Archive for the ‘Crispr’ Category

Excision BioTherapeutics has raised money to move what it sees as a cure for HIV into the clinic. Stemcentrx backer Artis Ventures led the $10 million seed round to equip Excision to start human testing of its CRISPR-enabled attack on latent HIV virus.

Philadelphia-based Excision is built on research conducted at Temple Universitys Lewis Katz School of Medicine. The work led to a paper published last year, in which Excision co-founder Kamel Khalili, Ph.D., and his partners administered a multiplex of guide RNAs (gRNAs) and Staphylococcus aureus Cas9 to HIV-infected mice. The team designed the treatment to remove a large, essential DNA fragment from HIV.

Results from the study furthered Excisions belief its candidate can wipe out HIV provirus from all tissues in the body without causing genotoxic effects and off-target editing.

That belief prompted the founding of Excision in 2015. Having generated animal data to back up the belief, Excision has high hopes for the approach.

We're in this to cure patients of HIV, Excision CEO Thomas Malcolm, Ph.D., said.

Excision sees an HIV CRISPR Cas9/gRNA multiplex biologic based on Khalilis workEBT101as its best shot of meeting this lofty goal. The plan is to wrap up IND-enabling studies of the candidate in the months to come and get it into the clinic around the end of next year. That small trial will act as an early test of the safety and, to a lesser extent, the efficacy of EBT101 and its delivery system.

Some of Khalilis projects used adeno-associated virus (AAV) vectors to deliver sgRNAs and Cas9. But Excision is now looking at a lentiviral approach.

It's really more specific for the types of cells that have that latent virus. HIV itself is a lentivirus so it makes sense to use a lentiviral shell to deliver the therapeutic, Malcolm said. Were showing we can easily access all of these reservoirs with this approach.

The plan for later trials is to use EBT101 to target these reservoirs in patients taking cocktails of HIV inhibitors to control the virus. These cocktails, such as Gileads Genvoya, lower HIV viral loads to undetectable levels in most patients. But, while that has improved outcomes significantly, Excision is confident a product that eradicates the virus would still find a market.

This confidence is based on what Malcolm calls the baggage that comes with cocktails. That term covers the risk of noncompliance to the daily treatment regimen and the comorbidities common in people who live with HIV, although there is evidence suggesting treatment with modern antiretroviral therapy cuts the risk of these complications.

The other shortcoming, which is linked to the risk of noncompliance, stems from the potential for HIV to develop resistance to drugs. That is happening today. A CDC study found 16% of patients diagnosed with HIV in 10 metropolitan areas from 2007 to 2010 carried antiretroviral-resistant virus. A WHO study found more than 10% of patients starting treatment in six of 11 surveyed countries in Africa, Asia and Latin America had a resistant strain.

Malcolm sees this causing big problems down the line.

It's a ticking time bomb, he said. It's just a matter of time before you're going to get another patient zero who is going to be completely unsusceptible to these inhibitor cocktails and we're going to be right back to where we were in the '80s.

Excision plans to head off that scenario by developing EBT101. In parallel, the biotech is working on a clutch of earlier-stage programs, two of which it will move into animal studies using the seed money. Success in those studies would tee Excision up to move candidates against JC virusthe cause of progressive multifocal leukoencephalopathyand herpes simplex virus into the clinic in the next couple of years.

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Artis funds Excision to test whether CRISPR can cure HIV ... - FierceBiotech

Markets Insider

New gene editing tech promises to be even better than CRISPR Digital Trends Just when we were getting used to the CRISPR/Cas9 gene editing revolution, a new fourth-generation DNA base editor has come along. University of South Carolina to provide Transomic Technologies ...Markets Insider all 4 news articles »

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New gene editing tech promises to be even better than CRISPR - Digital Trends

I've written a number of times about the tremendous rise in citizen science game platforms that allow players to contribute to scientific research. Arguably the most well known of these games is Stanford based Eterna.

Last year a paperhighlighted how players of the game were playing an ever increasing role in scientific research.

We see that in particular researchers in the natural sciences have collected and classified data with the help of interested volunteers. In the social sciences, there has been a focus on inviting select parts of the public to find out the effects of science on peoples everyday lives. This may for example concern environment problems and risks,the authors say.

The game began life by asking players to help scientists understand RNA, but it has recently branched out into new fields. For instance, last year they developed a version that aimed to further understanding of TB.

The latest version sees players tasked with designing a CRISPR-controlling molecule. The design of the challenge is to develop an RNA molecule that's capable of acting as an on/off switch for CRISPR. The resulting molecules will then be tested by molecular biologists.

The ability to turn off CRISPR is crucial as the editor is incredibly powerful and may have unexpected effects on the cells, so being able to turn it off is key to its safe usage. The researchers also believe the functionality could allow CRISPR to be deployed on a kind of timer so that it can be activated and deactivated according to a schedule.

"Great ideas can come from anywhere, so this is also an experiment in the democratization of science," the team say. "A lot of people have hidden talents that they don't even know about. This could be their calling. Maybe there's somebody out there who is a security guard and a fantastic RNA biochemist, and they don't even know it."

The aim is to get up to 100,000 players to contribute, with each player contributing around 10 solutions each. Should that number of players participate, it gives the team a good amount of data to work with, and their initial tests will then go into refining the game further to guide future players in their designs.

In addition to producing some invaluable inputs into scientific research, the team also hope to enhance interest in science among the wider population.

"The Eterna game is a powerful way to engage lots and lots of people," they say. "They're not just passive users of information but actually involved in the process."

As with other computer games, Eterna aims to incentivize players by allowing them to earn points, build expertise and advance to higher levels. The best players then gain the chance to have their designs implemented in a lab environment.

Citizen science games like Eterna have proven incredibly popular. For instance, I wrote recently about the Sea Hero Quest game developed by Deutsche Telekom to promote research into dementia. The original mobile game has been downloaded over 3 million times, providing data equivalent to 12,000 years of lab research.

As such, the Eterna team believe that the game is as much about the sociology of science as it is about the hard science itself.

"There is a misconception of science as something that happens in an ivory tower by someone in a white coat with a long beard. And they are saying things and drawing things that nobody understands. But it's not like that! It's really like a puzzle that anybody can get engaged with," they say.

You can play the game for free by clicking here, or alternatively watch the video below to learn more about it.

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Eterna Citizen Science Game Turns Its Attention To CRISPR - HuffPost

Morning Glory. Credit: University of Tsukuba

In a world-first, Japanese scientists have used the revolutionary CRISPR, or CRISPR/Cas9, genome- editing tool to change flower colour in an ornamental plant. Researchers from the University of Tsukuba, the National Agriculture and Food Research Organization (NARO) and Yokohama City University, Japan, altered the flower colour of the traditional Japanese garden plant, Japanese morning glory (Ipomoea nil or Pharbitis nil), from violet to white, by disrupting a single gene. This research highlights the huge potential of the CRISPR/Cas9 system to the study and manipulation of genes in horticultural plants.

Japanese morning glory, or Asagao, was chosen for this study as it is one of two traditional horticultural model plants in the National BioResource Project in Japan (NBRP). Extensive genetic studies of this plant have already been performed, its genome sequenced and DNA transfer methods established. In addition, as public concern with genetic technologies such as CRISPR/Cas9 is currently a social issue in Japan, studies using this popular and widely-grown plant may help to educate the public on this topic.

The research team targeted a single gene, dihydroflavonol-4-reductase-B (DFR-B), encoding an anthocyanin biosynthesis enzyme, that is responsible for the colour of the plant's stems, leaves and flowers. Two other, very closely related genes (DFR-A and DRF-C) sit side-by-side, next to DFR-B. Therefore, the challenge was to specifically and accurately target the DFR-B gene without altering the other genes. The CRISPR/Cas9 system was used as it is currently the most precise method of gene editing.

The CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)/Cas9 system is based on a bacterial defense mechanism. It is composed of two molecules that alter the DNA sequence. Cas9, an enzyme, cuts the two strands of DNA in a precise location so that DNA can be added or removed. Cas9 is guided to the correct location by gRNA, or guide RNA, a small piece of RNA that has been designed to be complementary to the target DNA sequence. Cas9 cuts the two strands of DNA at the target location, allowing DNA to be removed and/or added.

As reported on 30 August 2017 in Scientific Reports, a short DNA sequence in the Japanese morning glory DFR-B gene was selected as the target for the CRISPR/Cas9 system. This sequence contains the active site of the enzyme produced by the DFR-B gene. Disruption of this sequence should therefore de-activate the enzyme, resulting in an absence of the colour pigment, anthocyanin. The CRISPR/Cas9 system was inserted into tissue-cultured embryos of Japanese morning glory plants using the DNA-transferring capabilities of the plant bacterium Rhizobium. As expected, the DFR-B enzyme was successfully inactivated, resulting in approximately 75%of the transgenic plants with green stems and white flowers. Non-transformed plants with an active enzyme had violet stems and flowers. These changes in stem colour were observed very early in the tissue culture process. A series of genetic analyses confirmed that the DNA target sequence had been altered in the transgenic plants, with either DNA insertions or deletions in both copies of the DFR-B gene (so-called bi-allellic mutants). The other related genes, DFR-A and DFR-C, were examined and no mutations were found, confirming the high specificity of the CRISPR/Cas9 system.

Next, the researchers examined the inheritance of the CRISPR/Cas9-induced mutations by analyzing plants from the next generation. These plants looked exactly like their parents. Among these plants were some without any sign of the introduced DNA. This raises some interesting questions in terms

of the regulation of genetically modified organisms (GMOs), as these next-generation plants are considered transgenic, based on process-based definitions (how they were made), and non- transgenic, based on product-based definitions (the presence of foreign DNA in the final product).

This technology is also extremely useful in confirming the function of genes. Experiments in the 1930s and 1990s used 'forward' genetic screening techniques to find the genes responsible for flower colour production in the Japanese morning glory. The CRISPR/Cas9 system described here is the 'reverse' genetic approach, used to find out what an organism looks like after a known gene is disrupted, and confirms that the DFR-B gene is the main gene responsible for colour in Japanese morning glory plants.

Currently, CRISPR/Cas9 technology is not 100% efficient, that is, not all targeted plants will be transgenic. The mutation rate in this study, 75%, however, was relatively high. This is one of the reasons this research will greatly facilitate those interested in the modification of flower colours and shapes using the CRISPR/Cas9 system in ornamental flowers or vegetables.

The story of the Japanese morning glory started in the 8th century AD, with the introduction of wild blue-flowered plants into Japan from China. In 1631, the first white-flowered Japanese morning glory was painted in Japan. What took nature nearly 850years to achieve has taken less than one using the CRISPR/Cas9 system, indicating both its power and its potential.

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

More information: Kenta Watanabe et al. CRISPR/Cas9-mediated mutagenesis of the dihydroflavonol-4-reductase-B (DFR-B) locus in the Japanese morning glory Ipomoea (Pharbitis) nil, Scientific Reports (2017). DOI: 10.1038/s41598-017-10715-1

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Scientists use CRISPR technology to change flower colour - Phys.org - Phys.Org

Experts at a one-day workshop in Washington DC next week will discuss public interest aspects of patents and two breakthrough new medical technologies related to gene editing (CRISPR) and cancer treatment (CAR T).

The 15 September event, entitled, Patents, the Public Interest and Two New Medical Technologies: CRISPR and CAR T, will feature a unique mix of key health advocates, academics, licensing and standards experts, congressional staff and others.

A live webcast on YouTube will be available here.

Event moderators include William New of Intellectual Property Watch and Sarah Karlin-Smith of Politico.

The full KEI event announcement is reprinted below:

Workshop: Patents, the Public Interest and Two New Medical Technologies: Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR), Chimeric Antigen Receptors (CAR) technologiesOn September 15th, 2017, Knowledge Ecology International will be hosting a workshop on: Patents, the Public Interest and Two New Medical Technologies: CRISPR and CAR T.

CRISPR related inventions include breakthrough technologies to modify genes, which have broad applications for innovations in medicine, agriculture and other fields.

CAR T therapies are an exciting new approach to treating cancer and other diseases, including previously incurable cancers.

Both technologies were developed with significant funding from the U.S. federal government.

There are controversies over the licensing of several CRISPR related inventions, and over the pricing of new CAR Treatments, including most recently the decision by Novartis to charge $475,000 for Kymriah, a CAR T treatment for leukemia.

