Searching for ancient bears in an Alaskan cave led to an important human discovery

The first people to live in the Americas migrated from Siberia across the Bering land bridge more than 20,000 years ago. Some made their way as far south as Tierra del Fuego, at the tip of South America. Others settled in areas much closer to their place of origin where their descendants still thrive today.

In "A paleogenome from a Holocene individual supports genetic continuity in Southeast Alaska," published Friday in the journal iScience, University at Buffalo evolutionary biologist Charlotte Lindqvist and collaborators show, using ancient genetic data analyses, that some modern Alaska Natives still live almost exactly where their ancestors did some 3,000 years ago.

Lindqvist, PhD, associate professor of biological sciences in the UB College of Arts and Sciences, is senior author of the paper. In the course of her extensive studies in Alaska, she explored mammal remains that had been found in a cave in the state's southeast coast. One bone was initially identified as coming from a bear. However, genetic analysis showed it to be the remains of a human female.

"We realized that modern Indigenous peoples in Alaska, should they have remained in the region since the earliest migrations, could be related to this prehistoric individual," says Alber Aqil, a UB PhD student in biological sciences and the first author of the paper. This discovery led to efforts to solve this mystery, which DNA analyses are well suited to address when archeological remains are as sparse as these were.

Learning from an ancestor

The earliest peoples had already started moving south along the Pacific Northwest Coast before an inland route between ice sheets became viable. Some, including the female individual from the cave, made their home in the area that surrounds the Gulf of Alaska. That area is now home to the Tlingit Nation and three other groups: Haida, Tsimshian, and Nisga'a.

As Aqil and colleagues analyzed the genome from this 3,000-year-old individual -- "research that was not possible just 20 years ago," Lindqvist noted -- they determined that she is most closely related to Alaska Natives living in the area today. This fact showed it was necessary to carefully document as clearly as possible any genetic connections of the ancient female to present-day Native Americans.

In such endeavors, it is important to collaborate closely with people living in lands where archeological remains are found. Therefore, cooperation between Alaska Native peoples and the scientific community has been a significant component of the cave explorations that have taken place in the region. The Wrangell Cooperative Association named the ancient individual analyzed in this study as "Tatóok yík yées sháawat" (Young lady in cave).

Genetic continuity in Southeast Alaska persists for thousands of years

Indeed, Aqil and Lindqvist's research demonstrated that Tatóok yík yées sháawat is in fact closest related to present-day Tlingit peoples and those of nearby tribes along the coast. Their research therefore strengthens the idea that genetic continuity in Southeast Alaska has continued for thousands of years.

Human migration into North America, although it began some 24,000 years ago, came in waves -- one of which, about 6,000 years ago -- included the Paleo-Inuit, formerly known as Paleo-Eskimos. Importantly for understanding Indigenous peoples' migrations from Asia, Tatóok yík yées sháawat'sDNA did not reveal ancestry from the second wave of settlers, the Paleo-Inuit. Indeed, the analyses performed by Aqil and Lindqvist helped shed light on the continuing discussion of migration routes, mixtures among people from these different waves, as well as modern territorial patterns of inland and coastal people of the Pacific Northwest in the pre-colonial era.

Oral history links an ancient woman to people living in Southeast Alaska today

The oral origin narratives of the Tlingit people include the story of the most recent eruption of Mount Edgecumbe, which would place them exactly in the region by 4,500 years ago. Tatóok yík yées sháawat, their relative, therefore informs not just modern-day anthropological researchers but also the Tlingit people themselves.

Out of respect for the right of the Tlingit people to control and protect their cultural heritage and their genetic resources, data from the study of Tatóok yík yées sháawat will be available only after review of its use by the Wrangell Cooperative Association Tribal Council.

"It's very exciting to contribute to our knowledge of the prehistory of Southeast Alaska," said Aqil.

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Global research reveals countries where record-breaking heatwaves are likely to cause most harm

A new study has highlighted under-prepared regions across the world most at risk of the devastating effects of scorching temperatures.

The University of Bristol-led research, published today in Nature Communications, shows that unprecedented heat extremes combined with socioeconomic vulnerability puts certain regions, such as Afghanistan, Papua New Guinea, and Central America,most in peril.

