Daily Archives: July 25, 2017

July 25, 2017 by Marieke Oudelaar, Oxford Science Blog Abstract illustration of self-interacting domains and their boundaries. Hanssen and colleagues show that removal of such boundaries extends the self interacting domains to include other genes which are inappropriately activated. Credit: Oxford Science Blog

Our bodies are composed of trillions of cells, each with its own job. Cells in our stomach help digest our food, while cells in our eyes detect light, and our immune cells kill off bugs. To be able to perform these specific jobs, every cell needs a different set of tools, which are formed by the collection of proteins that a cell produces. The instructions for these proteins are written in the approximately 20,000 genes in our DNA.

Despite all these different functions and the need for different tools, all our cells contain the exact same DNA sequence. But one central question remains unanswered how does a cell know which combination of the 20,000 genes it should activate to produce its specific toolkit?

The answer to this question may be found in the pieces of DNA that lie between our protein-producing genes. Although our cells contain a lot of DNA, only a small part of this is actually composed of genes. We don't really understand the function of most of this other sequence, but we do know that some of it has a function in regulating the activity of genes. An important class of such regulatory DNA sequences are the enhancers, which act as switches that can turn genes on in the cells where they are required.

However, we still don't understand how these enhancers know which genes should be activated in which cells. It is becoming clear that the way DNA is folded inside the cell is a crucial factor, as enhancers need to be able to interact physically with genes in order to activate them. It is important to realise that our cells contain an enormous amount of DNA approximately two meters! which is compacted in a very complex structure to allow it to fit into our tiny cells. The long strings of DNA are folded into domains, which cluster together to form larger domains, creating an intricate hierarchical structure. This domain organisation prevents DNA from tangling together like it would if it were an unwound ball of wool, and allows specific domains to be unwound and used when they are needed.

Researchers have identified key proteins that appear to define and help organise this domain structure. One such protein is called CTCF, which sticks to a specific sequence of DNA that is frequently found at the boundaries of these domains. To explore the function of these CTCF boundaries in more detail and to investigate what role they may play in connecting enhancers to the right genes, our team studied the domain that contains the -globin genes, which produce the haemoglobin that our red blood cells use to circulate oxygen in our bodies.

Firstly, as expected from CTCF's role in defining boundaries, we showed that CTCF boundaries help organise the -globin genes into a specific domain structure within red blood cells. This allows the enhancers to physically interact with and switch on the -globin genes in this specific cell type. We then used the gene editing technology of CRISPR/Cas9 to snip out the DNA sequences that normally bind CTCF, and found that the boundaries in these edited cells become blurred and the domain loses its specific shape. The -globin enhancers now not only activate the -globin genes, but cross the domain boundaries and switch on genes in the neighbouring domain.

This study provides new insights into the contribution of CTCF in helping define these domain boundaries to help organise our DNA and restrict the regulation of gene activity within the cells where it is needed. This is an important finding that could explain the misregulation of gene activity that contributes to many diseases. For example in cancer, mutations of these boundary sequences in our DNA could lead to inappropriate activation of the genes that drive tumour growth.

The full study, 'Tissue-specific CTCFcohesin-mediated chromatin architecture delimits enhancer interactions and function in vivo', can be read in the journal Nature Cell Biology.

Explore further: New study helps solve a great mystery in the organization of our DNA

More information: Lars L. P. Hanssen et al. Tissue-specific CTCFcohesin-mediated chromatin architecture delimits enhancer interactions and function in vivo, Nature Cell Biology (2017). DOI: 10.1038/ncb3573

After decades of research aiming to understand how DNA is organized in human cells, scientists at the Gladstone Institutes have shed new light on this mysterious field by discovering how a key protein helps control gene organization.

It seems like a feat of magic. Human DNA, if stretched out into one, long spaghetti-like strand, would measure 2 meters (six feet) long. And yet, all of our DNA is compacted more than 10,000 times to fit inside a single cell. ...

Twenty years ago, the protein complex cohesin was first described by researchers at the IMP. They found that its shape strikingly corresponds to its function: when a cell divides, the ring-shaped structure of cohesin keeps ...

Scientists at the Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) have discovered that the transcriptional regulator CTCF plays an essential role in antibody production. The study, led by Dr. Almudena ...

Within almost every human cell is a nucleus six microns in diameterabout one 300th of a human hair's widththat is filled with roughly three meters of DNA. As the instructions for all cell processes, the DNA must be ...

