Chronic wounds are open wounds that heal slowly, if they heal at all. For example, sores that occur in some patients with diabetes are chronic wounds. These wounds are particularly problematic because they often recur after treatment and significantly increase the risk of amputation and death.

One of the challenges associated with chronic wounds is that existing treatment options are extremely expensive, which can create additional problems for patients.

“Our goal here was to develop a far less expensive technology that accelerates healing in patients with chronic wounds,” says Amay Bandodkar, co-corresponding author of the work and an assistant professor of electrical and computer engineering at North Carolina State University. “We also wanted to make sure that the technology is easy enough for people to use at home, rather than something that patients can only receive in clinical settings.”

“This project is part of a bigger DARPA project to accelerate wound healing with personalized wound dressings,” says Sam Sia, co-corresponding author of the work and professor of biomedical engineering at Columbia University. “This collaborative project shows that these lightweight bandages, which can provide electrical stimulation simply by adding water, healed wounds faster than the control, at a similar rate as bulkier and more expensive wound treatment.”

Specifically, the research team developed water-powered, electronics-free dressings (WPEDs), which are disposable wound dressings that have electrodes on one side and a small, biocompatible battery on the other. The dressing is applied to a patient so that the electrodes come into contact with the wound. A drop of water is then applied to the battery, activating it. Once activated, the bandage produces an electric field for several hours.

“That electric field is critical, because it’s well established that electric fields accelerate healing in chronic wounds,” says Rajaram Kaveti, co-first author of the study and a post-doctoral researcher at NC State.

The electrodes are designed in a way that allows them to bend with the bandage and conform to the surface of the chronic wounds, which are often deep and irregularly shaped.

“This ability to conform is critical, because we want the electric field to be directed from the periphery of the wound toward the wound’s center,” says Kaveti. “In order to focus the electric field effectively, you want electrodes to be in contact with the patient at both the periphery and center of the wound itself. And since these wounds can be asymmetrical and deep, you need to have electrodes that can conform to a wide variety of surface features.”

“We tested the wound dressings in diabetic mice, which are a commonly used model for human wound healing,” says Maggie Jakus, co-first author of the study and a graduate student at Columbia. “We found that the electrical stimulation from the device sped up the rate of wound closure, promoted new blood vessel formation, and reduced inflammation, all of which point to overall improved wound healing.”

Specifically, the researchers found that mice who received treatment with WPEDs healed about 30% faster than mice who received conventional bandages.

“But it is equally important that these bandages can be produced at relatively low cost — we’re talking about a couple of dollars per dressing in overhead costs.” says Bandodkar.

“Diabetic foot ulceration is a serious problem that can lead to lower extremity amputations,” says Aristidis Veves, a co-author of the study and professor of surgery at Beth Israel Deaconess Center. “There is urgent need for new therapeutic approaches, as the last one that was approved by the Food and Drug Administration was developed more than 25 years ago. My team is very lucky to participate in this project that investigates innovative and efficient new techniques that have the potential to revolutionize the management of diabetic foot ulcers.”

In addition, the WPEDs can be applied quickly and easily. And once applied, patients can move around and take part in daily activities. This functionality means that patients can receive treatment at home and are more likely to comply with treatment. In other words, patients are less likely to skip treatment sessions or take shortcuts, since they aren’t required to come to a clinic or remain immobile for hours.

“Next steps for us include additional work to fine-tune our ability to reduce fluctuations in the electric field and extend the duration of the field. We are also moving forward with additional testing that will get us closer to clinical trials and — ultimately — practical use that can help people,” says Bandodkar.

The paper, “Water-powered, electronics-free dressings that electrically stimulate wounds for rapid wound closure,” will be published Aug. 7 in the open-access journal Science Advances. The paper’s co-authors include Henry Chen, an undergraduate in the joint biomedical engineering department at NC State and UNC; Bhavya Jain, Navya Mishra, Nivesh Sharma and Baha Erim Uzuno?lu, Ph.D. students at NC State; Darragh Kennedy and Elizabeth Caso of Columbia; Georgios Theocharidis and Brandon Sumpio of Beth Israel Deaconess Medical Center; Won Bae Han of Korea University and the Georgia Institute of Technology; Tae-Min Jang of Korea University; and Suk-Won Hwang of Korea University and the Korea Institute of Science and Technology.