Countries yet to experience the most intense heatwaves are often especially susceptible, as adaptation measures are often only introduced after the event. A high chance of record-breaking temperatures, growing populations, and limited healthcare and energy provision, increase the risks.

Beijing and Central Europe are also on the list of hotspots, as if record-breaking heatwaves occurred in these densely populated regions millions of people would be adversely affected.

In light of the findings, the researchers are calling for policy makers in hotspot regions to consider relevant action plans to reduce the risk of deaths and associated harms from climate extremes.

Lead author, climate scientist Dr Vikki Thompson at the University of Bristol Cabot Institute for the Environment, said: "As heatwaves are occurring more often we need to be better prepared. We identify regions that may have been lucky so far -- some of these regions have rapidly growing populations, some are developing nations, some are already very hot. We need to ask if the heat action plans for these areas are sufficient."

The researchers used extreme value statistics -- a method to estimate the return periods of rare events -- and large datasets from climate models and observations to pinpoint regions globally where temperature records are most likely to be broken soonest and the communities consequently in greatest danger of experiencing extreme heat.

The researchers also cautioned that statistically implausible extremes, when current records are broken by margins that seemed impossible until they occurred, could happen anywhere. These unlikely events were found to have transpired in almost a third (31%) of the regions assessed where observations were deemed reliable enough between 1959 and 2021, such as the 2021 Western North America heatwave.

Co-author Dann Mitchell, Professor in Atmospheric Sciences at the University of Bristol Cabot Institute for the Environment, said: "Being prepared saves lives. We have seen some of the most unexpected heatwaves around the world lead to heat-related deaths in the tens of thousands. In this study, we show that such record smashing events could occur anywhere. Governments around the world need to be prepared."

Human-induced climate change is causing an increase in the frequency, intensity, and duration of heatwaves, which have the potential to lead to thousands more excess deaths globally.

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120-year-old storm's secrets key to understanding weather risks

A severe windstorm that battered the UK more than a century ago produced some of the strongest winds[OS1] that Britain has ever seen, a team of scientists have found after recovering old weather records.

Old weather measurements, first recorded on paper after Storm Ulysses hit the UK in February 1903, have shed new light on what was one of the most severe storms to have hit the British Isles.

By turning hand-written weather data into digital records, the research team has laid the way to better understand other historical storms, floods and heatwaves. These observations from the past can help experts to understand the risks of extreme weather now and in the future.

Professor Ed Hawkins, a climate scientist at the University of Reading and the National Centre for Atmospheric Science, led the research. He said: "We knew the storm we analysed was a big one, but we didn't know our rescued data would show that it is among the top four storms for strongest winds across England and Wales.

"This study is a great example of how rescuing old paper records can help us to better understand storms from decades gone by. Unlocking these secrets from the past could transform our understanding of extreme weather and the risks they pose to us today."

Into the archives

Published today (Monday, 24 April) in Natural Hazards and Earth System Sciences, the research indicates that many storms that occurred before 1950 are left unstudied as billions of pieces of data exist only on paper, stored in archives around the world.

But a team of scientists led by Professor Hawkins delved into the archives to convert hand-written observations relating to Storm Ulysses from paper to digital. The cyclone caused multiple deaths and heavily damaged infrastructure and ships when it passed across Ireland and the UK between 26 and 27 February 1903.

Using the new digital data, the research team was able to use techniques similar to modern weather forecasting to simulate the storm and accurately assess the strength of Storm Ulysses' winds. Comparisons with independent weather observations, such as rainfall data, as well as photographs and written accounts from 1903 that outlined the devastation caused by the cyclone, helped to provide credibility for the reconstruction.

The reanalysis is beneficial for understanding the risks of extreme weather events as it showed that the winds experienced in some locations during Storm Ulysses would be rarer than once in 100 years. Having information about such a rare event provides valuable insight into the potential damage a similar storm could cause now in the future.

The 1903 storm is named Storm Ulysses because the damage to thousands of trees in Dublin is mentioned in the novel Ulysses by James Joyce, the events of which are set the year after the storm.

Rescuing the weather

The rescuing of atmospheric observations related to Storm Ulysses is not the first time Professor Ed Hawkins has led weather record recovery. National rainfall data from as far back as 1836 became available in 2022 after the University's Department of Meteorology and 16,000 volunteers helped to restore 5.2 million observations.

