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Zware drinkers hebben minder kans op het ontwikkelen van spierziekte ALS.

By Samantha VoldThe classic tale of Jurassic Park, where dinosaurs once again walked the earth has tickled the fancy of many a reader. Dinosaur DNA preserved in a fossilized mosquito was used to bring these giants back to life. But in real life, it was previously thought that there was no possible way for organic materials to be preserved, that they often degraded within 1 million years if not rapidly attacked by bacteria and other organisms specialized in decomposition. Skin and other soft tissues, such as blood vessels, would never withstand the test of time. Or would they…? T. rex skeleton at Palais de la découverte. Image by David Monniaux at Wikimedia In 1992, Mary Schweitzer was staring through a microscope at a thin slice of fossilized bone, but this bone had something unusual. There were small red disks located in this tissue and each had a small dark circle in the middle resembling a cell nucleus, the command center of the cell. And these little disks very much resembled the red blood cells of reptiles, birds, and other modern-day vertebrates (excluding mammals). But it wasn’t possible, was it? These cells came from a 67 million-year old T. rex. And it was commonly accepted that organic material never lasted that long.Comparison of red blood cells. Image by John Alan Elson at Wikimedia This opened a huge controversy in the scientific community, but Schweitzer persisted. She consulted with her mentor, Jack Horner, a leading scientist in the paleontology field, and he told her to prove to him that they weren’t red blood cells. Schweitzer took the challenge and began to run some tests. The first clue to these mysterious scarlet-colored cells potentially being red blood cells was the fact that they were located within blood vessel channels of the dense bone that were not filled with mineral deposits. And these microscopic structures only appeared inside the vessel channels, as would be true of blood cells. Schweitzer then began to focus on the chemical composition of these puzzling structures. Tests showed that these “little red round things” were rich in iron, and that the iron was specific to them. Iron is important in red blood cells as it helps to transport oxygen throughout the body. And the elemental make-up of these little red round things differed greatly from the surrounding bone and sediment around them. The next test was looking for heme, a small iron-containing molecule that gives blood its characteristic color and allows hemoglobin proteins to transport oxygen throughout the body. Schweitzer tested for this through spectroscopy tests, which measure the light that a given material emits, absorbs, and scatters. Her results from these tests were consistent with what one would find in heme, suggesting that this molecule existed in the dinosaur bone she was analyzing. Schweitzer then conducted a few immunology tests to see if she indeed had found hemoglobin in these ancient bones. Antibodies are produced when the body detects a foreign substance that could potentially be harmful. Extracts from the dinosaur bone were injected into mice to see if antibodies were produced to ward against this new organic compound. When these antibodies were then exposed to hemoglobin from turkeys and rats, they bound to the hemoglobin. This suggested that the extracts that caused an antibody response in the mice included hemoglobin. This in turn suggested the T. rex bone contained hemoglobin, or something very similar.Through years of research, Schweitzer has shown that what was once believed to be impossible is indeed true. Soft tissues, blood cells, and proteins can withstand the test of time. This process is possibly done through iron binding to amino acids (the molecules that make up proteins) and thereby preserve them. Research is advancing in this area, but as of yet, no DNA has been found to bring Jurassic Park to life. But for the avid believer, don’t get up hope yet. Perhaps one day we truly could walk amongst dinosaurs. References:Fields, Helen. (May 2006). Dinosaur Shocker. Smithsonian. Smithsonian Magazine. Pappas, Stephanie. (13 Nov. 2013). Mysteriously Intact T. Rex Tissue Finally Explained : DNews. DNews. Live Science. Schweitzer, M. (2010). Blood from Stone Scientific American, 303 (6), 62-69 DOI: 10.1038/scientificamerican1210-62...

A biological clock that provides vital clues about how long a person is likely to live has been discovered by researchers. Researchers studied chemical changes to DNA that take place over a lifetime, and can help them predict an individual's age. By comparing individuals' actual ages with their predicted biological clock age, scientists saw a pattern emerging.

It had never been verified before: unlike other biopolymers, RNA, the long strand that is 'cousin' to DNA, tends not to form knots.

A protein newly found in the naked mole rat may help explain its unique ability to ward off cancer. The protein is associated with a locus that is also found in humans and mice. It's the job of that locus to encode several cancer-fighting proteins. The locus found in naked mole rats encodes a total of four cancer-fighting proteins, while the human and mouse version encodes only three.

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De Raspberry Pi-stichting heeft de Raspberry Pi 2 Model B aangekondigd. Wat ontwerp betreft lijkt de mini-computer sterk op het eerdere Model B, maar de soc is een krachtigere quadcore en het systeempje beschikt over 1GB werkgeheugen.

