Although a lifetime of immune-suppressing medicine is the standard regimen for transplant recipients, this comes with considerable dangers and side effects, including susceptibility to infection and decreased efficacy of vaccines.

Now, breakthrough research from a new University of Virginia biomedical engineering professor who recently joined both the School of Engineering and Applied Science and the School of Medicine is helping pioneer a new way for the body to accept transplanted organs without compromising the immune system.

Evan Scott is the Thomas A. Saunders III Family Jefferson Scholars Foundation Distinguished University Professor and David Goodman Family Bicentennial Professor of Nanomedicine in the biomedical engineering department, a joint program of UVA’s School of Engineering and Applied Science and School of Medicine, which he joins after 11 years at Northwestern University.

Scott is the co-author of a new article in the journal Proceedings of the National Academy of Science,describing a study in which Scott and fellow researchers used nanoparticles to make the cells of transplanted hearts in mice resistant to attack by their immune system.

“What we’re trying to do is modify the immune system in a controlled and therapeutic way, so that one day transplant patients won’t have to continuously take the immunosuppressive drugs that they do today, with all the risks they entail,” Scott said.

Beyond the area of transplant, Scott’s new lab at UVA will continue this line of research, which could have implications for other areas that deal with immune rejection, such as diabetes, cell therapy, and autoimmune disorders. He’ll also lead UVA’s Institute for Nanoscale Scientific and Technological Advanced Research, or NanoSTAR, as a part of the new Paul and Diane Manning Institute of Biotechnology.

“Evan’s innovative work with nanoparticles represents the kind of forward-thinking science that can reshape entire medical fields. We are thrilled to have him join our UVA community,” said Jennifer L. West, Dean of the School of Engineering and Saunders Family Professor of Engineering.

The Immune System’s Dilemma: Friend or Foe?

There are about 4,000 heart transplants in the United States each year, and the number is on the rise. However, in a significant percentage of cases, the body rejects the transplanted organ, misclassifying it as a threat and sending in the immune system to attack.

Existing treatments focus on one of two paths: suppressing the immune system so that it will not attack — but leaving the patient’s immune system compromised to viral and bacterial threats — or by building tolerance, which helps the body accept the new organ.

Scott and his lab are focused on the second approach; in the new study, he and his coauthors tried to rewire the cellular-level instructions that cause an immune system to attack a new organ, essentially retraining the immune system to tolerate the new cells.

The Role of Myeloid Cells in Organ Rejection

The body’s immune system uses a wide range of white blood cell types to address a diversity of threats and functions, including pathogenic infection, cancer and wound healing. Myeloid cells circulating in the blood stream are a particularly versatile white blood cell, capable of changing into several different forms as required by the task at hand. When they detect a threat, myeloid cells called monocytes can transform into inflammatory macrophages — attack cells that deal with intruders.

Targeting HIF-2α: A New Therapeutic Strategy

Dr. Scott’s long-term collaborator, Dr. Edward Thorp, discovered that these inflammatory macrophages didn’t always develop in response to transplanted cells. They found that a particular protein, HIF-2α, influenced this process, as it was present in the hearts of mice who accepted the transplant, but not present in those that rejected the new heart.

For researchers, this meant that the protein could be therapeutically targeted and used to signal to the host’s immune system that the newly transplanted heart cells were OK and do not need to be attacked, preventing the monocytes from transforming into inflammatory macrophages.

The research team therefore developed nanoparticles encapsulating the drug Roxadustat, which increases the levels of HIF-2α in monocyte. Since the spleen serves as a reservoir for monocytes, this organ was targeted by the nanoparticles to modify circulating white blood cells and maximize the effect of the therapy. This strategy ensured that a sufficient amount of circulating monocytes were modified to signal the immune system to specifically leave the transplanted heart cells alone while allowing the immune system itself to remain otherwise fully functional.

In the study, mice who received the treatment showed significantly better ability to accept their transplanted hearts.

