, for $7.2 billion.

Originally posted here:

Thermo Fisher Launches CRISPR and TALEN Genome-Editing Workshops - Genetic Engineering & Biotechnology News (press release)

Merck has been granted its first CRISPR technology patent by the Australian Patent Office.

On Wednesday, June 14, Merck issued a press release explaining that the office had granted it patent rights over the use of CRISPR in a genomic integration method for eukaryotic cells.

The patent covers chromosomal integration (or cutting of the chromosomal sequence of eukaryotic cells, such as mammalian and plant cells, and insertion of an external or donor DNA sequence into those cells using CRISPR).

Merck has patent filings for its insertion CRISPR method in Brazil, Canada, China, Europe, India, Israel, Japan, Singapore, South Korea and the US.

Udit Batra, member of the Merck executive board and CEO of life science, said: Merck has developed an incredible tool to give scientists the ability to find new treatments and cures for conditions for which there are limited options, including cancer, rare diseases and chronic conditions, such as diabetes.

In May this year, Merck revealed that it had developed an alternative CRISPR genome-editing method called proxy-CRISPR.

According to Merck, the proxy-CRISPR technique can cut previously unreachable cell locations, making CRISPR more efficient, flexible and specific, and giving researchers more experimental options.

Several patent applications have been filed on this technology.

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Merck granted its first CRISPR patent in Australia - Life Sciences Intellectual Property Review (subscription)

Paul Levine, a resident of West Tisbury, former professor at Harvard, and visiting professor at Stanford University, writes occasionally about scientific research taking place today, along with profiles of the Islands scientists and their work and facts of scientific note on the Island. This week, he follows up on his gene-editing column from six weeks ago, which described the genetics research that has led to CRISPR, which stands for clustered regularly interspaced short palindromic repeats. If youre wondering what that is, read on.

In this, the second column on the subject of gene editing, imagine a world in which many human genetic disorders have been eliminated, no children are born with cystic fibrosis, Tay-Sachs disease, sickle cell anemia, or other genetic disorders. Welcome to the world of CRISPR, an acronym for clustered regularly interspaced short palindromic repeats of the DNA of a gene. CRISPR can locate a defective gene and, along with an enzyme called Cas9, can, like a pair of scissors, snip out the unwanted gene and suture a desirable gene in its place. It is a technique of genetic editing that is more precise, efficient, and affordable than anything that has come before. What I describe below is specific to the Vineyard (the elimination of Lyme disease) and relevant to society as a whole for the potential for great good, but also for possible misuse use of the technology, which has raised questions of ethics and safety.

CRISPR-Cas9 as a tool for genetic editing has a history that goes back to a 2011 scientific conference at which microbiologist Emmanuelle Charpentier, now the director of the Max Planck Institute for Infection Biology in Berlin, met Jennifer Doudna, professor of chemistry and molecular and cell biology at the University of California, Berkeley. They talked about CRISPR-Cas9, and what follows is the story of one of the most significant achievements in genetics since the discovery of the structure and function of DNA. It is a story that involves brilliant scientists, competition, big egos, patent disputes, and the possibility of a Nobel Prize, not to mention the immense financial gain by biotech, agribusiness, and pharmaceutical companies.

Prior to todays application of CRISPR to edit genes, it was known that it was a means by which bacteria protected themselves from infection by viruses by recognizing and binding to viral DNA and destroying it with enzymes. Charpentier and Doudna wondered whether the technique could be applied to other things than the detection and destruction of viral DNA. If it could, it might lead to a way to snip out bad genes and possibly replace them with good ones. They began a collaborative research project with bacteria, and developed a technique for cutting out and replacing bacterial genes with CRISPR and an enzyme, Cas9. In other words, it was now possible to edit the bacterial genome by cutting and pasting genes. Doudna and Charpentier published their research in the journal Science in 2012. Aware of the great potential that the ability to edit genomes presented, the University of California patented their discovery.

At about the same time, Feng Zhang at the Broad Institute of MIT and Harvard was working with Cas9, and discovered that CRISPR-Cas9 could also be applied to edit the genes of animals and plants. His discovery was published a few months after the publication of the work of Doudna and Charpentier.

The Broad Institute applied for and received a patent based on the results of Zhangs research. However, prior to their filing, the University of California, Berkeley, had filed for and received a patent based on Doudnas and Charpentiers research.

In a patent dispute, it was ruled that the Broad Institutes patent took precedent over the University of California patent because it applies to animal and plant cells. The University of California, Berkeley, has asserted that although their patent involves bacteria, it includes all forms of life.

Unfortunately, a consequence of the dispute is the enmity that has developed between some of the parties involved.

It was not long before life scientists throughout the world began to develop the technique in order to advance progress in human genetic engineering to cure some of the 6,000 human genetic disorders.

With respect to applications of CRISPR-Cas9 to edit human genes, research is underway to use it to control insect- and spider-borne disease; for example, mosquitoes that carry the malaria parasite and the viruses that cause dengue, West Nile, and Zika fever. The object of the research is to produce sterile female mosquitoes by using CRISPR-Cas9 to edit out the genes required for their fertility, and distribute the sterile females in areas around the world where mosquito-borne diseases occur. This approach has been met with some success at the laboratory level.

Another research effort which might be familiar to you is to eliminate Lyme disease by distributing white-footed mice that have been manipulated with gene-editing techniques to effectively be immune to the bacteria which causes Lyme, all using CRISPR-Cas9. This would break the transmission cycle of the bacteria (see MV Times, Scientist proposes genetic attack on M.V. ticks, July 20, 2016).

I havent mentioned possible commercial applications of CRISPR-Cas9, and the great profits to be made by Monsanto and other agribusiness companies by the production of genetically modified plants and domestic animals. The technology is also appealing to Big Pharma. Its worth looking at the highly controversial and ethical questions that accompany the use of CRISPR-Cas9. In contrast with noninheritable somatic cell human gene editing described above, there is another technique called germ line gene editing, which makes gene changes at the level of human eggs, sperm, and embryos that would be heritable. Experiments on human embryos have been carried out by scientists in China and the U.K. that have raised concern that CRISPR-Cas9 could lead to the production of designer babies parents choosing the traits they want their children to have. Designer babies are a vast topic, too vast to bring up here, but there is an excellent discussion of the subject in Roger Gosdens The Brave New World of Reproductive Technology.

Jennifer Doudna, at U.C. Berkeley, and Feng Zhang at MIT, the principal developers and promoters of gene editing, appear to be at odds over the ethical questions surrounding the technology. Doudna is concerned with the ethics and the publics perception of CRISPR-Cas9, but Zhang appears less so, and prefers to drive the research to cure genetic disorders, putting aside the possibility of the production of designer babies.