A pair of papers in this week’s Nature introduces GROs — “genomically recoded organisms” — whose altered genetic code makes them require a synthetic amino acid to survive. Although this new type of biocontainment indeed keeps microorganisms from spreading to where they aren’t wanted, at least in a lab, I don’t think the approach is likely to convert many anti-GMO folks to biotech fans, based on my experience.

ROTTEN TOMATOES
Several years ago, I spoke about genetically modified organisms (GMOs) to a group of citizen environmentalists, my goal to explain the precise procedures behind the vague term “genetic engineering.” Alas, the audience rapidly nodded off as I distinguished a transgenic organism from a knockout. They didn’t believe my tale of the first GMO released to the environment, “ice-minus” bacteria, that were sprayed onto strawberry plants by Advanced Genetic Sciences in 1987 to block ice nucleation. Activists destroyed a treated strawberry patch, unaware that the GM bacteria actually lacked a gene, rather than harboring a foreign one.

The audience woke up, and became enraged, when I stated that traditional breeding is less precise than genetic manipulation. They yelled over my insistence that the same DNA triplets encode the same amino acids in all species. So unpleasant was the anti-science sentiment that I vowed never to speak about GMOs again.

My experience revealed that people fear GMOs – particularly plants – for a biological reason and an ethical reason:

#1: GMOs are perceived as not as safe to eat as unaltered vegetables and fruits.

#2 Any genetic manipulation beyond crossing and breeding is just wrong, an assault on nature.

Back then there was less concern about GMOs forcing reliance on certain herbicides and pesticides, and of “escape” to fields beyond where they’re intended to grow, two objections with which I agree.

TRIPLE-HEADED PURPLE MONSTERS
When I was in graduate school for genetics in the mid 1970s, the dawn of modern agricultural biotechnology, my mentor Thom Kaufman dubbed the unfounded fear of anything involving DNA the “triple-headed purple monster” mindset. It persists.

Even decades since we began regularly eating GMO crops, fear of their danger lingers. A January 17 article in the Washington Post proclaims “Over 80 Percent of Americans Support Mandatory Labels on Foods Containing DNA,” possibly the most idiotic headline of all time. Ever had a burger or banana that doesn’t contain DNA? All organisms do. And all use the same genetic code.

I can’t fathom why people vehemently object to GM corn and soybeans, but not to vaccines and pharmaceuticals consisting of recombinant DNA translated into protein in non-human cells. Does anyone find offensive the candidate Ebola vaccines and drugs that include genes from different viruses grown in tobacco cells? “You Won’t Believe How They’re Growing the Ebola Vaccine” shouted another recent headline, above an article that repeatedly refers to “a bacteria” (that’s plural), and confuses bacteria with viruses. I wrote about producing recombinant DNA-derived proteins in tobacco plants in “Building a Better Tomato” in High Technology magazine, circa 1984.

The fact that 80% of those polled are demanding labels announcing the presence of DNA in their food confirms that the palpable fear and anger I felt years ago still simmers. And if that’s so, then the new studies about altering the genetic code may ignite a firestorm, despite the initial news emphasis on the fact that GROs have a genetic “safety lock.”

INTRODUCING GENETICALLY RECODED ORGANISMS
The Nature papers are a bit hard to follow, and require familiarity with the genetic code. It is the 64 possible mRNA triplets (codons) that are combinations of the four types of RNA bases (uracil, cytosine, adenine, and guanine), which are complementary to 64 types of DNA triplets. Of the 64 RNA codons, 61 encode any of 20 types of biological amino acids, and 3 mean “stop”: UAA, UAG, and UGA. A protein being synthesized along an mRNA molecule is complete when it encounters a stop codon. UAA, UAG, and UGA spell “stop” in all organisms, as well as in viruses. (Disclaimer: I have a UGA stop codon tee shirt.)

George Church of Personal Genome Project fame, who is the Robert Winthrop Professor of Genetics at Harvard Medical School, and colleagues report in the January 21 Nature that they replaced UAG “stop” codons in E. coli with UAA codons altered to bind and insert a “nonstandard amino acid” (NSAA) into a growing protein. An NSAA is not among the 20 that the natural genetic code specifies. The result is a GRO: a genomically recoded organism. It can’t survive without the NSAA.

“We now have the first example of genome-scale engineering rather than gene editing or genome copying. This is the most radically altered genome to date in terms of genome function. We have not only a new code, but also a new amino acid, and the organism is totally dependent on it,” said Dr. Church in a news release.

By swapping in the altered UAAs at many places in the bacterial genome, plus required tRNAs and “computationally redesigned” enzymes, protein synthesis incorporates the unnatural amino acids. As a result, DNA can’t move from cell to cell aboard viruses and other mobile DNA elements (horizontal gene transfer) or be replicated and passed to the next generation (vertical gene transfer), unless the NSAA is present.