“We specifically targeted the delivery of the drug directly to the spleen, which proved highly effective. This ability to modify how circulating monocytes respond to their environment has an immense and broad therapeutic potential for treating a variety of different disorders,” Scott said.

A team of Rice University chemical engineers led by Lisa Biswal has found that exposing a certain class of such particles — micron-sized beads endowed with a special magnetic sensitivity — to a rapidly alternating, rotating magnetic field causes them to organize into structures that are direction-dependent or anisotropic. The finding is significant because anisotropy can be manipulated to create new, tunable material structures and properties.

“Our key finding is that by alternating the direction of the rotation of the magnetic field after each revolution, we can create an anisotropic interaction potential between particles, which has not been fully realized before,” said Aldo Spatafora-Salazar, a chemical and biomolecular engineering research scientist in the Biswal lab and one of the lead authors on a study about the research published in Proceedings of the National Academy of Sciences.

Dana Lobmeyer, the other first author on the study, explained that the particles under scrutiny in the study are collectively known as superparamagnetic colloids whose responsiveness to magnetic fields makes them a popular building block for high-performance materials with tailored functionality.

“This discovery is significant for bottom-up advanced materials design, especially because we honed in on an aspect of the interaction between the colloids and magnetic fields that is usually overlooked — magnetic relaxation time,” said Lobmeyer, a Rice doctoral alumna advised by Biswal.

The relaxation time refers to the delay in the beads’ magnetic response to changes in field direction. The researchers hypothesized that this delay combined with the effect of the alternating magnetic field affects the beads’ interactions, causing them to arrange into a crystal lattice in two dimensions and to form elongated, aligned clusters in three dimensions.

“The delayed magnetic response, or magnetic relaxation time, of superparamagnetic beads was previously considered negligible, but what we found is that taking it into account and coupling it with the effect of the alternating magnetic field is a powerful way to exercise precise control over the particles,” said Biswal, the corresponding author on the study and Rice’s William M. McCardell Professor in Chemical Engineering, professor of materials science and nanoengineering and senior associate dean for faculty development.

The research involved a combination of experiments, simulations and theoretical predictions. Experimentally, the team looked at both concentrated and dilute bead suspensions combined with alternating magnetic fields of different intensities and frequencies.

“Concentrated beads formed elongated, aligned clusters, and we analyzed how different parameters influenced their shape,” said Spatafora-Salazar. “Dilute suspensions simplified the system, allowing us to study interactions between two beads — a version of the system known as a dimer.”

Experimental insights from dimers helped explain the alignment and elongation in larger clusters. However, experimental data only matched simulations once the magnetic relaxation time measurements (which form the subject of a separate forthcoming study) were taken into consideration.

One fun twist to the data was the Pac-Man shape described by the distribution of a bead’s magnetization: In a magnetized state, each bead acquires a dipole — a pair of negative and positive charges like a north-south axis. In response to a rotating magnetic field, the dipole moves like a compass needle, aligning all the beads along the same orientation. However, due to magnetic relaxation, the needle does not turn a full 360 degrees, leaving what shows up as Pac-Man’s mouth when the data is mapped out.

“The interactions are weakest along the mouth but strongest along the head, causing the alignment of dimers and clusters,” Lobmeyer said. “We would not have been able to understand this phenomenon without deviating from the traditional assumptions used to study these beads.”

Other authors include Rice alumni Lucas H.P. Cunha ’23 and former Rice postdoctoral fellow Kedar Joshi. The research was supported by the National Science Foundation (214112, 1828869) and the ACS Petroleum Research Fund (65274-ND9).

“Given that magic is about the conflict between perceptual processes and our beliefs, we should be able to experience magic in other senses, but it turned out to be really difficult,” says corresponding author Gustav Kuhn, an Associate Professor in Psychology at the University of Plymouth. “If you’re born blind, you’ll likely never have experienced a magic trick. Why is that? Can we create tricks that could be enjoyed and experienced by people with blindness?”