If you want to explore CRISPR-Cas9 and come to an opinion regarding one of the most significant developments in genetics in this century, I urge you to read Robert Kolkers 2016 article in Bloomberg BusinessWeek, How Jennifer Doudnas Gene Editing Technique Will Change the World. It can be found at bit.ly/CRISPRdoudna. Listen to Doudnas TED Talk here: bit.ly/TEDdoudna.

Finally, I should mention that a two-act play named Gene Play, about the story of recDNA and CRISPR-Cas9, will be read by a cast of actors at the Vineyard Playhouse on June 19.

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Science and Scientists on the Vineyard: Genes at play with CRISPR - Martha's Vineyard Times

On a November evening last year, Jennifer Doudna put on a stylish black evening gown and headed to Hangar One, a building at NASAs Ames Research Center that was constructed in 1932 to house dirigibles. Under the looming arches of the hangar, Doudna mingled with celebrities like Benedict Cumberbatch, Cameron Diaz and Jon Hamm before receiving the 2015 Breakthrough Prize in life sciences, an award sponsored by Mark Zuckerberg and other tech billionaires. Doudna, a biochemist at the University of California, Berkeley, and her collaborator, Emmanuelle Charpentier of the Helmholtz Centre for Infection Research in Germany, each received $3 million for their invention of a potentially revolutionary tool for editing DNA known as CRISPR.

Doudna was not a gray-haired emerita being celebrated for work she did back when dirigibles ruled the sky. It was only in 2012 that Doudna, Charpentier and their colleagues offered the first demonstration of CRISPRs potential. They crafted molecules that could enter a microbe and precisely snip its DNA at a location of the researchers choosing. In January 2013, the scientists went one step further: They cut out a particular piece of DNA in human cells and replaced it with another one.

In the same month, separate teams of scientists at Harvard University and the Broad Institutereported similar success with the gene-editing tool. A scientific stampede commenced, and in just the past two years, researchers have performed hundreds of experiments on CRISPR. Their results hint that the technique may fundamentally change both medicine and agriculture.

Some scientists have repaired defective DNA in mice, for example, curing them of genetic disorders. Plant scientists have used CRISPR to edit genes in crops, raising hopes that they can engineer a better food supply. Some researchers are trying to rewrite the genomes of elephants, with the ultimate goal of re-creating a woolly mammoth. Writing last year in the journal Reproductive Biology and Endocrinology, Motoko Araki and Tetsuya Ishii of Hokkaido University in Japan predicted that doctors will be able to use CRISPR to alter the genes of human embryos in the immediate future.

Thanks to the speed of CRISPR research, the accolades have come quickly. Last year MIT Technology Review called CRISPR the biggest biotech discovery of the century. The Breakthrough Prize is just one of several prominent awards Doudna has won in recent months for her work on CRISPR; National Public Radio recently reported whispers of a possible Nobel in her future.

Even the pharmaceutical industry, which is often slow to embrace new scientific advances, is rushing to get in on the act. New companies developing CRISPR-based medicine are opening their doors. In January, the pharmaceutical giant Novartis announced that it would be using Doudnas CRISPR technology for its research into cancer treatments. It plans to edit the genes of immune cells so that they will attack tumors.

But amid all the black-tie galas and patent filings, its easy to overlook the most important fact about CRISPR: Nobody actually invented it.

Doudna and other researchers did not pluck the molecules they use for gene editing from thin air. In fact, they stumbled across the CRISPR molecules in nature. Microbes have been using them to edit their own DNA for millions of years, and today they continue to do so all over the planet, from the bottom of the sea to the recesses of our own bodies.

Weve barely begun to understand how CRISPR works in the natural world. Microbes use it as a sophisticated immune system, allowing them to learn to recognize their enemies. Now scientists are discovering that microbes use CRISPR for other jobs as well. The natural history of CRISPR poses many questions to scientists, for which they dont have very good answers yet. But it also holds great promise. Doudna and her colleagues harnessed one type of CRISPR, but scientists are finding a vast menagerie of different types. Tapping that diversity could lead to more effective gene editing technology, or open the way to applications no one has thought of yet.

You can imagine that many labs including our own are busily looking at other variants and how they work, Doudna said. So stay tuned.

The scientists who discovered CRISPR had no way of knowing that they had discovered something so revolutionary. They didnt even understand what they had found. In 1987, Yoshizumi Ishino and colleagues at Osaka University in Japan published the sequence of a gene called iap belonging to the gut microbe E. coli. To better understand how the gene worked, the scientists also sequenced some of the DNA surrounding it. They hoped to find spots where proteins landed, turning iap on and off. But instead of a switch, the scientists found something incomprehensible.

Near the iap gene lay five identical segments of DNA. DNA is made up of building blocks called bases, and the five segments were each composed of the same 29 bases. These repeat sequences were separated from each other by 32-base blocks of DNA, called spacers. Unlike the repeat sequences, each of the spacers had a unique sequence.

This peculiar genetic sandwich didnt look like anything biologists had found before. When the Japanese researchers published their results, they could only shrug. The biological significance of these sequences is not known, they wrote.

It was hard to know at the time if the sequences were unique to E. coli, because microbiologists only had crude techniques for deciphering DNA. But in the 1990s, technological advances allowed them to speed up their sequencing. By the end of the decade, microbiologists could scoop up seawater or soil and quickly sequence much of the DNA in the sample. This technique called metagenomics revealed those strange genetic sandwiches in a staggering number of species of microbes. They became so common that scientists needed a name to talk about them, even if they still didnt know what the sequences were for. In 2002, Ruud Jansen of Utrecht University in the Netherlands and colleagues dubbed these sandwiches clustered regularly interspaced short palindromic repeats CRISPR for short.

Jansens team noticed something else about CRISPR sequences: They were always accompanied by a collection of genes nearby. They called these genes Cas genes, for CRISPR-associated genes. The genes encoded enzymes that could cut DNA, but no one could say why they did so, or why they always sat next to the CRISPR sequence.

Three years later, three teams of scientists independently noticed something odd about CRISPR spacers. They looked a lot like the DNA of viruses.

And then the whole thing clicked, said Eugene Koonin.

At the time, Koonin, an evolutionary biologist at the National Center for Biotechnology Information in Bethesda, Md., had been puzzling over CRISPR and Cas genes for a few years. As soon as he learned of the discovery of bits of virus DNA in CRISPR spacers, he realized that microbes were using CRISPR as a weapon against viruses.