The workshop will bring feature a diverse group of experts and stakeholders to discuss the public policy challenges appropriate governance of CRISPR and CAR Ts intellectual property.

Date: Friday, September 15, 2017Location: Kaiser Permanente Center for Total Health, 700 Second St. NE (near Union Station), Washington, DC 20002

To Register: use this form.

A PDF version of the program is available here.

Related

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Workshop Next Week On Public Interest And CRISPR Gene Editing, CAR T Cancer Treatment - Intellectual Property Watch

CRISPR: The Next Generation

The latest news in genetic science has been dominated by the CRISPR/Cas9 technique over the past fiveyears. But a new fourth-generation DNA base editor could see CRISPR dethroned, according to a recent study published in Science Advances.

The fourth-generation base editor a tool used to modify the building blocks of genetic code, only now with an inhibitor added to protect DNA from accidental changes heightens editing accuracy and reduces unintentional DNA changes, which occur with current base-editing technologies.

DNA is a series of base pairs, or nucleotides: adenine, thymine, guanine and cytosine, called A-T-G-C for short. When CRISPR converts a C:G base pair to a T:A pair, sometimes it inadvertently changes the C:G base pair to a G:C or A:T base pair. Thismight seem like an insignificant mess of letters, but on the genetic level, even a single mistaken nucleotide can have devastating consequences for an organism.

Approximately two-thirds of known human genetic variants associated with disease are point mutations, said study co-author David R. Liu, Harvard University Professor of Chemistry and Chemical Biology and Howard Hughes Medical Institute Investigator, in an email interview with Futurism.The fourth-generation base editors to my knowledge are the most effective forms of these molecular machines that can directly correct certain types of point mutations.

Liu, co-author Alexis Komor, and their colleagues found that the number of undesired editing products depends on the level of a cutting enzyme called uracil N-glycosylase (UNG). Uracil is one of the four base pairs found in RNA, which is involved in the process of transcribing DNA so that its code is physically expressed by the organism.

Mechanistically, it made sense that [this]was leading to the undesired products we would occasionally observe, Liu explained. The teamhad a hunch that UNG, which initiates base excision repair at uracils, might be the culprit. Indeed, when we performed base editing in cells lacking UNG, essentially all undesired product formation went away.

Komoret al. then designed a fourth-generation base editor combined with an inhibitor, called BE4, which blocks UNG from cutting and altering DNA inadvertently. BE4 shuts down the cellular troublemaker (UNG) more effectively than our previous base editors, which results in higher efficiency of C to T base editing, and also fewer undesired products, said Liu.

Using BE4 formed with the bacteriaStreptococcus pyogenes, this base editing procedure increased the efficiency of swapping C:G to T:A by 50 percent, while halving the frequency of undesired byproducts. Click to View Full Infographic

This comes at a time when the number of incredible things CRISPR is doing extends beyond the medical field: into ecology, with the possibility of artificially designing algae to create a more efficient biofuel, and national security, with the U.S. Advanced Research Projects Agency (DARPA) investing $65 million in a project called Safe Genes.The DARPA Safe Genes program is very forward-thinking and focused on important issues including safest practices for genome editing, as well as helping to advance these technologies to realize their full potential, commented Liu.

Ultimately, the optimum balance lies in protecting the public with restrictions on gene editing technology, but not implementing so many that it decreases the number and diversity of efforts to use these technologies for the public good, Liu said.

For a nominal charge, Lius team has made the base editor available ona nonprofit genetic repository called Addgene: We definitely want the scientific community to use these tools.

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A Fourth-Generation DNA Base Editor Could Replace CRISPR - Futurism

Newly fertilized (left) and later-stage (right) human embryos that have had a disease mutation corrected by the CRISPR editing system.

OHSU

By Kelly ServickAug. 31, 2017 , 12:28 PM

When the first U.S. team to edit human embryos with CRISPR revealed their success earlier this month, the field reeled with the possibility that the gene-editing technique might soon produce children free of their parents genetic defects. But the way CRISPR repaired the paternal mutation targeted in the embryos was also a surprise. Instead of replacing the gene defect with strands of DNA that the researchers inserted, theembryos appeared to use the mothers healthy gene as a template for repairing the cut made by CRISPRs enzyme.

But such a feat has not been observed in previous CRISPR experiments, and some scientists are now questioning whether the repairs really happened that way. In a paper published online this week on the preprint server bioRxiv, a group of six geneticists, developmental biologists, and stem cell researchers offers alternative explanations for the results. And uncertainty about exactly how the embryos DNA changed after editing leaves many questions about the techniques safety, they argue. (The authors declined to discuss the paper while its being reviewed for publication.)

Embryologist Shoukhrat Mitalipov of Oregon Health and Science University in Portland, who led the now-disputed experiments, released a statement saying that his team stands by its explanation. We based our finding and conclusions on careful experimental design involving hundreds of human embryos, it says.

In the 2 August Nature paper, Mitalipov and his collaborators showed they could bump up the efficiency of human embryo editing by inserting the CRISPR machinery earlier in development than previous experiments. When they combined healthy eggs with sperm bearing a disease-causing mutation and immediately added CRISPR, they found that 72% of the resulting embryos were free of the mutationrather than the expected 50% that would have avoided inheriting the harmful gene anyway.

Although the researchers inserted short strands of DNA as templates for repair, the cells didnt seem to take them up; those specific sequences were absent from the embryos. The cells must have relied instead on the nonmutated sequence in the egg donors DNA when making the repairs, the team concluded.

The bioRxiv response, led by developmental biologist Maria Jasin of Memorial Sloan Kettering Cancer Center in New York City and Columbia University stem cell biologist Dieter Egli, challenges that interpretation. The authors, which also include well-known CRISPR researcher and Harvard University geneticist George Church, say that the Nature paper goes against conventional wisdom about how embryos are organized early in development. Right after an egg is fertilized, the DNA from the sperm and the egg arent believed to be in close enough proximity to interact or share genes, they explain.

Stem cell researcher Junjiu Huang of Sun Yat-Sen University in Guangzhou, China, who led the first published study of CRISPR editing of a human embryo, isnt on the bioRxiv paper, but shares that concern. Its not unexpected for a cell to use its own sequences to guide repair, he notes. In his groups study, which used nonviable embryos, a gene related to the CRISPR-targeted gene seemed to function as a template. But that gene was on the same chromosome as CRISPRs edits. Here, the sperm and egg nuclei are seemingly too far apart to cooperate in the repairs, he says.

The preprint authors lay out two other scenarios for what Mitalipovs team saw. Its possible that some of the embryos didnt take up paternal DNA at all, and thus never inherited the mutation to begin with. In some in vitro fertilization procedures, embryos can occasionally start to develop from maternal DNA alone, and the study didnt rule out this phenomenon for every embryo, they say.

They also suggest that mutated paternal gene could have been snipped out of young embryos but never actually replaced with a healthy version. CRISPRs cuts can sometimes cause chunks of DNA to be removed from the strand before the two cut ends are rejoined, they note. That would mean no detectable mutationbut it could also mean missing sections of DNA that could have unknown consequences for the embryo.

This possibility of allele dropout has been the subject of discussion in the field ever since the Nature paper was published, says developmental biologist Robin Lovell-Badge of the Francis Crick Institute in London. Many scientists are now waiting for a response from Mitalipov, he says.

In his statement, Mitalipov promised to respond to [the] critiques point by point in the form of a formal peer-reviewed response in a matter of weeks. He also urged follow-up to resolve the matter. We encourage other scientists to reproduce our findings by conducting their own experiments on human embryos and publishing their results.

*Update, 1 September, 1:30 p.m.: The new version of this story has additional comments from several researchers and clarifies the authorship of the preprint.

The rest is here:
Skepticism surfaces over CRISPR human embryo editing claims ... - Science Magazine

E. coli might best be known for giving street food connoisseurs occasional bouts of gastric regret. But the humble microbial workhorse, with its easy-to-edit genome, has given humankind so much moreinsulin, antibiotics, cancer drugs, biofuels, synthetic rubber, and now: a place to keep your selfies safe for the next millennium.

Scientists have already used plain old DNA to encode and store all 587,287 words of War and Peace, a list of all the plant material archived in the Svalbard Seed Vault, and an OK Go music video. But now, researchers have created for the first time a living library, embedded within, you guessed it: E. coli. In a paper published today in Nature, Harvard researchers1 describe using a Crispr system to insert bits of DNA encoded with photos and a GIF of a galloping horse into live bacteria. When the scientists retrieved and reconstructed the images by sequencing the bacterial genomes, they got back the same images they put in with about 90 percent accuracy.

The study is an interestingif slightly gimmickyway to show off Crispr's power to turn living cells into digital data warehouses. (As if E. coli didnt already have enough on its plate, what with securing global insulin supplies and weaning the world off fossil fuels.) But the real question: Why would anyone want to do this?

To the left are a series of frames from Eadweard Muybridges Human and Animal Locomotion. To the right are the frames after multiple generations of bacterial growth, recovered by sequencing bacterial genomes.

Seth Shipman

If youre Jeff Nivala, its not to preserve visual messages for people in the far-off future. Its so he can turn human cells like neurons into biological recording devices. The E. coli is just a proof of concept to show what cool things you can do with this Crispr system, says Nivala, a coauthor on the paper and geneticist at Harvard. Our real goal is to enable cells to gather information about themselves and to store it in their genome for us to look at later. That concept is called the molecular ticker tape. Its something George Church thought up before Nivala, a postdoc, arrived in his lab. But its a challenge Nivala thinks is uniquely suited to Crispr.

In case youve been living in a bunker, Crispr-Cas9 is a revolutionary molecular tool that combines special proteins and RNA molecules to precisely cut and edit DNA. It was discovered in bacteria, which use it as a sort of ancient immune system to fend off viral attackers. Cas9 is the protein that does all the cutting, i.e. gene editings heavy lifting. Lesser known are Cas1 and Cas2. Theyre the ones that tell Cas9 where to do the cutting.

Church's lab plans to leverage that system to get human brain cells to show how exactly they develop into neurons. Nivala thinks theyll be able to do that because of how Cas1 and Cas2 work. During a viral invasion, the proteins go out and grab a piece of the attackers DNA, which they slip into the bacterial genome for another enzyme to turn into a matching guide RNA. Thats what helps Cas9 find (and then chop up) copies of the virus in the cell. The really cool bit is that Cas1 and Cas2 dont just insert viral DNA into the genome at random. As they encounter new threats, they add DNA in the order in which it arrives. That turns a cells genome into a temporal recordthink ice cores for molecular historyof whatever the cell encounters.

To the left is an image of a human hand, which was encoded into nucleotides and captured by the Crispr-Cas adaptation system in living bacteria. To the right is the image after multiple generations of bacterial growth, recovered by sequencing bacterial genomes.

Seth Shipman

One day, Nivala thinks scientists will be able to use that system to record synaptic activity. Like a guest book at a wedding, embedded signals in the genome could tell researchers exactly which neurons were talking to each other at different times, in response to different stimuli.

If you think of a cell as a processor, this adds a thumb drive, which stores information for later processing, says Karin Strauss, lead researcher on Microsoft's own DNA storage project. Last year the company set a new record200 megabytesand has plans to get a DNA storage system up and running by the end of this decade. As for DNA data storage in the IT industry, it is more well served by standard DNA synthesis and sequencing at the moment because they are easier to control and a lot denser than whole cells, says Strauss, who is unconnected to the Harvard research.

Companies that make custom DNA, such as Twist Biosciences, are already selling to customers using it for storage purposes. But its still only a small piece of their businessabout 5 percent. Costs have to come down by a factor of about 10,000 before DNA becomes competitive with traditional storage methods. But the long-term benefits will be huge: Properly stored in a cold, dry place, DNA can keep data intact for at least 100,000 years.

Thats why scientists such as Ewan Birney, director of the European Bioinformatics Institute, are working on better tools and methods to make DNA storage truly scalable. In that endeavor he doesnt see a place for live cells, which start out at less than 100 percent accuracy and are susceptible to mutations over time that could further degrade data integrity. Its cute, and I wish Id done it, Birney says of the Nature paper. But it doesnt add much on the DNA storage side of things. What did impress me was the amount of edits they achieved with high fidelity. Its a real tour de force of Crispr.