Only a handful of tricks involve other senses, like touch, and virtually none focus solely on auditory perception. But auditory illusions are everywhere. Stereo sound manipulates audio timing between the ears, creating the illusion of sound coming from different directions. Movies use the Shepard tone, an auditory illusion that gives the impression of an endlessly rising pitch, to build unease and tension that keeps the audience on edge.

So, why are auditory magic tricks rare? The researchers argue that the reason may stem from the fundamental differences between how the brain processes visual and auditory information. Humans are visual creatures. We tend to trust what we see more than what we hear, making us more surprised when our vision fools us.

Visual perception also reflects the state of the world, while auditory perception is transient. In other words, sound provides information about an event that has happened. Because magic relies on manipulating the perceived state of the world, this distinction between vision and sound may be at the heart of why auditory tricks are elusive.

“If you see a trumpet, you don’t say ‘I saw a perception of a trumpet,'” says Kuhn. “But if you hear a trumpet, you’re more likely to say, ‘I heard the sound of a trumpet.’ This is the kind of difference we don’t think about.”

Another possibility is that magicians simply never considered creating auditory tricks, though the team believes it’s unlikely given the creativity and history of the craft. Still, to find out, the team launched a competition challenging magicians to conjure tricks using only sound, with results expected in November 2024.

“Magic should not rely on vision alone, and yet it’s nearly impossible to perform a trick that does not involve our visual perception,” says Kuhn. “We don’t fully understand why yet, but this is an interesting question that invites more investigation into our senses and may help make magic more inclusive.”

This work was supported by the Agence Nationale de Recherche grant.

They argue that subsidies can alter market pressures, leading to unintended consequences that not only perpetuate harmful subsidies over time but also diminish the overall effectiveness of those intended to promote environmental sustainability.

Therefore, when they must be used, subsidies should have clear end-dates, advise the authors.

“We’ve got this odd juxtaposition of trying to get rid subsidies in some sectors, and then ramping up subsidies in others,” says lead author Kathleen Segerson, Board of Trustees Distinguished Professor of Economics at the University of Connecticut. “The question that interested me was: is this a good thing or a bad thing?”

Segerson and her coauthors are a group of internationally leading economists, ecologists, geographers, psychologists, and other scientists who convened for the 2022 Askö Workshop sponsored by the Beijer Institute for Ecological Economics in Stockholm, Sweden.

Subsidies can be powerful motivators that further environmental and sustainability goals, say the authors. For example, the United States’ Inflation Reduction Act of 2022 uses tax credits and incentives for things like electric vehicles (EVs), solar power, and wind power to meet its renewable energy and efficiency targets.

They can also be a politically easier approach to enacting change than creating new laws or taxes, says Segerson, and are even sometimes viewed as political capital, to ensure support from particular interest groups.

But some subsidies that appear to encourage sustainability are not so simple, the authors explain. Sometimes they can have negative spillover effects.

Take the case of EVs: Switching from gasoline-powered cars to EVs reduces greenhouse gas emissions. When subsidies for EVs and their technology create more inexpensive EVs, however, that market will expand, increasing overall vehicle use.

“When you’re subsidizing any industry, you’re essentially promoting that industry,” says Segerson.

But if subsidies instead went to increased infrastructure for and access to public transportation, more people might get rid of their cars, making the net positive environmental impact much greater.

“A subsidy that might have initially been viewed as beneficial for society might eventually be recognized as having costs that greatly exceed benefits,” the authors write.

Many subsidies in place for decades have long been identified by economists and environmentalists alike as actively contributing to climate change and biodiversity threats.

The authors cite that U.S. agricultural input subsidies have been shown to drive 17% of nitrogen pollution, while production subsidies account for 14% of global deforestation. In 2018, nearly 70% of $35.4 billion in fishing subsidies went to increasing fishing capacity through aid like fuel purchases, capital investment, and infrastructure, all of which contribute to overfishing.

Despite the leaders of the G20 committing to phasing out inefficient fossil fuel subsidies more than a decade ago, some sources estimate that there were still $1.3 trillion in global fossil fuel subsidies in 2022, owing to the considerable vested interest and political pressure from benefiting corporations to keep them in place.