Koonin knew that microbes are not passive victims of virus attacks. They have several lines of defense. Koonin thought that CRISPR and Casenzymes provide one more. In Koonins hypothesis, bacteria use Casenzymes to grab fragments of viral DNA. They then insert the virus fragments into their own CRISPR sequences. Later, when another virus comes along, the bacteria can use the CRISPR sequence as a cheat sheet to recognize the invader.

Scientists didnt know enough about the function of CRISPR and Cas enzymes for Koonin to make a detailed hypothesis. But his thinking was provocative enough for a microbiologist named Rodolphe Barrangou to test it. To Barrangou, Koonins idea was not just fascinating, but potentially a huge deal for his employer at the time, the yogurt maker Danisco. Danisco depended on bacteria to convert milk into yogurt, and sometimes entire cultures would be lost to outbreaks of bacteria-killing viruses. Now Koonin was suggesting that bacteria could use CRISPR as a weapon against these enemies.

To test Koonins hypothesis, Barrangou and his colleagues infected the milk-fermenting microbe Streptococcus thermophilus with two strains of viruses. The viruses killed many of the bacteria, but some survived. When those resistant bacteria multiplied, their descendants turned out to be resistant too. Some genetic change had occurred. Barrangou and his colleagues found that the bacteria had stuffed DNA fragments from the two viruses into their spacers. When the scientists chopped out the new spacers, the bacteria lost their resistance.

Barrangou, now an associate professor at North Carolina State University, said that this discovery led many manufacturers to select for customized CRISPR sequences in their cultures, so that the bacteria could withstand virus outbreaks. If youve eaten yogurt or cheese, chances are youve eaten CRISPR-ized cells, he said.

As CRISPR started to give up its secrets, Doudna got curious. She had already made a name for herself as an expert on RNA, a single-stranded cousin to DNA. Originally, scientists had seen RNAs main job as a messenger. Cells would make a copy of a gene using RNA, and then use that messenger RNA as a template for building a protein. But Doudna and other scientists illuminated many other jobs that RNA can do, such as acting as sensors or controlling the activity of genes.

In 2007, Blake Wiedenheft joined Doudnas lab as a postdoctoral researcher, eager to study the structure of Cas enzymes to understand how they worked. Doudna agreed to the plan not because she thought CRISPR had any practical value, but just because she thought the chemistry might be cool. Youre not trying to get to a particular goal, except understanding, she said.

As Wiedenheft, Doudna and their colleagues figured out the structure of Cas enzymes, they began to see how the molecules worked together as a system. When a virus invades a microbe, the host cell grabs a little of the viruss genetic material, cuts open its own DNA, and inserts the piece of virus DNA into a spacer.

As the CRISPR region fills with virus DNA, it becomes a molecular most-wanted gallery, representing the enemies the microbe has encountered. The microbe can then use this viral DNA to turn Cas enzymes into precision-guided weapons. The microbe copies the genetic material in each spacer into an RNA molecule. Cas enzymes then take up one of the RNA molecules and cradle it. Together, the viral RNA and the Cas enzymes drift through the cell. If they encounter genetic material from a virus that matches the CRISPR RNA, the RNA latches on tightly. The Cas enzymes then chop the DNA in two, preventing the virus from replicating.

As CRISPRs biology emerged, it began to make other microbial defenses look downright primitive. Using CRISPR, microbes could, in effect, program their enzymes to seek out any short sequence of DNA and attack it exclusively.

Once we understood it as a programmable DNA-cutting enzyme, there was an interesting transition, Doudna said. She and her colleagues realized there might be a very practical use for CRISPR. Doudna recalls thinking, Oh my gosh, this could be a tool.

It wasnt the first time a scientist had borrowed a trick from microbes to build a tool. Some microbes defend themselves from invasion by using molecules known as restriction enzymes. The enzymes chop up any DNA that isnt protected by molecular shields. The microbes shield their own genes, and then attack the naked DNA of viruses and other parasites. In the 1970s, molecular biologists figured out how to use restriction enzymes to cut DNA, giving birth to the modern biotechnology industry.

In the decades that followed, genetic engineering improved tremendously, but it couldnt escape a fundamental shortcoming: Restriction enzymes did not evolve to make precise cuts only to shred foreign DNA. As a result, scientists who used restriction enzymes for biotechnology had little control over where their enzymes cut open DNA.

The CRISPR-Cas system, Doudna and her colleagues realized, had already evolved to exert just that sort of control.

To create a DNA-cutting tool, Doudna and her colleagues picked out the CRISPR-Cas system from Streptococcus pyogenes, the bacteria that cause strep throat. It was a system they already understood fairly well, having worked out the function of its main enzyme, called Cas9. Doudna and her colleagues figured out how to supply Cas9 with an RNA molecule that matched a sequence of DNA they wanted to cut. The RNA molecule then guided Cas9 along the DNA to the target site, and then the enzyme made its incision.

Using two Cas9 enzymes, the scientists could make a pair of snips, chopping out any segment of DNA they wanted. They could then coax a cell to stitch a new gene into the open space. Doudna and her colleagues thus invented a biological version of find-and-replace one that could work in virtually any species they chose to work on.

As important as these results were, microbiologists were also grappling with even more profound implications of CRISPR. It showed them that microbes had capabilities no one had imagined before.

Before the discovery of CRISPR, all the defenses that microbes were known to use against viruses were simple, one-size-fits-all strategies. Restriction enzymes, for example, will destroy any piece of unprotected DNA. Scientists refer to this style of defense as innate immunity. We have innate immunity, too, but on top of that, we also use an entirely different immune system to fight pathogens: one that learns about our enemies.

This so-called adaptive immune system is organized around a special set of immune cells that swallow up pathogens and then present fragments of them, called antigens, to other immune cells. If an immune cell binds tightly to an antigen, the cell multiplies. The process of division adds some random changes to the cells antigen receptor genes. In a few cases, the changes alter the receptor in a way that lets it grab the antigen even more tightly. Immune cells with the improved receptor then multiply even more.

This cycle results in an army of immune cells with receptors that can bind quickly and tightly to a particular type of pathogen, making them into precise assassins. Other immune cells produce antibodies that can also grab onto the antigens and help kill the pathogen. It takes a few days for the adaptive immune system to learn to recognize the measles virus, for instance, and wipe it out. But once the infection is over, we can hold onto these immunological memories. A few immune cells tailored to measlesstay with us for our lifetime, ready to attack again.

CRISPR, microbiologists realized, is also an adaptive immune system. It lets microbes learn the signatures of new viruses and remember them. And while we need a complex network of different cell types and signals to learn to recognize pathogens, a single-celled microbe has all the equipment necessary to learn the same lesson on its own.