So, at least for now, theres no reason to think your family photo albums will one day be backed up on an E. coli drive. More likely, the memories cells store will be their own.

1Disclosure: One of these researchers is married to a WIRED editor.

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Scientists Upload a Galloping Horse GIF Into Bacteria With ...

A few years ago, a team of researchers at Stanford University launched a video game called Eterna. The game was designed to harness the brain power of thousands of gamers, challenging them to design new chemical sequences of RNA. A new follow-up game has just been launched, and this time players are challenged to create a new RNA molecule that can essentially function as an on/off switch for the CRISPR/Cas9 gene editing process.

When Eterna was first launched in 2011 it was a bit of an experiment. Half-intended to simply educate people in an entertaining way, researchers hoped once the game scaled up to enough players the results would start to become clinically significant. And significant they became.

As players refined their RNA molecule-making skills, the game grew in complexity. Up to 100,000 registered players were engaging with the game at its peak, and in early 2016 a paper, co-authored by the game players, was published in the peer-reviewed Journal of Molecular Biology. The paper established a set of rules developed by the game players determining the difficulty of designing appropriate RNA molecular structures.

Earlier in 2016 Eterna players were tasked with designing a novel molecule to assist with the creation of a simple and accurate blood test for tuberculosis. Now researchers are turning their sights on CRISPR, hoping this gaggle of game players can inspire a new molecular structure that will help focus the gene-editing technology.

"Great ideas can come from anywhere, so this is also an experiment in the democratization of science," says Stanford's Professor Howard Chang. "A lot of people have hidden talents that they don't even know about. This could be their calling. Maybe there's somebody out there who is a security guard and a fantastic RNA biochemist, and they don't even know it."

The new Eterna challenge asks players to design a unique RNA molecule that can do several things, from being recognized by the CRISPR-associated enzyme to guiding it to a targeted gene. The researchers suspect that this new challenge may be slightly easier than other, more mathematically orientated Eterna challenges, but they are looking for thousands of diverse solutions that could be applied into laboratory outcomes.

"We're not sure yet if there will be unforeseen problems with the Cas9 protein experimentally," says Rhiju Das, the principle investigator for Eterna. "That's partially why we want as many diverse solutions as possible for the Greenleaf and Chang labs to test, even in this pilot round. We're hoping for 10,000 to 100,000 players to contribute 10 solutions each. If we get that many, we'll indeed work to get that many synthesized and tested."

This real-life laboratory outcome makes the Eterna game unique as it gives game players the possibility of having their designs actually created and tested in the lab. And anyone can play the game as long as they have access to the internet and an interest in learning how to play.

"There is a misconception of science as something that happens in an ivory tower by someone in a white coat with a long beard," says Das. "And they are saying things and drawing things that nobody understands. But it's not like that! It's really like a puzzle that anybody can get engaged with."

Learn more about the Eterna CRISPR challenge in the video below and join the Eterna community and play the game here.

Source: Stanford University

Excerpt from:
Video gamers tasked with helping develop new molecule for controlling CRISPR - New Atlas

CRISPR is typically used to edit disease-causing gene mutations, but is increasingly being tapped for broader applications. The latest? Identifying sequences that activate genes, which could help unravel the causes of autoimmune disease.

While CRISPR shows great promise in the treatment of genetic disease, the genes it cuts outthose that code directly for proteinsonly make up 2% of the human genome. The other 98% consists of regulatory gene sequences, including promoters, which switch on genes next to them, and enhancers, which activate genes that may sit far away from them in the genome.

When the balance of promoters and enhancers is out of whack, it can lead to disease. But its difficult to pinpoint just which regulators have a hand in causing disease, as specific regulators play a role in specific cells, under specific conditions.

Jacob Corn and Alexander Marson at the University of California, San Francisco, focused on T cells and the IL2RA protein, which tells T cells if they should step up or dampen an inflammatory response. If the enhancers that switch on IL2RA are faulty, the T cells dont suppress inflammation, which could cause autoimmune disorders, such as Crohns and inflammatory bowel disease (IBD).

Corn and Marson usedCRISPR activation, or CRISPRa, to homein on the IL2RA gene. This methoduses a guide RNA to target sections of the genome, much like regular CRISPR, but instead of cutting them, it activates those sequences to see how they affect gene expression.

They created 20,000 guide RNAs for use with CRISPRa: "We essentially performed 20,000 experiments in parallel to find all the sequences that turn on this gene," said Marson, an assistant professor of microbiology and immunology at UC San Francisco, in a statement.

The teamturned up several sequences that might be important for ILR2A expression, including a common genetic variant that was already linked to increased IBD riskbut was not well understood. The findings are published in Nature.

"This starts to unlock the fundamental circuitry of immune cell regulation, which will dramatically increase our understanding of disease," Marson said.

The utility of CRISPR is growing by the day. Recently, UC San Diego researchers created a new version of CRISPR that targets RNA rather than DNA, which could be used to treat diseases caused by errant repeats in RNA sequences, including Huntington disease and a type of amyotrophic lateral sclerosis.

And scientists at eGenesis have deployed the gene-editing tool in the organ transplant field. By snipping out a family of viruses in the pig genome, they have overcome one obstacle in xenotransplantation, or using animal organs for human transplant.

The next step forthe UCSF researchers isto modify their method so that it can screen for enhancers of many different genes at once.

"Not only can we now find these regulatory regions, but we can do it so quickly and easily that it's mind-blowing," said Corn, assistant adjunct professor of molecular and cell biology at Berkeley. "It would have taken years to find just one before, but now it takes a single person just a few months to find several."

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'Gentler' CRISPR sheds light on autoimmune disease | FierceBiotech - FierceBiotech

Early embryos two days after co-injection with a gene-correcting enzyme. (OHSU)

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A few weeks ago, two stories crossed paths. In MIT Technology Review, we learned that, for the first time in the United States, researchers had used the gene-editing technique known as CRISPR to modify a human embryo. Severaldays later, CBS Newsreleased a report that through nearly universal prenatal testing followed by selective abortion, Iceland has virtually eliminated Down syndrome. Ad Policy

The CRISPR story shows that we are on the cusp of an enormous leap of capability when it comes to shaping the genetic potential of our offspring. Meanwhile, Ive contended that the past decades of testing, genetic consultation, and decision-making about abortion related to prenatal diagnoses of Down syndrome have served as a kind of test run for the future of human procreation. Can we make informed choices? Can we understand that probability doesnt equate to outcome when were talking genetic makeup? Can we use science to build a more just, happier humanity?

If whats happening in Iceland is, indeed, a test run, its a test were failing. Prospective parents are making decisions based on fear and stigma, helped along by the medical profession. As our tools to make such decisions get even more powerful, we have to shift how we talk about genetic diversity.

Cards on the table: Im the father of a boy with Down syndrome. I am pro-choice, anti-eugenics, and pro-information. In preparation for the age of CRISPR, well need to develop new ways to talk about whats normal and whats good, because we face decisions that are nearly unprecedented in human history. I say nearly, because with Down syndrome prenatal testing, we have a body of evidence for what happens when we expand our power to determine who gets born without building systems to ensure that we make informed decisions.Related Article

CRISPR (short for Clustered Regularly Interspaced Short Palindromic Repeats) is wickedly powerful. It makes reasonably precise changes to a targeted cells DNA by means of a technique adapted from naturally occurring DNA-editing defense mechanisms in bacteria. Chinese scientists first modified human embryos two years ago. The researchers in Oregon used it to change the DNA of a large number of one-celled embryos with the goal of demonstrating both that the technique could be used at scale and that the genes causing disease could be effectively identified and eliminated.

Each new development, as previously covered in The Nation, sparks rounds of debates between those optimistic about fighting diseases and those concerned about implications. For example, sickle-cell patients hope for a cure, while the intelligence community worries that terror groups could weaponize CRISPR. Earlier this year, the National Academy of Sciences, Engineering, and Medicineagreedthat genome editing could be used to modify embryos, but should be allowed only for treating or preventing diseases or disabilities at this time. Ethicists demand more robust engagement of the questions we are about to face, as techniques move from the research to the practical stage. Still, most of the debates remain locked in abstract thought experiments.Most Popular

Prenatal testing followed by selective abortion is not genetic engineering. It is, however, a space in which we have real-world data about how people make choices about procreation when granted additional information about the genetic makeup of their potential offspring. It turns out, perhaps unsurprisingly, that fear, misinformation, and bias shape our decision-making.Current Issue

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Take Iceland. In the small island country, all pregnant women are informed of the availability of genetic screening. Between 80 and 85 percent take the test, and nearly 100 percent of all positive tests for Down syndrome result in termination. What are we to make of such an outcome? Each person hearing the words Down syndrome applied to their fetus does so as a consumer of a culture that, broadly speaking, denigrates life with developmental disabilities. Geneticist Kari Stefansson characterized the counseling as heavy-handed in favor of termination, and so thats where the momentum is. If Icelandic doctors, nurses, and genetic counselors dont find ways to mitigate that, the disability largely disappears.

This is typically the moment in essays about prenatal testing in which I assure you that my son is happy. He is. Hes 10. He likes Hamilton and Harry Potter, and is a wonderfully inventive communicator. We are privileged to live in a good community with good schools, and when we encountered obstacles to his long-term supports in one state, we could move. Weve never denied that there are challenges, but the greatest ones are constructed by an ableist society, not inherent to his disability. Society can be changed. His genes dont need to be.

But the decision whether or not to terminate is not about my sons outcomes, but accepting two general principles. First, with good social supports, theres no reason that people with Down syndrome cant lead good lives included within communities. For a doctor to assert the probability that Down syndrome leads to despair is simply not true. Second, in general, probabilities never guarantee outcomes. Our genes encode an array of probabilities into our bodies.

In recent years, rather than focusing on the abortion itself (or decision to carry to term), North American activists in Down-syndrome advocacy communities have tried to look at the communication in the period between the positive test and the decision about whether or not to terminate. The goal is to provide materials to better inform the tens of thousands of doctors, nurses, and counselors who encounter women in the context of prenatal testing. These efforts have coalesced around the nonpartisan rubric: pro-information.

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I e-mailed Stephanie Meredith,Lettercase program director at the University of Kentuckys Human Development Institute, where she has helped develop resources for distribution to people who talk to women about prenatal testing. She told me that many genetic counselors and obstetricians offer compassionate, sensitive, and balanced support following prenatal testing, but some clinicians may provide insufficient, outdated, or unintentionally biased counseling. Outcomes for people with Down syndrome and related conditions have changed remarkably over the past 50 years. But too many people involved in prenatal care lack up-to-date information, and theres no easy way for institutes like Merediths to reach every clinician in the country. Meanwhile, companies selling prenatal tests want to increase their market share. Meredith said that clinicians are constantly inundated by marketing from testing labs with very little educational support regarding the conditions included in the test.

Ive spent years talking to parents who received prenatal tests (we did not). Some were told flatly untrue statements about Down syndrome, breaking up marriages and leaving families overwhelmed by stress. In fact, theres evidence that families like mine divorce at lower ratesthan other families. Others were presented with outdated statistics about early death as a likely outcome. Its not (although the premature death rates of African Americans with the condition remainfar too high). Its true that people with Down syndrome once tended to die young and learn little, but thats a fact linked to the era of mass institutionalization. Inclusion has radically changed the probabilities. My son has as good a chance to live as long, happy, productive life as anyone of our socioeconomic status. But expectant parents hearing the words Down syndrome for the first time will only know this if theyre told.

Unfortunately, politics is making it hard to hold the pro-information coalition together, thanks to Americananti-choice efforts. Around the country, the GOP is proposing and passing lawsbanning abortion if a woman tells her doctor shes doing it because of a prenatal diagnosis. We cant be pro-information if we criminalize such conversations. Such a bill ispending right now in Ohio.

What does all this have to do with CRISPR? Right now, were still in a liminal state when it comes to predicting genetic outcomes for fetuses. Our tools, from amniocentesis (developed in the 1950s and 60s) to contemporary screenings that locate fetal blood cells in the mothers bloodstream, are reactive and postconception. Soon, theyll shift to preconception and proactive. What will the tens of thousands of clinicians tell would-be parents as they get flooded with messaging from companies eager to sell their high-tech CRISPR product lines?