In cells, DNA is transcribed into RNAs that provide the molecular recipe for cells to make proteins. Most of the genome is transcribed into RNA, but only a small proportion of RNAs are actually from the protein-coding regions ...

Researchers from Monash University's Biomedicine Discovery Institute have helped solve the mystery of how emus became flightless, identifying a gene involved in the development and evolution of bird wings.

Researchers at the University of California San Diego have found that microbial species living on cheese have transferred thousands of genes between each other. They also identified regional hotspots where such exchanges ...

A team of scientists from the Kunming Institute of Botany in China and the Max Planck Institute for Chemical Ecology in Jena has discovered that parasitic plants of the genus Cuscuta (dodder) not only deplete nutrients from ...

Our bodies are composed of trillions of cells, each with its own job. Cells in our stomach help digest our food, while cells in our eyes detect light, and our immune cells kill off bugs. To be able to perform these specific ...

Humpback whales learn songs in segments like the verses of a human song and can remix them, a new study involving University of Queensland research has found.

New research from Australia and Sweden has shown how a dragonfly's brain anticipates the movement of its prey, enabling it to hunt successfully. This knowledge could lead to innovations in fields such as robot vision.

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Breaking boundaries in our DNA - Phys.Org

Recently, a DNA test appeared with a premise so far-fetched that its fate was profane and merciless ridicule. Soccer Genomics offers personalized, DNA-based training regimens to young players, and its goofy ad went viral amid internet outrage. It is, alas, only the most recent example of the growing field of sometimes-dubious lifestyle DNA tests.

Its a jungle out there, says Eric Topol, a genomicist at the Scripps Research Institute. As DNA sequencing has gotten cheaper, a number of small companies have looked to fill niches around the two big consumer DNA-testing behemoths, 23andMe and AncestryDNA. These newer tests usually dont offer disease-risk information, which would bring the scrutiny of the FDA, but they skirt the boundaries by focusing on nutrition and fitness. Sometimes, they just aim for fun, like a DNA test for wine preferences. Ive likened these lifestyle tests to horoscopesvague, occasionally informative, sometimes amusing.

The DNA Test as Horoscope

Into this jungle now comes a new player with an impressive pedigree. Helix is a new venture from private equity firms and Illumina, the company that makes most of the DNA-sequencing machines in the United States. 23andMe and AncestryDNA use Illuminas machines, as do most research labs. On Monday, after two years of anticipation since the initial announcement, Helix officially launched a marketplace for products based on DNA tests.

Helix has an innovative business model. Most DNA-testing companies only look for a set number of variants in DNA. Helix sequences all of the expressed genes in the bodya technique called whole-exome sequencing. This is very expensive, but Helix subsidizes most of the cost aside from one-time $80 sequencing fee. Then, it has third-party developers create products focused on specific genetic information. The products available now include everything from a National Geographic ancestry test, to personalized diet coaching, to a custom DNA-based scarf. You pay for each individual product, and the prices range from under $100 to a couple hundred.

The companys CEO, Robin Thurston, likens Helix to the Apple app store, which is a very deliberate comparison. Unlike Google, which takes a fairly hands-off approach to apps in the Google Play store, Apple individually reviews every app. Helix has a 14-person team that reviews the science behind each of the products they feature, too, which is how the company plans to differentiate itself from the world of pseudoscientific DNA tests. Hopefully it will translate into us telling consumers that being on the Helix platform is different, says Thurston. You can trust Helix in the long run. (Just to be clear, Soccer Genomics has nothing to do with Helix.)

Oleksandr Savsunenko, the CEO of Titanovo, whose DNA Diet Coach product was slated to be sold on the Helix platform, gave me a rundown of Helixs scientific review process. He says his company had originally submitted 200 scientific studies to back up the recommendations in their product60 to 70 percent of which did not meet Helixs standards. That includes a 68-person study that an earlier version of Titanovos product used to recommend cloudy apple juice for fat loss. Of course I was disappointed when they started to say this is bad, this is bad, this is bad, but in the end the product we have obtained is really strong, says Savsunenko. Titanovo is now discontinuing the earlier product, called DNA Lifestyle Coach, to focus exclusively on its DNA Diet Coach product through Helix.

(Sometime after the interview with Savsunenko, a Helix spokesperson said DNA Diet Coach would no longer be included in Mondays marketplace launch: Titanovos beta testing identified some areas that need fine-tuning before broad release and hence decided to hold off launching on Monday.)