CRISPR is an impressive adaptive immune system for another reason: Its lessons can be inherited. People cant pass down genes for antibodies to their children because only immune cells develop them. Theres no way for that information to get into eggs or sperm. As a result, children have to start learning about their invisible enemies pretty much from scratch.

CRISPR is different. Since microbes are single-celled organisms, the DNA they alter to fight viruses is the same DNA they pass down to their descendants. In other words, the experiences that these organisms have alter their genes, and that change is inherited by future generations.

For students of the history of biology, this kind of heredity echoes a largely discredited theory promoted by the naturalist Jean-Baptiste Lamarck in the early 19th century. Lamarck argued for the inheritance of acquired traits. To illustrate his theory, he had readers imagine a giraffe gaining a long neck by striving to reach high branches to feed on. A nervous fluid, he believed, stretched out its neck, making it easier for the giraffe to reach the branches. It then passed down its lengthened neck to its descendants.

The advent of genetics seemed to crush this idea. There didnt appear to be any way for experiences to alter the genes that organisms passed down to their offspring. But CRISPR revealed that microbes rewrite their DNA with information about their enemies information that Barrangou showed could make the difference between life and death for their descendants.

Did this mean that CRISPR meets the requirements for Lamarckian inheritance? In my humble opinion, it does, said Koonin.

But how did microbes develop these abilities? Ever since microbiologists began discovering CRISPR-Cas systems in different species, Koonin and his colleagues have been reconstructing the systems evolution. CRISPR-Cas systems use a huge number of different enzymes, but all of them have one enzyme in common, called Cas1. The job of this universal enzyme is to grab incoming virus DNA and insert it in CRISPR spacers. Recently, Koonin and his colleagues discovered what may be the origin of Cas1 enzymes.

Along with their own genes, microbes carry stretches of DNA called mobile elements that act like parasites. The mobile elements contain genes for enzymes that exist solely to make new copies of their own DNA, cut open their hosts genome, and insert the new copy. Sometimes mobile elements can jump from one host to another, either by hitching a ride with a virus or by other means, and spread through their new hosts genome.

Koonin and his colleagues discovered that one group of mobile elements, called casposons, makes enzymes that are pretty much identical to Cas1. In a new paper in Nature Reviews Genetics, Koonin and Mart Krupovic of the Pasteur Institute in Paris argue that the CRISPR-Cas system got its start when mutations transformed casposons from enemies into friends. Their DNA-cutting enzymes became domesticated, taking on a new function: to store captured virus DNA as part of an immune defense.

While CRISPR may have had a single origin, it has blossomed into a tremendous diversity of molecules. Koonin is convinced that viruses are responsible for this. Once they faced CRISPRs powerful, precise defense, the viruses evolved evasions. Their genes changed sequence so that CRISPR couldnt latch onto them easily. And the viruses also evolved molecules that could block the Cas enzymes. The microbes responded by evolving in their turn. They acquired new strategies for using CRISPR that the viruses couldnt fight. Over many thousandsof years, in other words, evolution behaved like a natural laboratory, coming up with new recipes for altering DNA.

To Konstantin Severinov, who holds joint appointments at Rutgers University and the Skolkovo Institute of Science and Technology in Russia, these explanations for CRISPR may turn out to be true, but they barely begin to account for its full mystery. In fact, Severinov questions whether fighting viruses is the chief function of CRISPR. The immune function may be a red herring, he said.

Severinovs doubts stem from his research on the spacers of E. coli. He and other researchers have amassed a database of tens of thousands of E. coli spacers, but only a handful of them match any virus known to infect E. coli. You cant blame this dearth on our ignorance of E. coli or its viruses, Severinov argues, because theyve been the workhorses of molecular biology for a century. Thats kind of mind-boggling, he said.

Its possible that the spacers came from viruses, but viruses that disappeared thousands of years ago. The microbes kept holding onto the spacers even when they no longer had to face these enemies. Instead, they used CRISPR for other tasks. Severinov speculates that a CRISPR sequence might act as a kind of genetic bar code. Bacteria that shared the same bar code could recognize each other as relatives and cooperate, while fighting off unrelated populations of bacteria.

But Severinov wouldnt be surprised if CRISPR also carries out other jobs. Recent experiments have shown that some bacteria use CRISPR to silence their own genes, instead of seeking out the genes of enemies. By silencing their genes, the bacteria stop making molecules on their surface that are easily detected by our immune system. Without this CRISPR cloaking system, the bacteria would blow their cover and get killed.

This is a fairly versatile system that can be used for different things, Severinov said, and the balance of all those things may differ from system to system and from species to species.

If scientists can get a better understanding of how CRISPR works in nature, they may gather more of the raw ingredients for technological innovations. To create a new way to edit DNA, Doudna and her colleagues exploited the CRISPR-Cas system from a single species of bacteria, Streptococcus pyogenes. Theres no reason to assume that its the best system for that application. At Editas, a company based in Cambridge, Massachusetts, scientists have been investigating the Cas9 enzyme made by another species of bacteria, Staphylococcus aureus. In January, Editas scientists reported that its about as efficient at cutting DNA as Cas9 from Streptococcus pyogenes. But it also has some potential advantages, including its small size, which may make it easier to deliver into cells.

To Koonin, these discoveries are just baby steps into the ocean of CRISPR diversity. Scientists are now working out the structure of distantly related versions of Cas9 that seem to behave very differently from the ones were now familiar with. Who knows whether this thing could become even a better tool? Koonin said.

And as scientists discover more tasks that CRISPR accomplishes in nature, they may be able to mimic those functions, too. Doudna is curious about using CRISPR as a diagnostic tool, searching cells for cancerous mutations, for example. Its seek and detect, not seek and destroy, she said. But having been surprised by CRISPR before, Doudna expects the biggest benefits from these molecules to surprise us yet again. It makes you wonder what else is out there, she said.

This article was reprinted on BusinessInsider.com.

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CRISPR Natural History in Bacteria | Quanta Magazine

MilliporeSigma, the life science business of Merck KGaA, said today it has been awarded its first patent for CRISPR technologyan Australian patent relating to the use of CRISPR in a genomic integration method for eukaryotic cells.

The patent issued by the Australian Patent Office covers chromosomal integration or cutting of the chromosomal sequence of eukaryotic cells, and insertion of an external or donor DNA sequence into those cells using CRISPR.

Patent Application No. 2013355214 was filed December 5, 2013, and accepted on May 22, according to an online search of the Australian Patent Offices online database AusPat. The patent consists of 14 method claims.

MilliporeSigma says the CRISPR genomic integration technology is designed to enable researchers to replace a disease-associated mutation with a beneficial or functional sequence, a method important for creation of disease models and gene therapy. Researchers can also use the method to insert transgenes that label endogenous proteins for visual tracking within cells.