Preventing this potentially dystopian future where altered genes separates the haves from the have-nots starts by shifting discourse. A pro-information approach demands that everyone involved in genetic counseling have access to the best data and presents it in a value-neutral way. We must build systems now that grow as our tools evolve. If we do not, genetic diversity will gradually become code for poverty, and new stigmas will run all the way to the DNA.

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We're Failing Our Test Run for the Age of CRISPR | The Nation - The Nation.

In the new Eterna challenge, called OpenCRISPR, players will design a guide RNA molecule that leads CRISPR to the right sequence of DNA for editing or binding. The RNA is the part that confers gene specificity. Its the thing that says, Go after gene A, not gene B, said Chang.

The difficulty for Eterna players is to come up with an RNA molecule that does several things, said Greenleaf. The guide RNA has to be recognized by the CRISPR-associated enzyme. The CRISPR-enzyme system has to be able to recruit biochemical activity to the targeted gene. And lastly, the activity of the CRISPR-enzyme system has to be controlled by a small-molecule drug, so there needs to be a binding pocket for that small molecule. The RNA molecule has to function so that the CRISPR system is active when the small-molecule drug is present and inactive when its not. So far, experts have not been able to create such a drug-activated CRISPR, which is why Chang and Greenleaf are calling on the community of Eterna gamers for help.

The new puzzle will be quite different from the recent challenge in which Eterna players had to design a molecule that could do a mathematical calculation for a tuberculosis diagnostic test. The CRISPR puzzle actually should be pretty easy to solve in silico, even for new players who get to the switch design levels, said Rhiju Das, PhD, associate professor of biochemistry and principal investigator for Eterna.

How those Eterna-designed switches will behave in living cells is a big question. Das said the team will be asking players for different possible solutions to the same problem. Were not sure yet if there will be unforeseen problems with the Cas9 protein experimentally. Thats partially why we want as many diverse solutions as possible for the Greenleaf and Chang labs to test, even in this pilot round, Das said.

It will be an iterative process, said Greenleaf. His Stanford lab will test the first round of solutions and then return these data to the players with refinements that will guide their design work.

Were hoping for 10,000 to 100,000 players to contribute 10 solutions each. If we get that many, well indeed work to get that many synthesized and tested, Das said.

One of the goals of Stanfords Center for Personal Dynamic Regulomes is to get people interested in science, said Chang. The Eterna game is a powerful way to engage lots and lots of people, he said. Theyre not just passive users of information but actually involved in the process.

Like other computer games, Eterna allows players to accumulate points, build expertise and advance to higher levels. The best players have a chance of having their designs implemented in the lab.

One thing that makes the project exciting, said Chang, is that it is an experiment in the sociology of science. There is a misconception of science as something that happens in an ivory tower by someone in a white coat with a long beard. And they are saying things and drawing things that nobody understands. But its not like that! Its really like a puzzle that anybody can get engaged with, he said.

Anyone interested in playing Eterna can sign up here.

In addition to the funding from NIGMS and Stanfords Center for Personal Dynamic Regulomes, the new Eterna challenge is being launched with collaborative support from the Innovative Genomics Institute at the University of California-Berkeley. Stanfords departments of Biochemistry and of Genetics also supported the work.

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Online game challenges players to design on/off switch for CRISPR ... - Stanford Medical Center Report

Have researchers taken a step closer to developing an eventual cure for HIV? A Temple University-led team hopes so, by using a gene editing technique to successfully remove HIV infection from lab mice. The gene-editing tool calledCRISPR which allows scientists to basically cut out and insert specific portions of DNA was used to excise HIV DNA from the mice.

This was the first time CRISPR has been used to shut down HIV replication and eliminate the virus from animal cells. Think of CRISPR as working somewhat like microscopic scissors that snip out an unwanted piece of DNA and then replace that with a new piece. The research, published in the journal Molecular Therapy, involved three animal models, including a "humanized" model where human immune cells infected with the virus were transplanted in lab mice.

"Over our years of research, all of this was frankly a big surprise. This research, so far, has yielded all pleasant surprises, frankly. I never thought that this CRISPR system was going to be working out so beautifully with such efficiency and precision when it first came onto the scene," Kamel Khalili, director of Temple's center for neurovirology, told CBS News.

Khalili led the study along with Wenhui Hu, associate professor in Temple University School of Medicine's Center for Metabolic Disease Research and the Department of Pathology, and Won-Bin Young, who was at that time an assistant professor in the Department of Radiology at the University of Pittsburgh School of Medicine.

This work builds off the team's previously published research last year in which they introduced the HIV-1 DNA into the tissue of rat and mice subjects, and then removed these fragments using CRISPR. This new study is the first time this has been done in three animal models.

While the work signals progress, the medical community still sees years of work ahead before there's a reliable cure for HIV. According to the World Health Organization, 36.7 million people were reported to be living with HIV globally by the end of 2015. Since the start of the HIV/AIDS epidemic, more than 70 million people have been infected with the virus that has resulted in 35 million deaths.

The stakes are high, and the Temple team is one of many trying to find a cure for the virus, which has proven exceptionally difficult to eliminate from the body. While current drug treatments can reduce the virus to virtually undetectable levels enabling many patients to live longer, healthier lives HIV continues to lurk in hidden reservoirs and comes roaring back if treatment stops. In late 2015, theamfAR Institute for HIV Cure Research set the ambitious goal of developing a basis for cure for HIV by the end of 2020.

"The basic science community in HIV research is now very focused on finding a cure," Paul Volberding, head of the institute, wrote in an email to CBS News. "It still feels a long way off but the tools we now have definitely including the gene editing used in this report is accelerating our work and raising optimism. The cure field is in very close contact and collaborations are active world wide. It's really quite exciting!"

Volberding is also the director of the UCSF AIDS Research Institute and has a place in history for founding the first inpatient ward for people with AIDS at San Francisco General Hospital in 1983. How promising does he view this new research out of Temple?

"Gene editing is a potent and still rather new tool in HIV research and many other areas as well," he wrote. "It faces a challenge in scalability getting the technology simplified and inexpensive but is certainly worth following."

Since first being developed a mere five years ago, CRISPR has generated excitement and controversy in equal measures. While it was named "Breakthrough of the Year" in 2015 by Science magazine, ethical debate has swirled around CRISPR over how it could be used for good or ill to make changes to our DNA down the line.

Ellen Jorgensen, a molecular biologist and science communicator whose latest project is the yet-to-launch Biotech Without Borders, said she thinks it's important to focus on the potential of CRISPR, rather than feed into the "hysteria" that can surround such life-altering scientific technologies.

"I think CRISPR is an example of why the general public should embrace the chance to learn more about this sort of technology that will be more and more relevant to everyone's daily life as time goes on," Jorgensen told CBS News. "We are in an age of biotechnology as opposed to the last century, which was the 'age of physics.' There is an equal potential here to disrupt technologies, but it also creates ethical questions that the general public has to weigh in on. My thing is, I want them to weigh in on them, but have the understanding that this technology is something that is powerful and that can spur a lot of change moving forward."

In the case of this latest HIV research advance, Jorgensen, who cofounded Genspace, a nonprofit devoted to fostering better science literacy, said she believes there is "great potential" in finding a cure for something like HIV through gene editing technology.

Moving forward, Khalili and his team plan to try their technique on primate subjects, whose DNA is obviously closer to humans. He said they are working on securing more funding to move on to primate clinical trials.

Volberding added that "primates are a very good model for human trials," and that research like this is promising in the continued fight against HIV.

"I think that CRISPR and tools like it are revolutionizing the medical field and will bring about new ways for the treatment and cure for a broad range of diseases," Khalili said. "When it comes to treating HIV or cancer or other genetic diseases, I think there are a lot of good things that will come out of this."

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CRISPR gene editing eliminates HIV infection in mice ...

1. The gene editing tool CRISPR-Cas9 was used to correct a mutant paternal MYBPC3 allele in human preimplantation embryos.

2. No off-target effects were detected.

Evidence Rating Level: 1 (Excellent)

Study Rundown: A dominant mutation in the gene MYBPC3 causes hypertrophic cardiomyopathy (HCM), the most common cause of sudden death in otherwise healthy young athletes. While most current therapies focus on relieving symptoms of HCM, researchers in this study aimed to prevent transmission of the causative gene mutation by correcting it in preimplantation embryos.

Healthy donor eggs were injected with sperm that were heterozygous for the MYBPC3 mutation. After fertilization, recombinant Cas9 protein and single guide RNA that targeted MYBPC3 were microinjected into the zygotes. A majority of treated embryos survived and lost the mutation in this gene, without other genes being impaired. CRISPR-Cas9 targeting of MYBPC3 was found to be highly specific in the treated embryos.

This study was the first to use CRISPR-Cas9 to correct a harmful mutation without causing significant off-target effects. Although this genome editing technique is still far from clinical use and requires full discussion from a bioethics perspective, this research suggests the potential clinical efficacy of this therapy for in vitro fertilization and the correction of fatal mutations.

Click to read the study in Nature

Relevant Reading: Genome engineering through CRISPR/Cas9 technology in the human germline and pluripotent stem cells

In-Depth [in vitro study]: Human zygotes were produced by fertilizing 70 oocytes without MYBPC3 mutations with sperm from an HCM patient with a heterozygous mutation in MYBPC3. Eighteen days after fertilization, recombinant Cas9 protein, short guide RNA, and single-stranded oligodeoxynucleotideswere microinjected into the cytoplasm of the zygotes. A majority of zygotes survived this procedure, with a survival rate of 97.1%. Three days after injection of the Cas9 protein, 54 injected embryos were sequenced and 66.7% were found to be homozygous for the wild-type (WT) allele of MYBPC3. Almost half of the blastomeres from mosaic embryos were also found to be homozygous for the WT allele of this gene, demonstrating that the heterozygous mutation was repaired through homology-directed repair. These analyses demonstrated the efficient targeting by CRISPR-Cas9 in human embryos.

To improve the efficacy of gene correction, CRISPR-Cas9 was mixed with sperm and injected into 75 oocytes in metaphase II. This method resulted in an increase in WT embryos, with 72.4% successfully removing the mutation. Additionally, a majority of these oocytes developed into the eight-cell stage and then blastocysts, demonstrating no significant effect on embryonic development due to this therapy.

Finally, off-target effects were assessed through whole genome sequencing, digested genome sequencing, and whole exome sequencing. No insertions or deletions were detected in the WT blastomeres at 23 off-target loci, demonstrating the high targeting efficacy and potential safety of this treatment.

Image: PD

2017 2 Minute Medicine, Inc. All rights reserved. No works may be reproduced without expressed written consent from 2 Minute Medicine, Inc. Inquire about licensing here. No article should be construed as medical advice and is not intended as such by the authors or by 2 Minute Medicine, Inc.

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CRISPR-Cas9 corrects hypertrophic cardiomyopathy gene mutation in human preimplantation embryos [PreClinical] - 2 Minute Medicine

Gene editing made great strides this month when scientists reported success using a technique called CRISPR Clustered Regularly Interspaced Short Palindromic Repeats to correct a serious, disease-causing mutation in human embryos. Researchers fixed a mutation that leads to hypertrophic cardiomyopathy, a relatively common inherited disease of the heart muscle that affects about 1 in 500 people. The public response was wildly enthusiastic. But any new technology can spur confusion and hyperbole, and this one is no exception. Here are five myths about what CRISPR can and cant do.

Myth No. 1

CRISPR can build customized babies.

In February 2016, one CRISPR critic predicted in Mother Jones, We are this close to designer babies. And this month, biologist Richard Dawkins mused that the genetically edited designer babies on the horizon shouldnt be any more worrisome than children who are pushed by their parents to hone their natural talents.

But CRISPR is not on the cusp of creating a super-race for one main reason: We dont know how to do that. We dont know how to build baby Einsteins or order up a finely chiseled and uber-flexible Simone Biles, because there is no single smart gene or spunky, lithe gymnast gene.

Much of what goes on inside our bodies and our brains is influenced by a combination of genes and environment, nature and nurture. Beauty, athleticism and musicality dont hinge on a single sequence of base-pairs. Instead, these characteristics are considered complex traits that are shaped by the input of multiple genes, along with lifestyle and environmental factors. This is especially true of intelligence. Studies, many of which have tracked adopted children and twins, have indicated that just 50 percent of the variation in intelligence among people can be chalked up to genetics.

