Monthly Archives: July 2017

Gene drive technology might limit the ability of Anopheles gambiae mosquito to transmit malaria to humans.

CDC/James Gathany

By Kelly ServickJul. 19, 2017 , 4:00 PM

We dont yet know whether the gene-spreading approach known as gene drive, intended to wipe out invasive pests or reduce the spread of insect-borne disease, will work in the wild. But groups of genetic experts are already talking about how to make it stop working if needed.

And at a symposium today in Washington, D.C., organized by the International Life Sciences Instituteand the National Academies of Sciences, Engineering, and Medicine, researchers and policy experts discussed how to measure and limit a gene drive strategys environmental risks. And the U.S. militarys research arm announced it will fund efforts by several high-profile genetics labs to develop ways to reverse or limit the spread of an introduced gene if it should have unintended consequences on animals or an ecosystem.

Were in the business of preventing technological surprise, but also being prepared for the surprises that come from the use of these technologies, said Renee Wegrzyn, a program manager at the Defense Advanced Research Projects Agency (DARPA) in Arlington, Virginia, which today announced seven research teams that will share a $65 million pot of funding under the agencys Safe Genes program over the next 4 years.

Gene drive works by tinkering with the rules of inheritance, increasing the likelihood a gene will be passed to the next generation. The phenomenon occurs in nature by a variety of mechanisms, but all increase a genes ability to permeate a population quickly and thoroughly, even if it doesnt carry any survival advantage. Inspired by natural gene drives, researchers have spent decades trying to perfect a system that might endow a population of mosquitoes with a malaria resistance gene, for example, or spread a lethal gene that cuts down a local population of invasive insects or rodents.

Progress surged with the discovery of CRISPR/Cas9 gene editing. By inserting the gene for a new trait alongside genes for a DNA-cutting enzyme and an RNA guide, scientists can prompt a cell to slice out copies of the original, wild-type gene from its chromosomes and use the inserted gene as a template for repair. Its sperm and egg cells will thus bear two copies of the new gene, which radically increases the odds that its offspring will inherit it.

But the notion of wiping out an entire species or unleashing a gene that could spread like wildfire through a population has also bred controversy. Evidence that CRISPR gene drives could be extremely efficient in lab-reared insects led prominent researchers to urge caution.

Todays meeting included some practical discussion of how gene drive might be contained. Molecular biologist Bruce Hay of the California Institute of Technology in Pasadena presented his labs research into high-threshold gene drives, designed to spread effectively only if individuals with the new gene make up a large fraction of the total population. Wayward migrants thus wouldnt manage to spread the gene widely outside the intended area. And if an introduced gene had unexpected consequences, researchers might reverse a gene drive by introducing more wild, unmodified individuals to outnumber the new ones. I think we really can do safe, local, and reversible gene drive, Hay told the audience. This is not just a fantasy.

But CRISPR brings a whole new set of unknowns. It might have unpredictable, off-target effects on the genome, and scientists dont know how to shut it down. Among the seven teams selected for the Safe Genes program are some CRISPR pioneers. Harvard University geneticist George Church will lead efforts to develop more precise gene-editing systems that distinguish between similar sequences. Molecular biologist Jennifer Doudna of the University of California (UC), Berkeley, will, according to DARPAs news release, look for anti-CRISPR proteins that could prevent unwanted editing.

Several more projects explicitly focus on gene drive applications: A group at UC Riverside led by molecular biologist Omar Akbari will try to document the genetic diversity of the Aedes aegypti mosquito and test ways to limit or reverse gene drives in contained test environments. Biologist John Godwins team at North Carolina State University in Raleighwill test ways to cut down rodent populations by targeting gene variants present only in invasive communities.

Experts still predict that testing of gene drive in the field is still years away. This is such early days in the field, Wegrzyn told the audience today. Why dont we build those [control] tools in now, rather than trying to retrofit them into these systems?

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How will we keep controversial gene drive technology in check? - Science Magazine

Researchers in the Department of Physiology and Biophysics are studying genetic and epigenetic factors in Alzheimers disease to develop novel ways of restoring function to patients in the later stages of the neurodegenerative disorder.