Dr. Church calls the feat “irreversible, inescapable dependency.” All of this work is in very early stages and uses the standard E. coli and its T viruses, the stuff of classic molecular biology experiments from the 1960s and 1970s, and the microorganism in which many biological drugs are “pharmed.” It is a long way from being applied to fields of rhubarb.

GROs made their debut in a 2013 paper in Science from Dr. Church’s group, and were a candidate for the magazine’s “breakthrough of the year” in 2014. The 2013 paper describes the ability of GROs to resist viral infection, because they can’t be make viral proteins, as infected cells normally would. Viral infection can be disastrous for producing biopharmaceuticals or bioremediation agents.

In the second article on GROs in this week’s Nature, Farren J. Isaacs, an assistant professor of molecular, cell and developmental biology at Yale University, who did postdoctoral research in the Church lab, and colleagues describe retooling the UAG stop codons where they naturally occur in E. coli, but also introduce them into several essential genes. Their bacteria require two unnatural amino acids.

Dr. Isaacs and the Yale team also published an article with a headline I did like, “Multilayered genetic safeguards limit growth of microorganisms to defined environments,” in Nucleic Acids Research online January 7. They colorfully describe their multi-pronged approach as including “engineered riboregulators that tightly control expression of essential genes, and an engineered addiction module based on nucleases that cleaves the host genome.”

A NEW ROUTE TO BIOCONTAINMENT
In microbiological terms, a GRO is a “synthetic auxotroph.” Like bacteria before it genetically modified to resist an antibiotic or require a nutrient in order to survive, thereby providing a means of selection, the new breed of GROs depends on the NSAAs in the environment to make proteins, to stay alive and reproduce. A GRO can’t escape to where it isn’t wanted if it can’t get its NSAA.

In contrast to insecticide- or herbicide-resistant GMOs forcing reliance on a big company’s products, GROs work when something unnatural is not available in the environment. So they’d grow where the NSAA is, but not where it isn’t — if the technology ever extends beyond closed laboratory situations.

Wherever GROs end up, the researchers hope the altered genetic code will enable them to circumvent nature’s ways of surviving. New detoxifying mutations won’t help, for there is no toxin. Nor can natural selection or even horizontal gene transfer remove the altered codons. And GROs can’t suck up useful nutrients from neighbors – they need those NSAAs. But as mathematician Ian Malcolm pointed out in Jurassic Park, where genetically altered dinosaurs ran amok, “nature finds a way.”

Biocontainment based on altering the genetic code is an idea that was unimaginable back when such measures were first hammered out at the Asilomar conference on recombinant DNA held in 1975. In the 1990s, Dr. Dana (“I’m a scientist!”) Scully from the TV show The X-Files waxed melodramatic about a 5-base genetic code introduced by space aliens. It happens.

While GROs extend the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules, the new papers are more proof-of-concept than practical, for now. None of the trillion E. coli that the Church lab grew over two weeks bolted. That’s “10,000 times better than the NIH recommendation for escape rate for genetically modified organisms,” Dr. Church said.

THE MEDIA RESPONSE TO GROs

I eagerly awaited the media response to the reports on GROs, anticipating an uproar if the news aggregators went beyond the cautious news release to borrow phrases from the papers such as “whole organisms capable of sampling new evolutionary landscapes” and “reliance on synthetic metabolites.” Altering the genetic code is HUGE, a much more profound change than boosting beta carotene levels in rice or creating tomatoes with longer shelf lives, traits that result from single-gene changes.

The media coverage, so far, has been far less than I anticipated, with the usual suspects – the New York Times, Science Daily – doing a terrific job. But it wasn’t the stuff of CNN or the NBC evening news, and stories such as underinflated footballs, a cop singing along with Taylor Swift, and the arrest on corruption charges of the speaker of the New York State assembly, naturally got more coverage.

What would the anti-GMO organizations, places I don’t ordinarily visit since my traumatic lecture experience, say?

Greenpeace was concerned mainly with polar bears and whales. But GMO Awareness was apparently unaware that researchers had rewritten the genetic code and applied it to bacteria in a technology that could, someday, be used to reign in errant altered crops. The “breaking news” on their website is from October, and the featured story on their Facebook page concerns all-natural burgers, which I suspect in fact harbor some DNA.

It’s possible that the environmental groups do not yet comprehend the significance of what synthetic biology can do, or understand how it works. But maybe I’m wrong about that. Give it a few weeks.

