Category Archives: Genome

By David Cruz Senior Correspondent

You might just be hearing about it, but this technology has the potential to change pretty much everything and everyone in the world.

CRISPR is a programmable nucleus, so the power of it is. And what makes it work so well for gene editing and some of the techniques we use is this protein can use this small segment of RNA to find a site in the genome and cut it. And by making this DNA break in the genome is what allows us to introduce sequences and repair, explained Peter Romanienko, the managing director of the Genome Editing Core Facility at Rutgers University.

If you think of the genome as a Word document, youre basically cutting and pasting. And its that simplifying of the process that makes the potential for life-saving cures in cancer, HIV or heart disease possible.

You have this linear code of DNA and the CRISPR is programmable, so you can create a segment of this and say I want you to cut here, or I want you to cut there. So you can cut anywhere, and thats the power of it, he added. You can target it to any site in the genome to study any gene.

While Romanienko says the Genome Editing Core Facility at Rutgers University uses CRISPR mainly to study cells to fight disease, it has also raised concerns among some ethicists, who fear that the technology, available pretty much around the world, can fall into the hands of individuals, or states, that would unleash its power towards not so benevolent ends.

One could liken it to nuclear energy in that it serves a great purpose and is, in theory, clean burning energy, but it can also blow up the world.

I think if were smart enough to come up with a technology, I think were smart enough to control it we should be smart enough to control it. And if we cant, we shouldnt use that technology. Its like a cell phone. Its a very great tool, but you cant text and drive, Romanienko said.

But, you know, people text and drive all the time, and while the law in some countries, like ours, prohibits taxpayer funding of testing on human embryos, private funding is available around the world. In fact, a privately-funded team in Oregon did exactly that, editing the DNA of a human embryo to remove the gene for heart disease. Again, sounds like a good thing, but whats to stop anyone from editing embryonic DNA to create, for lack of a better term, a master race.

People have been manipulating genomes for hundreds of years, crossing different plants and animals, livestock, so its nothing new that weve been doing. Its just the precision with which we can do it is the main difference, noted Romanienko. If you can create it, you have to be responsible for it.

Scientists have been changing our world since the ancient Greeks. You could say the world has done OK since then, but Hippocrates never had the ability to edit the genome, and its worth wondering what kind of world this would be if he had.

The rest is here:
Rutgers scientists working on technology that could, literally, change the world - NJTV News

August 9, 2017 The importance of standards is dramatically illustrated when they dont exist or are not commonly accepted. an international team led by DOE JGI researchers has developed standards for the minimum metadata to be supplied with single amplified genomes (SAGs) and metagenome-assembled genomes (MAGs) submitted to public databases. Credit: Zosia Rostomian, Berkeley Lab Creative Services

During the Industrial Revolution, factories began relying on machines rather than people for mass production. Amidst the societal changes, standardization crept in, from ensuring nuts and bolts were made identically to maintain production quality, to a standard railroad gauge used on both sides of the Atlantic. The importance of standards is dramatically illustrated when they don't exist or are not commonly accepted, e.g., Macs, vs. PCs, or even pounds vs. kilograms.

More than a century after the Industrial Revolution, advances in DNA sequencing technologies have caused similarly dramatic shifts in scientific research, and one aspect is studying the planet's biodiversity. Microbes play crucial roles in regulating global cycles involving carbon, nitrogen, and phosphorus among others, but many of them remain uncultured and unknown. Learning more about this so-called "microbial dark matter" involves extracting microbial genomes from the amplified DNA of single cells and from metagenomes. As genomic data production has ramped up over the past two decades and is being generated on various platforms around the world, scientists have worked together to establish definitions for terms such as "draft assembly" and data collection standards that apply across the board. One critical term that needs standardization is "metadata," defined simply as "data about other data." In the case of sequence data, metadata can encompass what organism or cell was sequenced, where it came from, what it was doing, quality metrics, and a spectrum of other characteristics that add value to the sequence data by providing context for it and enabling greater biological understanding of the significance of the sequence.

Published August 8, 2017 in Nature Biotechnology, an international team led by researchers at the U.S. Department of Energy Joint Genome Institute (DOE JGI), a DOE Office of Science User Facility, has developed standards for the minimum metadata to be supplied with single amplified genomes (SAGs) and metagenome-assembled genomes (MAGs) submitted to public databases. "Over the last several years, single-cell genomics has become a popular tool to complement metagenomics," said study senior author Tanja Woyke, head of the DOE JGI Microbial Genomics Program. "Starting 2007, the first single-cell genomes from environmental cells appeared in public databases and they are draft assemblies with fluctuations in the data quality. Metagenome-assembled genomes have similar quality challenges. For researchers who want to conduct comparative analyses, it's really important to know what goes into the analysis. Robust comparative genomics relies on extensive and correct metadata."

Categories of Genome Quality

In their paper, Woyke and her colleagues proposed four categories of genome quality. Low-Quality Drafts would be less than 50 percent complete, with minimal review of the assembled fragments and less than 10 percent contaminated with non-target sequence. Medium-Quality Drafts would be at least 50 percent complete, with minimal review of the assembled fragments and less than 10 percent contamination. High-Quality Drafts would be more than 90 percent complete with the presence of the 23S, 16S and 5S rRNA genes, as well as at least 18 tRNAs, and with less than 5 percent contamination. The Finished Quality category is reserved for single contiguous sequences without gaps and less than 1 error per 100,000 base pairs.