This work was done with support from the Defense Advanced Research Projects Agency under grant D20AC00004 and from the Center for Advanced Self-Powered Systems of Integrated Sensors and Technologies at NC State, which is funded by National Science Foundation grant 1160483. Bandodkar and Kaveti are inventors on a patent application related to this work.

As with humans, nematodes’ guts are a common target of disease-causing bacteria. The nematode reacts by destroying iron-containing organelles called mitochondria, which produce a cell’s energy, to protect this critical element from iron-stealing bacteria. Iron is a key catalyst in many enzymatic reactions in cells — in particular, the generation of the body’s energy currency, ATP (adenosine triphophate).

The presence in C. elegans of this protective response to odors produced by microbes suggests that the intestinal cells of other organisms, including mammals, may also retain the ability to respond protectively to the smell of pathogens, said the study’s senior author, Andrew Dillin, UC Berkeley professor of molecular and cell biology and a Howard Hughes Medical Institute (HHMI) investigator.

“Is there actually a smell coming off of pathogens that we can pick up on and help us fight off an infection?” he said. “We’ve been trying to show this in mice. If we can actually figure out that humans smell a pathogen and subsequently protect themselves, you can envision down the road something like a pathogen-protecting perfume.”

So far, however, there’s only evidence of this response in C. elegans. Nevertheless, the new finding is a surprise, considering that the nematode is one of the most thoroughly studied organisms in the laboratory. Biologists have counted and tracked every cell in the organism from embryo to death.

“The novelty is that C. elegans is getting ready for a pathogen before it even meets the pathogen,” said Julian Dishart, who recently received his UC Berkeley Ph.D. and is the first author of the study. “There’s also evidence that there’s probably a lot more going on in addition to this mitochondrial response, that there might be more of a generalized immune response just by smelling bacterial odors. Because olfaction is conserved in animals, in terms of regulating physiology and metabolism, I think it’s totally possible that smell is doing something similar in mammals as it’s doing in C. elegans.”

The work was published June 21 in the journal Science Advances.

Mitochondria communicate with one another

Dillin is a pioneer in studying how stress in the nervous system triggers protective responses in cells — in particular, the activation of a suite of genes that stabilize proteins made in the endoplasmic reticulum. This activation, the so-called unfolded protein response (UPR), is “like a first aid kit for the mitochondria,” he said.

Mitochondria are not only the powerhouses of the cell, burning nutrients for energy, but also play a key role in signaling, cell death and growth.

Dillin has shown that errors in the UPR network can lead to disease and aging, and that mitochondrial stress in one cell is communicated to the mitochondria of cells throughout the body.

One key piece of the puzzle was missing, however. If the nervous system can communicate stress through a network of neurons to the cells doing the day-to-day work of protein building and metabolism, what in the environment triggers the nervous system?

“Our nervous system evolved to pick up on cues from the environment and create homeostasis for the entire organism,” Dillin said. “Julian actually figured out that smell neurons are picking up environmental cues and which types of odorants from the pathogens turn on this response.”

Previous work in Dillin’s lab showed the importance of smell in mammalian metabolism. When mice are deprived of smell, he found, they gained less weight while eating the same amount of food as normal mice. Dillin and Dishart suspect that the smell of food may trigger a protective response, like the response to pathogens, in order to prepare the gut for the damaging effects of ingesting foreign substances and converting that food to fuel.

“Surviving infections was the most important thing we did evolutionarily,” Dillin said. “And the most risky and taxing thing we do every single day is eat, because pathogens are going to be in our food.”

“When you eat food, it’s also incredibly stressful, because the body is metabolizing the food but also generating ATP in the mitochondria from the nutrients that they’re incorporating. And that generation of ATP causes a by-product called reactive oxygen species, which is very damaging to cells,” Dishart said. “Cells have to deal with this increased existence of reactive oxygen species. So perhaps smelling food can prepare us to deal with that enhanced reactive oxygen species load.”

