Monthly Archives: April 2017

Octopus, squid, and cuttlefish are famous for engaging in complex behavior, from unlocking an aquarium tank and escaping to instantaneous skin camouflage to hide from predators. A new study suggests their evolutionary path to neural sophistication includes a novel mechanism: Prolific RNA editing at the expense of evolution in their genomic DNA.

The study, led by Joshua J.C. Rosenthal of the Marine Biological Laboratory (MBL), Woods Hole and Eli Eisenberg and Noa Liscovitch-Brauer of Tel Aviv University, is published this week in Cell.

The research builds on the scientists' prior discovery that squid display an extraordinarily high rate of editing in coding regions of their RNA - particularly in nervous system cells - which has the effect of diversifying the proteins that the cells can produce. (More than 60 percent of RNA transcripts in the squid brain are recoded by editing, while in humans or fruit flies, only a fraction of 1 percent of their RNAs have a recoding event.)

In the present study, the scientists found similarly high levels of RNA editing in three other "smart" cephalopod species (two octopus and one cuttlefish) and identified tens of thousands of evolutionarily conserved RNA recoding sites in this class of cephalopods, called coleoid. Editing is especially enriched in the coleoid nervous system, they found, affecting proteins that are the key players in neural excitability and neuronal morphology.

In contrast, RNA editing in the more primitive cephalopod Nautilus and in the mollusk Aplysia occurs at orders of magnitude lower levels than in the coleoids, they found. "This shows that high levels of RNA editing is not generally a molluscan thing; it's an invention of the coleoid cephalopods," Rosenthal says.

In mammals, very few RNA editing sites are conserved; they are not thought to be under natural selection. "There is something fundamentally different going on in these cephalopods where many of the editing events are highly conserved and show clear signs of selection," Rosenthal says.

The scientists also discovered a striking trade-off between high levels of RNA recoding and genomic evolution in these cephalopods. The most common form of RNA editing is carried out by ADAR enzymes, which require large structures (dsRNA) flanking the editing sites.

These structures, which can span hundreds of nucleotides, are conserved in the coleoid genome along with the editing sites themselves. The genetic mutation rate in these flanking regions is severely depressed, the team reported.

"The conclusion here is that in order to maintain this flexibility to edit RNA, the coleoids have had to give up the ability to evolve in the surrounding regions - a lot," Rosenthal says. "Mutation is usually thought of as the currency of natural selection, and these animals are suppressing that to maintain recoding flexibility at the RNA level."

Rosenthal and colleagues at the MBL are currently developing genetically tractable cephalopod model systems to explore the mechanisms and functional consequences of their prolific RNA editing.

"When do they turn it on, and under what environmental influences? It could be something as simple as temperature changes or as complicated as experience, a form of memory," he says.

Liscovitch-Brauer et al (2017) Trade-off between transcriptome plasticity and genome evolution in cephalopods. Cell DOI: 10.1016/j.cell.2017.03.025

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'Smart' cephalopods trade off genome evolution for prolific RNA editing - Space Daily

Mapping a prostate tumour for the first time was a long, slow and difficult process

In a world first, Australian researchers have mapped the entire genome of a prostate tumour, providing a new lens through which to view this disease.

They mapped the most commonly diagnosed grade of prostate cancer. It was a tumour that scored 7 on the standard Gleason score and is clinically known to be highly unpredictable.

The mapping process, which useda biopsy sample taken from a patient, was long and slow.

It required the researchers to get DNA out of tissue without destroying it. Previously this had not been achieved in humans.

The results of their study of this single tumour are published in Oncotarget,a journal aimed at doctors and scientists.

Prostate cancer is the most commonly diagnosed cancer in Australian men and this work is proof of principle that next-generation mapping can provide insights into its subtypes.

The information gained by such mapping could be used to characterise an individual's tumour and reveal previously unrecognised information so treatment can be more targeted.

Conducted at Sydney's Garvan Institute of Medical Research, the mapping revealed previously undetected levels of DNA changes linked to the disease.

It uncovered 10 times more large-scale DNA rearrangements than have previously been detected in prostate cancer and identified 15 new potential drivers of this cancer.

"Although we've been researching prostate cancer for many years, very little is understood about what drives these tumours," says study leader, Professor Vanessa Hayes, Head of Garvan's Human Comparative and Prostate Cancer Genomics Laboratory.

"One of the biggest clinical challenges is distinguishing which cancers are going to spread and become life-threatening, and which patients could be spared harsh treatment they might not need.