The DOE JGI has generated approximately 80 percent of the over 2,800 SAGs and more than 4,500 MAGs currently accessible on the DOE JGI's Genomes OnLine Database (GOLD). DOE JGI scientist and study first author Bob Bowers said many of the SAGs already in GOLD would be considered Low-Quality or Medium-Quality Drafts. These are highly valuable datasets, though for some purposes, researchers might prefer to use High-Quality or Finished datasets. "Single cell and metagenomic datasets vary greatly in their overall quality. However, in cases where a low quality, fragmented genome is the only representative of a new branch on the tree of life, some data is better than no data," he added. "Bringing up the proposed categories will force scientists to carefully consider genome quality before submission to the public databases."

From Proposal to Community Implementation

Moving from a proposal in print to implementation requires community buy-in. Woyke and Bowers conceived of the minimum metadata requirements for SAGs and MAGs as extensions to existing metadata standards for sequence data, referred to as "MIxS," developed and implemented by the Genomic Standards Consortium (GSC) in 2011. The GSC is an open-membership working body that ensures the research community is engaged in the standards development process and includes representatives from the National Center for Biotechnology Information (NCBI) and the European Bioinformatics Institute (EBI). This is important since these are the main data repositories where the minimum metadata requirements are implemented. By working directly with the data providers, the GSC can assist both large-scale data submitters and databases to align with the MIxS standard and submit compliant data.

"Other key public microbiome data management systems such as MG-RAST, IMG and GOLD have also adapted the MIxS standards," said Nikos Kyrpides, head of the DOE JGI Prokaryote Super Program and GSC Board member. He notes that as part of the DOE JGI's core mission, the Institute has been involved in organizing the community to develop genomic standards. "The GSC has been instrumental in bringing the community together to develop and implement a growing body of relevant standards. In fact, the need to expand MIxS to uncultivated organisms was identified in one of the recent GSC meetings at the DOE JGI."

"These extensions complement the MIxS suite of metadata standards by defining the key data elements pertinent for describing the sampling and sequencing of single-cell genomes and genomes from metagenomes," said GSC President and study co-author Lynn Schriml of the Institute of Genome Sciences at University of Maryland School of Medicine. "These standards open up a whole new area of metadata data exploration as the vast majority of microbes, referred to as microbial dark matter, are currently not described within the MIxS standard."

She described the group and their mission as community-driven. "I think it helps that the people developing standards are the people conducting the studies," she said. "We have a vested interest in the data. Research is growing and expanding and it is critical that we capture this data in a rigorous way. Developing these novel metadata standards enables researchers to consistently report the most critical metadata for analysis. Capturing data using controlled vocabularies facilitates data consistency, thus making the databases richer and reusable." And in the end, it is to be hoped, sequence data accompanied by agreed-on standards for metadata will mean the same thing to everyone who wants to use it.

Explore further: New database of DNA viruses and retroviruses debuts

More information: Robert M Bowers et al, Minimum information about a single amplified genome (MISAG) and a metagenome-assembled genome (MIMAG) of bacteria and archaea, Nature Biotechnology (2017). DOI: 10.1038/nbt.3893

There are more microbes in, on, and around the planet than there are stars in the Milky Way. Microbes affect food production; air quality; natural breakdown of plants, trees and biomass; soil quality for agriculture; and ...

A new publically available database will catalog metadata associated with biologic samples, making it easier for researchers to share and reuse genetic data for environmental and ecological analyses.

The number of microbes in a handful of soil exceeds the number of stars in the Milky Way galaxy, but researchers know less about what's on Earth because they have only recently had the tools to deeply explore what is just ...

In a series of four articles published in the Database issue of the Nucleic Acids Research journal, DOE JGI researchers report on the latest updates to several publicly accessible databases and computational tools that benefit ...

Single cell genomics and metagenomics are pioneering techniques that have helped researchers assess environmental microbial community structure and function. As projects applying these techniques scale up, however, researchers ...

Massive amounts of data require infrastructure to manage and store the information in a manner than can be easily accessed for use. While technologies have scaled to allow researchers to sequence and annotate communities ...

If you've got plenty of burgers and beers on hand and your own stomach is full, an uninvited guest at your neighborhood barbecue won't put much strain on you.

Researchers at Newcastle University (UK) found that European sea bass experienced higher stress levels when exposed to the types of piling and drilling sounds made during the construction of offshore structures.

Small, seemingly insignificant mutations in fruit flies may actually hold clues as to how a species will evolve tens of millions of years in the future.

Most of us have had the experience of backing away when someone has stepped inside the bounds of our personal space. But, until now, little has been understood about the mechanisms that allow us to determine when someone ...

During the Industrial Revolution, factories began relying on machines rather than people for mass production. Amidst the societal changes, standardization crept in, from ensuring nuts and bolts were made identically to maintain ...

The color of T-shirts people wear affects escape behavior in western fence lizards, according to a study published August 9, 2017 in the open-access journal PLOS ONE by Breanna Putman from University of California, Los Angeles ...

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Defining standards for genomes from uncultivated microorganisms - Phys.Org

National Institutes of Health (press release)

NIH accelerates the use of genomics in clinical care National Institutes of Health (press release) The National Institutes of Health (NIH) is awarding $18.9 million towards research that aims to accelerate the use of genome sequencing in clinical care. The new awards will generate innovative approaches and best practices to ensure that the ... NIH accelerates genomics in clinical healthcareUPI.com all 3 news articles »

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NIH accelerates the use of genomics in clinical care - National Institutes of Health (press release)

Researchers in China thought they had sequenced the genomes of two snails that help transmit diseases to other species an important first step to stopping the spread. But their hopes were soon dashed after they realized they had misidentified one of the snails.