Dillin speculates further that mitochondria’s sensitivity to the smell of pathogenic bacteria may be a holdover from an era when mitochondria were free-living bacteria, before they were incorporated into other cells as power plants to become eukaryotes some 2 billion years ago. Eukaryotes eventually evolved into multicellular organisms with differentiated organs — so-called metazoans, like animals and humans.

“There’s a lot of evidence that bacteria sense their environment in some way, though it’s not always clear how they do it. These mitochondria have retained one aspect of that after being subsumed into metazoans,” he said.

In his experiments with C. elegans, Dishart found that the smell of pathogens triggers an inhibitory response, which unleashes a signal to the rest of the body. This became clear when he ablated olfactory neurons in the worm and found that all peripheral cells, but primarily intestinal cells, showed the stress response typical of mitochondria that are being threatened. This study and others also showed that serotonin is a key neurotransmitter communicating this information throughout the body.

Dillin and his lab colleagues are tracking the neural circuits that lead from smell neurons to peripheral cells and the neurotransmitters involved along the way. And he’s looking for a similar response in mice.

“I always hate it when I get sick. I’m like, ‘Body, why didn’t you prepare for this better?’ It seems really stupid that you turn on response mechanisms only once you’re infected,” Dillin said. “If there are earlier detection mechanisms to increase our chances of survival, I think that’s a huge evolutionary win. And if we could harness that biomedically, that would be pretty wild.”

Other UC Berkeley authors of the paper are Corinne Pender, Koning Shen, Hanlin Zhang, Megan Ly and Madison Webb. The work is supported by HHMI and the National Institutes of Health (R01ES021667, F32AG065381, K99AG071935).

Now, a new study from Simon Fraser University has given scientists the clearest picture yet when the giant mammals roamed Vancouver Island.

As part of SFU researcher Laura Termes’ PhD and published earlier this month in the Canadian Journal of Earth Sciences, the study examined 32 suspected mammoth samples collected on Vancouver Island. Of those samples, just 16 were deemed suitable for radiocarbon dating.

The youngest sample was found to be around 23,000 years old and the oldest turned out to be beyond the range radiocarbon dating could measure, meaning it was older than 45,000 years.

Prior to the study, only two mammoth remains found on Vancouver Island had ever been dated before. Both lived around 21,000 years ago, so the Termes’ study provides a greater understanding of when the massive mammals lived in the area.

“This is really exciting because it shows that mammoths have lived on Vancouver Island for a long time,” says Termes, a PhD candidate in the Department of Archaeology. “We were expecting similar results [to the two samples previously dated] but what we found were mammoths that were much older. It is fantastic that they could be preserved for that long.”

Termes says having the curatorial support at the Royal BC Museum and the Courtenay and District Museum and Palaeontology Centre allowing access to their collections was invaluable to the study.

“This research highlights the important role of museum collections for understanding how life has evolved and changed in British Columbia’s deep history,” says Victoria Arbour, curator of palentology at the Royal BC Museum. “It’s great to see Woolly’s relatives in the Royal BC Museum’s collections in the spotlight through this research study.”

The UBC ADaPT Facility (which was instrumental in helping determine if samples were indeed mammoths and not whales or other animals) also played an important role in the research, Termes says.

And archaeologists need all the help they can get because while mammoths were enormous, finding intact samples in British Columbia is actually quite rare.

“When we imagine great big giant animals of the last ice age being found, we might have imagined fully articulated and complete skeletons being systematically excavated. But in southern B.C., that simply does not happen,” says Termes. “Instead, we may get an isolated molar that’s been tumbled around in the water for a long time, or maybe a piece of a tusk. And these are what everyday people are encountering.”

For example, one sample she examined was a piece of mammoth tooth found by a child in the gravel at a local playground.

“So maybe it’s a dog owner, taking their puppy for a walk on a rainy day, or a gravel pit operator at work,” says Termes, who grew up in Qualicum Beach. “I really like how these magnificent animals are finding their way into people’s lives in routine and everyday ways.”

Termes says the study is part of a larger look at megafauna in B.C. and she plans on radiocarbon dating mammoth samples from other parts of the province.

