Category Archives: Gene Medicine

A core assumption in the study of disease-causing genes has been that they are clustered in molecular pathways directly connected to the disease. But work by a group of researchers at the Stanford University School of Medicine suggests otherwise.

The gene activity of cells is so broadly networked that virtually any gene can influence disease, the researchers found. As a result, most of the heritability of diseases is due not to a handful of core genes, but to tiny contributions from vast numbers of peripheral genes that function outside disease pathways.

Any given trait, it seems, is not controlled by a small set of genes. Instead, nearly every gene in the genome influences everything about us. The effects may be tiny, but they add up.

The work is described in a paper published June 15 in Cell. Jonathan Pritchard, PhD, professor of genetics and of biology, is the senior author. Graduate student Evan Boyle and postdoctoral scholar Yang Li, PhD, share lead authorship.

The researchers call their provocative new understanding of disease genes an omnigenic model to indicate that almost any gene can influence diseases and other complex traits. In any cell, there might be 50 to 100 core genes with direct effects on a given trait, as well as easily another 10,000 peripheral genes that are expressed in the same cell with indirect effects on that trait, said Pritchard, who is also a Howard Hughes Medical Institute investigator.

Each of the peripheral genes has a small effect on the trait. But because those thousands of genes outnumber the core genes by orders of magnitude, most of the genetic variation related to diseases and other traits comes from the thousands of peripheral genes. So, ironically, the genes whose impact on disease is most indirect and small end up being responsible for most of the inheritance patterns of the disease.

This is a compellingpaper that presents a plausible and fascinatingmodel to explain a number of confusing observations from genomewide studies of disease, said Joe Pickrell, PhD, an investigator at the New York Genome Center, who was not involved in the work.

Until recently, said Pritchard, he thought of genetically complex traits as conforming to the polygenic model, in which genes have direct effects on a trait, whether that trait is something like height or a disease, such as autism.

Read this article:
Thousands of genes influence most diseases - Stanford Medical Center Report

June 26, 2017 In this image of neurons in the cerebellum of the brain, the yellow cells are Purkinje cells in which the channelrhodopsin-2 gene is being produced. Credit: Horwitz Lab/UW Medicine Seattle

UW Medicine researchers have developed a technique for inserting a gene into specific cell types in the adult brain in an animal model.

Recent work shows that the approach can be used to alter the function of brain circuits and change behavior. The study appears in the journal Neuron in the NeuroResources section.

Gregory Horwitz, associate professor of physiology and biophysics at the University of Washington School of Medicine in Seattle, led the research team. He said that the approach will allow scientists to better understand what roles select cell types play in the brain's complex circuitry.

Researchers hope that the approach might someday lead to developing treatments for conditions, such as epilepsy, that might be curable by activating a small group of cells.

"The brain is made up of a mix of many cell types performing different functions. One of the big challenges for neuroscience is finding ways to study the function of specific cell types selectively without affecting the function of other cell types nearby," Horwitz said. "Our study shows it is possible to selectively target a specific cell type in an adult brain using this technique and affect behavior nearly instantly."

In their study, Horowitz and his colleagues at the Washington National Primate Research Center in Seattle inserted a gene into cells in the cerebellum, a small structure located at the back of the brain and tucked under the brain's larger cerebrum.

The cerebellum's primary function is controlling motor movements. Disorders of the cerebellum generally lead to often disabling loss of coordination. Recent research suggests the cerebellum may also be important in learning and may be involved in such conditions as autism and schizophrenia.

The cells the scientists selected to study are called Purkinje cells. These cells, named after their discoverer, Czech anatomist Jan Evangelista Purkinje, are some of the largest in the human brain. They typically make connections with hundreds of other brain cells.

"The Purkinje cell is a mysterious cell," said Horwitz. "It's one of the biggest and most elaborate neurons and it processes signals from hundreds of thousands of other brain cells. We know it plays a critical role in movement and coordination. We just don't know how."

The gene they inserted, called channelrhodopsin-2, encodes for a light-sensitive protein that inserts itself into the brain cell's membrane. When exposed to light, it allows ions - tiny charged particles - to pass through the membrane. This triggers the brain cell to fire.