Myth No. 2

CRISPR is the only hope for would-be parents with genetic conditions.

The Genetic Literacy Project, a group dedicated to increasing the publics understanding of gene research, wrote this year that parents worried about passing on genetic disorders to their children have hope: Gene editing. Likewise, an Australian newspaper greeted this months CRISPR news with an ebullient headline: Hope for parents as science deletes mutant killer gene.

While its undeniable that the ability to home in on and fix a genetic error would enable some would-be parents to sidestep the possibility of transmitting a disease to their offspring, gene editing is not the only option in such cases. Preimplantation genetic diagnosis has been used for decades to help couples who go through IVF ensure that they select healthy embryos from among those fertilized in a clinic. The technology has allowed carriers of genetic disease to conceive unaffected children, starting in 1991, when it was first used to avoid cystic fibrosis.

In the event that not enough healthy embryos are created during the IVF process, CRISPR could one day lend a helping hand and repair defective embryos, giving a couple more choices. Still, an essay that accompanied this months research report, published in Nature, concluded that embryo genetic testing during IVF remains the standard way to prevent the transmission of inherited diseases in human embryos.

Myth No. 3

CRISPR will be available for widespread use soon.

I think its really likely that in the not-too-distant future it will cure genetic disease, Jennifer Doudna, one of the scientists behind CRISPR, said at a recent conference . The Chicago Tribunes editorial board shared the sentiment in April 2016, claiming that for some people born with debilitating genetic diseases, scientists could give them relief from their symptoms and maybe even cure them in the not-too-distant future.

Not so fast. In the United States, a human-embryo research ban has been in place since 1996, prohibiting the use of federal money to support research in which embryos are created, destroyed or discarded. Recent embryo-editing studies were paid for by universities and foundations, but the lack of federal funding slows the science down.

Moreover, just because one experiment was successful doesnt mean the next one will be. In fact, even though most embryos were successfully repaired in the recently reported study, more than a quarter werent. Another concern is that CRISPR may solve one problem while unintentionally creating another. A challenge is to avoid off-target edits or mosaicism, a condition that occurred in previous attempts, in which CRISPR successfully edited the specific mutation in some but not all cells. The technique needs much more practice before its ready for widespread public use.

Myth No. 4

CRISPR means a future without genetic diseases.

There is widespread interest in using CRISPR, which allows the targeted editing of specific genes, to potentially end genetic disease in humans, Vice reported in December 2015 . A more recent headline from Wired cheered that CRISPR may cure all genetic disease one day.

While that would certainly be nice, its impossible to edit out all genetic diseases, because not all genetic diseases are simply inherited. There are about 10,000 single-gene disorders that weve discovered diseases caused by a specific, individual gene mutation. But there are thousands more that are caused by multiple genetic factors. Moreover, some genetic conditions are the result of new, spontaneous changes in DNA, called de novo mutations.

Cancer is a prime example. While some types of cancer can be inherited, many others dont appear to have a primary genetic component, and often respond to a variety of environmental factors and other outside causes. Ending genetic disease is a worthy goal, but an extremely complicated one that will require more than eliminating heritable disease.

Myth No. 5

CRISPR technology will one day be broadly available.

Recent advances in gene-editing technology have made the process cheaper , causing some commentators to predict a quick CRISPR proliferation on the horizon. Gene Editing Is Now Cheap and Easy, one 2015 headline claimed. A Wall Street Journal article concerned with amateurs imitating CRISPRs technology likewise fretted that DIY gene editing is fast, cheap and worrisome.

CRISPR may be cheaper than it once was, but its hard to foresee a future when all prospective parents who could benefit will be able to afford it. As a rule, genetic technologies are very expensive: Patients dont pay just for the supplies used, but for doctors time, labor and equipment, often over a number of appointments. You dont have to look any further than IVF to be reminded that using science to have babies costs a lot of money: The median cost of a single IVF cycle is $7,500. It is unclear whether insurance would cover CRISPR gene editing, but its highly unlikely considering that few pay for preimplantation genetic diagnosis or IVF in the first place.

If CRISPR were to become a safe, accepted embryo-editing technique, its likely that only the well-to-do would be able to afford it, essentially making genetic diseases into diseases of poverty. Its not too hard to imagine a wildly disparate economic playing field a dystopian vision, in the words of StatNews writer Jim Kozubek, in which these treatments will be available to only the wealthiest among us who can pay for them.

Twitter:@brochman

Five myths is a weekly feature challenging everything you think you know. You can check out previous myths, read more from Outlook or follow our updates on Facebook and Twitter.

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Five myths about gene editing - The Washington Post - Washington Post

In BriefSickle-cell disease, which afflicts approximately 100,000 Americans with immense pain and shortened life-span, is caused by a single mutated nucleotide within the gene that codes for hemoglobin, making it a top candidate for CRISPR and maybe a cure.

Approximately 100,000 people in the US have sickle-cell disease. Most sufferers are African-Americans, but there are also many Latino patients as well as people of Mediterranean, Middle Eastern, Asian, and Southeast Asian descent who have sickle-cell disease. The disease is painful, and shortens the lifespan of sufferers to about 40 to 60 years.

Although its cause has been understood for more than a century, patients with sickle-cell have historically been underserved by both the pharmaceutical industry and the medical establishment. However, as CRISPR is changing the face of medicine, it may also be changing this lived reality for people with sickle-cell disease, which is caused by a single mutation that is well-studied, making it an appealing candidate for correction with the gene-editing tool.

CRISPR works by cutting into a DNA sequence in a specific place and either deleting a sequence or editing it. In the case of sickle-cell disease, the mutation that causes the illness is a single nucleotide: a T where an A should be within the HBB gene, which codes for hemoglobin. Red blood cells with healthy hemoglobin are the typical disc-shaped red cells seen microscopically, but the mutation causes unhealthy sickle-shaped cells that stick together. Eventually this causes a buildup of cells, blocked blood vessels, and lack of oxygen to different regions in the body along with pain, organ damage, and eventually premature death.

This one mutated nucleotide is an easy fix for CRISPR, which can simply cut and edit that nucleotide. Thus far researchers have had great success with CRISPR in mice and on human sickle cells in the lab, making the next step a clinical trial and maybe a cure.

CRISPR as a tool is not free from safety concerns, but many sickle-cell patients are eager to take part in clinical trials. Lab experiments have shown impressive results, with CRISPR successfully editing about 85 percent of stem cells extracted from sickle-cell patients in order to create healthy red blood cells a great result, given that patients with sickle cells below 30 percent exhibit no symptoms.

Once those healthy cells are reintroduced to the body, they go back to the bone marrow where they create more healthy blood cells for the body. The researchers say these healthy blood cells will proliferate because they will outnumber the sickled cells, particularly since they live 4.5 to 12 times longer.Click to View Full Infographic

Although CRISPR clinical trials have yet to begin in the US, the National Institutes of Health (NIH) is launching a study at the end of August 2017 to explore the opinions people with sickle-cell have about CRISPR technology. If a CRISPR sickle-cell cure does hit the market, access to it will be a defining issue. Ghana-born physician Isaac Odame, who specializes in sickle-cell disease and works at the Hospital for Sick Children in Toronto, told MIT Technology Review that drug costs for hydroxyurea, commonly used to treat the disease, are too expensive for many to afford, even at one to two dollars per day. Scientists and others from all over the world have been meeting and talking about ensuring that people have equal access to CRISPR, although thus far the issue has not passed the discussion stage.

Continued here:
CRISPR May One Day Cure Sickle-Cell Disease - Futurism

Marcela V. Maus

CRISPR Therapeutics $CRSP is allying with some top immuno-oncology researchers at Mass General to collaborate on some new gene editing working aimed at creating a new and better generation of T cell therapies.

The biotech based in Switzerland with a big research group in Cambridge, MA has tied the partnership knot with Marcela V. Maus, who runs the cellular immunotherapy group at Mass General. Shell be using the biotechs pioneering CRISPR/Cas9 tech to see how it works in building a new-and-improved T cell therapy just as the original models appear poised to hit the market later in the year.

This is by no means the first such gene editing effort in I/O, but it does reflect the companys continuing effort to build a pipeline of I/O drugs. They hired Jon Terrett (a vet at the South San Francisco-based cancer biotech CytomX) to run the operation on I/O back in February and struck a deal with MaSTherCell SA on making their CAR-T CTX101, targeting CD19 cancers. And they believe that they have potential for next-gen therapies that can work in both liquid as well as solid tumors the Holy Grail in I/O now.

A little more than a year ago Carl June and his team at the University of Pennsylvania, backed by The Parker Institute, obtained permission to run the first gene editing experiment for an immunotherapy with human subjects. That project involved using CRISPR in 18 subjects, extracting T cells and then editing them to add a protein that recognizes cancer cells and issues an attack order, then edit out a protein that interferes with the attack and finally disable the cloaking mechanism cancer cells use to hide from the immune system.

We have already seen the profound benefit that T cell therapies can have for certain patients with a specific set of tumor types, said Maus in a prepared statement.Now the potential with gene editing, and specifically CRISPR/Cas9, exists to create improved versions of these cells that may work for a wider variety of patients with a more diverse set of tumor types. Im glad to see the commitment CRISPR Therapeutics is making to this area, and am excited to collaborate with them.

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Building up its I/O ops, CRISPR Therapeutics allies with Marcela Maus at Mass General - Endpoints News

In BriefCRISPR Therapeutics has teamed up with General Hospital of Massachusetts to further-widen CRISPR's near-ubiquitous applications. Within this two-year collaboration, CRISPR/Cal9 will also be used in T cell cancer therapies.

In a recent development, CRISPR Therapeutics, the subsidiary of CRISPR AG, has signed onto a two-year research collaboration with Massachusetts General Hospital (MGH), to research the use of CRISPR/Cas9 in T cell cancer therapies.

This comes on the heels of a seemingly-endless list of advances. Two weeks ago, the CRISPR/Cas9 gene editing tool successfully removed genetic disorders from human embryos and additionally,successfully extracted HIV from a living organism. It was used to develop semi-synthetic organisms, targeted the command center of cancer, and even coerced superbugs to kill themselves on the genetic level.

The application of CRISPR/Cas9 to T cell therapies is expected to address unmet needs in hematologic and solid tumors, masses which from the cells are typically extracted and programmed to recognize and attach to. Leading the scientific work at MGH is the director of the Cellular Immunotherapy Program, Marcela V. Maus, MD, Ph.D. Anticipating the benefits of the collaboration, head of Immuno-oncology Research and Translation at CRISPR Therapeutics, Jon Terrett, Ph.D., told GlobeNewswire:

It is becoming increasingly clear that CRISPR/Cas9 can play a major role in enabling the next generation of T cell therapies in oncology. By combining our gene editing capabilities with Dr. Maus pioneering expertise in T cell therapy, we hope to accelerate our progress toward making these therapies a reality for patients suffering from cancer.

This partnership is CRISPR Therapeutics latest step toward advancing immuno-oncology. Terrett was brought aboard in February of this year as the companys leader in this regard.

Mausadded:

We have already seen the profound benefit that T cell therapies can have for certain patients with a specific set of tumor types. Now the potential with gene editing, and specifically CRISPR/Cas9, exists to create improved versions of these cells that may work for a wider variety of patients with a more diverse set of tumor types. Im glad to see the commitment CRISPR Therapeutics is making to this area, and am excited to collaborate with them.

Expect to see CRISPR/Cas9 expand its applications to include a more diverse spectrum of tumor types and molecular targets, as the revolutionary medical technology carries on.

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CRISPR Therapeutics Joins Hospital For Cancer Treatment Tests - Futurism

CRISPR keeps cancer in check

SPL

By Michael Le Page

The CRISPR genome editing revolution continues to advance at an astounding pace. As many as 20 human trials will be under way soon, mostly in China, New Scientist has learned.

One of these trials will involve the first-ever attempt to use CRISPR to edit cells while they are inside the body. The aim is to prevent cervical cancers by targeting and destroying the genes of the human papillomavirus (HPV) that cause tumour growth. This study is due to begin in July at the First Affiliated Hospital of Sun Yat-Sen University in China.

Gene therapy, which involves adding extra genes to cells, was first used to cure people in 1990, but it is mainly useful for treating rare genetic disorders. In contrast, gene-editing, which involves altering existing genes inside cells, promises to treat or cure a much wider range of conditions, from HIV infection to high blood cholesterol.