While most research on Alzheimers has focused on early diagnosis and treatment, the new study is focusing on finding novel ways to restore cognitive function and will utilize studies in mouse models carrying gene mutations for familial Alzheimers (where more than one family member has the disease) and in human stem cell-derived neurons from Alzheimers patients.

The work involving preclinical research to unravel genetic and epigenetic factors that cause Alzheimers is funded by a five-year, $2 million grant from the National Institutes of Healths National Institute on Aging. Zhen Yan, PhD, professor of physiology and biophysics, is principal investigator.

Epigenetic factors can change gene expression without altering the underlying DNA sequence which in turn affects how cells read the genes. Such changes may profoundly impact human health.

We hypothesize that Alzheimers is produced by a combination of genetic risk factors and environmental factors, such as aging, that induce the dysregulation of specific epigenetic processes that lead to impaired cognition, Yan says.

The research will explore how epigenetic changes that accompany Alzheimers disease also might help identify a much sought-after biomarker for the disease, which could allow for novel treatment.

Numerous clinical trials in recent years have focused on reducing amyloid beta plaque in the brain. So far, such efforts havent yet translated into improving cognitive function, Yan says.

Our research, by contrast, will target synaptic function, which is at the root of cognitive function, she explains. Our hypothesis is that this approach will have a more fundamental effect.

Yan and her colleagues will investigate aberrant histone methylation, an epigenetic process that affects the expression of genes encoding key proteins that allow for signals to be transmitted between neurons.

When this process is dysregulated in Alzheimers disease, neuronal signaling doesnt function properly, leading to cognitive impairment.

Even though Alzheimers patients can often easily remember something that happened 20 years ago, the later stages of the disease are characterized by a growing inability to recall recently learned information.

That kind of short-term working memory, Yan explains, is dependent on excitatory transmission in the frontal cortex, mediated by glutamate receptors.

At the later stages of the disease, we know that there is a loss of glutamate receptors that are crucial for learning and memory, she says. When these receptors lose the ability to communicate, there is a loss of cognition.

Our research will try to restore gene expression in these glutamate receptors using epigenetic tools, with the ultimate goal of restoring cognitive function.

Jian Feng, PhD, professor of physiology and biophysics, is a co-investigator on the grant titled A Novel Epigenetic Mechanism for Alzheimers Disease.

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Restoring Cognitive Function for Alzheimer's Disease - UB School of Medicine and Biomedical Sciences News

The discovery that the brain can generate new cells about 700 new neurons each day has triggered investigations to uncover how this process is regulated. Researchers at Baylor College of Medicine and Jan and Dan Duncan Neurological Research Institute at Texas Childrens Hospital have developed a novel mouse model that for the first time selectively identifies neural stem cells, the progenitors of new adult brain cells. In these mice, researchers have found a novel mechanism by which descendants of neural stem cells can send feedback signals to alter the division and the fate of the mother cell. These findings appear in eLife.

Our initial goal for this study was to find a gene that is selectively expressed in primary neural stem cells. Based on the information obtained from publicly available expression databases, we started with roughly 750 potential candidate genes. It took an enormous amount of hard work and meticulousness to systematically narrow it down to a single gene it was like looking for a needle in a haystack, said Dr. Mirjana Maleti-Savati, assistant professor of pediatrics and neurology at Baylor and Texas Childrens Hospital, who led this study. After extensive analysis, we were convinced that the gene lunatic fringe, a member of the well-studied Notch signaling pathway, was the selective marker of neural stem cells.

Previous studies in a number of animal models have shown that members of the Notch signaling pathway participate in the regulation of stem cell fate.The finding that lunatic fringe is a selective marker for neural stem cells and a member of the Notch family was a clue of its possible role as regulator of neural stem cell fate. This represented a potentially significant step forward in the field of neurogenesis because the precise mechanism and the fine-tuning of Notch signaling in the hippocampus of the adult brain, where new neurons are born, had remained elusive until now.

Lunatic fringe helps keep the brain renewable

Maleti-Savati and her colleagues show that lunatic fringe mediates a mechanism that helps preserve neural stem cells, so that they can form new neurons throughout life while also ensuring optimal number of neurons.