Many questions remain, especially if GROs transition from initial roles in bioremediation and specialty chemicals and pharmaceuticals to food production. Will the NSAAs harm health if eaten or spread in the environment? Will the approach work for plants, which are so much more complex than E. coli?

As for me, I was recently asked again to speak about GMOs, in an adult education course next fall. I initially said no. But these two papers are so exciting that I’ve changed my mind.

The post From GMOs to GROs: Will Life Find a Way? appeared first on DNA Science Blog.

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Noncoding oligonucleotides: the belle of the ball in gene therapy.

Adv Genet. 2015;89:153-77

Authors: Shum KT, Rossi JJ

Abstract
Gene therapy carries the promise of cures for many diseases based on manipulating the expression of a person's genes toward the therapeutic goal. The relevance of noncoding oligonucleotides to human disease is attracting widespread attention. Noncoding oligonucleotides are not only involved in gene regulation, but can also be modified into therapeutic tools. There are many strategies that leverage noncoding oligonucleotides for gene therapy, including small interfering RNAs, antisense oligonucleotides, aptamers, ribozymes, decoys, and bacteriophage phi 29 RNAs. In this chapter, we will provide a broad, comprehensive overview of gene therapies that use noncoding oligonucleotides for disease treatment. The mechanism and development of each therapeutic will be described, with a particular focus on its clinical development. Finally, we will discuss the challenges associated with developing nucleic acid therapeutics and the prospects for future success.

PMID: 25620011 [PubMed - in process]

Scientists find translucent fish in a wedge of water hidden under 740 meters of ice, 850 kilometers from sunlight

-- Read more on ScientificAmerican.com

Onderzoekers van het Hubrecht Instituut en het UMC Utrecht zijn er in geslaagd een kweeksysteem te ontwikkelen voor menselijke leverstamcellen én voor stamcellen uit alvleesklierkanker.

Related Articles

In Vitro Selection Using Modified or Unnatural Nucleotides.

Curr Protoc Nucleic Acid Chem. 2014;56:9.6.1-9.6.33

Authors: Stovall GM, Bedenbaugh RS, Singh S, Meyer AJ, Hatala PJ, Ellington AD, Hall B

Abstract
Incorporation of modified nucleotides into in vitro RNA or DNA selections offers many potential advantages, such as the increased stability of selected nucleic acids against nuclease degradation, improved affinities, expanded chemical functionality, and increased library diversity. This unit provides useful information and protocols for in vitro selection using modified nucleotides. It includes a discussion of when to use modified nucleotides; protocols for evaluating and optimizing transcription reactions, as well as confirming the incorporation of the modified nucleotides; protocols for evaluating modified nucleotide transcripts as template in reverse transcription reactions; protocols for the evaluation of the fidelity of modified nucleotides in the replication and the regeneration of the pool; and a protocol to compare modified nucleotide pools and selection conditions. Curr. Protoc. Nucleic Acid Chem. 56:9.6.1-9.6.33. © 2014 by John Wiley & Sons, Inc.

PMID: 25606981 [PubMed - as supplied by publisher]

10X Genomics has exited stealth mode with $80 million in VC funding and a plan to solve a significant sequencing problem without going head to head with Illumina. The Pleasanton, CA-based startup is set to unveil an add-on for Illumina sequencers that improves their ability to map long reads of DNA.

Illumina welcomed the new year with three/four new sequencing systems with a wide range of sequencing capabilities. This year Illumina mainly focused of HiSeq X and HiSeq systems and announced new HiSeq X Five, HiSeq 3000/4000, and, NextSeq 550.  Announcing the new set of sequencers, Jay Flatley, Illumina’s Chief Executive Officer, said

Illumina technology has broken down barriers in genomics by increasing data throughput at an astounding rate, while at the same time dramatically reducing the price per data point. These advancements enable us to deliver the industry’s simplest, most efficient sequencing experience to our research and clinical customers as they work to forever transform our understanding of genomics and medicine.

HiSeq X Five System

As the name suggests, HiSeq X Five system is a smaller scale HiSeq X Ten system. HiSeq X Five has a set of five HiSeq X machines instead of ten HiSeq X machines. The goal of HiSeq X Five is to offer production-scale sequencing at a lower capitol cost than HiSeq X Ten.  HiSeq X Five can sequence over 9,000 Human genomes in a year.

Illumina HiSeq 3000 and HiSeq 4000

HiSeq 3000 and HiSeq 4000 are Illumina’s next iteration sequencing system for the current HiSeq 2500.  HiSeq 3000 has single flow cell, while HiSeq 4000 has two flow cells. Illumina brings its patterened flow cell design to the HiSeq 3000 and HiSeq 4000 and makes the to deliver more data at lower cost than the current HiSeq 2500. Illumina claims that the HiSeq 4000 can sequence up to 12 genomes, 100 whole transcriptome samples, or 180 exomes in 3.5 days or less.