This patent decision recognizes our expertise in CRISPR technologya body of knowledge that we are committed to grow, MilliporeSigma CEO Udit Batra said in a statement.

MilliporeSigma has filed for patents covering its insertion CRISPR method in the U.S., as well as in Europe, Brazil, Canada, China, India, Israel, Japan, Singapore, and South Korea.

The Australian Patent Office website also lists six applications covering CRISPR claims, by applicants that include Cellectis, CRISPR Therapeutics, The Johns Hopkins University, MIT and the Broad Institute, Moderna Therapeutics, and the Regents of the University of Colorado.

MilliporeSigma said in May that it had developed the alternative CRISPR genome-editing method, called proxy-CRISPR, a month after publishing the results of its research in Nature Communications. According to the company, proxy-CRISPR differs from other genome editing systems in its ability to cut previously unreachable cell locations, making CRISPR more efficient, flexible, and specific, and giving researchers more experimental options.

Since 2012, MilliporeSigma has filed multiple CRISPR patent filings, including its filings related to proxy-CRISPR technology.

The company has been involved in genome editing for 14 years, having been the first company to offer custom biomolecules for genome editing globally (TargeTron RNA-guided group II introns and CompoZr zinc finger nucleases). MilliporeSigma was also first to manufacture arrayed CRISPR libraries covering the entire human genome.

Later this year, MilliporeSigma is expected to launch its next suite of genome editing tools for the research community, to include novel and modified versions of Cas and Cas-like proteins.

MilliporeSigma is the combined life sciences tools and technologies company formed in 2015 when Merck KGaA completed its $17 billion acquisition of Sigma-Aldrich.

Read the original here:

MilliporeSigma Wins Its First CRISPR Patent in Australia - Genetic Engineering & Biotechnology News

The CRISPR-Cas9 Technology Developed by Doudna and Charpentier

In June 2012, University of California, Berkeley professor and Howard Hughes Medical Institute investigator Jennifer Doudna and Umea University professor Emmanuelle Charpentier (now at the Max Planck Institute for Infection Biology) and their research team, which included Martin Jinek from UC and Krzysztof Chylinski from the University of Vienna, published an article in the journal Science that first revealed what has been described as the scientific breakthrough of the century. This international team of researchers determined how a bacterial immune system known as CRISPR-Cas9 is able to cut DNA, and then engineered CRISPR-Cas9 to be used as a powerful gene editing technology.

To understand this powerful new technology, think of the CRISPR-Cas9 system as special scissors that cut DNA threads. In nature, bacteria use these scissors to cut the DNA threads of invading viruses. The Doudna/Charpentier team figured out how to engineer and use these scissors to cut any DNA thread of their choosing, thereby allowing the system to be used to make repairs or modifications to the intricate, multicolored tapestry that is the human genome.

Additionally, the natural CRISPR-Cas9 system has three separate parts the scissors portion, which actually cuts the DNA thread, and a two-piece homing beacon portion that directs the scissors to the DNA thread. The two pieces of the homing beacon must find eachother and come together before the natural CRISPR-Cas9 system can home in on and cut a targeted thread. The Doudna/Charpentier team devised a way to make a one-piece homing beacon, thus simplifying the system and vastly increasing the ease of use of this technology.

The Doudna/Charpentier groups Science publication immediately ushered in a new and revolutionary era of gene editing. Within six months of the Doudna/Charpentier teams Science publication describing the engineering and use of the CRISPR-Cas9 system, many research groups successfully applied the CRISPR-Cas9 technology as originally described in that landmark publication, further verifying how readily the Doudna/Charpentier teams engineered CRISPR-Cas9 system can be used for gene editing in any cell type.

Since publication of the Doudna/Charpentier teams seminal paper, CRISPR-Cas9 gene editing has transformed biological research across the globe. CRISPR-Cas9 allows scientists to permanently edit the genetic information of any organism including human cells with unprecedented ease, accuracy and efficiency. CRISPR-Cas9s power and versatility has opened up new and wide-ranging uses across biology, including medicine and agriculture. The foundational research of the Doudna/Charpentier research team enabled subsequent work by many laboratories throughout the world that used CRISPR-Cas9 to treat and cure disease in animal models and to create pathways to sustainable biofuels, to more robust crops and to countless other applications that will continue to dramatically advance human health and well-being (for example, therapies for sickle cell disease).

The University of California has a rich history of scientific discovery and development. Our researchers have introduced many of the most significant technologies that have bettered our world and vastly improved the lives of its people. The ongoing work of Doudna and her team is another example of the universitys commitment to pursuing basic and applied research that is in the public interest, which is consistent with UCs standing as the worlds leading public research university system.

As part of that focus on, and commitment to, the greater good, the University of California, along with the University of Vienna, has reserved the right to allow educational and other nonprofit institutions to use the CRISPR-Cas9 related intellectual property for educational and research purposes.

How was CRISPR-Cas9 gene editing developed?

The invention of CRISPR-Cas9 gene editing technology was the result of basic research science at its best. More than 10 years ago, Jillian Banfield, UC Berkeley professor of earth and planetary sciences and of environmental science, policy and management, asked Doudna to analyze a genetic peculiarity of bacteria known generally as CRISPR. At that time, CRISPRs function in bacterial cells was only beginning to be understood. After several years of research by Doudna and her team into various proteins that make up bacterial CRISPR systems, Doudna began collaborating with Charpentier and her team, who had also been researching CRISPR systems, including the identification of tracrRNA.

Their research teams collaborated on studies to determine how the CRISPR-Cas9 system acts like a pair of molecular scissors to cleave the DNA of invading viruses. Through their scientific collaboration, the Doudna/Charpentier research team determined exactly what components were responsible for this DNA cleavage and the team engineered those components to modify target DNA outside of bacterial cells. The studies included making various modifications to the natural components of the system, and even included studies where two separate RNA components from the natural system were combined into a single molecule, thereby simplifying the system and making it easier to employ. This work demonstrated that engineered CRISPR-Cas9 can be used for gene editing. The Doudna/Charpentier research teams seminal 2012 publication of these results in Science is widely seen as the event that launched a new era of progress in genome editing.

What are the applications for CRISPR-Cas9?

With its vast potential for drug discovery and development, human applications are of particular interest to CRISPR-Cas9 researchers. On a new front in the battle against cancer, scientists are already working to use CRISPR-Cas9 as a means to edit a patients T-cells (immune cells) so that they have the capability to target particular types of tumors. Within the next 10 years it is likely that we will see CRISPR-Cas9-based therapies for blood disorders such as sickle cell disease, as well as other genetic diseases. For non-human applications, researchers are applying the CRISPR-Cas9 technology to engineer pest and disease-resistant crops and protect trees from bark beetles, as well as exploring the technologys ability to control mosquito populations and reduce their ability to spread Zika virus and malaria.