The researchers published their findings earlier this year in the journal Parasites & Vectors. In the paper, the authors stressed that understanding the genetic makeup of these molluscs is important because many freshwater snails are intermediate hosts for flatworm parasites and transmit infectious diseases to humans and other animals. They also acknowledged that identifying snail species from their appearance alone can be tricky.

Indeed, not long after the study was published, a reader raised concerns that the authors had misidentified one of the snails. After re-examining their data, the authors realized their mistake: They had not checked their results against a genome database, called Basic Local Alignment Search Tool (BLAST), which compares biological sequences against known ones and finds regions of similarity. If they had, the authors may have discovered they had sequenced the wrong species.

Heres theretraction notice for The complete mitochondrial genomes of two freshwater snails provide new protein-coding gene rearrangement models and phylogenetic implications, published in January 2017:

The authors are retracting this article [1]. A reader recently raised questions related to the identification of one of the snail species whose complete mitochondrial (mt) genomes have been characterised in our article, because the gene order and mt genome sequence of the sample of Radix swinhoei (family Lymnaeidae) strongly resemble those of Physella acuta (family Physidae) (GenBank JQ390525.1 and JQ390526.1) published by Nolan et al. [2].

The initial morphology-based identification of the snail as Radix swinhoei was not tested with BLAST searches and as a result we did not realise that we had characterised the mitochondrial genome of a different species. Upon re-examination of our data, we suggest that the sample Radix swinhoei does in fact represent a species of Physella (referred to as Physella sp.). Because of this misidentification and the fact that the phylogenetic analysis did not include members of the family Physidae, the conclusions drawn from the Radix swinhoei sample in our article are incorrect.

All authors agree with this retraction.

We contacted the papers corresponding author, Yinchan Hu, based at the Chinese Academy of Fishery Sciences in the Ministry of Agriculture in Guangzhou, as well as the first author, Xidong Mu, and second-to-last author, Hongmei Song, both based at the same institution. We will update the post if we hear back.

Hat tip: Rolf Degen

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Researchers retract a paper when they realize they had sequenced the wrong snail's genome - Retraction Watch (blog)

Genes carry the information that make you you . So it's fitting that, when sequenced and stored in a computer, your genome takes up gobs of memoryup to 150 gigabytes. Multiply that across all the people who have gotten sequenced, and you're looking at some serious storage issues. If that's not enough, mining those genomes for useful insight means comparing them all to each other, to medical histories, and to the millions of scientific papers about genetics .

Sorting all that out is a perfect task for artificial intelligence . And plenty of AI startups have bent their efforts in that direction. On August 3, sequencing company Veritas Genetics bought one of the most influential: seven-year old Curoverse. Veritas thinks AI will help interpret the genetic risk of certain diseases and scour the ever-growing databases of genomic, medical, and scientific research. In a step forward, the company also hopes to use things like natural language processing and deep learning to help customers query their genetic data on demand.

It's not totally surprising that Veritas bought up Curoverse. Both companies spun out of George Church's prolific Harvard lab . Several years ago, Church started something called the Personal Genomics Project, with the goal of sequencing 100,000 human genomesand linking each one to participants' health information. Veritas' founders helped lead the sequencing partstarting as a prenatal testing service and launching a $1,000 full genome product in 2015while Curoverse worked on academic strategies to store and sort through all the data.

But more broadly, genomics and AI practically call out for one another. As a raw data format, a single person's genome takes up about 150 gigabytes. How!?! OK so, yes, storing a single base pair only takes up around two bits. Multiply that by roughly 3 billionthe total number of base pairs in your 23 chromosome pairsand you wind up with around 750 megabytes. But genetic sequencing isn't perfect. Mirza Cifric, Veritas Genetics cofounder and CEO, says his company reads each part of the genome at least 30 times in order to make sure their results are statistically significant. "And you gotta keep all that data, so you can refer back to it over time," says Cifric.

That's just storage. "Everything after that is going to specific areas and asking questions: Theres a variant at this location, a substitution of this base, a deletion here, or multiple copies of this same gene here, here, and here," says Cifric. Now, interpret all that. Oh, and do it across a thousand, hundred thousand, or million genomes. Querying all those genetic variations is how scientists get leads to find new drugs, or figure out how existing drugs work differently on different people.

But cross-referencing all those genomes is just the beginning. Curoverse, which was focusing on projects to store and sort genomic data, also has its work cut out for it in searching through the 6 millionand countingjargon-filled academic papers detailing gene behavior, including visual information found in charts, graphs, and illustrations.

That's pretty ambitious. Natural language processing is one of the stickiest problems in AI . "Look, I am a computer scientist, I love AI and machine learning, and no amount of coding makes sense to solve this," says Atul Butte , the director of UCSF's Institute of Computational Health Sciences. At his former job at Stanford University, Butte actually tried to do the same thinguse AI to dig through genetics research. He says in the end, it was way cheaper to hire people to read the papers and input the findings into his database manually.