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One of these trials will involve the first-ever attempt to edit cells insidethe body

The first gene-editing trial in humans started in 2009. Doctors removed immune cells from people with HIV, disabled the gene for the CCR5 receptor which the virus uses to get into cells and returned the HIV-resistant cells to the body. The treatment appears to keep HIV in check.

But subsequent progress in gene editing was slow because developing a way to target each particular sequence is costly and time consuming. All that changed in 2012 when CRISPR genome editing was developed, making it cheap and easy to target almost any sequence.

The first clinical trial involving CRISPR began at the West China Hospital in Chengdu in October 2016. Doctors removed immune cells from the blood of a person with lung cancer, used CRISPR to disable a gene called PD-1 and then returned the cells to the body.

PD-1 codes for an immune cell off switch. Tumours can flip this switch to prevent immune cells attacking so if immune cells lack the PD-1 switch then cancer cells cannot manipulate them. However, there is a risk that the always on immune cells could begin attacking healthy cells.

The lung cancer trial isnt due to finish until 2018, but other teams are forging ahead. Clinical trial registries show that a dozen more trials that will disable PD-1 with CRISPR are planned in China. These target conditions including breast, prostate, bladder, oesophageal, kidney, colorectal and Epstein-Barr virus-associated cancers.

The HPV trial, meanwhile, will break new ground. Instead of editing cells outside the body, a gel containing DNA coding for the CRISPR machinery will be applied to the cervix. The CRISPR machinery should leave the DNA of normal cells untouched, but in cells infected by HPV, it should destroy the viral genes, preventing them from turning cancerous.

Targeting HPVs seems a sensible approach if they can deliver the genome-editing components to sufficient numbers of cells, says Robin Lovell-Badge of the Crick Institute in the UK.

It is tricky to do these experiments in animals as they are not infectable by HPV, says Bryan Cullen of Duke University Medical Center in North Carolina, whose group also hopes to use gene editing to get rid of HPV. But there is a risk of off-target mutations leading to cancer, he warns.

If these trials are successful, it could benefit millions of people. Vaccination against HPV is now possible, but there is no way to get rid of the virus in people who have it already. It can cause mouth, throat and anal cancers in both sexes, as well as being the main cause of cervical cancer.

While the HPV trial looks set to be the first to use CRISPR to edit cells inside the body, it may not be the first ever such use of genome editing. Three trials getting underway in the US will use another genome editing method known as zinc finger nucleases to add genes to liver cells to try to treat haemophilia B, and Hurler and Hunter syndromes.

A further four planned CRISPR trials involve changing immune cells to make them better at killing cancers. First, a virus will be used to add a gene to immune cells that makes them attack specific tumours creating so-called CAR-T cells. Then two or more genes usually including PD-1 will be disabled with CRISPR to make the cells even more effective.

Such UCART19 cells have already saved the lives of two girls, but these cells were created with an older gene-editing method. Now a clinical trial is due to start in the UK. Our lab is moving over to CRISPR, team leader Waseem Qasim of University College London told a meeting in February.

Two similar UCART19 trials areplanned in China, with another in the US. Trials are also planned for Duchenne muscular dystrophy, says Lovell-Badge, butthese are probably some way from starting.

This article will appear in print under the headline Boom in gene-editing clinical trials

We clarified what is unique about the reported trials.

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Boom in human gene editing as 20 CRISPR trials gear up | New ...

The first test-tube baby made headlines around the world in 1978, setting off intense debate on the ethics of researching human embryos and reproductive technologies. Every breakthrough since then has raised the same questions about designer babies and playing God but public response has grown more subdued rather than more engaged as assisted reproductive technologies have become increasingly sophisticated and powerful.

As the science has advanced, doctors are able to perform more complex procedures with better-than-ever success rates. This progress has made in vitro fertilization and associated assisted reproductive technologies relatively commonplace. Over one million babies have been born in the U.S. using IVF since 1985.

And Americans acceptance of these technologies has evolved alongside their increased usage, as weve gotten used to the idea of physicians manipulating embryos.

But the ethical challenges posed by these procedures remain and in fact are increasing along with our capabilities. While still a long way from clinical use, the recent news that scientists in Oregon had successfully edited genes in a human embryo brings us one step closer to changing the DNA that we pass along to our descendants. As the state of the science continues to advance, ethical issues need to be addressed before the next big breakthrough.

Louise Brown was born in the U.K. on July 25, 1978. Known as the first test-tube baby, she was a product of IVF, a process where an egg is fertilized by sperm outside of the body before being implanted into the womb. IVF opened up the possibility for infertile parents to have their own biologically related children. But Browns family was also subjected to vicious hate mail, and groups opposed to IVF warned it would be used for eugenic experiments leading to a dystopian future where all babies would be genetically engineered.

The reaction in the U.S. had another layer to it when compared to other developed countries. Here, research on embryos has historically been linked to the debate on abortion. The 1973 Supreme Court decision to make abortion legal in Roe v. Wade fueled anti-abortion groups, who also oppose research on human embryos.

Embryonic research and procedures offer the hope of eliminating devastating diseases, but scientists also destroy embryos in the process. Under pressure from these groups over the ethical implications of embryo creation and destruction, Congress issued a moratorium in 1974 on federally funded clinical research on embryos and embryonic tissue, including on IVF, infertility and prenatal diagnosis. To this day, federal funds are still not available for this type of work.

In hindsight, the sharp media attention and negative response from anti-abortion groups to IVF didnt accurately represent overall public opinion. The majority of Americans (60 percent) were in favor of IVF when polled in August 1978, and 53 percent of those polled said they would be willing to try IVF if they were unable to have a child.

So while the intense media coverage at the time helped inform the public of this new development, the insensitive labeling of Louise Brown as a test-tube baby and warnings about dystopian results didnt stop Americans from forming positive opinions of IVF.

In the nearly 40 years since IVF was introduced for use in humans, scientists have developed several new technologies from freezing eggs to genetically testing embryos before implantation that have improved patient experience as well as the chances that IVF will result in the birth of a baby. The announcement of each of these breakthroughs has resulted in flurries of media attention to the ethical challenges raised by this type of research, but there has been no consensus social, political or scientific on how to proceed.

Americans general opinion of assisted reproductive technologies has remained positive. Despite opposition groups efforts, surveys show that Americans have separated out the issue of abortion from embryonic research. A Pew Research Center poll from 2013 revealed that only 12 percent of Americans say they personally consider using IVF to be morally wrong. Thats a significant decrease from the 28 percent of respondents in 1978 who replied that they opposed the procedure for being not natural. In addition, the 2013 poll showed that twice as many Americans (46 percent) said they do not personally consider using IVF to be a moral issue compared to the number of Americans (23 percent) who said they personally do not consider having an abortion to be a moral issue.

Although most Americans dont think of embryonic research and procedures like IVF as a moral issue or morally wrong, the introduction of new technologies is outpacing Americans understanding of what they actually do.

Polls from 2007-2008 showed that only 17 percent of respondents reported that they were very familiar with stem cell research, and that there was a relative absence of knowledge about even the most prominent of the embryo-research issues. When Americans are asked more specific questions that explain IVF, they show less support for certain procedures, like freezing and storing eggs or using embryos for scientific research.

In light of recent developments, surveys show that nearly 69 percent of Americans have not heard or read much or know nothing at all about gene editing. Additionally, support for gene editing depends on how the technology will be used. A majority of Americans generally accept gene editing if the purpose is to improve the health of a person, or if it will prevent a child from inheriting certain diseases. The scientists in Oregon used a gene-editing technique that allowed them to correct a genetic defect in human embryos that causes heart disease. This type of progress falls into the category that most Americans would support.

But the technique thats used to make this correction, known as CRISPR-Cas9, can potentially be used for editing genes in other ways, not just to eliminate diseases. The success of the Oregon team opens the door to many possibilities in gene editing, including ones unrelated to health, such as changes to appearance or other physical characteristics.

Advancements in assisted reproductive technologies have happened rapidly over the last few decades, leading to over five million births worldwide. But as common as these procedures have become, scientists are not yet in agreement over how to integrate CRISPR and gene editing to the IVF toolkit. There are concerns about changing the genomes of human embryos destined to be babies, particularly since any modifications would be passed on to future generations. Scientific committees have noted that decisions on whether and how to use gene editing should be revisited on a regular basis. The newest breakthrough with CRISPR is providing us with one of those opportunities.

We should focus our attention on answering the ethical questions that have long gone unanswered: What are the boundaries to this type of research? Who decides what is an ethical use of CRISPR? What responsibility do we have to people affected by genetic conditions? Who pays for these medical procedures? How will this research and potential clinical use be regulated?

The successful use of assisted reproductive technologies has skyrocketed in the last decade, making Americans complacent about some of the ethical concerns that these procedures raise. Its important that we engage with these issues now, before gene editing becomes as familiar to us as IVF.

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Will CRISPR fears fade with familiarity? - The Conversation US

AUGUST 23, 2017

A CRACK IN CREATION is not The Double Helix. They are both stories of revolutionary biological advances, told by one of the discoverers, but The Double Helix feels like a novel. And, like a historical novel, it was eventually understood to be based on real events but not always reliable history.

A Crack in Creation is also not a history that is, a detailed and precise explanation of who did what and when to produce CRISPR/Cas9, this centurys biggest biological discovery to date. That history awaits its Horace Freeland Judson, whose magisterial The Eighth Day of Creation provided a gripping blow-by-blow account of the birth and adolescence of molecular biology, or its Robert Cook-Deegan, whose The Gene Wars illuminated the beginnings of the Human Genome Project.

Nor is this a how to book for aspiring do-it-yourself CRISPR users; or a deep analysis of the ethical, legal, and social issues CRISPR and its progeny will raise; or a legal analysis of the already (in)famous CRISPR patent fight; or a look at the unresolved Nobel Prize race. And it is not a gossipy inside look at the people intimately involved in CRISPRs invention.

So what is A Crack in Creation? It is an essential start to educating the public.

Humans use of the bacterial defense mechanism called clustered regularly interspaced short palindromic repeats (CRISPR), with or without CRISPR associated protein 9 (Cas 9) along with the technologies that eventually will modify or displace it is of vast importance. Thats not because it is the first way we have found to edit DNA. It misses that distinction by over 40 years. But it is the first truly fast, cheap, easy, and accurate way to do so. It is biotechnologys Model T. The Model T was not, by several decades, the first automobile, but it transformed cars from expensive, unreliable, inconvenient, and rare objects to something everyone could, and soon did, own. It is the change in degree, not in kind, that has transformed the world we live in (nowhere more than California). Similarly, humans have been manipulating living organisms, including ourselves, at least since the dawn of modern man, but CRISPR is the change in degree that turns gene editing from expensive, unreliable, inconvenient, and rare to ubiquitous. It vastly increases our powers to edit all life, including our own.

A Crack in Creation tells the story of CRISPR through the eyes and in the voice of Jennifer Doudna, the UC Berkeley biochemist who was a central figure in harnessing it. (The co-author, Samuel Sternberg, is Doudnas former graduate student.) It divides elegantly into two four-chapter parts, plus prologue and epilogue. The first part describes what CRISPR is and how it was discovered; and the second sets out CRISPRs possible uses in the environment and medicine, and in editing humankind.

It is not, however, the first publication to recount the origins of CRISPR. Indeed, as with the double helix, the identity of the originators is contested. In January 2016, Eric Lander, director of the Cambridge, Massachusettsbased Broad Institute (jointly owned by Harvard and MIT), published a 7,200-word essay titled The Heroes of CRISPR in Cell, one of three leading journals for bioscience publications. It was widely criticized for minimizing the contributions of Doudna and one of her key collaborators, Emmanuelle Charpentier, and highlighting instead the work of Feng Zhang, a researcher at the Broad (and hence Landers employee). As well as triggering, fairly or not, debate over the issue of sexism in science, Landers piece was particularly controversial in that the publication never mentioned its authors conflicts of interest, not just in promoting Zhang as CRISPRs hero, but because of the very expensive patent fight over CRISPR between the Broad Institute and Doudnas employer, the University of California (UC).