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Making better measurements of the composition of galaxies

A study using data from telescopes on Earth and in the sky resolves a problem plaguing astronomers working in the infrared and could help make better observations of the composition of the universe with the James Webb Space Telescope and other instruments. The work is published April 20 in Nature Astronomy.

"We're trying to measure the composition of gases inside galaxies," said Yuguang Chen, a postdoctoral researcher working with Professor Tucker Jones in the Department of Physics and Astronomy at the University of California, Davis.

Most elements other than hydrogen, helium and lithium are produced inside stars, so the composition and distribution of heavier elements -- especially the ratio of oxygen to hydrogen -- can help astronomers understand how many and what kinds of stars are being formed in a distant object.

Astronomers use two methods to measure oxygen in a galaxy, but unfortunately, they give different results. One common method, collisionally excited lines, gives a strong signal, but the results are thought to be sensitive to temperature changes, Chen said. A second method uses a different set of lines, called recombination lines, which are fainter but not thought to be affected by temperature.

The recombination line method consistently produces measurements about double those from collisionally excited lines. Scientists attribute the discrepancy to temperature fluctuations in gas clouds, but this has not been directly proven, Chen said.

Chen, Jones and colleagues used optical and infrared astronomy to measure oxygen abundance in dwarf galaxy Markarian 71, about 11 million light years from Earth. They used archived data from the recently retired SOFIA flying telescope and the retired Herschel Space Observatory, as well as making observations with telescopes at the W.M. Keck Observatory in Mauna Kea, Hawaii.

SOFIA (Stratospheric Observatory For Infrared Astronomy) was a telescope mounted in a Boeing 747 aircraft. By flying at 38,000 to 45,000 feet, the aircraft could get above 99% of the water vapor in Earth's atmosphere, which effectively blocks infrared light from deep space from reaching ground level. A joint project of NASA and the German space agency, SOFIA made its last operational flight in September 2022 and is now headed for a museum display in Tucson.

The Herschel Space Observatory, named after astronomers William and Caroline Herschel, was an infrared space telescope operated by the European Space Agency. It was active from 2009 to 2013.

A surprising result

With data from these instruments, Chen and Jones examined oxygen abundance in Markarian 71 while correcting for temperature fluctuations. They found that the result from collisionally excited infrared lines was still 50% less than that from the recombination line method, even after eliminating the effect of temperature.

"This result is very surprising to us," Chen said. There is no consensus on an explanation for the discrepancy, he said. The team plans to look at additional objects to figure out what properties of galaxies correlate with this variation, Chen said.

One of the goals of the James Webb Space Telescope, launched in 2022, is to make infrared observations of the composition of distant galaxies in the first billion years of the universe. The new results provide a framework for making these measurements with the JWST and the Atacama Large Millimeter Array in Chile.

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New programmable smart fabric responds to temperature and electricity

A new smart material developed by researchers at the University of Waterloo is activated by both heat and electricity, making it the first ever to respond to two different stimuli.

The unique design paves the way for a wide variety of potential applications, including clothing that warms up while you walk from the car to the office in winter and vehicle bumpers that return to their original shape after a collision.

Inexpensively made with polymer nano-composite fibres from recycled plastic, the programmable fabric can change its colour and shape when stimuli are applied.

"As a wearable material alone, it has almost infinite potential in AI, robotics and virtual reality games and experiences," said Dr. Milad Kamkar, a chemical engineering professor at Waterloo. "Imagine feeling warmth or a physical trigger eliciting a more in-depth adventure in the virtual world."

The novel fabric design is a product of the happy union of soft and hard materials, featuring a combination of highly engineered polymer composites and stainless steel in a woven structure.

Researchers created a device similar to a traditional loom to weave the smart fabric. The resulting process is extremely versatile, enabling design freedom and macro-scale control of the fabric's properties.

The fabric can also be activated by a lower voltage of electricity than previous systems, making it more energy-efficient and cost-effective. In addition, lower voltage allows integration into smaller, more portable devices, making it suitable for use in biomedical devices and environment sensors.

"The idea of these intelligent materials was first bred and born from biomimicry science," said Kamkar, director of the Multi-scale Materials Design (MMD) Centre at Waterloo.

"Through the ability to sense and react to environmental stimuli such as temperature, this is proof of concept that our new material can interact with the environment to monitor ecosystems without damaging them."