The technique, called optogenetics, is commonly used to study brain function in mice. But in these studies, the gene must be introduced into the embryonic mouse cell.

"This 'transgenic' approach has proved invaluable in the study of the brain," Horwitz said. "But if we are someday going to use it to treat disease, we need to find a way to introduce the gene later in life, when most neurological disorders appear."

The challenge for his research team was how to introduce channelrhodopsin-2 into a specific cell type in an adult animal. To achieve this, they used a modified virus that carried the gene for channelrhodopsin-2 along with segment of DNA called a promoter. The promoter stimulates the cell to start expressing the gene and make the channelrhodopsin-2 membrane protein. To make sure the gene was expressed only by Purkinje cells, the researchers used a promoter that is strongly active in Purkinje cells, called L7/Pcp2."

In their paper, the researchers reported that by painlessly injecting the modified virus into a small area of the cerebellum of rhesus macaque monkeys, the channelrhodopsin-2 was taken up exclusively by the targeted Purkinje cells. The researchers then showed that when they exposed the treated cells to light through a fine optical fiber, they were able stimulate the cells to fire at different rates and affect the animals' motor control.

Horwitz said that it was the fact that Purkinje cells express L7/Pcp2 promoter at a higher rate than other cells that made them more likely to produce the channelrhodopsin-2 membrane protein.

"This experiment demonstrates that you can engineer a viral vector with this specific promoter sequence and target a specific cell type," he said. "The promoter is the magic. Next, we want to use other promoters to target other cell types involved in other types of behaviors."

Explore further: New insights into control of neuronal circuitry could lead to treatments for an inherited motor disorder

More information: Yasmine El-Shamayleh et al, Selective Optogenetic Control of Purkinje Cells in Monkey Cerebellum, Neuron (2017). DOI: 10.1016/j.neuron.2017.06.002

Journal reference: Neuron

Provided by: University of Washington

Viruses have evolved to be highly effective vehicles for delivering genes into cells. Seeking to take advantage of these traits, scientists can reprogram viruses to function as vectors, capable of carrying their genetic cargo ...

Carnegie Mellon University scientists can now use brain activation patterns to identify complex thoughts, such as, "The witness shouted during the trial."

Since scientists began studying the brain, they have asked whether the biology they observed can really be tied to external behaviors. Researchers are building a substantial understanding of the biophysical, molecular, and ...

UW Medicine researchers have developed a technique for inserting a gene into specific cell types in the adult brain in an animal model.

In a new systematic review in JAMA Neurology, Michigan Medicine researchers found reason to further explore the surprising effects of zolpidem that have been observed outside the scope of its primary Food and Drug Administration ...

Humans are diurnal animals, meaning that we usually sleep at night and are awake during the day, due at least in part to light or the lack thereof. Light is known to affect sleep indirectly by entrainingmodifying the length ...

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

More here:
Study shines light on brain cells that coordinate movement - Medical Xpress

Regular exercise may offer some protection against Alzheimer's disease, even for people who are genetically at risk, according to recent research.

In the study, published in the Journal of Alzheimers Disease, people who did more moderate-intensity physical activity were more likely to have healthy patterns of glucose metabolism in their brainsa sign of healthy brain activitythan those who did less. Light-intensity physical activity, on the other hand, was not associated with similar benefits.

The study involved 93 adults with an average age of 64, all of whom had at least one parent with Alzheimers disease, at least one gene variation linked to Alzheimers disease, or both. This put them at high risk for developing the disease themselves, although none showed any cognitive impairment at the time of the study.

To illuminate the relationship between brain activity and exercise levels, everyone wore an accelerometer for a week to measure their daily physical activity and received PET scans to measure glucose metabolism, which reveals neuron health and activity, in several regions of the brain. For people with Alzheimers disease, these regions tend to have depressed glucose metabolism.

Researchers found that people who spent at least 68 minutes a day engaged in physical activity at a moderate levelthe equivalent of a brisk walkhad better glucose metabolism in all of those regions than those who spent less time doing so.

