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Creative Minds

Skin Cells Can Be Reprogrammed In Vivo

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Daniel Gallego-Perez
Credit: The Ohio State University College of Medicine, Columbus

Thousands of Americans are rushed to the hospital each day with traumatic injuries. Daniel Gallego-Perez hopes that small chips similar to the one that he’s touching with a metal stylus in this photo will one day be a part of their recovery process.

The chip, about one square centimeter in size, includes an array of tiny channels with the potential to regenerate damaged tissue in people. Gallego-Perez, a researcher at The Ohio State University Colleges of Medicine and Engineering, Columbus, has received a 2018 NIH Director’s New Innovator Award to develop the chip to reprogram skin and other cells to become other types of tissue needed for healing. The reprogrammed cells then could regenerate and restore injured neural or vascular tissue right where it’s needed.

Gallego-Perez and his Ohio State colleagues wondered if it was possible to engineer a device placed on the skin that’s capable of delivering reprogramming factors directly into cells, eliminating the need for the viral delivery vectors now used in such work. While such a goal might sound futuristic, Gallego-Perez and colleagues offered proof-of-principle last year in Nature Nanotechnology that such a chip can reprogram skin cells in mice. [1]

Here’s how it works: First, the chip’s channels are loaded with specific reprogramming factors, including DNA or proteins, and then the chip is placed on the skin. A small electrical current zaps the chip’s channels, driving reprogramming factors through cell membranes and into cells. The process, called tissue nanotransfection (TNT), is finished in milliseconds.

To see if the chips could help heal injuries, researchers used them to reprogram skin cells into vascular cells in mice. Not only did the technology regenerate blood vessels and restore blood flow to injured legs, the animals regained use of those limbs within two weeks of treatment.

The researchers then went on to show that they could use the chips to reprogram mouse skin cells into neural tissue. When proteins secreted by those reprogrammed skin cells were injected into mice with brain injuries, it helped them recover.

In the newly funded work, Gallego-Perez wants to take the approach one step further. His team will use the chip to reprogram harder-to-reach tissues within the body, including peripheral nerves and the brain. The hope is that the device will reprogram cells surrounding an injury, even including scar tissue, and “repurpose” them to encourage nerve repair and regeneration. Such an approach may help people who’ve suffered a stroke or traumatic nerve injury.

If all goes well, this TNT method could one day fill an important niche in emergency medicine. Gallego-Perez’s work is also a fine example of just one of the many amazing ideas now being pursued in the emerging field of regenerative medicine.

Reference:

[1] Topical tissue nano-transfection mediates non-viral stroma reprogramming and rescue. Gallego-Perez D, Pal D, Ghatak S, Malkoc V, Higuita-Castro N, Gnyawali S, Chang L, Liao WC, Shi J, Sinha M, Singh K, Steen E, Sunyecz A, Stewart R, Moore J, Ziebro T, Northcutt RG, Homsy M, Bertani P, Lu W, Roy S, Khanna S, Rink C, Sundaresan VB, Otero JJ, Lee LJ, Sen CK. Nat Nanotechnol. 2017 Oct;12(10):974-979.

Links:

Stroke Information (National Institute of Neurological Disorders and Stroke/NIH)

Burns and Traumatic Injury (NIH)

Peripheral Neuropathy (National Institute of Neurological Disorders and Stroke/NIH)

Video: Breakthrough Device Heals Organs with a Single Touch (YouTube)

Gallego-Perez Lab (The Ohio State University College of Medicine, Columbus)

Gallego-Perez Project Information (NIH RePORTER)

NIH Support: Common Fund; National Institute of Neurological Disorders and Stroke


Building Nanoparticles for Kidney Disease

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Eun Ji Chung
Photo courtesy of Eun Ji Chung

Great things sometimes come in small packages. That’s certainly true in the lab of Eun Ji Chung at the University of Southern California, Los Angeles. Chung and her team each day wrap their brains around bioengineering 3-D nanoparticles, molecular constructs that measure just a few billionths of a meter.

Chung recently received an NIH Director’s 2018 New Innovator Award to bring the precision of nanomedicine to autosomal dominant polycystic kidney disease (ADPKD), a relatively common inherited disorder that affects about 600,000 Americans and 12 million people worldwide.

By age 60, about half of those battling ADPKD will have kidney failure, requiring dialysis or a kidney transplant to stay alive. For people with ADPKD, a dominantly inherited gene mutation causes clusters of fluid-filled cysts to form in the kidneys that grow larger over time. The cysts can grow very large and displace normal kidney tissue, progressively impairing function.