Illumina NextSeq 550

Illumina also annouced a new sequencing system NextSeq 550 – combining its current NextSeq 500 and its microarray scanning system. Illumina plans to use NextSeq 550 to a range of applications in “reproductive health, genetic health, and oncology-related research”.

 

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Sjon shared this story from Hacker News 100.

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Het gebruik van vrije software is essentieel om surveillance tegen te gaan. Dat stelt Richard Stallman, de oprichter van de Free Software Foundation en GNU, in een interview met Tweakers. "Vrije software zorgt ervoor dat je apparaat je gedrag niet meer verraadt."

On December 10th, 2014, I was formally awarded tenure at UC Davis, where I will start as an Associate Professor in the School of Veterinary Medicine on January 5th, 2015. In my research statement for my job application, I wrote:

Open science and scientific reproducibility: I am a strong advocate of open science, open source, open data, open access, and the use of social media in research as a way to advance research more broadly.

I've been an advocate of "open" for decades, and since becoming an Assistant Professor at Michigan State University in spring 2008, I have explored a variety of approaches to doing science more openly:

• I blog and tweet about our research.
• All my senior-author papers are open access and were posted as preprints.
• I post all of my single-author grants openly, as soon as I submit them.
• All of our source code is openly available on github and most of our papers are written in public on github.
• I sign almost all of my paper reviews and post many of them (the ones that I remember to post ;) on my blog.

While being open, I achieved several career milestones, including publishing several senior author papers, graduating several doctoral students, giving an invited talk at a Gordon Conference, keynoting several international conferences, having several highly ranked universities recruit me, getting an NIH R01 (and overall bringing in more than $2m in grants while at MSU), getting recruited and hired at an Associate Professor level, gaining tenure, and becoming a Moore Investigator with sustained medium-term funding. There are certainly many more successful people than me out there, but I personally don't know what else I could wish for - my plate is full and I'm pursuing research I believe to be important.

Here are some things I've observed over the years.

It is possible to achieve some measure of traditional success while being open. Grants; publications; tenure. 'nuff said.

Being open has become an increasingly positive driver of my career. Over the years, the benefit of openness has become increasingly obvious. I can't actually point to many negatives - the biggest specific problem I saw was that various people in my administrative chain at MSU didn't understand why I was pursuing open, but it's not clear that that had any negative consequences on my career. Meanwhile, thousands of people are using our software, I have a reasonably large and very enthusiastic blog and Twitter following, a number of papers with lots of citations, more invitations to speak than I can take, and excellent applications for grad student and postdoc positions.

My current research program developed independently of open. I think I would have been doing approximately the same things at a research level whether or not I had been so open about it. (With my Moore award, that's changing in the future.) In particular, some grant awards resulted from connections made through my blog, but most did not.

Open is not the point, and maybe shouldn't be. I would still rather hire an excellent closed scientist than a mediocre open scientist. But I would definitely push hiring an excellent open scientist over an excellent closed scientist. In my case, Davis definitely didn't hire me because I was an open scientist; they hired me because they liked my research and training efforts, and because there was a need for them at Davis. Open simply didn't figure in.

Some people will argue that your time is better spent elsewhere... Of the six or so letters evaluating my tenure case at Davis, I reportedly had one letter that was rather negative and argued that I was not living up to my potential. My chair agreed with my suspicion that one of the reasons for this backhanded compliment was the author of the letter felt I was wasting my time by investing in social media, open science, and reproducible research.

...but people can always find a reason to criticize you. There are very few science faculty who I think are doing everything right, and even fewer to whom I wouldn't offer friendly advice if asked. Certainly, If I wanted to tear someone down I could probably do so. The majority of my tenure letter writers, the entirety of my new department, and (presumably) the rest of the hierarchy at Davis all strongly supported my tenure case.

Most of my colleagues have been very supportive. Virtually none of the active research faculty in my departments at MSU question the need for change, or the utility of open science/access/source/data. However, they do get stuck on the details of how to incentivize, drive, and implement open science. The majority of negative or "WTF?" comments I've received have been from a subset of administrators; my most charitable perspective on this is that administrators are generally much more concerned with policy and incentives than individual faculty, and consequently weight the obstacles higher than the opportunities.

Open science will (eventually) win out in basic research... There are too many reasons for granting agencies to support open science for science to remain closed, absent significant monetary drivers for it to remain closed.

...but there's a fundamental asymmetry in closed vs open that's retarding progress towards open, and scientific progress more broadly. A closed scientist can make use of preprints, open source and open data; an open scientist cannot make use of closed science products until they are published. See: Prisoner's Dilemma. I will have more to say on this over the next years...