The amounts of time spent being sedentary or doing less-intense physical activity (like slow walking) were not associated with changes in any of the brain regions studied. Vigorous activity was linked to better glucose metabolism in one brain regionthe hippocampus but not in the others.

Larger doses of high-intensity exercise may be needed to provide the benefits of just a modest increase in moderate activity, the authors wrote, suggesting that you don't have to exercise to the extreme to get brain benefits. Past research comparing the brain-boosting power of moderate- and vigorous-intensity exercise has been mixed, says lead author Ozioma Okonkwo, assistant professor of medicine at the University of Washington School of Medicine and Public Health. But in general, he says, the evidence suggests that light activity is insufficient, and vigorous activity might be unnecessary.

Being able to quantify the connection between moderate-intensity activity and brain health is an exciting and important step in Alzheimers research, the researchers say, although further studies are needed in order to show a cause-and-effect relationship between exercise and glucose metabolismand to demonstrate real-life benefits. (The team is currently recruiting people with concerns about their brain health for a clinical trial to help determine the right dose of exercise for people with mild memory problems.)

But Okonkwo points out that previous research has already established a connection between glucose metabolism and cognitive function. Were showing now that a moderate-intensity active lifestyle actually boosts neuronal function, he says. "I dont think its too much of a leap to make the argument that this probably is one of the pathways through which exercise prevents cognitive decline in middle life.

Okonkwo says this research offers reassurance that people can take steps to protect themselves against Alzheimers disease, even if they are at high genetic risk. The evidence shows that its never too late to take up and maintain a physically active regimen, he says. It also suggests that the earlier you begin and the longer you continue it, the more benefits you tend to accrue.

Continued here:
How Exercise May Protect the Brain From Alzheimer's Disease - TIME

Standard vaccines to prevent infectious diseases consist of killed or weakened pathogens or proteins from those microorganisms. Vaccines that treat cancer also rely on proteins. In contrast, a new kind of vaccine, which is poised to make major inroads in medicine, consists of genes. Genomic vaccines promise to offer many advantages, including fast manufacture when a virus, such as Zika or Ebola, suddenly becomes more virulent or widespread. They have been decades in the making, but dozens have now entered clinical trials.

Most vaccines work by teaching the immune system to recognize a foe. They accomplish this trick by delivering a dead or weakened pathogen; the immune system recognizes that certain bits of protein, called antigens, on the surface of the pathogen are foreign and prepares to pounce the next time it encounters them. (Many modern vaccines deliver only the antigens, leaving out the pathogens.) To treat cancer, doctors may deliver other proteins that enhance immune responses. These proteins can include the immune systems own guided missilesantibodies.

Genomic vaccines take the form of DNA or RNA that encodes desired proteins. On injection, the genes enter cells, which then churn out the selected proteins. Compared with manufacturing proteins in cell cultures or eggs, producing the genetic material should be simpler and less expensive. Further, a single vaccine can include the coding sequences for multiple proteins, and it can be changed readily if a pathogen mutates or properties need to be added. Public health experts, for instance, revise the flu vaccine annually, but sometimes the vaccine they choose does not match the viral strains that circulate when flu season comes. In the future, investigators could sequence the genomes of the circulating strains and produce a better-matched vaccine in weeks. Genomics also enables a new twist on a vaccination approach known as passive immune transfer, in which antibodies are delivered instead of antigens. Scientists can now identify people who are resistant to a pathogen, isolate the antibodies that provide that protection and design a gene sequence that will induce a persons cells to produce those antibodies.

With such goals in mind, the U.S. government, academic labs and companies large and small are pursuing the technology. A range of clinical trials to test safety and immunogenicity are under way, including for avian influenza, Ebola, hepatitis C, HIV, and breast, lung, prostate, pancreatic and other cancers. And at least one trial is looking at efficacy: the National Institutes of Health has begun a multisite clinical trial to see if a DNA vaccine can protect against Zika.

Meanwhile researchers are working to improve the technologyfor example, by finding more efficient ways to get the genes into cells and by improving the stability of the vaccines in heat. Oral delivery, which would be valuable where medical personnel are scarce, is not likely to be feasible anytime soon, but nasal administration is being studied as an alternative and is under study. Optimism is highthat any remaining obstacles can be solved.