In a groundbreaking study published Aug. 7 in Science Advances, researchers from the University of Chicago, Northwestern University, and the University of Central Florida have proposed a revolutionary approach towards terraforming Mars. This new method, using engineered dust particles released to the atmosphere, could potentially warm the Red Planet by more than 50 degrees Fahrenheit, to temperatures suitable for microbial life — a crucial first step towards making Mars habitable.

The proposed method is over 5,000 times more efficient than previous schemes to globally warm Mars, representing a significant leap forward in our ability to modify the Martian environment.

What sets this approach apart is its use of resources readily available on Mars, making it far more feasible than earlier proposals that relied on importing materials from Earth or mining rare Martian resources.

This strategy would take decades. But it appears logistically easier than other plans proposed so far.

“This suggests that the barrier to warming Mars to allow liquid water is not as high as previously thought,” said Edwin Kite, an associate professor of geophysical sciences at the University of Chicago and corresponding author on the study. The lead author was Samaneh Ansari, a graduate student in Prof. Hooman Mohseni’s group at Northwestern University.

Astronauts still won’t be able to breathe Mars’ thin air; making the planet suitable for humans to walk on the surface unaided requires much more work. But perhaps groundwork could be laid, by making the planet habitable for microbes and food crops that could gradually add oxygen to the atmosphere — much as they have done for Earth during its geologic history.

A new approach to an age-old dream

There is a rich history of proposals to make Mars habitable; Carl Sagan himself came up with one back in 1971. These have ranged from outright daydreams, such as science fiction writers depicting turning one of Mars’ moons into a sun, to more recent and scientifically plausible ideas, such as engineering transparent gel tiles to trap heat.

Any plan to make Mars habitable must address several hurdles, including deadly UV rays and salty soil. But the biggest is the planet’s temperature; the surface of Mars averages about -80 degrees Fahrenheit.

One strategy to warm the planet could be the same method that humans are unintentionally using here on Earth: releasing material into the atmosphere, which would enhance Mars’ natural greenhouse effect, trapping solar heat at the surface.

The trouble is that you would need tons of these materials — literally. Previous schemes depended on bringing gases from Earth to Mars, or attempting to mine Mars for a large mass of ingredients that aren’t very common there — both are costly and difficult propositions. But the team wondered whether it could be done by processing materials that already exist abundantly on Mars.

We know from rovers like Curiosity that dust on Mars is rich in iron and aluminum. By themselves, those dust particles aren’t suitable to warm the planet; their size and composition mean they tend to cool the surface slightly rather than warm it. But if we engineered dust particles that had different shapes or compositions, the researchers hypothesized, perhaps they could trap heat more efficiently.

The researchers designed particles shaped like short rods — similar in size to commercially available glitter. These particles are designed to trap escaping heat and scatter sunlight towards the surface, enhancing Mars’ natural greenhouse effect.

“How light interacts with sub-wavelength objects is fascinating. Importantly, engineering

nanoparticles can lead to optical effects that far exceed what is conventionally expected from

such small particles,” said Ansari. Mohseni, who is a co-author, believes that they have just scratched the surface: “We believe it is possible to design nanoparticles with higher efficiency, and even those that can dynamically change their optical properties.”

“You’d still need millions of tons to warm the planet, but that’s five thousand times less than you would need with previous proposals to globally warm Mars,” said Kite. “This significantly increases the feasibility of the project.”

Calculations indicate that if the particles were released into Mars’ atmosphere continuously at 30 liters per second, the planet would warm by more than 50 degrees Fahrenheit — and the effect could be noticeable within as soon as months. Similarly, the warming would be reversible, stopping within a few years if release was switched off.

Potential impact and future research

Much work remains to be done, the scientists said. We don’t know exactly how fast the engineered dust would cycle out of Mars’ atmosphere, for example. Mars does have water and clouds, and, as the planet warms, it’s possible that water would increasingly start to condense around the particles and fall back to the surface as rain.

“Climate feedbacks are really difficult to model accurately,” Kite cautioned. “To implement something like this, we would need more data from both Mars and Earth, and we’d need to proceed slowly and reversibly to ensure the effects work as intended.”

While this method represents a significant leap forward in terraforming research, the researchers emphasize that the study focuses on warming Mars to temperatures suitable for microbial life and possibly growing food crops — not on creating a breathable atmosphere for humans.