Interestingly, neural stem cells and their progeny physically cluster closely around one another, which makes it an ideal environment for direct cell-cell communication between neural stem cells and adjacent cells. The scientists found that lunatic fringe allows neural stem cells to distinguish between and respond differently to surrounding cells expressing other markers, namely those expressing the Delta marker and those expressing the Jagged1 marker.

When surrounded by Delta-neurons, most neural stem cells remain in a stand-by mode, protected from random activation and unnecessary division. On the other hand, when neural stem cells interact with Jagged1-neurons, they begin to divide. Combined, these processes allow division of every neural stem cell to be finely regulated to prevent excessive division and premature exhaustion of its potential.

This study and the mouse model we have generated is a huge step forward in the field of neural stem cell biology because now we not only have a benchmark to specifically label primary neural stem cells, but have identified a key quality control step that determines their fate, said Fatih Semerci, postdoctoral student in Maleti-Savati lab and the lead author of this study. Lunatic fringe allows neural stem cells to decide whether to stay dormant or not, and, once they start to divide, whether to continue or to stop.

This study has far-reaching implications on the field of neurogenesis because age-related mental decline and psychiatric disorders such as anxiety and depression have been associated with a reduced ability to generate new neurons in the hippocampus, the center of learning and memory. The formation of new neurons is affected by many factors, both internal and external. For example, physical activity and enriched environment enhance it, while loneliness and depression dampen it. Adult hippocampal neurogenesis has garnered significant interest because targeting it could result in new therapies for many disorders.

Others who contributed to this study include William Tin-Shing Choi, Aleksander Bajic, Aarohi Thakkar, Juan Manuel Encinas, Andrew Groves of Baylor College of Medicine; Frederic Depreux of the Rosalind Franklin University of Medicine and Science in Chicago and Neil Segil of University of Southern California.

Funding for this study comes from the Nancy Chang Award and the CPRIT grant (RP130573CPRIT), and in part by the Microscopy, RNA In Situ Hybridization and Neuropathology Core facility at Baylor College of Medicine, supported by the NIH Shared Instrumentation grant (1S10OD016167) and the NIHIDDRC grant U54HD083092. Further support was provided by the Cytometry and Cell Sorting Core (NCRR grant S10RR024574, NIAID AI036211 and NCI P30CA125123).

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Lunatic Fringe gene plays key role in renewable brain | Baylor ... - Baylor College of Medicine News (press release)

Recent research from Intermountain Healthcare's clinicians shows the successful application of genomic-based approaches to studying individual cancer cases.

Oncologists Lincoln Nadauld, MD, and Derrick Haslem, MD, work at the Southwest Cancer Center in St. George, Utah. In addition to treating patients, they conduct research aimed at improving cancer care and precision medicine.

Their recent research has been published in two national peer-reviewed journals in collaboration with Intermountain Healthcare doctors and researchers from Stanford School of Medicine.

[Also:Precision medicine: Hype today but the promise is even bigger than we think]

One study outlines what the doctors call an "impressive" clinical course and positive outcome of a patient with metastatic colon cancer treated with a precision oncology approach. It was published in the Journal of Clinical Oncology-Precision Oncology, a research publication outlet from the American Society of Clinical Oncologists.

The second publication, co-authored by Nadauld and published in Genome Medicine, shows that linked read sequencing is useful in characterizing oncogenic rearrangements in cancer metastasis.

Both studies were done in collaboration with Hanlee P. Ji, MD, senior associate director of the Stanford Genome Technology Center and Associate Professor at Stanford's School of Medicine.

Linked read sequencing, the researchers note, is a process that allows scientists and doctors to look at the molecular structure of tumor DNA in longer reads of 50,000 base pairs, as opposed to the typical 200-300, and thus "revealing the genomic complexity of patient tumors."

In reference to the Genome Medicine study, Nadauld points out: "In this patient, we were able to identify an amplification of a gene called FGFR2, which is critical because there are drugs that target that mutation.

"This case indicates there are broader applications for linked read technology, including diagnostic purposes and defining additional treatment options for patients along with new genes to target," he added. "With further study, pharmaceutical and biotech technologies can start to develop new drugs that target different molecular phenomena."

Twitter: @Bernie_HITN Email the writer: bernie.monegain@himssmedia.com

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Intermountain, Stanford University see promise for precision medicine in cancer cases - Healthcare IT News