Here is the original post:
Genomic Vaccines - Scientific American

While much of the excitement surrounding precision medicine focuses on using genomics to tailor personalized treatment plans, speakers at the Precision Medicine Summit said theres more to it.

We cannot achieve precision medicine without having everyone be a participant and benefit and understand, said India Barnard-Hook, director of strategy and associate director of precision medicine at University of California, San Francisco. Precision medicine is about much more than genomics.

Social determinants of health, for instance, typically occur outside the healthcare system and have a significant impact on both health and individual outcomes.

You have to know a lot more than the clinical phenotype, said Linda Chin, chief innovation officer for health affairs at The University of Texas Health System.If you understand all the other factors that contribute to diseases, those can alter the course of the disease and ultimately prevent it.

Penn Medicine associate vice president of health technology and academic computing Brian Wells even made the bold prediction that genetic sequencing may become less relevant as cancer treatments become increasingly sophisticated.

If we discover one immunotherapy that applies to all cancers, we really dont need to sequence your genome anymore, Wells said. Were at a tipping point and sequencing could become less important.

The GLP aggregated and excerpted this blog/article to reflect the diversity of news, opinion, and analysis. Read full, original post:With precision medicine, social determinants could be more insightful than genetics

Continue reading here:
Will patients' lifestyles become more important to precision medicine than gene sequencing? - Genetic Literacy Project

According to a study published in the journal Frontiers in Immunology, mind-body interventions such as mindfulness, yoga, Tai Chi, Qigong, relaxation response, and breath regulation dont simply relax us, they can reverse the molecular reactions in our DNA which cause ill-health and depression.

Ivana Buric et al analyze how the behavior of our genes is affected by different MBIs including mindfulness and yoga. Image credit: Nato Pereira.

When a person is exposed to a stressful event, the sympathetic nervous system the system responsible for the fight-or-flight response is triggered, in turn increasing production of a molecule called nuclear factor kappa B (NF-kB) which regulates how our genes are expressed.

NF-kB translates stress by activating genes to produce proteins called cytokines that cause inflammation at cellular level a reaction that is useful as a short-lived fight-or-flight reaction, but if persistent leads to a higher risk of cancer, accelerated aging and psychiatric disorders like depression.

However, people who practice mind-body interventions (MBIs) exhibit the opposite effect namely a decrease in production of NF-kB and cytokines, leading to a reversal of the pro-inflammatory gene expression pattern and a reduction in the risk of inflammation-related diseases and conditions, according to the study.

The inflammatory effect of the fight-or-flight response which also serves to temporarily bolster the immune system would have played an important role in mankinds hunter-gatherer prehistory, when there was a higher risk of infection from wounds, the authors said.

In todays society, however, where stress is increasingly psychological and often longer-term, pro-inflammatory gene expression can be persistent and therefore more likely to cause psychiatric and medical problems.

Millions of people around the world already enjoy the health benefits of mind-body interventions like yoga or meditation, but what they perhaps dont realize is that these benefits begin at a molecular level and can change the way our genetic code goes about its business, said lead author Ivana Buric, a PhD student at Coventry University, UK.

These activities are leaving what we call a molecular signature in our cells, which reverses the effect that stress or anxiety would have on the body by changing how our genes are expressed.

Put simply, MBIs cause the brain to steer our DNA processes along a path which improves our wellbeing.

More needs to be done to understand these effects in greater depth, for example how they compare with other healthy interventions like exercise or nutrition.

But this is an important foundation to build on to help future researchers explore the benefits of increasingly popular mind-body activities, Buric said.

_____

Ivana Buric et al. What Is the Molecular Signature of Mind-Body Interventions? A Systematic Review of Gene Expression Changes Induced by Meditation and Related Practices. Front. Immunol, published online June 16, 2017; doi: 10.3389/fimmu.2017.00670

Visit link:
Study: Meditation, Yoga and Related Practices Can 'Reverse' DNA Reactions - Sci-News.com