By remaining so closed, science is ignoring the role of serendipity in progress. I regularly read articles bemoaning the cost of openness, and I think many of these people are choosing the somewhat certain (but suboptimal) consequences of being closed over the insecurity of the uncertain (but potentially very positive) consequences of being open. As scientific funding becomes every more stringent and competitiveness grows, the advantages of being conservative will evaporate for all but the academic 1%. (As Shirley Tilghman says, for many "who have succeeded in the system, there appears to be little to be gained from messing with it". That's going to change quickly as the data science asteroid hits science, among other things; I expect to see fairly rapid turnover in that 1%.)

Open science needs more practitioners. A few years back I made a conscious decisions to be less of a cheerleader and more of a practitioner. I enjoy doing science, and I enjoy talking about it, and I think the experiments we do in my lab on how to promulgate and accelerate our science through openness are just as important as the policy making, the grant funding, the infrastructure building, and yes, the publicity and cheerleading that is going on. We need it all!

Scientific culture is generational; change will come, but slowly. Most senior scientists (the ones who sit on editorial boards, review panels, and tenure committees) are already overwhelmed and are unlikely to change -- as Mike Eisen says, "the publishing behavior of most established scientists has proven [...] to be beyond amendment." But there's hope; here's a great quote in the Atlantic article, from Virginia Barbour:

"There's a generation of scientists who are running labs and running tenure committees who were brought up on a very different system" said Barbour. "I have huge hopes on the generation that's coming up, because they’re a generation built on openness and availability, and for a lot of things we're talking about it may well take a generational change. It may not be until those people are in positions of authority that things will really change," she said.

Word.

---titus

Thanks to Tracy Teal for reading and commenting on a draft of this post!

The fountain of youth might be just right around the corner, I know here at the labs we’ve reported several different ways to get to that fabled place, but now we have one more. New research shows that seniors received a significant boost to their immune systems when given a drug that targets a genetic signaling […]...

Vanaf vandaag behoren onder andere The Big Lebowski en Saving Private Ryan officieel tot het Amerikaanse nationaal erfgoed. Daarmee zijn Steven Spielberg en de Coen Brothers weer een stukje dichter bij ontsterfelijkheid gekomen.

MakeUseOf: The king of Linux distributions has come a long way since its inception in 2004, so it’s a good idea to go down memory lane and take a look at the journey it has gone through so far.

Arriving with all the trimmings we showed you back in July, cloud storage service Dropbox 3.0 is now stable for Linux, Windows and Mac.

The post Dropbox 3 for Linux Goes Stable With New Qt UI, Setup Wizard first appeared on OMG! Ubuntu!.

“Exome” hasn’t yet entered the normal lexicon, like genome has. Yesterday, for example, I wore my clinical exome T-shirt from Ambry Genetics to Zumba class, and a woman came up and peered at my chest.

“What the heck is that? What are all those letters? And what’s that little gap? A misprint?”

So I explained to the class what an exome is, and that no, my shirt had a small deletion, not a fabric defect.

Within 5 years, though, I think people will know what an exome is, because analyzing it will be as common as a CBC or blood lipid profile is today before visiting the doc. As costs decrease and gene discoveries increase, we’ve reached a tipping point, by definition when “a series of small changes or incidents becomes significant enough to cause a larger, more important change.”

Until “exome” becomes a household world, clever studies are illuminating pioneering applications of the technology.

THE EVOLUTION OF EXOME STUDIES
The exome, the part of the genome that encodes protein, harbors 85% of disease-causing gene variants (we’re not supposed to say “mutation” anymore, but that’s what I mean). Results from several large studies have been published over the past 3 years, but a paper in last week’s Science Translational Medicine from Stephen Kingsmore’s group at Children’s Mercy–Kansas City offers the most promising results yet.

“It heralds the dawning of the new age of clinical genetics. We’ve been waiting for this to come around for 10 to 15 years, and it’s finally here,” says Robert Marion, MD, chief of the division of genetics at The Children’s Hospital at Montefiore and a  developmental pediatrician at the Albert Einstein College of Medicine, about the paper (he’s not part of the team). I devoured his book “Genetic-Rounds: A Doctor’s Encounters in the Field that Revolutionized-Medicine.”

Last month, the Journal of the American Medical Association published findings of two ongoing prospective exome sequencing studies of individuals with symptoms suggesting an inherited condition. A group from UCLA diagnosed 213 of 814 (26%) cases that hadn’t been diagnosed clinically or with single-gene tests or panels. The 26% rose to 31% if parents had their exomes sequenced too. The second report, from Baylor College of Medicine, diagnosed 504 of 2000 (25.2%) patients. Both studies weren’t just children.