"To have any hope of targeting treatment in this way, we first need to understand the genetic drivers of each individual tumour. "

The researchers used new mapping technology in tandem with whole genome sequencing to uncover the most complete picture to date of the prostate cancer genomic landscape.

While genomic sequencing is a close up exercise which reads each letter of a genetic code, mapping takes a few steps back and provides a bigger picture. It gives a bird's eye view, orientating the sequence in its context.

She says prostate cancer has unique features.

"From previous genome sequencing studies we know it has very few small genetic changes, but rather, is more likely driven by large complex rearrangements of DNA within the genome. "

"This is different to most cancers, which are driven by small DNA mutations in a number of key genes."

"Until now, we had no way of observing these DNA rearrangements or structural variants in prostate cancer."

Professor Hayes says the synergy with whole genome sequencing was very important.

"We could not have done this with sequencing technology alone. Whole genome sequencing is invaluable in identifying small DNA mutations, but it may not detect when a gene has been completely deleted, transferred to another chromosome, or multiplied many times - which is what we see here."

"Using next-generation mapping, we saw huge amounts of large-scale rearrangements, and genome sequencing then enabled us to identify the genes affected by these rearrangements."

"Several cancer-promoting genes were multiplied many times, increasing their potency, and potentially driving this prostate tumour."

"Whole genome sequencing opened a huge number of doors for our understanding of prostate cancer next-generation mapping just doubled the number of doors," says Prof Hayes.

Her team was first in Australia to obtain next-generation mapping technology, and first in the world to apply it to understanding an individual tumour.

"I believe that in the future this technology will complement next generation sequencing as a key to personalised medicine for prostate cancer."

The study was performed as part of the Prostate Cancer Metastasis (ProMis) program, an Australian-led international initiative. Since it began, mapping technology has improved and is now faster.

The Garvan team has since mapped a further four tumours which will be the subject of another paper. Professor Hayes says this new work confirms the significance of these large DNA changes detected in the first study.

When it comes to mapping technology for cancer in humans, Australia is a world leader.

"This is a very promising research breakthrough," says Professor Allan Spigelman, Director of Cancer Genetics at Sydney's St Vincents' Hospital.

"In time, it will complement some current treatment options that are based on genetic testing of blood samples. Using prostate cancer tissue genetic analysis may hopefully lead to even more precise and targeted treatments."

Professor Spigelman, who conducts cancer genetics services across NSW, say at present men with prostate cancer can have genetic testing to see if they have a good chance of responding to particular medication.

"Current cancer gene testing of blood samples target DNA repair genes such as BRCA2."

"Detection of a mutation here opens up novel drug treatments to which those carrying mutations in that gene respond best."

*Jill Margo is an adjunct associate professor at the University of NSW

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Australian researchers first to map entire prostate cancer genome - The Australian Financial Review

April 11, 2017

In recent years, science and the media have been buzzing with the term CRISPR. From speculation around reviving the woolly mammoth to promises of distant cures for cancer, the unproven potential for this genome editing tool has been stretched far and wide.

It's therefore no surprise that CRISPR has piqued the interest of many scientists and the public alike. So in this post we'll be exploring this innovation by answering some of the most common questions that pop up.

1. What is CRISPR?

CRISPR, or more precisely CRISPR-Cas9, is a molecular toolkit that scientists have developed to make precise edits to DNA our code of life. It was actually borrowed from bacteria, where in its original form it was used to protect microbes from attack by viruses.

2. How does it work?

The system is made up of 2 parts. The first is a strand of RNA DNA's chemical cousin which matches up with a region of DNA inside a cell that a scientist may want to target. This then acts as a shepherd to guide the second component a pair of 'molecular scissors' called Cas9 to the site of action, where it makes a snip across the DNA.

3. What can it do?

Once scientists have chopped their target region of DNA, a number of possibilities are opened up: they could disrupt the function of a particular gene, cut it out, make precise spelling changes to the DNA sequence, or slip in an entirely new gene. It's an extremely precise method of genetic modification.

4. Is it worth the hype?

CRISPR allows scientists to edit DNA in a way that's quicker, cheaper and more accurate than ever before. So it's an exciting development that's opening up new possibilities for scientists across the globe working in a number of different fields. But looking beyond the lab it's still very early days. Ideas for how the technology might be adapted to treat diseases are only just beginning to be considered. So it's important to be wary of premature promises made in the media when there is a lot of research to be done, and risks to be measured.

