Even dying stars can still give birth to planets

Planets are usually not much older than the stars around which they revolve. Take the Sun: it was born 4.6 billion years ago, and not long after that, Earth came into the world. But KU Leuven astronomers have discovered that a completely different scenario is also possible. Even if they are near death, some types of stars can possibly still form planets. If this is confirmed, theories on planet formation will need to be adjusted.

Planets such as Earth, and all other planets in our solar system, were formed not long after the Sun. Our Sun started to burn 4.6 billion years ago, and in the next million years, the matter around it clumped into protoplanets. The birth of the planets in that protoplanetary disc, a gigantic pancake made of dust and gas, so to speak, with the Sun in the middle, explains why they all orbit in the same plane.

But such discs of dust and gas needn't necessarily only surround newborn stars. They can also develop independently from star formation, for example around binary stars of which one is dying (binary stars are two stars that orbit each other, also called a binary system). When the end approaches for a medium-sized star (like the Sun), it catapults the outer part of its atmosphere into space, after which it slowly dies out as a so-called white dwarf. However, in the case of binary stars, the gravitational pull of the second star causes the matter ejected by the dying star to form a flat, rotating disc. Moreover, this disc strongly resembles the protoplanetary discs that astronomers observe around young stars elsewhere in the Milky Way.

This we already knew. However, what is new is that the discs surrounding so-called evolved binary stars not uncommonly show signs that could point to planet formation, as discovered by an international team of astronomers led by KU Leuven researchers. What's more, their observations show that this is the case for one in ten of these binary stars. "In ten per cent of the evolved binary stars with discs we studied, we see a large cavity (a void/opening, ed.) in the disc," says KU Leuven astronomer Jacques Kluska, first author of the article in the journal Astronomy & Astrophysics in which the discovery is described. "This is an indication that something is floating around there that has collected all matter in the area of the cavity."

Second-generation planets

The clean-up of the matter could be the work of a planet. That planet might not have formed at the very beginning of one of the binary stars' life, but at the very end. The astronomers moreover found further strong indications for the presence of such planets. "In the evolved binary stars with a large cavity in the disc, we saw that heavy elements such as iron were very scarce on the surface of the dying star," says Kluska. "This observation leads one to suspect that dust particles rich in these elements were trapped by a planet." By the way, the Leuven astronomer doesn't rule out the possibility that in this way, several planets can be formed around these binary stars.

The discovery was made when the astronomers were drawing up an inventory of evolved binary stars in our Milky Way. They did that based on existing, publicly available observations. Kluska and his colleagues counted 85 of such binary star pairs. In ten pairs, the researchers came across a disc with a large cavity on the infrared images.

Current theories put to the test

If new observations confirm the existence of planets around evolved binary stars, and if it turns out the planets were only formed after one of the stars had reached the end of its life, the theories on planet formation will need to be adjusted. "The confirmation or refutation of this extraordinary way of planet formation will be an unprecedented test for the current theories," according to Professor Hans Van Winckel, head of the KU Leuven Institute of Astronomy.

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What the rise of oxygen on early Earth tells us about life on other planets

When did the Earth reach oxygen levels sufficient to support animal life? Researchers from McGill University have discovered that a rise in oxygen levels occurred in step with the evolution and expansion of complex, eukaryotic ecosystems. Their findings represent the strongest evidence to date that extremely low oxygen levels exerted an important limitation on evolution for billions of years.

"Until now, there was a critical gap in our understanding of environmental drivers in early evolution. The early Earth was marked by low levels of oxygen, till surface oxygen levels rose to be sufficient for animal life. But projections for when this rise occurred varied by over a billion years -- possibly even well before animals had evolved," says Maxwell Lechte, a postdoctoral researcher in the Department of Earth and Planetary Sciences under the supervision of Galen Halverson at McGill University.

Ironstones provide insights into early life

To find answers, the researchers examined iron-rich sedimentary rocks from around the world deposited in ancient coastal environments. In analyzing the chemistry of the iron in these rocks, the researchers were able to estimate the amount of oxygen present when the rocks formed, and the impact it would have had on early life like eukaryotic microorganisms -- the precursors to modern animals.

"These ironstones offer insights into the oxygen levels of shallow marine environments, where life was evolving. The ancient ironstone record indicates around less than 1 % of modern oxygen levels, which would have had an immense impact on ecological complexity," says Changle Wang, a researcher at the Chinese Academy of Sciences who co-led the study with Lechte.

"These low oxygen conditions persisted until about 800 million years ago, right when we first start to see evidence of the rise of complex ecosystems in the rock record. So if complex eukaryotes were around before then, their habitats would have been restricted by low oxygen," says Lechte.

Earth remains the only place in the universe known to harbor life. Today, Earth's atmosphere and oceans are rich with oxygen, but this wasn't always the case. The oxygenation of the Earth's ocean and atmosphere was the result of photosynthesis, a process used by plants and other organisms to convert light into energy -- releasing oxygen into the atmosphere and creating the necessary conditions for respiration and animal life.