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But hey, never say never, right? However they accomplish it, Veritas wants to move past what companies like 23andMe and Color offer: genetic risk based on single-variant diseases. Some of America's biggest dangers come from diseases like diabetes and heart disease, which are activated by interactions between multiple genesin addition to environmental factors like diet and exercise. With AI, Cifric believes Veritas will be able to not only dig up these various genetic contributors, but also assign each a statistical score showing how much it contributes to the overall risk.

Again, Butte hates to be a spoilsport, but ... there's all sorts of problems with doing predictive diagnostics with genetic data. He points to a 2013 study that used polygenic testing to predict heart disease using the Framingham Heart Study dataabout as good as you can get, when it comes to health data and heart disease. "They authors showed that yes, given polygenic risk score, and blood levels, and lipid levels, and family history, you can predict within 10 years if someone will develop heart disease," says Butte. "But doctors could do the same thing without using the genome!"

He says the problems come down to just how messy it is trying to square up all the different research on each gene alongside the environmental risks, and all the other compounding factors that come up when you try to peer into the future. "Its been the holy grail for a long time, structured genome reporting," says Butte. Even attempts to get researchers to write and report data in a standard, machine-readable way, have fallen flat. "You get into questions that never go away. One researcher defines autism different from another one, or high blood pressure, or any number of things," he says.

Butte isn't a total naysayer. He says partnerships like the one between Veritas and Curoverse are becoming more commonlike the data processing deal between genetic sequencing giant Illumina and IBM Watsonbecause there's a clear need for new computing methods in this area. "You want to get to a point where you are developing stuff that improves clinical care," he says.

Or how about directly to the owners of the genomes? Cifric hopes the merger will improve the consumer experience of using genetic data, even seamlessly integrating it into daily life. For instance, linking your genome and health records to your digital assistant. Alexa, should I eat this last piece of pizza? Maybe you should skip it, depending on your baseline genetic risk for cholesterol and latest blood test results. Diet isn't the only area where genomics could help improve your day to day life. Some people are more or less sensitive to over the counter drugs. A quick query might tell you whether you should take a little less Tylenol than is recommended.

Cifric thinks this acquisition could position Veritas as a global powerhouse of genomic data. "Apple recently announced that they had shipped 41 million iPhones in a quarter, right? I think in not too distant future, well be doing 41 million genomes in a quarter," he says. That might seem ambitious, given that the cost to consumers is nearly $1,000. But that cost is bound to come down. And artificial intelligence will make paying for the genome a matter of common sense.

This story has been updated to reflect that the company is named Veritas Genetics, not Veritas Genomics.

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Veritas Genetics Scoops Up an AI Company to Sort Out Its DNA - WIRED

04 Aug 2017

Scientists have used the CRISPR-Cas9 precision gene-editing system to snip a disease-causing mutation right out of viable human embryos. They did so without accidentally cutting DNA elsewhere, or inducing a heretofore common problem with editing human DNA known as mosaicism, where embryos end up with a mix of edited and unedited cells. Further improvements will be needed before any embryos are implanted for pregnancy, but the research offers hope that this and some other autosomal-dominant mutations can be erased from futuregenerations.

The August 3 Nature paper was led by an international team of researchers, including Paula Amato, Sanjiv Kaul, and Shoukhrat Mitalipov of Oregon Health and Science University, Portland, along with Juan Carlos Izpisua Belmonte from the Salk Institute for Biological Studies, La Jolla, California, and Jin-Soo Kim at the Institute for Basic Science, Daejeon, Republic of Korea. The news made headlines across the news media (see, e.g., The New York Times;The Atlantic; and Wired).

Two days after fertilization and injection with CRISPR-Cas9, early embryos grow without a disease-causing mutation. The embryos were not implanted. [Courtesy ofOHSU.]

This study is paving the way to CRISPRCas9 reaching the clinic in the future, wrote Nerges Winblad and Fredrik Lanner at Karolinska University Hospital, Stockholm, in an accompanying News and Views. They added that although the technique is promising, further studies and optimization will be needed before it is considered safe for therapy. The authors readilyagree.

The study has direct implications for familial Alzheimers disease, but we are not ready for prime-time use of CRISPR in AD, said Murali Doraiswamy, Duke University, Durham, North Carolina, who was not involved in the study.Other AD and amyotrophic lateral sclerosis (ALS) experts echoed the caution, saying the technique is promising for autosomal-dominant neurodegenerative disorders, but limited at the moment (see image above). For starters, the Alzforum mutations database lists about 320 different pathogenic mutations in APP, PS-1, PS-2, and tau known to cause dominantly inherited AD or other tauopathies, respectively. Scientists would have to target each one and study how well CRISPR repairs it. Pouring a bit more cold water on any excitement that may be heating up in the AD community, the authors themselves note that correcting point mutations, which make up a large majority of those that cause neurodegenerative diseases, is hard with the currenttechnology.

To inform public debate about the ethics of editing germline DNA, the American Society of Human Genetics issued a position statement timed to the appearance of thispaper.

Editing the Human Genome Since its discovery in 2013, CRISPR-Cas9 has taken the research community by storm (Sep 2014 news series).Based on a bacterial defense system, this DNA-cutting technology directs a Cas9 enzyme to a particular spot on the genome using a matching guide RNA and creates a double-strand break there. The break is fixed either by non-homologous end joining (NHEJ), which introduces random insertions and deletions to turn off the gene, or by homology-directed repair (HDR), which uses a new piece of DNAusually introduced along with CRISPRas a template to insert a new sequence. CRISPR has been used three times before to edit germline DNA in human embryos (see Liang et al., 2015; Kang et al., 2016; Tang et al., 2017). Two of those studies used nonviable embryos; all three saw extensivemosaicism.