I wrote in Medscape about the Baylor team’s interim results presented at the American Society of Human Genetics annual meeting in November 2012. At the same time I pitched the story to a top science magazine, whose editors had no idea what I was talking about. Now lots of magazines run kid exome stories. (I’ve a long history of being too-soon with biotech stories.)

By late 2012 the Baylor team had analyzed 300 exomes, with a 25% diagnosis rate. Most interesting to me, as always, were the cases. They reported several that illustrate two scenarios in which exome sequencing shines: a 2-year-old had Marfan syndrome but not the usual long limbs (“atypical presentation”), and a 9-year-old boy actually had two genetic diseases (“co-morbidities”).

Both boys were treated, once physicians knew what to treat. That also happened with the Children’s Mercy–Kansas City study that achieved a “molecular diagnosis” for 45% of their 100 families. They set up their study to extract a ton of information.

The more recent higher percentage – 45% compared to 25% — might be because the Children’s Mercy group considered only neurodevelopmental disorders (which include developmental delay, autism, and intellectual disability). By comparing newborns in intensive care units to older children who are veterans of multi-year “diagnostic odysseys,” the study revealed the great value of early exome sequencing. And they showed that the technology is cheaper and faster than a gene-by-gene approach.

COSTS CONVERGE
When it comes to genetic testing, more is indeed better. Finally.

It’s been clear that exome and even genome sequencing would eventually cost less than single-gene tests ever since Myriad Genetics began charging $3,200+ for sequencing just the two BRCA genes. The new study homes in on the converging costs.

The investigation began at Children’s Mercy 3 years ago when the Center for Pediatric Genomic Medicine formed. “This is a retrospective look at the first 100 families enrolled in the genome center repository for diagnosis of neurodevelopmental disabilities,” Sarah Soden, MD, a developmental pediatrician and first author of the paper, told me. The 119 kids of those first 100 families had symptoms that didn’t exactly match those of any of the 2,400 or so known single-gene nervous system conditions.

Given my non-existent math skills I appreciate the cut-off at 100 families. Fifteen of the families had children hospitalized in the neonatal or pediatric ICU, and the rest were veterans of the average 7-year trek to diagnosis. The acutely-ill 15% had their genomes sequenced too, because exome sequencing can miss genes buried in GC-rich genome regions, which confound DNA replication enzymes like a stutter disrupts speech. Illumina provided instruments that can sequence genomes in under 50 hours, although analyzing the data takes a few days.

Considering the kids by the direness of their clinical situation proved telling. Genome sequencing diagnosed 11 of 15 (73%) of the families with kids in the ICU, while exome sequencing diagnosed 34 of 85 (40%) of the families with older children. The older kids were less likely to be diagnosed because their years of testing had ruled out many illnesses.

And that previous testing was expensive: on average $19,100 per nonacute family. The researchers estimate that sequencing would be cost-effective at up to $7,640 per family. Plus, there’s no metric for diagnosis of a child that takes days rather than years.

Of the 119 children, 18 had many symptoms because they had two genetic diseases. Five young patients had been receiving the wrong treatment, which was stopped, and 12 were treated correctly following accurate molecular diagnosis. So exome/genome sequencing isn’t only informational, it’s practical.

TWO INTERESTING CASES
My favorite parts of exome and genome sequencing papers are the cases, as well as those I learn about when seeking comments for articles in Medscape. That happened when I talked recently with Dr. Marion, who says exome sequencing is already routine in clinical genetics.

“Our group had been following a family for 6 years, and they’d had every test that could be imagined. High-resolution chromosome testing, FISH, single gene mutation analysis for specific disorders — everything normal. The child had growth retardation, developmental delay, and multiple congenital anomalies,” he told me.

The parents, first cousins, knew that if the condition was inherited, they were carriers and every child would face a 1 in 4 risk. Dr. Marion sent a blood sample from the 6-year-old to have his exome sequenced just when the couple had become pregnant again.

“We found a mutation in a gene we’d considered (H syndrome), but the child didn’t fit completely. We then tested the fetus and unfortunately it was affected,” Dr. Marion continues. The parents ended the pregnancy because they felt they couldn’t care for two children with the condition, and appreciated the information. Only 50 cases of H syndrome have been reported.

Sequencing the exomes of parent-child trios, like in the syndrome H family, is especially informative because if the parents don’t have mutations that could cause the condition, then their child probably has a new and dominant mutation. And that means it’s unlikely to repeat in a sibling.

Dr. Soden describes a child in the Children’s Mercy trial who also “didn’t fit.” He had autism, up to 30 seizures a day, and by age 3 had a tremor and difficulty walking. By 10 he was wheelchair bound. A series of photos in the paper show his initially beautiful face becoming slightly skewed as he grew, a common finding in inherited conditions.