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How CRISPR works | Berkeley News

JOHNSTON, Iowa Green stalks have only just begun to sprout in the test fields where biotech giant DuPont Pioneer is planting rows of a new genetically edited corn. But across the street, in the companys sprawling research campus, executives are already fretting about how to sell it to the world.

On one hand, this corn is a revolution: It will probably be the first plant to market developed through the cutting-edge genome-editing technique called CRISPR-Cas.

On the other, the industrys last big breakthrough of this kind genetically modified organisms, or GMOs was an unqualified public-relations disaster, even according to its progenitor, Monsanto.

[We're having the wrong argument about GMOs]

Wary of that, DuPont Pioneer, which is developing a strain of drought-resistant waxy corn, is proactively neutralizing skeptical consumers years before these crops will even be available. The company recently began hosting CRISPR focus groups and launched a website on the technique, complete with animated videos.

The goal is to avoid the sort of public backlash that rocked Monsanto in the late 1990s and still plagues agriculture two decades later. In the United States,consumerskepticism of genetically modifiedcrops has forced biotech companies into long, costly battles over issues such as whether thesefoods should be labeled; elsewhere in the world, the public outcry has prevented seeds from winning government approval.

Its more about social science than science, said Neal Gutterson, the vice president of research and development at DuPont Pioneer. [Its] ultimately about getting social license for this technology.

Odes to plant technology are ubiquitous in DuPont Pioneers Iowa offices, where even the conference space boasts glossy, museum-like exhibits devoted to genetically modified foods. Plus-sized photos show farmers standing idly in golden corn fields, and mystery hands reaching into overflowing bowls.

But the problem for DuPont Pioneer, and agribusiness generally, is that large swaths of the public do not share this sunny vision of biotech. Since the late '90s, when Monsanto botched the introduction of genetically modified crops in Europe, consumers have treated the term GMO as if it were a dirty word.

According to the Pew Research Center, nearly 40 percent of Americans believe GMOs are bad for their health. This assertion is not supported by science, which has concluded that the genetically modified crops on the market are safe for consumption.

But science has made little headway in a fierce debate that hasoften focused on the perceived values of the companies developing these products.Each year, activists in hundreds of cities worldwide march against Monsanto and millions of consumers buy "Non-GMO Project Verified" products.

The biotech industry has taken strides to clean up its image in recent years: In 2013, Monsanto shook up its public-relations team, and the industry has banded behind a consumer education effort called GMO Answers.

But with CRISPR a breakthrough gene-editing tool the field gets a chance at its first real do-over.

Unlike conventional genetic modification, CRISPR works directly on the DNA of the plant or animal being bred. While GMOs, as we have traditionally known them, involve inserting target DNA from a different species, CRISPR can directly edit an organisms DNA for a result that falls within the genetic diversity of that animal or plant.

The technique was discovered almost simultaneously at several research universities and has since been licensed out to a number of bothnoncommercial researchers and private companies. Outside of agriculture, CRISPRhas diverse applications in medicine, where it's currently being used to develop everything from cancer therapies to noveldisease models.

In agriculture, scientists say it takes far less time, and is more precise, than both traditional and genetically modified breeding techniques.DuPont Pioneer expects its CRISPR-edited waxy corn to be on the market withinthree years.The Agriculture Departmenthas indicated that it does not intend to regulate the CRISPR-edited corn because its creation does not involve any plant pests' genetic materials.

That comes with a lot of responsibility, said Kerrey Kerr-Enskat, the publicist who handles DuPonts CRISPR outreach efforts. Its not just about row crops we dont want to waste that opportunity [to engage with the public].

Accordingly, DuPont Pioneer has spent the past several months convening regular focus groups with leaders from government, agriculture and environmental organizations, Kerr-Enskat said. The goal is to learn more about the publics CRISPR concerns and use them to inform future messaging efforts.

In April, the company launched a website that it calls the first step in a larger campaign to win consumers trust for the technology. Its an unusual move for a company that sees farmers, not food consumers, as its direct customers. Its product is, after all, seeds and its first CRISPR product, waxy corn, is for industrial use, not human consumption.

The homepage shows a stock photo of a smilingfamilyeating corn on the cob behind a green banner that calls CRISPR-Cas one of the greatest breakthroughs in biology. A guiding principles page promises the company's commitment to safety and open, transparent and timely communications. In a slick animated video, a measured female narrator claims that CRISPR is not so different from traditional plant breeding techniques deployed at the dawn of agriculture.

Ironically, the video is also not so different from the marketing that DuPont used 100 years ago: It was among the first companies to use silent film to advertise to consumers. In fact, DuPont which sold explosives and plastics, long before it bought Pioneer and got into seeds built interest in novel products such as nylon through what it called educational advertising.

Since then, of course, the atmosphere has changed. Its not clear if consumers see DuPont Pioneer as a scientific authority or if the company hurts its own position by wading into the debate.

Already, the controversy over GMOs has become so fractious, said Glenn Davis Stone, a professor of anthropology and environmental studies at Washington University, that even independent scientists havelet their role in educating be trampled by their interest in convincing. Many are so frustrated by the impasse, he added, that they'll gloss over questions such as regulation, rather than risk giving the other side anti-GMO ammunition.

Meanwhile, two decades of sociological research have shown that skepticism of genetic modification is largely fueled not by ignorance or technophobia but by a lack of trust in large companies, some of which is arguably well-deserved.Before they sold seeds, for instance, both Monsanto and DuPontmanufactured Agent Orange, a defoliant used extensively during the Vietnam War, and DDT, an insecticide that caused widespread environmental damage.

Even pro-GMO advocates, such as Sarah Davidson Evanega of the Cornell Alliance for Science, say that public-sector scientists may be best positioned to deliver messages about CRISPR.

Theres great optimism that this time well do communications better, Evanega said. The great hope is that CRISPR is going to be different.

Whether consumers will eventually embrace CRISPR is still, of course, anybodys guess. As with GMOs, there is compelling science here. There are also, particularly when it comes to human genome editing, worrying potential drawbacks.

But Kerr-Enskat, of DuPont Pioneer, is quick to emphasize that her company wont be the only or the loudest voice, no matter how the debate evolves.In fact, if you click the contact link on the new CRISPR site, your email will eventually make its way to her inbox.

For GMOs, they waited until the product hit the market before there was a lot of communication, she said. But this is a two-way engagement.