In the present study, first authors Hong Ma and Nuria Marti-Gutierrez at OHSU, Sang-Wook Park in Daejeon, and Jun Wu at the Salk wanted to see if CRISPR-Cas9 could correct a pathogenic mutation in viable human embryos without causing mosaicism. They reasoned that this could improve preimplantation genetic diagnosis (PGD), an extension of in vitro fertilization that doctors already use in rare cases to ensure that parents who carry dominant mutations have healthy children. With PDG, doctors test whether fertilized embryos have a genetic mutation, such as those for familial Alzheimers or Huntingtons disease, then implant only unaffected ones (July 2014 news series). What if affected embryos could be repaired to become implantable? That could reduce the number of rounds of in vitro fertilization cycles women have to endure before getting pregnant with an unaffected baby, Amato said at a pressbriefing.

To see if it was possible, the researchers chose to work on the gene encoding cardiac myosin-binding protein C. Mutations in MYBPC3 are a common cause of autosomal-dominant hypertrophic cardiomyopathy. In this disease, the heart muscles thicken, often unbeknownst to the victim, and can result in sudden death, most prominently in athletes. As in dominantly inherited AD and certain tauopathies, a single copy of the mutated allele suffices to causedisease.

A man with hypertrophic cardiomyopathy served as a donor in the experiments. The researchers derived induced pluripotent stem cells from his fibroblasts, used them to ascertain his exact mutation, then developed a guide RNA to match, and created a single-stranded oligodeoxynucleotide (ssODN) to serve as a corrected template for HDR. The CRISPR-Cas9 system they came up with cut DNA in 27 percent of the iPSCs grown in culture. About 40 percent of those were repaired by HDR and the ssODN, while NHEJ took care of therest.

The researchers then used the patients sperm to fertilize eggs from 12 healthy egg donors, simultaneously injecting the CRISPR-Cas9 complex and the ssODN into half of the eggs. After three days, they tested each cell in every embryo to learn how many had two copies of the wild-type allele. About half of the untreated controls were homozygous for the wild-type allele, as would be expected in ordinary PGD. By contrast, 72 percent of the treated embryos had a double wild-type allele; this meant some of the affected ones had been repaired by HDR. The remaining 16 treated embryos showed signs of NHEJ, which is unhelpful for gene editing. Allowed to grow for five days, the embryos developed as they normallywould.

Exploring the mechanism of repair yielded a surprise. These human embryos almost always used the wild-type strand on the healthy allele to guide the repair, rather than the introduced ssODN. In mice, its the opposite, where embryos more frequently use the ssODN as a template in HDR (Wu et al., 2013). The scientists could tell the difference because the ssODN included unique nucleotides that distinguished it from wild-type. This suggests humans and mice use different repair mechanisms in their embryos. The embryos mechanisms also appear to differ from iPSCs, which tended to use the ssODN forHDR.

Importantly, the researchers found that injecting the CRISPR-Cas9 complex at the same time as the sperm prevented mosaicism almost completely. They guessed that doing so ensured the gene editing would occur before the first division. By contrast, if CRISPR is injected even a short while after fertilization, it may operate after the zygote has already started dividing, correcting the mutation in only a subset of cells (see imagebelow).

Mosaic Work-Around: CRISPR injected after fertilization operates after the first division and results in a subset of cells being fixed. Injecting CRISPR and sperm together ensures that repair occurs before the zygote has time to split. [Courtesy of Winblad and Lanner,Nature.]

Lastly, the authors scoured the rest of the embryos genes with whole-genome and exome sequencing, finding no evidence that the CRISPR complex had cut anywhere else. These off-target cleavages have been a big concern withCRISPR-Cas9.

Much work remains to be done before researchers can implant these embryos to result in pregnancy. For example, the technique needs to approach 100 percent efficiency, said Mitalipov. He plans to try small molecules that downregulate NHEJ and upregulate HDR, but needs to study whether embryos exposed to those compounds develop normally. Once such safety data is in hand, regulators will decide whether researchers can go ahead with clinical trials, Mitalipovsaid.

For now, the National Institutes of Healthdoes not support research on gene editing in human embryos. Neither can the Food and Drug Administration consider clinical trials that deal with germline genetic modification. A 2017 reportby the U.S National Academy of Sciences and National Academy of Medicine stipulated that germline gene editing should only happen in cases where there are no reasonable alternatives, such as PGD. Mitalipov hopes committees will loosen their restrictions once they see more evidence that the problems of mosaicism and off-target DNA changes have beensolved.

Coinciding with Mitalipovs paper, the American Society of Human Genetics released a statement saying that it is too early to perform germline editing that will result in pregnancy in people (Ormond et al., 2017). Ten other international organizations are part of the report, including the National Society of Genetic Counselors, the Human Genetics Society of Australasia, the Southern African Society for Human Genetics, and the Asia Pacific Society of Human Genetics. However, the groups consensus supports germline genome editing research, with appropriate oversight and consent, that explores the relevant questions. Importantly, it supports public funding for suchresearch.