This said, what both Lander and Doudna do well is reveal the complex, interlocking, and thoroughly international nature of todays bioscience. They acknowledge the work of a dizzying number of contributors to CRISPR. The first publication to show that CRISPR could be used to edit bacterial DNA was Doudna and Charpentiers Science article in June 2012 but, by that time, scores of researchers had already been exploring what was regarded as a tantalizing bacterial curiosity.

In his Cell article, Lander writes that [t]he story starts in the Mediterranean port of Santa Pola, on Spains Costa Brava, with Francisco Mojica who published a report in 2005 on the existence of, and possible immune system function of, certain odd, largely palindromic, DNA repeats in several bacterial species. Researchers at a yogurt company, Danisco, also played important roles, as did Sylvain Moineau in Quebec and John van der Oost from the Netherlands. Even before her first meeting with Doudna in March 2011, Charpentier and her lab at the University of Ume in Sweden had also contributed to the development of the CRISPR system.

Virginijus iknys, a Lithuanian researcher, greatly improved researchers understanding of the proteins bacteria used with CRISPR. He saw some of the possibilities of CRISPR as a tool and submitted a paper to Cell on the topic on April 6, 2012. Cell rejected his paper, which was eventually published on September 4, 2012, in the Proceedings of the National Academy of Sciences. In the meantime, Doudna and Charpentiers paper was submitted to Science on June 8 and published 20 days later.

But if this is more or less the beginning of the CRISPR discovery story, it is certainly not the end.

Feng Zhang, a brilliant young researcher at the Broad, had spent much of 2011 and 2012 working on a way to use CRISPR in mammalian cells. Zhang submitted his first CRISPR publication on October 5, 2012. Later that month, George Church, an exceptionally wide-ranging and creative Harvard researcher, submitted a paper on using CRISPR in human cells, which Science published in the same issue as Zhangs on January 3, 2013.

This summary does not come close to mentioning all the laboratories involved in discovering and developing CRISPR and does not even begin to talk about the vital contributions of the post-docs and graduate students in those labs, all of them highlighted in A Crack in Creation.

Whose version is closest to the true history of CRISPR? Landers history was widely attacked and A Crack in Creation has already been criticized in a review in Nature for downplaying Zhangs role (though it mentions him more than Lander mentioned Doudna). I suspect neither Lander nor Doudna and Sternberg could tell the full story for at least one sad reason lawyers probably wouldnt let them. Their employers are locked in a patent struggle. The details of who did, said, or knew what when could be crucial to its outcome. How many changes in the manuscripts came as a result of lawyers comments? Probably more than a few.

In fairness, A Crack in Creation never promises to be the definitive history of CRISPR much less a story of all its heroes. It tells Doudnas CRISPR story, as well as the authors thoughts on its potential uses and implications. These uses and implications make up the books second part, The Task. It begins with the use of CRISPR in the non-human world for agricultural purposes and beyond, including the ongoing development of gene drives, an important adaptation of CRISPR that can speed the spread of desired genetic changes in sexually reproducing species, as well as plausible speculation about future unicorns (in this case, the mythical animal). It then addresses the medical applications of CRISPR to living people in the form of so-called somatic gene editing, intended to heal their bodies without changing their eggs or sperm and so not affecting future generations. The authors rightly view this as the least controversial use of CRISPR. The last chapters address what has become the stickiest question for most people: the use of CRISPR to make changes in the genome of the human germline (eggs and sperm) that can be inherited from generation to generation.

Doudnas interest in these last issues is neither new nor shallow. In October 2014, I was invited to a small meeting she was organizing in Napa Valley the following January to discuss the ethical issues of CRISPR. (Coincidentally, this was almost exactly 40 years after the famous 1975 Asilomar meeting to assess safety issues of the first gene editing, recombinant DNA.) The Napa meeting involved about a dozen prominent scientists including Paul Berg and David Baltimore, the two Nobel Prize winners who helped organize the Asilomar meeting and two law professors who work in the field, Alta Charo from the University of Wisconsin and myself. Doudnas genuine concern was evident, not just in calling the meeting but in her active and thoughtful participation in it. And human germline genome editing was clearly the focus of that concern.

The Napa meeting reached consensus surprisingly quickly: the somatic cell uses of CRISPR should be pursued actively, but human germline modifications needed more thought. Doudna took the lead in drafting a commentary, signed by the meetings participants and several others, which Science published in March 2015.

The commentary made four recommendations about human germline editing:

The Science article was not alone. Nature had published a commentary on human gene editing the week before, endorsing somatic cell uses of genome editing, but rejecting germline changes. And two weeks later, an obscure journal published an article in which Chinese scientists reported their (slightly) successful efforts using CRISPR to edit human embryos.

The Chinese group had carefully used human embryos that were not viable and thus could never become babies, but the article still set off a firestorm. One of its results was a US National Academies of Sciences, Engineering, and Medicine initiative to study genome editing. A major part of that initiative was an International Summit on Human Gene Editing held in Washington, DC in December 2015, with additional sponsorship from the Chinese Academy of Sciences and the UK Royal Society. At its end, the summits planning committee (not the sponsoring academies) issued its conclusions, roughly echoing the March Science commentary.

As A Crack in Creation usefully points out, the debate over germline modification is not new. The issue was discussed in print at least 30 years before CRISPR was imagined. But a sense of urgency and some specificity about both the likely intervention and the societies into which it will be launched helps focus discussions. Since the International Summit (and submission of the last manuscript of the book), the National Academies alone have published at least three relevant reports two concerning non-human uses of CRISPR in October 2016 and March 2017, and the third, issued in February 2017 on Valentines Day, on CRISPR and humans, endorsing somatic cell uses of CRISPR and opening the door for possible germline editing for medical reasons.

A Crack in Creation hints that the discussions thus far have modified Doudnas views. Like the February 2017 report, the book shows some openness to human germline modification, at least for addressing clearly genetic diseases.

Personally, I think we focus too much on human germline genome modification. There is no human germline genome there are over seven billion of them, each changing slightly by mutation in every generation. Editing out rare, disease-causing DNA variations or replacing them with the more common safe variants hardly seems radical. The real concerns for germline or somatic human gene editing should be about enhancements (as opposed to disease), but that is just one part of a much wider conversation about all kinds of biological, electronic, and mechanical enhancements. The combination of our great concern about the safety of babies and our ignorance regarding enhancing genetic variants, however, means we have time to get this right. But were way behind in regulating the use of CRISPR in non-humans. The medical, practical, and political constraints around human babies do not exist for mosquito babies, let alone genetically modified microbes or plants. For the moment, we need to concentrate on this much less constrained use of CRISPR, which is already beginning.

Doudna called for discussions about the uses of CRISPR in Napa in January 2015 and A Crack in Creation amplifies that plea, providing the interested public with the background critical to such discussions. But CRISPR has raised two other interesting questions, which, though not discussed in the book, are worth mentioning: the Nobel Prize and the patent fight.

A Crack in Creation says nothing about the likely Nobel Prize for CRISPR, but CRISPR junkies regularly discuss it. A Nobel Prize in either Chemistry or in Medicine and Physiology seems almost certain, and will likely be granted soon. But who will receive it?

Scores of people in many countries contributed to its discovery, but Nobel Prizes in the sciences are limited to not more than three people. Doudna and Charpentier should be shoo-ins, for their own insights, for the work of their labs, and for their first publication. Plausible other candidates include at least Mojica, iknys, Zhang, and Church but four into one wont go.

Many have read Landers Cell article as an effort to tilt the third spot toward his faculty member, Zhang, but the fight over the patent rights for CRISPR could also influence who wins the prize. A Crack in Creation mentions the patent fight only once, as a disheartening twist to what had begun as collegial interactions and genuine shared excitement about the implications of the research. But the patent cases over CRISPR have been unusual, and unusually fascinating, from the beginning. (For more details see various pieces by Jacob Sherkow, the law professor who has followed this most closely.)

In December 2012, Zhang and others (meaning the Broad Institute on behalf of Zhang and others) filed a patent application on the use of CRISPR in any cells from complex organisms, called eukaryotic cells, which include everything from algae to us, as opposed to prokaryotic cells (bacteria and archaebacteria) and viruses. Doudna and Charpentiers patent application had been filed seven months earlier, claiming the use of CRISPR in all cells. But the Broad paid for and got a special expedited patent procedure so that its patent application, though filed after the UCs, was granted in April 2014, before the UCs was decided.

A year later, in April 2015, the UC invoked an interference proceeding, asking the Patent and Trademark Office (PTO) to resolve an apparent inconsistency in patent applications and determine who was the first inventor. In February 2017, the PTO ruled in favor of Zhang and the Broad. But the UC has appealed this decision, and even if it stands, it is possible that the Doudna and Charpentier patent and the Zhang patent will be held valid, in which case someone who wanted to use CRISPR in eukaryotic cells, including human cells, would need licenses from both UC and the Broad.

Furthermore, all patents are limited to the jurisdiction that granted them. US patents have no force outside the United States. This past March, the European Patent Organization granted CRISPR patents to UC, as have the patent authorities in China and the United Kingdom. So we could have a world where the Broad seems to control important US uses and the UC the European, British, and Chinese uses. The rest of the world is, at this point, up for grabs.

What does all this mean? In terms of the ultimate ownership of the most basic CRISPR patent rights, stay tuned. It is too soon to tell. But, in a larger sense, I dont think it matters.

This is mainly a fight about money: about which American universities will make money, and how much of it, off some uses of CRISPR. If the money goes to the UC system, as a Californian I would be pleased. But the question of who profits shouldnt change the adoption of CRISPR. That is, as long as either entity uses a good licensing strategy. Of course, even that may not matter. The CRISPR patents will give the players ownership of some approaches, but they will be of little value if novel approaches are developed. Already various inventors have come up with alternatives to Cas9 as part of the CRISPR complex. Bacteria invented CRISPR billions of years ago and have had time, and selective pressure, to invent variations on it. The harder the Broad or UC try to enforce rigorous patent terms, the more they encourage researchers to invent around their patents. The more they tighten their grip, the sooner the money will slip through their hands.

This raises the more fundamental question of why the CRISPR patent fight is happening at all. Like many people, I initially thought the UC and the Broad would settle their patent dispute quickly. Each would take a certain percent of the royalties for their combined patents and be happy not least because they would avoid tens of millions of dollars of expense, months of distraction for their researchers, and years of uncertainty. If one of the institutions involved were a novice in technology licensing, then it might get greedy and seek a complete victory, but neither the UC system nor the Broad (and certainly not the Broads owners, Harvard and MIT) are novices. They have some of the most experienced and sophisticated technology licensing offices in the world.

So why are they spending so much money on this fight? It might, in part, relate to the Nobel Prize. If Lander really wants to bolster Feng Zhangs case for winning a CRISPR Nobel Prize, then he may think that having Feng win some or all of the patents will be helpful. That seems a bit far-fetched, and yet it could be one factor in the Broads litigation strategy. If so, it is not clear whether it will succeed, even if the Broad patents eventually sweep the field. The Nobel Prize decision-makers need not follow the patent office of any country.

In the end, the history, the prizes, and the patents dont really matter. The structure of DNA would have been discovered without Watson and Crick, and CRISPR did not require Doudna and Charpentier (or Zhang). The discoveries, not those who make them, are important and those discoveries are only important as they affect people. CRISPR heralds a new era of massively increased human control over life, one that will affect every person on Earth, directly or indirectly, and much of the rest of our planets biosphere. If humans are to have any chance of harnessing its benefits, avoiding its risks, and using it in ways consistent with our values and cultures, then we all not just the scientists, ethicists, and patent lawyers need to understand something about CRISPR and its implications. A Crack in Creation is a great place to start.

In the interest of full disclosure, the author has met, been on panels with, and likes Doudna, Charpentier, Zhang, Church, and many of the other scientists discussed in the review. He also has lectured the last three summers in a CRISPR program held by the Innovative Genomics Institute at UC Berkeley for modest honoraria.

Henry T. Greely is a professor of Law, and professor by courtesy of Genetics, at Stanford University, where he directs its Center for Law and the Biosciences and Program in Neuroscience and Society. He is an expert on the ethical, legal, and social implications of advances in the biosciences.