“This research opens new avenues for exploration and potentially brings us one step closer to the long-held dream of establishing a sustainable human presence on Mars,” said Kite.

Ansari is the lead author of the study. Other coauthors of the study were Ramses Ramirez of the University of Central Florida and Liam Steele, formerly a postdoctoral researcher at UChicago, now with the European Center for Medium-Range Weather Forecasts.

The authors used the Quest high-performance computing facility at Northwestern and the University of Chicago Research Computing Center.

With a goal of understanding and addressing immunotherapy’s limitations, researchers at Washington University School of Medicine in St Louis have found that the immune system can be its own worst enemy in the fight against cancer. In a new study in mice, a subset of immune cells — type 1 regulatory T cells, or Tr1 cells — did its normal job of preventing the immune system from overreacting but did so while inadvertently restraining immunotherapy’s cancer-fighting power.

“Tr1 cells were found to be a heretofore unrecognized obstacle to immunotherapy’s effectiveness against cancer,” said senior author Robert D. Schreiber, PhD, the Andrew M. and Jane M. Bursky Distinguished Professor in the Department of Pathology & Immunology, and director of the Bursky Center for Human Immunology & Immunotherapy at Washington University School of Medicine. “By removing or circumventing that barrier in mice, we successfully reenergized the immune system’s cancer-fighting cells and uncovered an opportunity to expand the benefits of immunotherapy for more cancer patients.”

The study is available in Nature.

Cancer vaccines represent a new approach to personalize cancer immunotherapy. Aimed at the mutant proteins specific to a patient’s tumor, such vaccines induce killer T cells to attack tumor cells while leaving healthy cells unharmed. Schreiber’s group previously showed that more effective vaccines also activate helper T cells, another immune cell type, that recruit and expand additional killer T cells to destroy the tumors. But when they tried to add increased amounts of the helper T cell target to supercharge the vaccine they found they generated a different type of T cell that inhibited rather than promoted tumor rejection.

“We tested the hypothesis that by increasing helper T cell activation we would induce enhanced elimination of the sarcoma tumors in mice,” said first author Hussein Sultan, PhD, an instructor in pathology & immunology. So he injected groups of tumor bearing mice with vaccines that activated killer T cells equally while triggering a different degree of helper T cell activation.

Much to the researchers’ surprise in this latest study, the vaccine meant to hyperactivate helper T cells produced the opposite effect and inhibited tumor rejection.

“We thought that more helper T cell activation would optimize elimination of the sarcoma tumors in mice,” Sultan said. “Instead, we found that vaccines containing high doses of helper T cell targets induced inhibitory Tr1 cells that completely blocked tumor elimination. We know that Tr1 cells normally control an overactive immune system, but this is the first time they have been shown to dampen its fight against cancer.”

Tr1 cells normally put the brakes on the immune system to prevent it from attacking the body’s healthy cells. But their role in cancer has not been seriously explored. Looking through previously published data, the researchers found that tumors from patients who had responded poorly to immunotherapy had more Tr1 cells compared with tumors of patients who had responded well. The number of Tr1 cells also increased in mice as tumors grew bigger, rendering the mice insensitive to immunotherapy.

To bypass the inhibiting cells, the researchers treated the vaccinated mice with a drug that enhances killer T cells’ fighting power. The drug, developed by biotechnology startup Asher Biotherapeutics, carries modifications in the immune-boosting protein called interleukin 2 (IL-2) that specifically revs up killer T cells and reduces the toxicity of unmodified IL-2 treatments. The additional boost from the drug overcame Tr1 cells’ inhibition and rendered the immunotherapy more effective.

“We are committed to personalizing immunotherapy and broadening its effectiveness,” said Schreiber. “Decades of researching basic tumor immunology have expanded our understanding of how to trigger the immune system to achieve the most robust antitumor response. This new study adds to our understanding of how to improve immunotherapy to benefit more people.”

As co-founder of Asher Biotherapeutics — which provided the mouse version of the modified IL-2 drugs — Schreiber is indirectly involved in the company’s clinical trials testing the human version of the drug as a monotherapy in cancer patients. If successful, the drug has the potential to be tested in combination with cancer treatment vaccines.