What About Neurodegenerative Disease? Will this technique work for other autosomal-dominant mutations? Eventually, yes, said Mitalipov, citing the breast and ovarian cancer mutations BRCA1 and 2 as examples. The specificity of CRISPR-Cas9 will depend on each individual mutation and the donors genetic background. Off-target effects likely will be more common for mutations that look similar to their wild-typealleles.

Kim cautioned that single nucleotide mutations are more challenging to correct than larger insertions or deletions such as the one targeted in this paper. Since the error in single base pair substitutions is so small in size, it will be difficult for Cas9 to home in on the mutant allele. This pertains in particular to neurodegeneration. The report provides some clear translatability to many autosomal dominant Alzheimers disease (ADAD) mutations, wrote Eric McDade, Washington University School of Medicine in St. Louis, to Alzforum. However, the mutation that was the focus of this research was a deletion, and most ADAD-causing mutations are single base pair substitutions. (See McDades full commentbelow.)

What about other neurodegenerative diseases? This new success could be relevant for dominantly inherited ALS and FTD, wrote Ronald Klein, LSU Health Sciences Center-Shreveport, to Alzforum. Between 10 and 20 percent of ALS and FTD cases are considered to be heritable, and most of the underlying mutations are dominant, Klein said. Of those, it might be promising to explore gene editing for C9ORF72 hexanucleotide repeats; also for ALS mutations in the genes NEK1, SOD1, TDP-43, FUS, and others; as well as FTD mutations in tau, progranulin, VCP, CHMP2B and other genes. As in Alzheimers, however, most ALS and FTD mutations are single nucleotide substitutions, Klein cautioned. Removing extra stretches of disease-causing repeats by CRISPR-Cas9 might work better, heagreed.

Not many ADAD families know about DNA repair with CRISPR just yet; however, McDade says he expects interest to grow in the near future, and Mitalipovs paper is already being posted on private familial AD discussion groups. If the procedure becomes more efficient, less expensive, and is proven in models to lead to normal development, it will become more attractive, he said. Some families with ADAD mutations are using IVF/PGDalready.

On the other hand, Ammar Al-Chalabi, Kings College London, who studies the human genetics of ALS, pointed out that PGD is simpler and still comes up with about half the embryos being healthy. Merit Cudkowicz, Massachusetts General Hospital, Boston, noted that if some of the allele-specific oligonucleotide (ASO) and gene therapies for ALS that are already going into people in clinical trials are effective, then families and clinicians may not need advanced PGD approaches employingCRISPR-Cas9.

This paper is an important milestone in using CRISPR for genome editing of familial disease mutations in the germline, said Martin Kampmann, University of California, San Francisco. Ahmet Yildiz, University of California at Berkeley, agreed. This technique has great power to repair genetic diseases, and I believe we have to make the best use of it for health, he said. Both Kampmann and Yildiz emphasized that ethical and safety standards have to be developed before this technology can be applied topatients.

For safety, limiting off-target cleavage by Cas9 will be critical. On this front, Yildiz, working with CRISPR-Cas9 co-discoverer Jennifer Doudna, also at Berkeley, on August 4 described in Science Advances why CRISPR-Cas9 cuts at specific target sequences in the genome, and where the tendency for off-target binding comes from. First authors Yavuz Dagdas and Janice Chen found that Cas9s cutting region, the HNH domain, takes one conformation when it binds its guide RNA, and another when it cleaves DNA. It passes through a checkpoint intermediate to get from point A to point B, and has to break free of that intermediate before it can adopt its cleaving form. If CRISPR-Cas9 binds DNA with more than three mismatches to its guide RNA, the HNH domain cannot overcome this energy hump to cut. Our work explains why Cas9 binds to many off-target sites but cleaves only a subset of them, Yildiz wrote toAlzforum.

One way to improve that accuracy would be to adjust the guide RNA. While Cas9 with a guide RNA of 20 nucleotides tolerates several mismatches on the DNA, one with 17 is more sensitive to them, and so binds fewer off-target sequences. Scientists are also engineering Cas9 to make it more specific. While these approaches significantly reduce off-target editing, none of them can fully eliminate cleavage of off-targets with a single mismatch at the moment, Yildiz said. He agreed that variations of just a single base pair may not be trivial to edit with the current CRISPR technology.Gwyneth DickeyZakaib

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CRISPR Edits Genome of Human Embryos - Alzforum

An international team of researchers recently published, in the journal Nature, their study using genome editing to correct a heterozygous mutation in human preimplantation embryos using a technique called CRISPR-Cas9. This bench research, while far from bedside use, raises questions about the medical ethics of what could be considered genetic engineering. The AMA Code of Medical Ethics has guidance for physicians conducting research in this area.

In Opinion 7.3.6, Research in Gene Therapy and Genetic Engineering, the Code explains:

Gene therapy involves the replacement or modification of a genetic variant to restore or enhance cellular function or the improve response to nongenetic therapies. Genetic engineering involves the use of recombinant DNA techniques to introduce new characteristics or traits. In medicine, the goal of gene therapy and genetic engineering is to alleviate human suffering and disease. As with all therapies, this goal should be pursued only within the ethical traditions of the profession, which gives primacy to the welfare of the patient.

In general, genetic manipulation should be reserved for therapeutic purposes. Efforts to enhance desirable characteristics or to improve complex human traits are contrary to the ethical tradition of medicine. Because of the potential for abuse, genetic manipulation of nondisease traits or the eugenic development of offspring may never be justifiable.