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How alcohol consumption contributes to chronic pain

Chronic alcohol consumption may make people more sensitive to pain through two different molecular mechanisms -- one driven by alcohol intake and one by alcohol withdrawal. That is one new conclusion by scientists at Scripps Research on the complex links between alcohol and pain.

The research, published in the British Journal of Pharmacology on April 12, 2023, also suggests potential new drug targets for treating alcohol-associated chronic pain and hypersensitivity.

"There is an urgent need to better understand the two-way street between chronic pain and alcohol dependence," says senior author Marisa Roberto, PhD, the Schimmel Family Chair of Molecular Medicine, and a professor of neuroscience at Scripps Research. "Pain is both a widespread symptom in patients suffering from alcohol dependence, as well as a reason why people are driven to drink again."

Alcohol use disorder (AUD), which encompasses the conditions commonly called alcohol abuse, alcohol dependence and alcohol addiction, affects 29.5 million people in the U.S. according to the 2021 National Survey on Drug Use and Health. Over time, AUD can trigger the development of numerous chronic diseases, including heart disease, stroke, liver disease and some cancers.

Among the many impacts of long-term alcohol consumption is pain: more than half of people with AUD experience persistent pain of some type. This includes alcoholic neuropathy, which is nerve damage that causes chronic pain and other symptoms. Studies have also found that AUD is associated with changes in how the brain processes pain signals, as well as changes to how immune system activation occurs. In turn, this pain can lead to increased alcohol consumption. Moreover, during withdrawal, people with AUD can experience allodynia, in which a harmless stimulus is perceived as painful.

Roberto and her colleagues were interested in learning the underlying causes of these different types of alcohol-related pain. In the new study, they compared three groups of adult mice: animals that were dependent on alcohol (excessive drinkers), animals that had limited access to alcohol and were not considered dependent (moderate drinkers), and those that had never been given alcohol.

In dependent mice, allodynia developed during alcohol withdrawal, and subsequent alcohol access significantly decreased pain sensitivity. Separately, about half of the mice that were not dependent on alcohol also showed signs of increased pain sensitivity during alcohol withdrawal but, unlike the dependent mice, this neuropathy was not reversed by re-exposure to alcohol.

When Roberto's group then measured levels of inflammatory proteins in the animals, they discovered that while inflammation pathways were elevated in both dependent and non-dependent animals, specific molecules were only increased in dependent mice. This indicates that different molecular mechanisms may drive the two types of pain. It also suggests which inflammatory proteins may be useful as drug targets to combat alcohol-related pain.

"These two types of pain vary greatly, which is why it is important to be able to distinguish between them and develop different ways to treat each type," says first author Vittoria Borgonetti, PhD, a postdoctoral associate at Scripps Research.

Roberto's group is continuing studies on how these molecules might be used to diagnose or treat alcohol-related chronic pain conditions.

"Our goal is to unveil new potential molecular targets that can be used to distinguish these types of pain and potentially be used in the future for the development of therapies," says co-senior author Nicoletta Galeotti, PhD, associate professor of preclinical pharmacology at the University of Florence.

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Algae in Swedish lakes provide insights to how complex life on Earth developed

By studying green algae in Swedish lakes, a research team, led by Lund University in Sweden, has succeeded in identifying which environmental conditions promote multicellularity. The results give us new clues to the amazing paths of evolution.

The evolution of multicellular life has played a pivotal role in shaping biological diversity. However, we have up until now known surprisingly little about the natural environmental conditions that favour the formation of multicellular groups.

The cooperation between cells within multicellular organisms has enabled eyes, wings and leaves to evolve. The predominant explanation for why multicellularity evolves is that being in a group enables species to better cope with environmental challenges -- where being in a large group can, for instance, protect cells against being eaten.

"Our results challenge this idea, showing that multicellular groups form, not because they are inherently beneficial, but rather as a by-product of single-celled strategies to reduce environmental stress. In particular, cells produce a range of substances to protect themselves from the environment and these substances appear to prevent daughter cells from dispersing away from their mother cell," says Charlie Cornwallis, biology researcher at Lund University.