Products currently available through Helix have gotten criticism though, especially a DNA test for wine preference, made by a company called Vinome. The gist of the skepticism goes like this: DNA can tell you what a person can taste, but it cant really tell you if that person will like it. Thurston says he thinks Vinome meets their scientific standard because the company makes clear that their taste algorithm is based on more than DNA. Vinome also uses an questionnaire, and sure, that can get at your personal taste preferences.

At that point, though, how much value is the DNA test itself adding? Even when there is solid evidence linking a gene to a predisposition, the relationship is probabilistic. Its more like you are 30 percent more likely to grow blue hair than you will definitely grow blue hair. Genes and the environment interact to affect health outcomes. At least some of the products on Helixs platform seem to resolve this ambiguity by basing advice on things that have nothing to do with DNA.

Another partner, EverlyWell, sells a number of tests for proteins and fats in the blood and breast milk. It is now selling through Helix a plus version of its food-sensitivity, metabolism, and breast-milk tests that also looks at DNA. If you already have the blood test that reveals what your body is doing now, whats the additional value of the DNA test that reveals what your body could potentially be doing?

My perspective is that genetic data is valuable to give you a baseline, says EverlyWells CEO, Julia Cheek. She points out that someone who has low magnesium levels might want to know they have a predisposition to low magnesium so they can adjust their diet. Alternatively, one or two low magnesium tests might prompt the same diet adjustments.

On one hand, this strategy of integrating DNA tests with other sources of information allows Helixs partners to hew closer to the established science of genetics. On the other, DNA sequencing is obviously the real draw of Helixs marketplace, and whole exome sequencing is orders of magnitude more expensive than a questionnaire or blood test.

Topol, who follows genomic medicine closely, is skeptical that current direct-to-consumer DNA tests have much utility for healthy people. Helix was created to help Illumina sell more DNA-sequencing machines by growing the space for consumer tests. And if these new tests dont actually demonstrate the value of DNA sequencing, Topol says it could lead to backlash. It could lead to a lesser opinion of genomics, he says. Im afraid of that as well.

Since Helix was announced in 2015 to fanfare and a $100 million investment, its unusual business model has been the subject of much speculation. Now its marketplace is finally here, and you can decide for yourself.

Excerpt from:
How Do You Know When a DNA Test Is BS? - The Atlantic

July 25, 2017 Credit: Cancer Research UK

Inhibitors of the DNA repair enzyme poly (ADP-ribose) polymerase (PARP) kill BRCA-deficient tumours, and have significant activity in single agent and combination therapy. Professor Herbie Newell, of Newcastle University (with Hilary Calvert, Nicola Curtin, Barbara Durkacz, Bernard Golding, Roger Griffin and Ruth Plummer), was part of the team responsible for making the PARP inhibitor rucaparib.

In December 2016, the FDA fast-tracked rucaparib (Rubraca) into the clinic to treat women with advanced ovarian cancer who have received two or more prior chemotherapies and whose tumours have a BRCA gene mutation. Here Herbie explains the start of the story.

"In the late 1980s, temozolomide, a DNA-methylating agent, was the drug of the moment. We reasoned that a PARP inhibitor should make temozolomide, as well as some other drugs and ionising radiation, more active by inhibiting DNA repair. There was lots of scepticism from pharma as they said a PARP inhibitor wouldn't be a standalone drug and would increase toxicity; consequently there was no major commercial interest. Nevertheless, in a collaboration between the Cancer Research Unit and the School of Chemistry, we established a drug discovery group in Newcastle in 1990 to make and test PARP inhibitors. Rucaparib was subsequently identified in collaboration with Agouron and Pfizer GRD, and is now being developed and marketed by Clovis Oncology.

The critical breakthrough for PARP inhibitors was the recognition of single agent activity in cells defective for homologous recombination repair, as found in BRCA-deficient tumours (reported independently in Nature in 2005 by two UK teams). With the help of the CRUK Centre for Drug Development, rucaparib went into phase 1 trials in 2003, and went on to stimulate high levels of commercial interest in PARP inhibitors in multiple companies. The FDA approved rucaparib in December 2016, having previously identified it as a breakthrough drug."

In 2003, Professor Ruth Plummer, now the chair of the New Agents Committee, wrote the prescription for the first patient in the world to be treated by rucaparib, the first ever cancer patient to be treated by a PARP inhibitor. "It was always clear we had a drug that did something. We have some patients whose scans are currently clear and have been for some years now. It's fantastic really great. The patient from our first trial doesn't even come to clinic now he's been discharged!"