Moreover, genetic manipulation can carry risks to both the individuals into whom modified genetic material is introduced and to future generations. Somatic cell gene therapy targets nongerm cells and thus does not carry risk to future generations. Germ-line therapy, in which a genetic modification is introduced into the genome of human gametes or their precursors, is intended to result in the expression of the modified gene in the recipients offspring and subsequent generations. Germ-line therapy thus may be associated with increased risk and the possibility of unpredictable and irreversible results that adversely affect the welfare of subsequent generations.

Thus, in addition to fundamental ethical requirements for the appropriate conduct of research with human participants, research in gene therapy or genetic engineering must put in place additional safeguards to vigorously protect the safety and well-being of participants and future generations.

Physicians should not engage in research involving gene therapy or genetic engineering with human participants unless the following conditions are met:

(a) Participate only in those studies for which they have relevant expertise.

(b) Ensure that voluntary consent has been obtained from each participant or from the participants legally authorized representative if the participant lacks the capacity to consent, in keeping with ethics guidance. This requires that:

(i) prospective participants receive the information they need to make well-considered decisions, including informing them about the nature of the research and potential harms involved;

(ii) physicians make all reasonable efforts to ensure that participants understand the research is not intended to benefit them individually;

(iii) physicians also make clear that the individual may refuse to participate or may withdraw from the protocol at any time.

(c) Assure themselves that the research protocol is scientifically sound and meets ethical guidelines for research with human participants. Informed consent can never be invoked to justify an unethical study design.

(d) Demonstrate the same care and concern for the well-being of research participants that they would for patients to whom they provide clinical care in a therapeutic relationship. Physician researchers should advocate for access to experimental interventions that have proven effectiveness for patients.

(e) Be mindful of conflicts of interest and assure themselves that appropriate safeguards are in place to protect the integrity of the research and the welfare of human participants.

(f) Adhere to rigorous scientific and ethical standards in conducting, supervising, and disseminating results of the research.

AMA Principles of Medical Ethics: I,II,III,V

At the 2016 AMA Interim Meeting, the AMA House of Delegates adopted policy on genome editing and its potential clinical use. In the policy, the AMA encourages continued research into the therapeutic use of genome editing and also urges continued development of consensus international principles, grounded in science and ethics, to determine permissible therapeutic applications of germline genome editing.

Chapter 7 of the Code, Opinions on Research & Innovation, also features guidance on other research-related subjects, including informed consent, conflicts of interest, use of placebo controls, and the use of DNA databanks.

The Code of Medical Ethics is updated periodically to address the changing conditions of medicine. The new edition, adopted in June 2016, is the culmination of an eight-year project to comprehensively review, update and reorganize guidance to ensure that the Code remains timely and easy to use for physicians in teaching and in practice.

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Genome editing and the AMA Code of Medical Ethics - American Medical Association (blog)

Where genetic engineering really can do something that embryo selection cannot is in genetic enhancement better known as designer babies. Photograph: Roger Bamber / Alamy Stock Photo/Alamy Stock Photo

Hope for families with genetic conditions, and scientific breakthrough: that is how headlines are proclaiming a project that modified human embryos to remove mutations that cause heart failure. But anyone who has concerns about such research is often subjected to moral blackmail. We are regularly lumped in with religious reactionaries or anti-abortion campaigners.

The medical justification for spending millions on such research is thin: it would be better spent on developing cures

I am neither. If you peel away the hype, the truth is that we already have robust ways of avoiding the birth of children with such conditions, where that is appropriate, through genetic testing of embryos. In fact, the medical justification for spending millions of dollars on such research is extremely thin: it would be much better spent on developing cures for people living with those conditions. Its time we provided some critical scrutiny and stopped parroting the gospel of medical progress at all costs.

Where genetic engineering really can do something that embryo selection cannot is in genetic enhancement better known as designer babies. Unfortunately, thats where its real market will be. We have already seen that dynamic at work with the three-parent IVF technique, developed for very rare mitochondrial genetic conditions. Already, a scientist has created babies that way in Mexico (specifically to avoid US regulations) and a company has been set up with the aim of developing the science of designer babies.

Scientists who started their careers hoping to treat sick people and prevent suffering are now earning millions of dollars creating drugs to enhance cognitive performance or performing cosmetic surgery. We already have consumer eugenics in the US egg donor market, where ordinary working-class women get paid $5,000 for their eggs while tall, beautiful Ivy League students get $50,000. The free market effectively results in eugenics. So its not a matter of the law of unintended consequences or of scaremongering the consequences are completely predictable. The burden of proof should be on those who say it wont happen.

Once you start creating a society in which rich peoples children get biological advantages over other children, basic notions of human equality go out the window. Instead, what you get is social inequality written into DNA. Even using low-tech methods, such as those still used in many Asian countries to select out girls (with the result that the world is short of more than 100 million women), the social consequences of allowing prejudices and competitiveness to control which people get born are horrific.

Most enhancements in current use, such as those in cosmetic surgery, are intended to help people conform to expectations created by sexism, racism and ageism. More subtly, but equally profoundly, once we start designing our children to perform the way we want them to, we are erasing the fundamental ethical difference between consumer commodities and human beings. Again, this is not speculation: there is already an international surrogacy market in which babies are bought and sold. The job of parents is to love children unconditionally, however clever/athletic/superficially beautiful they are; not to write our whims and prejudices into their genes.