To understand how and why single-celled organisms evolve to be multicellular, the scientists experimented on green algae where some species are always single-celled, some are single-celled but become multicellular under certain conditions, while others are always multicellular containing thousands of cells.They could then identify the environmental conditions that promote multicellularity and find out the benefits and costs for organisms. The researchers then combined data with information on the environments that single-celled and multicellular green algae are adapted to across the whole of Sweden.

"I was surprised that there were no benefits or costs to living in multicellular groups. The conditions that individual cells experience can be extremely different when swimming around on their own, to being stuck to other cells and having to coordinate activities. Imagine you were physically tied to your family members, I think it would have quite an effect on you," says Charlie Cornwallis.

The study was conducted in Swedish lakes, and it not only provides information on which green algae occur where, and why -- it also helps us understand the origins of biological diversity that shape the world around us.

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Colorado's spicy ancient history of chili peppers

Botanists and paleontologists, led by researchers from the University of Colorado Boulder, have identified a fossil chili pepper that may rewrite the geography and evolutionary timeline of the tomato plant family.

The team's findings, published last month in the journal New Phytologist, show that the chili pepper tribe (Capsiceae) within the tomato, or nightshade (Solanaceae), family is much older and was much more widespread than previously thought. Scientists previously believed that chili peppers evolved in South America at most 15 million years ago, but the new research pushes that date to at least 50 million years ago -- and suggests that chili peppers were in fact present in North America at that time.

Rocío Deanna, a postdoctoral researcher in ecology and evolutionary biology, and Abel Campos, an undergraduate double majoring in evolutionary biology and molecular, cellular and developmental biology, weren't planning to rewrite history when they met up one afternoon at the CU Boulder Museum of Natural History in 2021. Yet among a group of specimens in its collections gathered from the Green River Formation -- geological treasure trove in northwestern Colorado and southwestern Wyoming -- Deanna spotted a specific, solanaceous trait embedded in one fossil: little spikes on the end of a fruiting stem.

"At first, I thought 'No way! This can't be true,'" said Rocío Deanna, lead author of the study. "But it was so characteristic of the chili pepper."

After they discovered two of these fossils in the CU Boulder collections, Deanna and Campos, a co-author of the study, found one more from the chili pepper tribe in collections at the Denver Museum of Nature and Science. All three fossils are from the Green River Formation in Colorado: the CU specimens from Garfield County and the DMNS fossil from Rio Blanco County.

These chili pepper fossils from the Eocene geological epoch (34 to 56 million years ago) match the timeline of another nightshade fossil found in the Esmeraldas Formation in Colombia, revealing that the family was already distributed across all of the Americas by as early as 50 million years ago.

"The family is way older than we thought," said Deanna, also a faculty member at the National University of Cordoba.

A fruit-fossil history

The nightshade family comprises 3,000 species and almost 100 different genera, including chili peppers. The ancient chili pepper was technically a fruit -- and a berry, at that. While tomatoes and peppers are commonly associated with vegetables, they have seeds on the inside, which officially categorizes them as fruits.

The researchers cannot be sure of the chili's exact shape or color, but it was probably on the smaller end compared to modern day chili peppers. And like its relatives, it could have been quite spicy, according to Deanna.

Deanna and Campos identified the fossil by the unique shape of its calyx teeth: spikes on the end of the fruiting stem that hold on to the pepper, like those which hold a gemstone in a ring.

"The world has maybe 300,000 plant species. The only plants with that kind of calyx is this group of 80 or 90 species," said Stacey Smith, senior author of the paper and associate professor of evolutionary biology at CU Boulder.

Paleontologists collected the CU Boulder fossil from the Green River Formation in the 1990s. But its exact identity remained a mystery for years, in part because there are only a handful of "solanologists," botanists who study the nightshade family, in the world. When Deanna found these Colorado-based fossils, she had just returned from a global search for tomato family fossil specimens, only to find some "just ripe for the picking" right on campus.

"A lot of discoveries happen decades after the specimens have been collected," said Smith. "Who knows how many other new fossil species are sitting in any of these museums? They're just waiting for the right eyes to look at them."

Trickle-down evolution

These chili pepper fossils were around during the Eocene, a geologic epoch that lasted from about 34 to 56 million years ago as the continents drifted toward their present positions. During this balmy time in Earth's history, carbon dioxide levels ranged between 700 and 900 parts per million (twice as high as they are today), and palm trees grew as far north as Alaska. Because little to no ice was present on Earth, sea level was as much as 500 feet higher than it is today.

