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Newswise Its the most basic of ways to find out what something does, whether its an unmarked circuit breaker or an unidentified gene flip its switch and see what happens. New remote-control technology may offer biologists a powerful way to do this with cells and genes. A team at Rockefeller University and Rensselaer Polytechnic Institute is developing a system that would make it possible to remotely control biological targets in living animals rapidly, without wires, implants or drugs.

Today (December 15) in the journal Nature Medicine, the team describes successfully using electromagnetic waves to turn on insulin production to lower blood sugar in diabetic mice. Their system couples a natural iron storage particle, ferritin, to activate an ion channel called TRPV1 such that when the metal particle is exposed to a radio wave or magnetic field it opens the channel, leading to the activation of an insulin producing gene. Together, the two proteins act as a nano-machine that can be used to trigger gene expression in cells.

The method allows one to wirelessly control the expression of genes in a living animal and could potentially be used for conditions like hemophilia to control the production of a missing protein. Two key attributes are that the system is genetically encoded and can activate cells remotely and quickly, says Jeffrey Friedman, Marilyn M. Simpson Professor head of the Laboratory of Molecular Genetics at Rockefeller. We are now exploring whether the method can also be used to control neural activity as a means for noninvasively modulating the activity of neural circuits. Friedman and his Rensselaer colleague Jonathan S. Dordick were co-senior researchers on the project.

Other techniques exist for remotely controlling the activity of cells or the expression of genes in living animals. But these have limitations. Systems that use light as an on/off signal require permanent implants or are only effective close to the skin, and those that rely on drugs can be slow to switch on and off.

The new system, dubbed radiogenetics, uses a signal, in this case low-frequency radio waves or a magnetic field, to heat or move ferritin particles. They, in turn, prompt the opening of TRPV1, which is situated in the membrane surrounding the cell. Calcium ions then travel through the channel, switching on a synthetic piece of DNA the scientists developed to turn on the production of a downstream gene, which in this study was the insulin gene.

In an earlier study, the researchers used only radio waves as the on signal, but in the current study, they also tested out a related signal a magnetic field to activate insulin production. They found it had a similar effect as the radio waves.

The use of a radiofrequency-driven magnetic field is a big advance in remote gene expression because it is non-invasive and easily adaptable, says Dordick, who is Howard P. Isermann Professor of Chemical and Biological Engineering and vice president of research at Rensselaer. You dont have to insert anything no wires, no light systems the genes are introduced through gene therapy. You could have a wearable device that provides a magnetic field to certain parts of the body and it might be used therapeutically for many diseases, including neurodegenerative diseases. Its limitless at this point.

The choice to look at insulin production was driven by the equipment they used to generate the radio waves and magnetic fields. Because the coil that generates these signals is currently small i.e; only three centimeters in diameter, it was necessary to anesthetize the mice to keep them still. Since anesthesia can repress the production of insulin, the hormone that reduces blood sugar, Stanley and her colleagues designed the genetically encoded system to replace the insulin that is normally reduced by anesthesia in mice.

Excerpt from:
'Radiogenetics' Seeks to Remotely Control Cells and Genes

ANN ARBOR (PRWEB) December 15, 2014

Gene therapy pioneer and longtime Veterans Affairs researcher Dr. David Fink received the 2014 Paul B. Magnuson Award from VA in a ceremony at the VA Ann Arbor Healthcare System on Dec. 15, 2014.

Dr. Fink is a staff neurologist and an investigator with the Geriatric Research, Education and Clinical Center at the Ann Arbor VA. He is also the Robert Brear Professor and Chair of Neurology at the University of Michigan. He has been with VA since 1982.

A Harvard Medical School graduate, Fink has pioneered methods to introduce genes into the body to treat chronic pain and other nervous-system diseases. His team led the first human clinical trial of gene therapy for pain. The phase 1 trial, published in the Annals of Internal Medicine in 2011, involved 10 cancer patients with severe pain who had failed to respond even to high doses of morphine or other pain drugs. Finks group gave them skin injections of an inactive form of the herpes simplex virus as a means to deliver a gene known as PENK. The gene helps the body produce an opioid-like molecule called proenkephalin.

The gene treatment, based on years of research, is safe in humans and led to pain reduction. A larger phase 2 clinical trial of the approach is now being planned.

Besides cancer pain, Finks work focuses on Veterans and others with nerve-related conditions such as spinal cord injury and diabetic neuropathy. The team is developing non-replicating viral vectors, similar to the one used in the 2011 human trial, to ferry genes into the nervous system that code for the production of the bodys own pain relievers. A related approach, now being funded by VA, is to use the vectors to bring about the continuous release of proteins that protect nerve cells from dying. This could help prevent neuropathy and the sharp chronic pain it entails.