“This patient had gone years without diagnosis and enrolled for whole exome sequencing, with his parents. That identified a mutation in the PIGA gene that has historically been associated with a blood disease, but had very recently been associated with neurologic disability in infants. All patients described had passed away before a year of age, and this kid was 10 at the time,” Dr. Soden says. Pyridoxine (vitamin B6) has helped children with similar syndromes, so maybe it will help him.

TURNING THE TABLES: EXOMES FIRST
The new study shows that exome sequencing can reverse the diagnostic trajectory, going from genotype to phenotype. Dr. Soden loves it. “What’s so exciting about genomic medicine is the practical side. Diagnosing the patient provides answers to families and physicians, and at the same time we can make discoveries.”

But Dr. Marion waxes wistful about handing over the excitement of the hunt to the precise new tool that is exome sequencing.

“The bad part for me, being a cranky old clinical geneticist, is that it takes out of our hands the art of clinical genetics. In the old days we’d look at a child and analyze the information and come up with a differential diagnosis that might include 3 or 4 disorders. We’d go through the list, ruling out diagnoses. Now we recognize a kid has multiple congenital anomalies and send off samples for testing and get answers and try to fit the kid into the identified condition. But it’s definitely worth the benefit to families, siblings and patients.” Dr. Marion has solved many such mysteries in his career. In the photo he’s with a patient, now a teen, whose genetic disease (mucopolysaccharidosis type VI) he could name just by looking at her, followed up with genetic testing of course.

Although studies from Baylor, UCLA, Children’s Mercy, the NIH’s Undiagnosed Diseases Program, and others have certainly validated exome (and back-up genome) sequencing, it might be a few more years until the neighborhood nurse practitioner or urgent care physician pops a patient’s sample into a sequencer before venturing a diagnosis. “People trained more than 5 to 10 years ago have no idea how to use this information and will have to be retrained to do so,” says Dr. Marion. Medical schools are educating future physicians  in genomics.

Dr. Soden expects to see exome sequencing enter subspecialty care first, and Children’s Mercy is helping with the education effort. “We have a genomic medicine master class where physicians spend a week with us and really learn what genome medicine is all about. Broad applications may be down the road, but in a center like ours we’re going to see it faster,“ she says. And Illumina holds regular workshops for health care providers to have their own genomes sequenced and interpreted, to learn the potential for diagnosing their patients.

Dr. Marion suggests another way that exome sequencing may nudge into the medical mainstream. “There’s going to be pressure on state labs to offer this in newborns. It will come from industry, because they will market directly to pregnant women: ‘Send blood from the newborn and we’ll predict the child’s health for the rest of his or her life.’ State labs will then say, ‘we have a 2-tiered system in which families that can pay get better screening’ and state health departments will say ‘we have to fix that.’ Babies will go home from the hospital and pediatricians will get readouts from the state lab of every polymorphism and mutation and predict what the person’s health will be like.”

It’ll be like cord blood storage.

But Kevin Davies, PhD, author of “The $1,000 Genome” and publisher of Chemical & Engineering News, tempers exome excitement.

“Even newborn genome screening becomes more and more plausible as the cost of sequencing continues to drop, we still await definitive evidence that this makes medical sense. I’m thrilled by the wondrous stories of diagnostic odysseys ending thanks to genome screening, but we need more than intermittent anecdotal reports to judge the clinical benefits. Trials are underway to address this key question. I also think the genetics community has a massive task ahead to communicate the benefits of genome screening to a general public that is still nervous, skeptical and even afraid of losing their genomic privacy.”

Thoughts?

The post Sequencing Kids’ Exomes: More Good News appeared first on DNA Science Blog.

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PLoS One. 2014;9(12):e114693

Authors: Tolle F, Wilke J, Wengel J, Mayer G

Abstract
The selection of nucleic acid aptamers is an increasingly important approach to generate specific ligands binding to virtually any molecule of choice. However, selection-inherent amplification procedures are prone to artificial by-product formation that prohibits the enrichment of target-recognizing aptamers. Little is known about the formation of such by-products when employing nucleic acid libraries as templates. We report on the formation of two different forms of by-products, named ladder- and non-ladder-type observed during repetitive amplification in the course of in vitro selection experiments. Based on sequence information and the amplification behaviour of defined enriched nucleic acid molecules we suppose a molecular mechanism through which these amplification by-products are built. Better understanding of these mechanisms might help to find solutions minimizing by-product formation and improving the success rate of aptamer selection.

PMID: 25490402 [PubMed - as supplied by publisher]

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