Scientists had assumed that the origins of chili peppers began in South America roughly 10 to 15 million years ago, where they then dispersed over land and water to the other continents. While Colorado today is home to very few native nightshades and no chili peppers, this new discovery hints that a plethora of plants from the tomato plant family may have existed in North America 40 to 50 million years ago, which have since largely disappeared.

But how did these peppers first get to North America? It's now a case of "the chicken or the chili pepper?"

Experts have theorized that fruit-eating birds, which existed as early as 60 million years ago, may have carried seeds and plants around the world with them in their guts, stuck to their feathers or in the mud on their feet. But these birds also had to be eating something to fuel their journeys -- and fleshy berries, or peppers, make the perfect fuel. Birds may have distributed peppers from continent to continent, but peppers may also have been crucial to the success of those same birds.

So the nightshade family could have easily started in North America instead of South America, then dispersed in the other direction -- and with this discovery, scientists can no longer say for sure, said Smith.

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Most people feel 'psychologically close' to climate change

When spurring action against climate change, NGOs and governmental agencies frequently operate on the assumption that people are unmotivated to act because they view climate change as a problem that affects distant regions far in the future. While this concept, known as psychological distance, seems intuitive, researchers report in the journal One Earth on April 21 that most people see climate change as an important and timely issue even if its impacts are not immediately noticeable.

"There is no consistent evidence that perceiving climate change as psychologically distant hinders climate action, with studies reporting mixed results," write the authors, led by Dr. Anne M. van Valkengoed of the University of Groningen in the Netherlands.

van Valkengoed and her colleagues collected results from public opinion polls surveying people about their views on climate change, some of which included over 100,000 people from 121 different countries. The polls showed that over 50% of participants actually believe that climate change is happening either now or in the near future and that it will impact their local areas, not just faraway places.

The team also looked at the results of several studies designed to test the relationship between psychological distance and climate action. Out of 26 reviewed studies, only nine found a positive association between psychological distance and climate action. In fact, some studies showed that viewing climate change as impacting distant places and communities made people want to take more action. The researchers also found that 25 out of 30 studies failed to prove that experimentally decreasing psychological distance increased climate action.

The pervasive misconception about the relationship between psychological distance and climate action could actually be impeding progress in mitigating climate change due to social influence, suggest the authors. For example, if people think others perceive climate change as psychologically distant and therefore aren't taking action, they might be less likely to act themselves. Also, they might think that their efforts are futile because real environmental change relies on the combined efforts of many.

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A backpack full of multiple sclerosis therapy

Multiple sclerosis (MS) is a devastating autoimmune disease that destroys the protective myelin covering around nerves, disrupting communication between the brain and body, and causing patients' ability to move and function to progressively decline. The MS atlas reported in 2020 that someone is diagnosed with MS every five minutes around the world, adding to about 2.8 million individuals that currently have to live with the disease. Alarmingly, since 2013, the world-wide prevalence of MS has risen by 30%.

A key driver of MS is the sudden inflammation of nerves caused by so-called myeloid cells of the "innate" immune system in vulnerable regions of the brain and spinal cord, which together form the central nervous system (CNS). These "acute inflammatory lesions" then attract other myeloid cells, as well as self-reactive T and B cells that belong to the immune system's second arm, known as the "adaptive immune system" and directly attack the myelin covering. While no cure is available for MS, existing disease-modifying therapies in the form of small molecule and protein drugs either directly target the self-reactive immune cells or broadly dampen inflammation. However, many of those therapies cause severe side effects in different parts of the body, including the immune system itself, and thus carry significant health risks.

Now, a research team at the Wyss Institute for Biologically Inspired Engineering at Harvard University and Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) has developed a cell therapy as a strong alternative to existing small molecule and protein therapies that leverages myeloid cells, the very type of immune cells that cause the MS-triggering nerve inflammation in patients.

To transform potentially inflammatory myeloid cells into therapeutic cells, they isolated and cultured monocytes (a type of myeloid cell) from the bone marrow of donor mice and stably attached tiny microparticles, termed "backpacks," to the cells' surfaces. These backpacks are loaded with anti-inflammatory molecules that direct the carrier cells' differentiation into anti-inflammatory cells in vivo. When infused back into a mouse model of MS, the backpack-laden monocytes were able to affect MS-specific immune responses, and partially reverse hind limb paralysis and improve motor functions. The results are published in the Proceedings of the National Academy of Sciences (PNAS).