In the United States, the Biden administration has tried repeatedly to repeal tax breaks for fossil fuels but hasn’t succeeded, leading a New York Times article to call the subsidies “zombies of the tax code: impossible to kill.”

From an economic efficiency perspective, it’s better to tax activities that generate negative effects, such as a carbon tax, says Segerson — but they are a hard sell.

“Environmental taxes are very difficult to get passed, so you’d rather have the subsidy than nothing,” she says.

Subsidies that reduce negative environmental impacts are therefore a second-best solution, she says. Imposing time limits is of great importance to ensure the subsidies that are the best we can do now can be removed when something better is possible.

“We can subsidize these greener production processes, but cautiously, and recognizing that we don’t want to have a reliance on these subsidies over the long term,” says Segerson.

The advantage of this new technique is that it can create brain activation without the use of an implanted device in the brain to deliver physical light, according to Manuel Gomez-Ramirez, an assistant professor of brain and cognitive sciences and with the University’s Del Monte Institute for Neuroscience, and the senior author of the study, which appears in the journal NeuroImage.

“BL-OG is an ideal method for noninvasively teasing apart neural circuits in the brain,” says Emily Murphy, the first author of the study and manager of the Haptics Lab, led by Gomez-Ramirez. “There are still so many things to learn about the structure and function of distinct brain areas and neuronal cell types that will help us understand how healthy brains function.”

How to turn on a light — without a switch

To turn on light in the brain, researchers need a few tools. The first one is optogenetics, an established research technique that uses light to activate or inactivate cells in the brain. The next tool is bioluminescence, the same chemical reaction that gives a firefly its glow, which provides the light optogenetics needs to work.

Combining these tools creates the material needed for BL-OG. But in order to work, BL-OG still needs something to “turn on” the light. The organic substance luciferin, when combined with bioluminescence, creates light that activates the optogenetics and modulates cellular response in the brain without an incision. Previous work by Gomez-Ramirez has shown that the chemical luciferin is harmless to the body.

The researchers in the Haptics Lab tested this combination. They put BL-OG into a pre-determined brain region in mice. They then injected luciferin through a vein in the animal’s tail to activate the targeted cells in the brain. They found that BL-OG effects occur rapidly in the brain, but that these effects could be controlled by scaling the dosage of the luciferin in the animal.

‘Fine-tuning’ bioluminescent optogenetics

“The advantage of this technique is we can create brain activation without a cable. There is less risk for infection and other things to go awry because it is a noninvasive method,” Gomez-Ramirez says. “If we want to standardize this technique in the lab, and potentially in the clinic, it is critical to map all the important parameters around using it. These latest findings allow us to now work on fine-tuning the desired effects of BL-OG based on need and requirements.”

Researchers were also able to track the neuromodulation effects of BL-OG through the bioluminescent activity, another potential feature of this method that could provide insight into how the brain works.

The Alfred P. Sloan Foundation supported this research.

According to a new study, colonies of ants began farming fungi when an asteroid struck Earth 66 million years ago. This impact caused a global mass extinction but also created ideal conditions for fungi to thrive. Innovative ants began cultivating the fungi, creating an evolutionary partnership that became even more tightly intertwined 27 million years ago and continues to this day.

In a paper published today, Oct. 3, in the journal Science, scientists at the Smithsonian’s National Museum of Natural History analyzed genetic data from hundreds of species of fungi and ants to craft detailed evolutionary trees. Comparing these trees allowed the researchers to create an evolutionary timeline of ant agriculture and pinpoint when ants first began cultivating fungi.

“Ants have been practicing agriculture and fungus farming for much longer than humans have existed,” said entomologist Ted Schultz, the museum’s curator of ants and the lead author of the new paper. “We could probably learn something from the agricultural success of these ants over the past 66 million years.”