For Chung, the goal is to design nanoparticles of the right size and configuration to deliver therapeutics to the kidneys in safe, effective amounts. Our kidneys constantly filter blood, clearing out wastes that are removed via urine. So, Chung and her team will exploit the fact that most molecules in the bloodstream measuring less than 10 nanometers in diameter enter the kidneys, where they are gradually processed and eliminated from the body. This process will give nanoparticles time to bind there and release any therapeutic molecules they may be carrying directly to the cysts that cluster on the kidneys of people with ADPKD.

Chung’s research couldn’t be more timely. Though ADPKD isn’t curable right now, the Food and Drug Administration (FDA) last year approved Jynarque™ (tolvaptan), the first treatment in the United States to slow the decline in kidney function in ADPKD patients, based on tests of the rate of kidney filtration. Other approved drugs, such as metformin and rapamycin, have shown potential for repurposing to treat people with ADPKD. So, getting these and other potentially life-saving drugs directly to the kidneys, while minimizing the risk of serious side effects in the liver and elsewhere in the body, will be key.

Most FDA-approved nanoparticle therapies are administered intravenously, often for treatment of cancer. Because ADPKD is chronic and treatment can last for decades, Chung wants to develop an easy-to-take pill to get these nanoparticles into the kidneys.

But oral administration raises its own set of difficulties. The nanoparticles must get from the stomach and the rest of the gastrointestinal tract to the bloodstream. And then if nanoparticles exceed 10 nanometers in diameter, the body typically routes them to the liver for clearance, rather than the kidneys.

While Chung brainstorms strategies for oral administration, she’s also considering developing a smart bandage to allow the nanoparticles to pass readily through the skin and, eventually, into the bloodstream. It would be something similar to the wearable skin patch already featured on the blog.

In the meantime, Chung continues to optimize the size, shape, and surface charge of her nanoparticles. Right now, they have components to target the kidneys, provide a visual signal for tracking, enhance the nanoparticle’s lifespan, and carry a therapeutic molecule. Because positively charged molecules are preferentially attracted to the kidney, Chung has also spent untold hours adjusting the charge on her nanoparticles.

But through all the hard work, Chung and her team continue to prove that great things may one day come in very small packages. And that could ultimately prove to be a long-awaited gift for the millions of people living with ADPKD.

Links:

Polycystic Kidney Disease (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)

Video: Faculty Profile – Eun Ji Chung (University of Southern California, Los Angeles)

Chung Laboratory (USC)

Chung Project Information (NIH RePORTER)

NIH Director’s New Innovator Award (Common Fund)

NIH Support: Common Fund; National Institute of Diabetes and Digestive and Kidney Diseases


Can Childhood Stress Affect the Immune System?

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Katie Ehrlich

Katie Ehrlich
Credit: Alan Flurry, University of Georgia, Athens

Whether it’s growing up in gut-wrenching poverty, dealing with dysfunctional family dynamics, or coping with persistent bullying in school, extreme adversity can shatter a child’s sense of emotional well-being. But does it also place kids at higher of developing heart disease, diabetes, and other chronic health conditions as adults?

Katherine Ehrlich, a researcher at University of Georgia, Athens, wants to take a closer look at this question. She recently received a 2018 NIH Director’s New Innovator Award to study whether acute or chronic psychosocial stress during childhood might sensitize the body’s immune system to behave in ways that damage health, possibly over the course of a lifetime.


A Scientist Who Bends Musical Notes

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As a pioneer in cancer immunotherapy, Jim Allison has spent decades tackling major scientific challenges. So it’s interesting that Allison would consider one of the top five moments in his life jamming onstage with country star Willie Nelson. Yes, in addition to being a top-flight scientist at the University of Texas MD Anderson Cancer Center, Houston, Allison plays a mean harmonica.

Allison taught himself how to bend notes on the harmonica as a teenager growing up in a small Texas town. By his 20s, Allison was good enough to jam a couple of nights a week with the now legendary Clay Blaker & the Texas Honky Tonk Band. When Blaker asked if he wanted to hit the road with the band, Allison declined. He had his postdoctoral training to finish in molecular immunology.


From Songbird Science to Salsa Dancing

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Erich Jarvis spends his days at the Rockefeller University, New York, studying songbirds and searching for clues about the origins of language. But at least two nights a week, you won’t find this highly accomplished neurobiologist mulling over the latest neuroscience results or shooting an email to colleagues about their ongoing efforts to sequence bird genomes. He’ll be in the dance studio, practicing his latest salsa dancing moves.

In fact, before even considering a career as a scientist, Jarvis was a dancer. He danced ballet in grade school, later enrolling in New York’s High School of the Performing Arts as a dance major. Between academic classes, he spent three hours each day practicing ballet at school and, as a teen, another three hours each night practicing solos and pas de deux at the renowned Joffrey Ballet School and, later, the Alvin Ailey American Dance School. Jarvis even received an invitation as a high school senior to audition for the Alvin Ailey American Dance Theater.


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