Susan Ross: a patient's perspective on rucaparib

Susan Ross from Whitley Bay in Tyne and Wear was first diagnosed with ovarian cancer with a BRCA gene mutation 10 years ago. Here Susan explains her experience of being part of a clinical trial of rucaparib (Rubraca) at the Northern Centre for Cancer Care in Newcastle.

"Early in 2015 I was told the ovarian cancer had returned and unfortunately an operation was not possible. I was facing the prospect of having chemotherapy again. Previously I had had three rounds of chemotherapy as well as four operations, so knowing what treatment was going to entail, my heart sank. I thought 'Can I go through this again?' and 'Do I really want to go through this again?'

My consultant organised a BRCA gene mutation test, which showed I was a BRCA2 mutation carrier. I was then offered the opportunity to go on a clinical trial of this new treatment rucaparib, and I grabbed it with both hands.

My care is overseen by Dr Yvette Drew, and I attend the unit every three weeks to be monitored, and discuss any worries with the nurses and doctors. I've been taking rucaparib as part of this trial since December 2015 and it's the best I've felt in 10 years, both physically and mentally. With the help and support of all the staff, it feels like I've got my life back.

Being part of a clinical trial means I'm monitored very closely. I am so thankful for all those who have been involved in the development of rucaparib and for making this clinical trial possible. Being part of a clinical trial is an opportunity to help make a difference, help cancer patients in the future and hopefully find a cure for this awful disease. I'd do it again in an instant."

Explore further: Ovarian cancer patients get access to life-extending drug

Journal reference: Nature

Provided by: Cancer Research UK

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Rucaparibtargeting DNA repair and a patient's perpective - Medical Xpress

Microsoft has taken quite an interest in the potential of DNA in computing over the years. Last year Microsoft researchers set a record for DNA data storage.(Itsrecord was beaten this year).

Now Microsoft is turning its attention to the other half of DNA computing, the processor. Researchers at Microsoft have teamed up with scientists at the University of Washington to find a way toward creating super fast computations using DNA molecules.

In research described in the journal Nature Nanotechnology, the scientists have developed a method for spatially organizing DNA molecules in regular intervals on a DNA origami surface. That surface is essentially a bunch of DNA strands that have been folded in ways similiar to the techniques of the Japanese art of paper folding. The results offer a new approach to creating DNA logic gates and and the interconnects that link them.

These nanoscale computational circuits are made from synthetic DNA, dubbbed DNA dominocircuits. These are made from several different strands of synthetic DNA. For example a transmission line consists of hairpin loops of DNA strands with one end afixed to the origami surface. When inputand fuel DNA strands are poured on, they break the loops in the transmission line strands and force them to bend over and link up with their neighbor strandone after another like dominoes fallinguntil they form a line of DNA on the substrate.

They used these transmission lines and other structures to make elementary AND and OR gates with two inputs. The researchers were able to to make more complex circuits by linking these elementary gates together.

The molecular components of the device are spatially positioned in close proximity to one another, explained Andrew Phillips, the head of biological computation group at Microsoft, in an e-mail interview with IEEE Spectrum. In our case, the molecular components are DNA strands, and they are fixed in place by attaching them to a DNA origami wafer, which acts as a sort of molecular breadboard.

In the past, most computational DNA devices consisted mainly of freely-diffusing DNA strands in a chemical soup. Since all of the strands are freely diffusing, they can bump into each other at random and interfere with each other.

In our case, the components of the devices are positioned closeto each other and held in place by a molecular breadboard, such that they are much more likely to interact with their immediate neighbors, and much less likely to interact with other components that are further away, which substantially reduces interference, said Phillips.

Our devices do still rely on the presence of a diffusible fuel molecule, so they are not fully-localized, but since most of the components are localized the computation is still significantly faster than a system in which all of the components are feely diffusing, said Phillips.

All of this close positioning leads to molecular scale computation that is much faster than the relatively slow process of random diffusionminutes instead of hours. In the research, the scientists measured these devices computing a logical AND using three molecular inputs in seven minutes, compared to four hours for an equivalent DNA circuit with diffusible components.

The production of these devices could be fairly scalable, because they leverage self-assembly, in which the molecules organize themselves. The devices are designed to be integrated within a DNA breadboard and we rely on the self-assembly of the breadboard to precisely position the interacting DNA components, said Phillips.

The next step for the researchers will be to investigate how to build larger circuitsby increasing the size of the DNA breadboard. This will require advances in DNA origami techniques.

Phillips added: In addition, we plan to interface these devices with disease biomarkers such as RNA, so that computational logic can be used to accurately diagnose the presence of certain viruses or cancers, initially in blood samples and, ultimately, inside a living cell.