Dr. Finks work holds tremendous potential for treating Veterans with chronic neurological disease, said Robert McDivitt, an Army Veteran and director of the VA Ann Arbor Healthcare System.

Fink was presented the award by Dr. Carolyn Clancy, VAs Interim Undersecretary for Health. Also attending the ceremony was Dr. Patricia Dorn, director of VA Rehabilitation Research and Development, which each year presents the Magnuson Award as the highest honor for VA rehabilitation investigators.

The award is named for Paul B. Magnuson, a bone and joint surgeon who was a key figure in the expansion of the VA research program after World War II. He was known for his dedication to finding new treatments and devices to help Veterans cope with their disabilities, and, as he put it, to restoring each patient to his family, his job, and his life. Established in 1998, the Magnuson Award consists of a plaque, a one-time award of $5,000, and $50,000 per year for up to three years to supplement ongoing peer-reviewed research.

About the VA Ann Arbor Healthcare System Since 1953, VA Ann Arbor Healthcare System which includes the VA Ann Arbor Medical Center, the VA Toledo Community Based Outpatient Clinic [CBOC], the VA Flint CBOC, and the VA Jackson CBOC, as well as the VA Center for Clinical Management Research, an HSR&D Center of Innovation, has provided state-of-the-art healthcare services to the men and women who have proudly served our nation. More than 65,000 Veterans living in a 15-county area of Michigan and Northwest Ohio utilized VAAAHS in fiscal year 2014. The Ann Arbor Medical Center also serves as a referral center for specialty care.

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VAs Magnuson Award to Gene Therapy Pioneer in Ann Arbor

Consider the relationship between an air traffic controller and a pilot. The pilot gets the passengers to their destination, but the air traffic controller decides when the plane can take off and when it must wait. The same relationship plays out at the cellular level in animals, including humans. A region of an animal's genome -- the controller -- directs when a particular gene -- the pilot -- can perform its prescribed function.

A new study by cell and systems biologists at the University of Toronto (U of T) investigating stem cells in mice shows, for the first time, an instance of such a relationship between the Sox2 gene which is critical for early development, and a region elsewhere on the genome that effectively regulates its activity. The discovery could mean a significant advance in the emerging field of human regenerative medicine, as the Sox2 gene is essential for maintaining embryonic stem cells that can develop into any cell type of a mature animal.

"We studied how the Sox2 gene is turned on in mice, and found the region of the genome that is needed to turn the gene on in embryonic stem cells," said Professor Jennifer Mitchell of U of T's Department of Cell and Systems Biology, lead invesigator of a study published in the December 15 issue of Genes & Development.

"Like the gene itself, this region of the genome enables these stem cells to maintain their ability to become any type of cell, a property known as pluripotency. We named the region of the genome that we discovered the Sox2 control region, or SCR," said Mitchell.

Since the sequencing of the human genome was completed in 2003, researchers have been trying to figure out which parts of the genome made some people more likely to develop certain diseases. They have found that the answers are more often in the regions of the human genome that turn genes on and off.

"If we want to understand how genes are turned on and off, we need to know where the sequences that perform this function are located in the genome," said Mitchell. "The parts of the human genome linked to complex diseases such as heart disease, cancer and neurological disorders can often be far away from the genes they regulate, so it can be dificult to figure out which gene is being affected and ultimately causing the disease."

It was previously thought that regions much closer to the Sox2 gene were the ones that turned it on in embryonic stem cells. Mitchell and her colleagues eliminated this possibility when they deleted these nearby regions in the genome of mice and found there was no impact on the gene's ability to be turned on in embryonic stem cells.

"We then focused on the region we've since named the SCR as my work had shown that it can contact the Sox2 gene from its location 100,000 base pairs away," said study lead author Harry Zhou, a former graduate student in Mitchell's lab, now a student at U of T's Faculty of Medicine. "To contact the gene, the DNA makes a loop that brings the SCR close to the gene itself only in embryonic stem cells. Once we had a good idea that this region could be acting on the Sox2 gene, we removed the region from the genome and monitored the effect on Sox2."

The researchers discovered that this region is required to both turn Sox2 on, and for the embryonic stem cells to maintain their characteristic appearance and ability to differentiate into all the cell types of the adult organism.

"Just as deletion of the Sox2 gene causes the very early embryo to die, it is likely that an abnormality in the regulatory region would also cause early embryonic death before any of the organs have even formed," said Mitchell. "It is possible that the formation of the loop needed to make contact with the Sox2 gene is an important final step in the process by which researchers practicing regenerative medicine can generate pluripotent cells from adult cells."

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Cell biologists discover on-off switch for key stem cell gene