5. What are the concerns over safety as the tech develops?

Although CRISPR is hailed for its precision, concerns lie with what might happen if it misses its target, which it can. DNA is complex and many genes are intricately linked, so it could well be that modifying one gene has the scientists' desired outcome, but also inadvertently affects the function of other genes and molecules.

DNA is also written using an alphabet of just 4 chemical letters, meaning stretches of DNA that look very similar might both be targeted by CRISPR, which again may cause unintended effects. So scientists need to thoroughly scrutinise the consequences of their edits in these early lab development stages to ensure that they're not accidentally disrupting something important, which might not immediately be apparent.

6. How is it used in cancer research?

Cancer is caused by faulty genes, so recreating these in the lab with CRISPR allows researchers to explore the underlying biology of the disease and understand more about how it develops. That's what our scientists are doing for a type of brain tumour called glioblastoma.

Tweaking genes in cancer cells could also help identify those that are essential for the cells' survival, and therefore could be targeted with new treatments. On top of that, scientists could use the technique to explore ways that cancer cells become resistant to drugs, potentially opening up new ways to stop this from happening.

7. Could it help cure cancers?

Cancer isn't a single disease in fact, it's a group of more than 200 unique diseases so it's unlikely that any single treatment could act as a one-size-fits-all panacea. That includes CRISPR. And while there's no evidence yet that CRISPR can be used to treat cancer, it's possible that as the technology develops it could be used in treatments in some way. The most promising idea so far is to use it in cell therapy, where patients' own immune cells would be taken out and tweaked, giving them a 'power-up' so that they can better attack the cancer when given back to the patient. But this idea still needs testing in clinical trials.

8. What can't it do (yet)?

With the advent of gene editing came the idea that this technique could potentially be used to correct faulty, disease-causing genes in people, therefore curing their illness. This remains a long way off, and would be an incredibly complex area to study, but it's not impossible. Much more research is needed first and where the desired edits might involve correcting inherited faulty genes, there are huge ethical questions to address, particularly around editing human embryos. These kinds of public debates, discussions and expert recommendations are already underway.

9. So, where are we now?

In the context of cancer, CRISPR is beginning to move from lab bench to bedside. Last year scientists in China began trialling CRISPR-edited immune cells in lung cancer patients, where they'd snipped out a gene that produces a stop signal, called PD-1, for the immune system. They plan to test if this edit will boost the cells' cancer-killing abilities, but we won't know the results for a while.

A team in the US is also nipping at their heels, launching a similar trial this year but for several different cancers.

These could mark the beginnings of a new wave of cancer treatment. And those clinical trials will hopefully provide some early answers.

Whether or not CRISPR will ultimately match its promise is unknown. But it's an exciting time for science.

Of that there is no doubt.

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

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

Researchers from Memorial Sloan Kettering Cancer Center (MSK) have harnessed the power of CRISPR/Cas9 to create more-potent chimeric antigen receptor (CAR) T cells that enhance tumor rejection in mice. The unexpected findings, ...

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

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

The gene-editing tool called CRISPR that can quickly and cleanly remove specific pieces of DNA has revolutionized biotechnology. Many researchers believe the technique could end thousands of ailments. So what's needed to ...

Genome editing using CRISPR/Cas9 "gene scissors" is a powerful tool for biological discovery and for identifying novel drug targets. In pooled CRISPR screens, a large number of cells are edited simultaneously using CRISPR ...

A University of Wyoming weed scientistfrustrated with the noise surrounding genetically modified organisms and glyphosate useanalyzed data to see for himself if biotech adoption has had a negative or positive effect ...

How can you tell if an individual is expressing sexual interest? With males, it's usually quite obvious and can be anything from lavish theatrical displays of song and dance to downright relentless insistence. Females, on ...

Researchers at the University of Alberta have demystified the way that polar bears search for their typical prey of ringed seals. The answer, it turns out, is simple: they follow their nose using the power of wind.

Asian elephants are able to recognise their bodies as obstacles to success in problem-solving, further strengthening evidence of their intelligence and self-awareness, according to a new study from the University of Cambridge.

Millions of years before humans discovered agriculture, vast farming systems were thriving beneath the surface of the Earth. The subterranean farms, which produced various types of fungi, were cultivated and maintained by ...

One of the largest colonies of gentoo penguins in Antarctica was decimated by volcanic eruptions several times during the last 7,000 years according to a new study. An international team of researchers, led by British Antarctic ...

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Nine burning questions about CRISPR genome editing answered - Phys.Org

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Seven Bridges, the biomedical data analysis company, today announced that it has made the Simons Genome Diversity Project (SGDP) dataset available for analysis by researchers via the Seven Bridges Platform.