IEEE Spectrums nanotechnology blog, featuring news and analysis about the development, applications, and future of science and technology at the nanoscale.

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DNA Logic Gets Much Faster - IEEE Spectrum

DNA testing is not new to consumers, but its a one-shot deal. You send in your sample, then you get to see ancestry and health data provided by the company you chose to use for testing. Some new insights might be added over time, but theres not much else you can do with that genetic data. A startup called Helix is counting on people being curious enough to drop cash in its DNA app store on a regular basis. The initial testing costs $80, and after that you can buy the applications you want.

Helix uses a type of genetic testing called DNA sequencing. Other companies like 23andme are using the far simpler genotyping; Helix is actually finding the pattern of nucleic acids (using flow cells like the one above) in your DNA for around 20,000 different genes, known as the exome. A genotyping test only tells you which variant you have of specific genes, so a full sequence generates about 100 times as much data. Helix is taking this approach because the company is not deciding what sort of data to show users. Instead, thats all up to third-parties that decide to sell DNA apps to people in the Helix store, and the full sequence includes more precision.

For consumers, the testing process is much the same as other services. You spit in a tube, send it off, and your results are available in a few weeks. The kit itself is only $80, whereas many other services cost around $200 for a testing kit. However, Helix expects people will buy at least a few DNA apps. It appears right now the only way to buy the testing kit is in combination with at least one app.

The apps come in various categories like family, fitness, and entertainment. These apps will be a bit more expensive than the ones for your phone, though. A company called Institome will tell you about your Neanderthal DNA and what that means for your health with its $30 app. Meanwhile, National Geographic had a population genetics app. This app is one of the more expensive at $70. You can also get a personalized scarf based on your genetic code for the low, low price of $150. It only costs a little less ($125) to find out what your genetic code says about your cholesterol levels.

Thats just a samplingHelix is launching with about 30 DNA apps for your perusal. Although, buying even a few of them will probably end up costing you quite a bit more than the genetic tests you can get from other providers. Still, Helix hopes youll come back over time and buy more DNA apps and form a long-term relationship with your genetic code. That would be a profitable relationship for Helix.

Now read: How DNA sequencing works

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The First App Store For Your DNA Is Here - ExtremeTech

Scientists have known for some time that abnormal DNA repetitions in the C9orf72 gene contribute to neuron death in ALS and frontotemporal dementia.

Now they have learned how it happens: The anomalies leave DNA susceptible to damage, prompting a cell repair mechanism to become over-active. That hyperactivity cause neuron deaths.

The study,C9orf72 expansion disrupts ATM-mediated chromosomal break repair, waspublished in the Nature Neuroscience.

Too many DNA repetitions in theC9orf72 gene are the most common genetic cause for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, the researchers wrote. Growing evidence suggests that C9orf72 repeat expansions also contribute to a wide spectrum of neurodegenerative diseases, such as Alzheimers, Huntingtons, multiple sclerosis, Parkinsons disease and cerebellar ataxias.

The team wanted to learn how the DNA expansions in the C9orf72 gene trigger neuron death in ALS and frontotemporal dementia. Studying neurons in human tissue and rats, theydiscovered that the expansions interact with RNA molecules to form what are called R-loops.

R-loops make DNA more susceptible to breaking. This susceptibility triggers the excessive activation of a cell repair mechanism called autophagy.

Autophagy is useful to cells that need to eliminate and recycle old or faulty molecules or components. But if it is too active, cells end up eating themselves, leading to neuron death.

The researchers were able to prevent neuron damage by fine-tuning the activity of DNA repair mechanisms.

We were able to shut down the out-of-control degradation process, which runs down the cells ability to fix genomic breaks, Sherif El-Khamisy, the studys co-senior author, said in a news release written by Clara Rodrguez Fernndez. Even though the DNA was still damaged, the cells were able to cope and did not die.

By learning how DNA repetitions cause neuron death, the team believes it has helped thescientific community take a step toward understanding the mechanisms underlying the development of movement neuron diseases such as ALS.

More research needs to be done, but its possible that this newly discovered mechanism contributes to the death of nerve cells in people suffering from diseases such as Alzheimers, Parkinsons and during the aging process, El-Khamisy said. Im really excited [that], if we modulate this degradation process, we can preserve our DNA repair toolkit and take away the pathology, the cell death.

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Scientists Learn How Abnormal DNA Repetitions in a Gene Cause Neuron Death In ALS - ALS News Today