Read more:

The government is going to counter 'misinformation' about GMO foods

The apple that never browns wants to change your mind about genetically modified foods

Industry is counting on Trump to back off rules that tell you what's in your food

See the original post:

Forget GMOs. The next big battle is over genetically 'edited' foods - Washington Post

NEW YORK (GenomeWeb) The discovery of bacterial CRISPR systems has created a cottage industry of researchers and biotechnology companies hoping to use the genome-editing method to cure disease or create better medications for a variety of illnesses. But there have been problems along the way many naturally occurring CRISPR proteins are unsuitable for use in human cells, either because they don't work at all, work very ineffectively, or create off-target effects that end up causing more problems than they solve.

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MilliporeSigma's Proxy-CRISPR Tech Aims to Increase Usability of Native CRISPR Proteins - GenomeWeb

The findings of a recent study on the CRISPR gene editing technique have been called into question (Credit: vchalup2/Depositphotos)

Last month, a study was published claiming that the groundbreaking CRISPR-Cas9 gene-editing technique could potentially introduce hundreds of unintended mutations into an animal's genome. Unsurprisingly, this study sent shockwaves through the scientific community, with the stock prices from several gene-editing companies falling. Critics are now calling into question the veracity of the study, claiming it is filled with flawed assumptions.

Published in the journal Nature Methods, the research from a team of scientists from Stanford, the University of Iowa and Columbia University examined the entire genome of mice that had undergone CRISPR gene-editing. The study claimed to find over 100 unintended large deletions or insertions in each of the two mice examined, and attributed these alterations to the CRISPR gene-editing process.

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Within 24 hours of the research being published, stocks in several major biotech companies fell up to 14 percent. Two of these companies have since published open letters to the journal Nature Methods, criticizing the veracity of the study.

Editas Medicine, in a letter co-signed by 13 of the company's scientists, claimed the conclusions drawn from the study could not be ascribed to CRISPR and any observed mutations were likely present prior to the genome-editing procedure.

A letter from Intellia Therapeutics made similar claims, questioning the study's conclusions and pointing out flaws in the study design. Nessan Bermingham, CEO of Intellia, has even called for Nature Methods to retract the study.

While it is not unexpected to see these letters criticizing the study coming from companies with a financial interest in CRISPR, several independent scientists have also voiced concerns over the findings of the study.

Gaetan Burgio, a geneticist from Australia National University, has been working with CRISPR for several years and was vocal in his skeptical response to the study. He published a comprehensive essay detailing several misgivings around the study. He noted numerous factors as to why the mutations found in the research should not be necessarily attributed to CRISPR.

From an unusual delivery mechanism to a low sample size, Burgio explained the abnormal number of mutations are unlikely to be CRISPR related. He also wrote a scathing critique of the journal itself for publishing what he felt to be dubious research.

"I find absolutely astonishing this paper got published in Nature Methods," Burgio writes. "This is a terrible paper and as a reviewer I would have dissmiss (sic) it from the first round of review. This is a worrying trend from 'high impact' journals to promote the hype over good science. The publication of this paper is clearly a failure in the peer review process."

Other CRISPR specialists including Dr Lluis Montoliu, from the Spanish National Centre for Biotechnology, and Matthew Taliaferro, from MIT, backed up Burgio's concerns, tweeting doubts about the study's conclusions.

With such a public, and vociferous backlash, focus has now turned to the journal Nature Methods. If the original study's findings are so easily called into question then, as Gaetan Burgio noted, the question over how this article was published in the first place needs to be answered.

A spokesperson from the publishing company behind Nature Methods commented to MIT Technology Review, "We are carefully considering all concerns that have been raised with us and are discussing them with the authors."

With human trials involving CRISPR already underway, it is no surprise that a study like this has kicked up such a controversy. There has already been plenty of time and money invested in CRISPR, so it's not unexpected to see such vociferous criticisms of a study claiming flaws in the technology.

What is surprising is the broad spectrum of critics pointing out such a volume of flaws in the study. Only time will tell whether it is ultimately discredited or vindicated.

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The CRISPR controversy: Scientists skeptical over recent critical study - New Atlas

When people talk about the gene-editing technology CRISPR, its usually accompanied by adjectives like revolutionary or world-changing. For this reason, its no surprise that a study out last month questioning just how game-changing the technology really is caused quite a stir.

Its well-known that using CRISPR can sometimes also result in some unintended genomic changes, and scientists have long been working on ways to fine-tune it. But the researchers found that when they had used CRISPR to cure blindness in mice, it had resulted in not just a few but more than a thousand, unintendedoff-target effects.

This finding warns that CRISPR technology must be further tailored, particularly before it is used for human gene therapy, the researchers wrote. The technique has already been used in two human trials in China, and next year one is slated to kick off in the US.

Their finding kicked off a battle for CRISPRs honor, with some researchers speaking out to question the studys methods while others piped up to agree that CRISPR is not yet ready for people.

The first criticism came the day after the study was published, via a comment from a researcher on PubMed who argued careless mistakes and flaws in the methodology cast serious doubts about the results or interpretation, concluding that it was hard to imagine CRISPR-cas9 causes so many [unintended] homozygous deletions in two independent mice.

On social media, scientists raised red flags about basic mistakes, such as misidentifying genes, mislabeling genetic defects, and the small number of animals the researchers had included in their research.

I think the Nature Methods paper was a false alarm on CRISPR induced mutations, the geneticist Eric Topol told Gizmodo. Ironically, the methods used were flawed. While we remain aware of such concerns unintended genomic effects that might occur with editingthat report was off-base.

Scientists from the CRISPR-focused companies Intellia Therapeutics and Editas Medicine sent separate letters to the journal, Nature Methods, chiming in with their own critique.

Based on the information available on the mouse study, the more plausible conclusion is that the genetic differences reflect a normal level of variation between individuals in a colony.

We believe that the conclusions drawn from this study are unsubstantiated by the disclosed experiments as they were designed and carried out, the scientists from Editas wrote. Further, it is impossible to ascribe the observed differences in the subject mice to the effects of CRISPR per se. The genetic differences seen in this comparative analysis were likely present prior to editing with CRISPR.

The study sent the stocks of those two companiesand a third, CRISPR Therapeuticstumbling. Nearly two weeks later, those market prices had still not fully recovered. Some went so far as to call for a retraction.

All of our methods are described in our peer reviewed Correspondence and sopplemental materials in Nature Methods and the raw data have all been publicly deposited, so that others may further learn from our data, one of the authors, Alexander Bassuk, told Gizmodo via email.

Springer Nature, which owns Nature Methods, said that they have received a number of communications regarding the paper and said that it had undergone peer review as all papers in the journal do.