The SGDP is the largest dataset of human genetic variation ever collected, including whole genomes from 300 individuals representing 142 diverse populations across the globe. The SGDP dataset is now available for Seven Bridges Platform users to analyze in conjunction with their own data and other large datasets including The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE). The Platform is used by thousands of researchers around the world to drive research and development in the worlds largest biopharmaceutical organizations.

Partnering with Seven Bridges will put this diverse and unique dataset into the hands of more researchers, in turn, speeding the discovery process, said Dr. David Reich of Harvard Medical School, one of the directors of the project. One of the most important components of scientific practice is the ability of scientists to replicate analysis, reanalyze data, build on it and come to their own conclusions. The Seven Bridges Platform and tools provide a new way for researchers all over the world to leverage our data and make new discoveries.

The SGDP dataset is particularly valuable to researchers because it differs from most other large-scale genomic datasets. The Simons Foundation selected samples with the explicit intent of capturing as much geographic, anthropological, and linguistic diversity as possible. As a result, this dataset captures modern human genetic diversity that is not well represented in other genomics datasets. As a result, the SGDP dataset provides valuable guidance to understand evolutionary pressures towards identifying important parameters in the search for disease-related genes. Once researchers identify data of interest, it can be immediately imported into their project tobuild reproducible bioinformatic analyses.

The Simons Foundation has long been committed to advancing the frontiers of scientific research, with a focus on creating collaborations that will generate discovery for years to come. said Brandi Davis-Dusenbery, CEO of Seven Bridges. The release of SGDP on our Platform will help researchers around the world more effectively use this powerful dataset.

More information on the Simons Genome Diversity Project dataset is available on the Seven Bridges blog.

About Seven Bridges Seven Bridges is the biomedical data analysis company accelerating breakthroughs in genomics research for cancer, drug development and precision medicine. The scalable, cloud-based Seven Bridges Platform empowers rapid, collaborative analysis of millions of genomes in concert with other forms of biomedical data. Thousands of researchers in government, biotech, pharmaceutical and academic labs use Seven Bridges, including three of the largest genomics projects in the world: U.S. National Cancer Institutes Cancer Genomics Cloud pilot, the Million Veteran Program, and Genomics Englands 100,000 Genomes Project. As the NIHs only commercial Trusted Partner, Seven Bridges authenticates and authorizes access to one of the worlds largest cancer genomics dataset. Named one of the worlds smartest companies by MIT Technology Review, Seven Bridges has offices in Cambridge, Mass.; Belgrade; London; Istanbul; and San Francisco.

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Seven Bridges Brings The Simons Foundation's Genome Diversity Project Dataset to the Cloud - Business Wire (press release)

The Ewing Marion Kauffman Foundations vice president of research and policy is departing the organization for a San Francisco-based firm focused on startup ecosystem research.

Dane Stangler

A 12-year veteran at the Kansas City-based foundation, Dane Stangler is now the head of policy at Startup Genome, a company that researches ecosystems and advises policymakers to increase the success rate of startups and accelerate economic growth. Starting with Kauffman in 2004 as a senior analyst, Stangler worked up the ranks at the Kauffman Foundation and in 2014 was named vice president of research and policy. In addition to representing the foundation at conferences around the U.S., hes published in such publications as the Wall Street Journal and Huffington Post.

At Startup Genome, Stangler will work on the firms Lifecycle Model, which aims to help entrepreneurial ecosystems around the world.

I am absolutely thrilled to join Startup Genomes global platform and help contribute to their mission of increasing startup success around the world, bringing more people and places into the startup revolution, Stangler said in a release. Too many places continue to take public and private actions that harm or drive away startups. Startups deserve better. We want to make sure that policy everywhere is the most conducive it can be to startups.Startup Genomes mission is to empower cities around the world to capture their fair share of the new economy by accelerating the economic growth of startup ecosystems through benchmarking, networking, and exposure. The firm conducts research with more than 10,000 startups each year and aims to build consensus for action on key challenges.Kauffman Foundation CEO Wendy Guillies said shes excited about Stanglers future.

This is a natural fit for Dane, leveraging both his talent and dedication to helping entrepreneurs succeed, Guillies said in a release. We are proud of his accomplishments at the Foundation, and we look forward to seeing him bring his wealth of experience to help Startup Genome strengthen ecosystems around the world.

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Kauffman exec departs for leadership role at Startup Genome - Startland News