Nearly 250 different species of ants in the Americas and Caribbean farm fungi. Researchers organize these ants into four agricultural systems based on their cultivation strategies. Leafcutter ants are among those that practice the most advanced strategy, known as higher agriculture. These ants harvest bits of fresh vegetation to provide sustenance for their fungi, which in turn grow food for the ants called gongylidia. This food helps fuel complex colonies of leaf cutter ants that can number in the millions.

Schultz has spent 35 years studying the evolutionary relationship between ants and fungi. He has conducted more than 30 expeditions to locales in Central and South America to observe this interaction in the wild and has reared colonies of leafcutter and other fungus-farming ants in his lab at the museum. Over the years, Schultz and colleagues have collected thousands of genetic samples of ants and fungi from throughout the tropics.

This stockpile of samples was crucial to the new paper.

“To really detect patterns and reconstruct how this association has evolved through time, you need lots of samples of ants and their fungal cultivars,” Schultz said.

The team used the samples to sequence genetic data for 475 different species of fungi (288 of which are cultivated by ants) and 276 different species of ants (208 of which cultivate fungi) — the largest genetic dataset of fungus-farming ants ever assembled. This allowed the researchers to create evolutionary trees of the two groups. Comparing wild fungal species with their cultivated relatives helped the researchers determine when ants began utilizing certain fungi.

The data revealed that ants and fungi have been intertwined for 66 million years. This is around the time when an asteroid struck Earth at the end of the Cretaceous period. This cataclysmic collision filled the atmosphere with dust and debris, which blocked out the sun and prevented photosynthesis for years. The resulting mass extinction wiped out roughly half of all plant species on Earth at the time.

However, this catastrophe was a boon for fungi. These organisms proliferated as they consumed the plentiful dead plant material littering the ground.

“Extinction events can be huge disasters for most organisms, but it can actually be positive for others,” Schultz said. “At the end of Cretaceous, dinosaurs did not do very well, but fungi experienced a heyday.”

Many of the fungi that proliferated during this period likely feasted on decaying leaf litter, which brought them in close contact with ants. These insects harnessed the plentiful fungi for food and continued to rely on the hardy fungi as life rebounded from the extinction event.

The new work also revealed that it took nearly another 40 million years for ants to then develop higher agriculture. The researchers were able to trace the origin of this advanced practice back to around 27 million years ago. At this time, a rapidly cooling climate transformed environments around the globe. In South America, drier habitats like woody savannas and grasslands fractured large swaths of wet, tropical forests. When ants took fungi out of the wet forests and into drier areas, they isolated the fungi from their wild ancestral populations. The isolated fungi became completely reliant on ants to survive in the arid conditions, setting the course for the higher agriculture system practiced by leafcutter ants today.

“The ants domesticated these fungi in the same way that humans domesticated crops,” Schultz said. “What’s extraordinary is now we can date when the higher ants originally cultivated the higher fungi.”

In addition to Schultz, the new paper included contributions from several coauthors affiliated with the National Museum of Natural History, including Jeffrey Sosa-Calvo, Matthew Kweskin, Michael Lloyd, Ana Ješovnik and Scott E. Solomon. The study also includes authors affiliated with the University of Utah; the Royal Botanic Gardens, Kew; the University of California at Berkeley; the U.S. Department of Agriculture; São Paulo State University; the Instituto de Investigaciones Científicas y Servicios de Alta Tecnología; the Smithsonian Tropical Research Institute; the University of Copenhagen; Emory University; McMaster University; Universidade Federal de Uberlândia; Arizona State University; the University of Hohenheim; and Louisiana State University.

The research was supported by the U.S. National Science Foundation; the Smithsonian; the University of Maryland; Louisiana State Board of Regents; Sistema Nacional de Investigación; Cosmos Club Foundation; Explorer’s Club in Washington, D.C.; São Paulo Research Foundation; Brazilian Council of Research and Scientific Development; Brazilian Federal Agency for Support and Evaluation of Graduate Education; the Royal Botanic Gardens, Kew; and the Carl Zeiss Foundation.