We are carefully considering all concerns that have been raised with us and are discussing them with the authors, a spokesperson said.

On his blog, UC Davis professor Paul Knoepfler asked several scientists about the study and got mixed results. One cited the same flaws in methodology others have brought us. Another posited that it was a good reminder to hunt thoroughly for off-target effects.

Overall, this study adds a bit to the knowledge base, but it has been over-interpreted in the media, Knoepfler concluded. It was unlikely, he wrote, that so many unintended edits were occurring in most research, but it still suggested more studies to investigate the problem are necessary.

This brings us to the one thing that is definitely true: Despite all our recent progress, there is still a lot we dont know about CRISPR. It does indeed allow us to make precise gene edits more easily than ever before, but this ability has limitations that could wind up being disastrous if used in humans, and disappointing when genetically engineering everything else. CRISPR is still a nascent technology, and whether one day it might really be used to cure diseases or create a unicorn, there are still a whole lot of things that need to happen first.

Update: This story has been updated to include comments from one of the study authors, Nature Methods and Eric Topol.

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A Controversial Study Is Tearing the CRISPR World Apart - Gizmodo - Gizmodo

I

f there was one misstep that doomed the long and bitter fight by the University of California to wrest key CRISPR patents from the Broad Institute, it was star UC Berkeley scientistJennifer Doudnas habit of being scientifically cautious, realistic, and averse to overpromising.

A biochemist who co-led a breakthrough 2012 study of CRISPR-Cas9, Doudna repeatedly emphasized in interviews the challenges of repurposing the molecular system, which bacteria use to fend off viruses, to edit human genomes. The U.S. patent office, in a February rulingthat let the Broad keep its CRISPR patents (for now), relied heavily on those statements We werent sure if CRISPR/Cas9 would work in animal cells, for example to conclude that when scientists at the Broad CRISPRd human cells in 2013, it was a non-obvious advance and therefore deserving of patents.

So its striking that the careful, measured Doudna who said CRISPRing human cells and thereby curing devastating diseases would be a challenge is hardly in evidence in A Crack in Creation: Gene Editing and the Unthinkable Power to Control Evolution, the new book she co-authored with her former student Samuel Sternberg. It goes on sale Tuesday.

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This Doudna doesnt hold back. We are on the cusp of a new age in genetic engineering and biological mastery, she and Sternberg write, dangling the prospect of life-changing treatments and lifesaving cures. She says she is not kidding that CRISPR could bring about woolly mammoths, winged lizards, and unicorns. It wont be long before CRISPR allows us to bend nature to our will.

University of California appeals CRISPR patent setback

The hyperbole contrasts with CRISPRs stumbles, including altering parts of genomes (in lab studies, not patients yet) it wasnt supposed to. I dont think well have a version of CRISPR thats 100 percent perfect, so it comes down to a risk-benefit analysis, Sternberg, a biochemist at Caribou Biosciences (which Doudna co-founded), said in an interview. There has been phenomenal progress in understanding off-target effects; I think its a solvable problem. We have every reason to be optimistic but I hope we avoided overhyping and didnt give the impression that there would be windfall of cures in the next couple of years.

This is not a tell-all. The farthest Doudna goes in addressing the patent fight a disheartening twist is to say that because of such rivalries she experienced the gamut of human relationships, from deep friendships to disturbing betrayals. She doesnt name the betrayers.

An early reviewchastised Doudna for presenting herself as so flawless the book seems more concealing than revealing, not insightful [and] candid.

So what she does choose to reveal is fascinating, especially about her collaboration with Emmanuelle Charpentier. The two are so closely linked that all the prizes theyve won for CRISPR, theyve won together; among CRISPR watchers DoudnaandCharpentier is virtually a macro.

But the books account of their breakthrough experiment showing that CRISPR could be programmed to edit a precise spot in a genomeleaves a different impression. We read that Martin [Jinek, Doudnas postdoctoral fellow] showed and Martin labored tirelessly, Martin and I brainstormed and designed an experiment, and when Martin walked me through the data, Doudnaknew wed done it.

That work was described in the 2012 paper, which is widely recognized by prize committees, the European Patent Office, and many scientists as the Bastille moment for the CRISPR revolution. It identified the three crucial molecules in the CRISPR system one to cut, one to guide the cutting enzyme to its target DNA, one to activate the cutting enzyme that produced a programmable DNA-cutting machine. We had built the means to rewrite the code of life, Doudnaand Sternberg write. Nothing after that would ever be the same.

Although Doudna and her collaborators didnt actually change genomes in cells their CRISPR molecules altered cell-free DNA in test tubes that was an obvious next step. How difficult a next step was the core dispute in the patent fight and one that she repeatedly cautioned was no slam dunk. But Crack in Creation says that doing so was immediately clear to us, and there were good reasons to expect success.

That contrasts with her cautious statements, cited by the patent office, at the time. When Feng Zhang of the Broad Institute and George Church of Harvard used CRISPR to edit genes, it was just as we had proposed in 2012, according to the book. She waselated that her 2012 work inspired others to pursue a line of experimentation similar to our own.

Doudna became a public scientist shes given aTED talkand will appear on Sunday Night with Megyn Kelly because of her research, but also because she was instrumental in getting the scientific community to focus on ethical issues it raises, especially about editing embryos in a way that would be inherited by future generations (germline editing). She writes that she had nightmares that a man asking her about this was Hitler and that she began to feel a bit like Dr. Frankenstein.

No red line against CRISPRing early embryos, experts rule

Her own moral journey is intriguing. She feels germline editing can be safe, and the its unnatural! argument doesnt carry much weight with me anymore, she writes. It seems to me that wed be justified in using CRISPR to eliminate genes that cause untold suffering, such as those for Huntingtons disease. When I think about the pain that genetic diseases cause families, the stakes are simply too high to exclude the possibility of eventually using germline editing, as an expert panel also concluded.

Doudnaacknowledges, however, that its difficult to see how wed do it equitably, especially when the line between therapy and enhancement is paper thin: Some families might purchase a genetic legacy that gives them less need for sleep, greater endurance, extra-strong bones, leaner or larger muscles, lower risk of diabetes and Alzheimers, even less armpit odor while other families muddle through with the genes nature gave them.

That threatens to transcribe our societies financial inequality into our genetic code, Doudna writes.

Her solution? Redoubl[ing] our commitment to building a society in which all humans are respected and treated equally, regardless of their genetic makeup.

Sharon Begley can be reached at sharon.begley@statnews.com Follow Sharon on Twitter @sxbegle

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CRISPR pioneer Doudna envisions a world of woolly mammoths and unicorns - STAT