"Current MS therapies do not specifically target myeloid cells. These are very plastic cells that can toggle between different states and are thus hard to control. Our biomaterial-based backpack approach is a highly effective way to keep them locked into their anti-inflammatory state," said senior author Samir Mitragotri, Ph.D., who is a Core Faculty member at the Wyss Institute. "In many ways simpler than other cell therapies, myeloid cells can be easily obtained from patients' peripheral blood, modified with backpacks in a short culture step, and reinfused back into the original donor, where they find their way to inflammatory lesions and affect the MS-specific immune response not only locally, but more broadly." Mitragotri is also the Hiller Professor of Bioengineering and Hansjörg Wyss Professor of Biologically Inspired Engineering at SEAS.

Many cell therapies, such as the famed CAR-T cell therapies, require the mobilization of immune cells from specific tissue compartments in the body with drugs, genetic modification, and then amplification over weeks outside of the body. Myeloid cells can be directly retrieved using established methods and modified with backpacks within hours, making the therapy more easily translatable. In addition, some myeloid cell types possess the ability to traverse the blood-brain barrier, which makes them particularly suitable for treating CNS diseases.

New spin for cellular backpacks

Mitragotri's group had previously found that when they attached small disc-shaped backpacks to cells of the myeloid lineage, they remained stably exposed on the cells' surface, whereas many other cells would readily internalize and inactivate them. Adding certain molecules to the backpacks allowed the team sustained control over the cells' behavior. They made use of this finding in a tumor-fighting cell therapy consisting of backpack-laden macrophages, which is a specific type of myeloid cell. In their new study, they focused on monocytes, which also belong to the myeloid differentiation lineage and are a precursor to macrophages. Monocytes can effectively infiltrate the brain and then differentiate into macrophages, which are one of the predominant inflammatory cell types in active MS lesions.

"Because of their ability to invade the CNS, infiltrate inflammatory lesions, and differentiate into macrophages, a backpack strategy allowing control over monocyte differentiation made extreme sense," said first author Neha Kapate, a graduate student working with Mitragotri. "We decided on backpacks that contained interleukin-4 [IL-4] and dexamethasone, two molecules that we later found to provide a synergistic anti-inflammatory effect."

The team fabricated their micrometer-size backpacks via a process known as serial "spin coating," in which thin films made up of a PLGA polymer and other biocompatible substances, and containing the anti-inflammatory molecules are layered on top of each other like layers of an onion. As a final step, the outer surface of the backpack was furnished with an antibody fragment to allow it to stick to monocytes.

Cellular backpacks get legs

To test the backpack-laden monocytes for their therapeutic efficacy, the researchers isolated monocytes from healthy donor mice and, in a short cell culture step, attached the backpacks to them. They then infused the modified cells into a mouse model of MS, known among researchers as experimental autoimmune encephalomyelitis (EAE) model. "When we infused backpack-carrying monocytes and, in parallel, unaltered control monocytes into EAE mice with ongoing nerve inflammation, backpack-carrying monocytes more effectively infiltrated into inflamed CNS lesions. They also reduced inflammation inside the lesions and shifted the local and systemic MS-associated immune response towards a therapeutic outcome," said Kapate. "The resulting anti-inflammatory monocytes also elicited cross-talk effects with other immune cell populations, such as specific T helper cells that are linked to the self-directed adaptive auto-immune response."

The disease symptoms in EAE mice treated with backpack-laden monocytes were significantly improved and, by the end of the study, the animals merely exhibited a limp tail, compared to complete a paralysis in the control animals' hind limbs. The treatment also extended the animals' survival -- all mice receiving backpack-carrying monocytes survived to the end of the study, whereas a significant number of the control mice had died. Importantly, the magnitude of therapeutic benefit the team observed is on par with reported therapeutic treatments that had been tested in other studies using the same model. Since the EAE model mainly mimics the progressive form of MS and not the more prevalent "relapsing-remitting" form, with which the disease begins in about 85% of MS patients, and which at later stages can also become progressive, the team plans to also investigate their approach in models of relapsing-remitting MS. Being able to suppress inflammation early on could have enormous benefits for patients.

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