Dr. Francis Collins
Posted on by Dr. Francis Collins
Seeing the development of an organ under a microscope for the first time can be a truly unforgettable experience. But for a class taught by Crystal Rogers at California State University, Northridge, it can also be an award-winning moment.
This image, prepared during a biology lab course, was one of the winners in the 2018 BioArt Scientific Image & Video Competition, sponsored by the Federation of American Societies for Experimental Biology (FASEB). This colorful image shows the tip of an ovary from a fruit fly (Drosophila melanogaster), provided by Mariano Loza-Coll. You can see that the ovary is packed with oocytes (DNA stained blue). The orderly connective structure (pink) and signal-transmitting molecules like STAT (yellow) are common to egg maturation and reproductive processes in humans.
What makes this image unique among this year’s BioArt winners is that the prep work was done by undergraduate students just learning how to work in a lab. They did the tissue dissections, molecular labeling, and beautiful stainings in preparation for Rogers to “snap” the photo on her research lab’s optical-sectioning microscope.
What’s also fantastic is that many of Rogers’s students are from groups traditionally underrepresented in biomedicine. Many are considering careers in research and, from the looks of things, they are off to a beautiful start.
After teaching classes, Rogers also has an NIH-supported lab to run. She and her team study salamanders and chickens to determine how biological “glue” proteins, called cadherins, help to create neural crest cells, a critical cell type that arises very early in development .
For developmental biologists, it’s essential to understand what prompts these neural crest cells to migrate to locations throughout the body, from the heart to the skin to the cranium, or head. For example, cranial neural crest cells at first produce what appears to be the same generic, undifferentiated facial template in vertebrate species. And yet, neural crest cells and the surrounding ectodermal cells go on to generate craniofacial structures as distinct as the beak of a toucan, the tusk of a boar, or the horn of a rhinoceros.
But if the organ of interest is an ovary, the fruit fly has long been a go-to organism to learn more. Not only does the fruit fly open a window into ovarian development and health issues like infertility, it showcases the extraordinary beauty of biology.
 A catenin-dependent balance between N-cadherin and E-cadherin controls neuroectodermal cell fate choices. Rogers CD, Sorrells LK, Bronner ME. Mech Dev. 2018 Aug;152:44-56.
Rogers Lab (California State University, Northridge)
BioArt Scientific Image & Video Competition (Federation of American Societies for Experimental Biology, Bethesda, MD)
NIH Support: Eunice Kennedy Shriver National Institute of Child Health and Human Development
Posted on by Dr. Francis Collins
People with diabetes often must inject insulin multiple times a day to keep their blood glucose levels under control. So, I was intrigued to learn that NIH-funded bioengineers have designed a new kind of “pill” that may someday reduce the need for those uncomfortable shots. The inspiration for their design? A tortoise!
The new “pill”—actually, a swallowable device containing a tiny injection system—is shaped like the shell of an African leopard tortoise. In much the same way that the animal’s highly curved shell enables it to quickly right itself when flipped on its back, the shape of the new device is intended to help it land in the right position to inject insulin or other medicines into the stomach wall.
The hunt for a means to deliver insulin in pill form has been on ever since insulin injections first were introduced, nearly a century ago. The challenge in oral delivery of insulin and other “biologic” drugs—including therapeutic proteins, peptides, or nucleic acids—is how to get these large biomolecules through the highly acidic stomach and duodenum, where multiple powerful digestive enzymes reside, and into the bloodstream unscathed. Past efforts to address this challenge have met with only limited success.
In a study published in the journal Science, a team, led by Robert Langer at Massachusetts Institute of Technology, Cambridge, and Giovanni Traverso, Brigham and Women’s Hospital, Harvard Medical School, Boston, took a new approach to the problem by developing a tiny, ingestible injection system . They call their pea-sized device SOMA, short for “self-orienting millimeter-scale applicator.”
In designing SOMA, the researchers knew they had to come up with a design that would orient the injection apparatus correctly. So they looked to the African leopard tortoise. They knew that, much like a child’s “weeble-wobble” toy, this tortoise can easily right its body if tipped over due to its low center of gravity and highly curved shell. With the shape of the tortoise shell as a starting point, the researchers used computer modeling to perfect their design. The final result features a partially hollowed-out, polymer-and-steel capsule that houses a tiny, spring-loaded needle tipped with compressed, freeze-dried insulin. There is also a dissolvable sugar disk to hold the needle in place until the time is right.
Here’s how it works: once a SOMA is swallowed and reaches the stomach, it quickly orients itself in a way that its needle-side rests against the stomach wall. After the protective sugar disk dissolves in stomach acid, the spring-loaded needle tipped with insulin is released, injecting its load of insulin into the stomach wall, from which it enters the bloodstream. Meanwhile, the spent SOMA device passes on through the digestive system.
The researchers’ tests in pigs have shown that a single SOMA can successfully deliver insulin doses of up to 3 milligrams, comparable to the amount a human with diabetes might need to inject. The tests also showed that the device’s microinjection did not damage the animals’ stomach tissue or the muscles surrounding the stomach. Because the stomach is known for being insensitive to pain, researchers expect that people receiving insulin via SOMA wouldn’t feel a thing, but much more research is needed to confirm both the safety and efficacy of the new device for human use.
Meanwhile, this fascinating work serves as a reminder that when it comes to biomedical science, inspiration sometimes can come from the most unexpected places.
 An ingestible self-orienting system for oral delivery of macromolecules. Abramson A, Caffarel-Salvador E, Khang M, Dellal D, Silverstein D, Gao Y, Frederiksen MR, Vegge A, Hubálek F, Water JJ, Friderichsen AV, Fels J, Kirk RK, Cleveland C, Collins J, Tamang S, Hayward A, Landh T, Buckley ST, Roxhed N, Rahbek U, Langer R, Traverso G. Science. 2019 Feb 8;363(6427):611-615.
Diabetes (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)
Langer Lab (MIT, Cambridge)
Giovanni Traverso (Brigham and Women’s Hospital, Harvard Medical School, Boston)
NIH Support: National Institute of Biomedical Imaging and Bioengineering
Posted on by Dr. Francis Collins
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. 
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.
 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.
Stroke Information (National Institute of Neurological Disorders and Stroke/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