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CRISPR, Patents, and Nobel Prizes - lareviewofbooks

Next-Generation Immunotherapies

CRISPR Therapeutics interest in next-generation T-cell cancer immunotherapies comes as both Kite Pharma and Novartis await FDA decisions on their CAR-T immuno-oncology treatments, with the companies emerging as leading developers of CAR-T therapies. Last month, Novartis won an FDA advisory committees unanimous recommendation of approval for Novartis leukemia-fighting treatment CTL019 (tisagenlecleucel), a CAR-T therapy developed through a collaboration between the pharma giant and researchers from the University of Pennsylvania launched in 2012.

CRISPR Therapeutics drug development efforts also include partnerships with Bayer and Vertex Pharmaceuticals intended to develop CRISPR-based therapeutics in diseases with high unmet need. CRISPR Therapeutics and Bayer have formed a $335 million-plus joint venture, Casebia Therapeutics, to develop treatments aimed at curing blood disorders, blindness, and congenital heart disease.

CRISPR Therapeutics is among four companies to have licensed CRISPR technology for which a European patent was granted in March to 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.

The European patent holders are appealing a February 15 decision by the Patent Trial and Appeal Board (PTAB), which sided with the Broad Institute of MIT and Harvard in the bitter legal battle over who invented the gene-editing platform. The PTAB found no interference in fact between 12 patents related to CRISPR technology that list as inventor Feng Zhang, Ph.D., of the Broad, and a patent application by Dr. Charpentier and Jennifer Doudna, Ph.D., of UC Berkeley.

The European patent holders have cited decisions by other countries to grant them patents for CRISPR/Cas9 in all settings, including eukaryotic cellsincluding the U.K., nearly 40 other countries that are members of the European Patent Convention, and Asia-Pacific nations such as Australia, New Zealand, Singapore, and China.

Joining CRISPR Therapeutics in licensing the European-patented CRISPR technology are Caribou Biosciences, ERS Genomics, and Intellia Therapeutics.

Also last month, the European Patent office granted Cellectis a patent to use CRISPR in T cells, to be issued in August and valid until 2034. Were not a company thats here to block the other [companies], Cellectis chairman and CEO Andre Choulika, Ph.D., told GEN. Were here to develop products on our sidebut, if there are people that are interested in using CRISPR in T cells, were definitely open to talk to them.

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CRISPR Therapeutics, MGH Partner to Develop T-Cell Cancer Therapies - Genetic Engineering & Biotechnology News

CrisprCon is not a place where spandexed, beglittered, refrigerator drawer fans come together for an all-you-can-eat celebration of unwilted produce. No. Crispr-Cas9 (no E), if you havent been paying attention, is a precise gene editing tool thats taken the world by storm, promising everything from healthier, hangover-free wine to cures for genetic diseases. Like, all of them. And CrisprCon is where people come not to ask how to do those things, but rather, should we? And also, whos the we here?

On Wednesday and Thursday, the University of California, Berkeley welcomed about 300 peoplescientists, CEOs, farmers, regulators, conservationists, and interested citizensto its campus to take a hard look at the wnderenzyme known as Cas9. They discussed their greatest hopes and fears for the technology. There were no posters, no p-values; just a lot of real talk. You can bet it was the first Crispr conference to sandwich a Cargill executive between a septagenarian organic farmer and an environmental justice warrior. But the clashing views were a feature, not a bug. "When you feel yourself tightening up, that's when you're about to learn something," said moderator and Grist reporter, Nathanael Johnson.

Which, to be honest, was totally refreshing. Serious conversations about who should get to do what with Crispr have been largely confined to ivory towers and federal agencies. In February the National Academy of Sciences released a report with its first real guidelines for Crispr, and while it suggested limitations on certain applicationslike germline modificationsit was largely silent on questions outside of scientific research. What sorts of economies will Crispr create; which ones will it destroy? What are the risks of using Crispr to save species that will otherwise go extinct? Who gets to decide if its worth it? And how important is it ensure everyone has equal access to the technology? Getting a diverse set of viewpoints on these questions was the explicit goal of CrisprCon

Why was that important? Greg Simon, director of the Biden Cancer Initiative and the conferences keynote speaker, perhaps said it best: Crispr is not a light on the nation, its a mirror. In other words, its just another technology thats only as good as the people using it.

Panel after panel took the stage (each one, notably, populated with women and people of color) and discussed how other then-cutting-edge technologies had failed in the past, and what history lessons Crispr users should not forget. In the field of conservation, one panel discussed, ecologists failed to see the ecosystem-wide effects of introduced species. As a result, cane toads, red foxes, and Asian carp created chaos in Australia and New Zealand. How do you prevent gene drivesa technique to spread a gene quickly through a wild populationfrom running similarly amok?

From the agricultural field, the lessons were less nebulous. First-generation genetically modified organisms failed to gain public support, said organic farmer Tom Willey, because they never moved agriculture in a more ecologically sustainable direction and it never enhanced the quality of food people actually ate. At least, noticeably so. Instead, most modifications were to commodity crops like corn and soy to improve their pest resistance or boost yields.] It was a convenience item for farmers, he said. And a profit center for corporations. In order for gene-edited foods to avoid the same fate, companies like Monsanto, Dupont Pioneer, and Cargill, who have already licensed Crispr technologies, will need to provide a more tangible value than corn you can spray the bejeezus out of. Like say, extra-nutritious tomatoes, or a wine with 10-times more heart-healthy resveratrol and fewer of the hangover-causing toxins.

The presence of executives from each of these three companies signaled that theyre serious about not making the same mistakes they did in the 90s when GMOs first came to market. Back then we were only talking to farmers, said Neal Gutterson, vice president of R&D at Dupont Pioneer during a break between panels. I cant remember anyone going to anything like this or casting as wide a net in our discussions with the public.

Of all the fields Crispr will touch, medicine is the one most primed for disruption. So its of great concern to conference-goers that Crispr doesnt become a technology only for the haves and not the have-nots. Shakir Cannon, founder of the Minority Coalition for Precision Medicine, pointed out the myriad ways doctors and researchers have exploited people of color in the name of scientific advancement, while neglecting diseases that hit underserved communities the hardest. In a breakout session on Wednesday, Rachel HaurwitzCEO of Caribou Biosciences, one of the big three Crispr companiesasked Cannon and his colleague, Michael Friend, how industry leaders could help make sure that doesnt happen. First, you have to build trust with communities, said Friend, whose work focuses on sickle cell anemia. But we think Crispr could be a real turning point.

Still, CrisprCon was just more talkwhich the field has seen a lot of recently. Crisprs co-discoverer Jennifer Doudna has taken a step back this past year from her lab at Berkeley to travel the world and discuss the importance of coming to what she calls a global consensus on appropriate uses for gene editing technologies. And in her opening address on Wednesday, the standing-room-only auditorium heard a line shes trotted out many times before. I've never seen science move at the pace its moving right now, Doudna said. Which means we cant put off these conversations." The conversations happening at CrisprCon were all the right ones. But action, whether in the form of regulations, laws, or other populist social contracts, still feels a long way off.

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Crispr Fans Dream of a Populist Future for Gene Editing | WIRED - WIRED

In BriefCRISPR co-discoverer Jennifer Doudna stressed the importance of using the technology with proper consideration at CrisprCon this week.

The CRISPR gene editing tool has already been used to perform some incredible feats of science, from manipulating the social behavior of ants to making superbugs kill themselves. Its an incredibly powerful asset, but this week at CrisprCon, there was plenty of discussion about where we should draw a line on its usage.

Ive never seen science move at the pace its moving right now, said CRISP co-discoverer Jennifer Doudna, who has spent recent months touring the world campaigning for a global consensus on appropriate implementations of gene-editing technologies. Which means we cant put off these conversations.

CRISPR has already been used to edit harmful conditions out of animals and even viable human embryos. From this point, it wouldnt take a great leap to start using the technology to enhance healthy organisms which is why now is the time for discussions about the consequences.

While medical uses of CRISPR are perhaps the most ethically urgent, the conversation about its usage goes beyond medicine. Companies like Monsanto and Cargill have already licensed CRISPR technologies to help with their agricultural efforts. However, early attempts at genetically modified crops struggled to gain mainstream acceptance, and thats something these firms need to keep in mind as they implement the latest techniques.

It was a convenience item for farmers, observed organic farmer Tom Wiley at the convention, according to Wired. And a profit center for corporations. To combat genetically modified foods perception problem, companies using CRISPR will have to make sure that the technology benefits the consumer, not just the production process.

The convention addressed CRISPR usage in many different fields: from the importance of ensuringit is used to address the widest range of medical conditions as possible, to the potentially damaging effects of gene drives on a delicate ecosystem.

Science is moving at a rapid pace, and CRISPR is too but if we dont carefully consider which applications are safe and valid, it could quickly cause as many problems as it solves.

Crispr is not a light on the nation, its a mirror, said CrisprCon keynote speaker Greg Simon, director of the Biden Cancer Initiative;Wiredreporter Megan Molteni interpreted those words as,its just another technology thats only as good as the people using it.

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CRISPR Co-Discoverer: "I've Never Seen Science Move at the Pace ... - Futurism

Science and ethics experts took part in a first-of-its-kind conference on the role of gene editing, and nearly half of the sold-out crowd was involved in the food and agriculture sector. CRISPRcon a summit named for the genome editing technique known as clustered regularly interspaced short palindromic repeats (CRISPR) brought together a diverse set of panelists to discuss this emerging technology.

CRISPR technology allows precise changes to be made to the DNA of living cells, which holds the potential to eradicate diseases, transform agriculture and enable massive leaps forward in environmental and life sciences. Through a series of keynote speakers, panels and interactive discussions, CRISPRcon offered a single forum for those with a stake in gene editing to share ideas, ask and answer questions and explore the path forward.

Since the CRISPR-Cas9 technology was invented five years ago by a team led by Dr. Jennifer Doudna, professor of chemistry and of molecular and cell biology at the University of California-Berkeley, and her colleague Emmanuel Charpentier, it has revolutionized biomedical and agricultural research while fueling angst about questionable applications, such as designer crops, farm animals and humans.

Its really a very cross-cutting technology, Doudna told attendees.

In fact, she said unlike earlier ways of manipulating genetic information in cells, the thing that makes CRISPR particularly powerful is the fact that it really is a democratizing tool. Its a technology that is easy enough to use and to employ that its accessible to a wide range of people, Doudna said.

It has been possible to globally adopt the technology for use in any organism, she added.

Doudna discussed applications of gene editing, including producing cattle with no horns, finding ways to treat human genetic diseases of the blood, cancer-related research, generating animals that would be better organ donors for humans, as well as plant and crop research.

The agriculture industry was represented among speakers. Thomas Titus, a pork producer from Illinois, was one of only two farmers who presented among the scientific experts, physicians, patients, environmentalists, consumers and community leaders.

Gene editing will have great impact on the future of farming, and especially on livestock production, Titus said. Although in its very early stages of development and acceptance, gene editing could ultimately be used to make pigs resistant to diseases, thereby improving food safety, animal welfare and the environmental impact of agriculture.

Titus, who raises pigs and also grows grain on his Illinois farm, was part of a panel discussing where CRISPR technology could take society by 2050. His appearance was supported by the pork checkoff and the National Pork Producers Council. Other panelists included representatives from the Center for Genetics & Society, the Institute for the Future, PICO National Network and The Breakthrough Institute.

Todays consumer is educated and asking questions about where their food comes from and how it is raised, Titus said. Thats why I welcome every chance I get to talk about todays pork production. I appreciated the opportunity to once again open my barn doors to share how I raise pigs with these key influencers in food production.

Other topics addressed during the conference included societal perception and acceptance of CRISPR application in surgery, human health and food production and conservation.

Doudna said just understanding the science is a challenge for many people, but then they also have to understand how the technology is going to affect them.

She encouraged scientist to take a very active role in engaging in conversation about gene editing, adding that its always challenging to explain technical work in a non-technical setting.

Its important to appreciate what the technology can and cannot do. Its not a magical technology; its not perfect, she said. While there are still a number of aspects of the technology that are still at the beginning phase, Doudna said the field is an incredibly fast-moving area. Ive never seen science move at the pace it is moving right now, she added.

When asked how to know when to use the cutting-edge technique, Doudna said the recommendation is to look for situations where there really is no other reasonable way to deal with a genetic disease other than gene editing. When you think about it that way, those situations are rare, she noted.

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Genome editing CRISPR technique takes center stage | Feedstuffs - Feedstuffs