Its for these reasons that most industrialised countries have had legal bans against human genetic engineering for the last 30 years. Think about that for a moment: its pretty unusual for societies that normally put technological innovation at the centre of their policies to ban technologies before theyre even feasible. There have to be very good reasons for such an unprecedented step, and its not to do with protecting embryos. Its to do with the social consequences.

Genetically modified crops are a good comparison. Faced with a similarly irresponsible absolutism from the scientific community as well as with the obvious competition for fame and profit the green movement and the left felt they had to take the issue of GM food into their own hands. Now it looks like its time to campaign for a global ban on the genetic engineering of people. We must stop this race for the first GM baby.

Dr David King is a former molecular biologist and founder of Human Genetics Alert, an independent secular watchdog group that supports abortion rights

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Editing the human genome brings us one step closer to consumer eugenics - The Guardian

A Midsomer Norton family are taking part in the largest national genome sequencing project of its kind in the world.

The West of England NHS Genomic Medicine Centre (WEGMC) has enrolled 1,000 patients and family members from across the region to take part in the 100,000 Genomes Project.

Nicola Windless's twin daughters, Kayleigh and Michelle, have an undiagnosed condition and she hopes that research like 100,000 Genomes can help provide some answers.

Kayleigh and Michelle have global learning difficulties and epilepsy and we want to know more about their condition and whether there is a genetic link.

Ive always been optimistic about our situation but its the factor of the unknown which can be a struggle. I know that the project may not give us all the answers but I strongly believe that the more you know, the better so thats why my daughters, my husband Paul and I have enrolled on this important project, said Nicola.

Professor Andrew Mumford, clinical director of the WEGMC, said: Thanks to the support of people like Nicola and her family and hospitals across Bristol, Bath and Gloucestershire, we have been able to achieve this significant milestone for our Genomic Medicine Centre.

The enthusiasm around the project from patients, and their families, and the healthcare community has been incredible and we are thrilled to be part of this very important initiative that will help shape the future of personalised medicine in the NHS.

What is the Genome project?

The 100,000 Genomes project in a major NHS initiative that aims to sequence 100,000 genomes from patients with rare inherited diseases or with cancer and to transform NHS services to include genome sequencing as standard care for future patients.

A genomics medicine centre was established in the West of England at the end of 2015 to enable access to this service for patients and their families across region.

Professor Dame Sally Davies, chief medical officer of NHS England, recently called on the NHS to make genome sequencing as standard as blood tests and biopsies for people with cancer, rare diseases and infections.

Genome sequencing could result in more personalised treatment for patients and faster diagnoses for people with rare diseases.

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Why this Midsomer Norton family are taking part in the Genome project - Somerset Live

August 3, 2017 Helicoverpa armigera. Credit: CSIRO

For the first time, researchers from Australia's Commonwealth Scientific and Industrial Research Organisation (CSIRO) have mapped the complete genome of two closely related megapests potentially saving the international agricultural community billions of dollars a year.

Led by CSIRO, in collaboration with a team of renowned experts, the researchers identified more than 17,000 protein coding genes in the genomes of the Helicoverpa armigera and Helicoverpa zea (commonly known as the Cotton Bollworm and Corn Earworm, respectively).

They also documented how these genetics have changed overtime.

This level of detail makes it easier for scientists to predict both the caterpillars' weak spots, how they will mutate and even breed plants they will not want to eat.

The bollworm and earworm are the world's greatest caterpillar pests of broad-acre crops, causing in excess of US $5 billion in control costs and damage each year across Asia, Europe, Africa, America and Australia.

The bollworm, which is dominant in Australia, attacks more crops and develops much more resistance to pesticides than its earworm counterpart.

"It is the single most important pest of agriculture in the world, making it humanity's greatest competitor for food and fibre," CSIRO Scientist Dr John Oakeshott said.

"Its genomic arsenal has allowed it to outgun all our known insecticides through the development of resistance, reflecting its name - armigera which means armed and warlike."

In Brazil the bollworm has been spreading rapidly and there have been cases of of it hybridising with the earworm, posing a real threat that the new and improved "superbug" could spread into the United States.

In the mid-90s CSIRO assisted Australian cotton breeders to incorporate Bt insect resistance genes in their varieties to try and tackle the bollworm.

"Bt cotton" plants dispatch an insecticide from a bacteria - Bacillus thuringiensis (Bt) - that is toxic to the caterpillar.

In the following 10 years, there was an 80 per cent reduction in the use of chemical pesticides previously required to control bollworms.

However the bollworm soon fought back with a small percentage of them building resistance to BT cotton and scientists introducing further strains of insecticides to manage the problem.

CSIRO Health and Biosecurity Honorary Fellow Dr Karl Gordon said while a combination of BT and some insecticides was working well in Australia, it can be costly and it was important to comprehensive studying the pest themselves to manage the problem world-wide.

"We need the full range of agricultural science," Dr Gordon said.

"Our recent analyses of the complete genome, its adaptations and spread over the years are a huge step forward in combating these megapests."

Identifying pest origins will enable resistance profiling that reflects countries of origin to be included when developing a resistance management strategy, while identifying incursion pathways will improve biosecurity protocols and risk analysis at biosecurity hotspots including national ports.

As part of the research, CSIRO and the team updated a previously developed potential distribution model to highlight the global invasion threat, with emphasis on the risks to the United States.

The findings further provide the first solid foundation for comparative evolutionary and functional genomic studies on related and other lepidopteran pests, many of considerable impact and scientific interest.

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