Searching for signs of life beyond our solar system

According to the researchers, the new findings suggests that Earth's atmosphere was capable of maintaining low levels of atmospheric oxygen for billions of years. This has important implications for exploration of signs of life beyond our solar system, because searching for traces of atmospheric oxygen is one way to look for evidence of past or present life on another planet -- or what scientists call a biosignature.

Scientists use Earth's history to gauge the oxygen levels under which terrestrial planets can stabilize. If terrestrial planets can stabilize at low atmospheric oxygen levels, as suggested by the findings, the best chance for oxygen detection will be searching for its photochemical byproduct ozone, say the researchers.

"Ozone strongly absorbs ultraviolet light, making ozone detection possible even at low atmospheric oxygen levels. This work stresses that ultraviolet detection in space-based telescopes will significantly increase our chances of finding likely signs of life on planets outside our solar system," says Noah Planavsky, a biogeochemist at Yale University.

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The two types of climate coping and what they mean for your health

When it comes to coping with climate change, there may be two types of people: those who take action to try to improve the environment and those who don't bother because they don't believe their actions will make a difference.

Knowing who's who could help public policymakers better target their messaging around climate change, suggests a new study led by University of Arizona researcher Sabrina Helm.

Helm, an associate professor in the College of Agriculture and Life Sciences' Norton School of Family and Consumer Sciences, studies climate anxiety and consumer behavior.

In her latest research, published in the journal Anxiety, Stress and Coping, Helm set out to identify how different people cope, psychologically and behaviorally, with the stressor of a changing climate.

She and her collaborators surveyed 334 parents who had children between the ages of 3 and 10 living with them. They were asked about their general climate change beliefs, how stressed they feel about environmental issues, how they cope with that stress and how effective they think consumers can be in combating climate change. They also were asked how often they engage in certain behaviors, such as eating meat, traveling by air or making efforts to conserve energy and water. And they were asked questions about their mental and overall health.

Based on the survey responses, the researchers identified two prevailing climate change coping profiles: adaptive approach coping and maladaptive avoidance coping.

About 70% of survey respondents belonged to the first group -- the adaptive approach coping profile. They tended to have higher levels of environmental concern, and related stress, and believed more in consumer effectiveness. They expressed more wishful thinking and a desire to problem solve, and were more likely to engage in pro-environmental behaviors.

The remaining 30% were in the maladaptive avoidance coping group. They were less likely than those in the first group to feel guilt or personal responsibility for climate change. They also had less wishful thinking and were less likely to engage in pro-environmental behaviors or believe that their actions would make a difference.

Helm and her collaborators wondered whether people in the adaptive approach group -- who tend to feel more climate-related stress -- would have worse mental health overall, since previous studies have linked environmental stress to negative mental health outcomes.

Surprisingly, Helm said, they found no differences between the two groups with regard to general health, anxiety or depressive symptoms.

"Overall, we know that climate change-related anxiety is on the rise, and that may be the case for both of these profiles," Helm said. "We didn't look at climate anxiety specifically, but we looked at depressive and anxiety symptoms in general; the two groups didn't differ in their level of anxiety or mental health outcomes."

There also were not significant differences in the demographic makeup of the two groups when it came to factors such as race, income, education level or employment status. However, women were more likely to be in the adaptive approach coping group, which is consistent with the findings of prior research, Helm said.

"There's a whole host of literature suggesting that females have more environmental concern," she said.

The fact that the demographics of the two groups were so similar suggests that targeting climate change-related messaging based on demographic information alone might not be the most effective strategy, Helm said. While it might be tougher to do, determining a person's climate change coping profile could be more useful for those attempting to communicate about environmental issues and what people can do to make a difference.

"If you think in terms of messaging about climate change or environmental problems, very often we look at social demographic targeting, and according to our findings, that's not very useful because those two profiles should probably be receiving different kinds of messaging," Helm said. "Those who are already acting pro-environmentally need reinforcement of that behavior, versus those who are in the maladaptive avoidance coping profile who don't do much at all and need to be incentivized to start doing something."

Helm said future research should look at whether the same two coping profiles exist in children and teenagers, who may be experiencing greater anxiety about climate change.

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Complex three-dimensional kidney tissue generated in the lab from the scratch

A research team based in Kumamoto University (Japan) has created complex 3D kidney tissue in the lab solely from cultured mouse embryonic stem (ES) cells. These organoids could lead the way to better kidney research and, eventually, artificial kidneys for human transplant.

By focusing on an often-overlooked tissue type of organoid generation research, a type of organ tissue made up of various support and connective tissues called the stroma, Dr. Ryuichi Nishinakamura and his team were able to generate the last of a three-part puzzle that they had been working on for several years. Once the three pieces were combined, the resulting structure was found to be kidney-like in its architecture. The researchers believe that their work will be used to advance kidney research and even lead to a transplantable organ in the future.

The kidney is a very important organ for continued good health because it acts as a filter to extract waste and excess water from blood. It is a complex organ that develops from the combination of three components. Protocols have already been established by various research teams, including Dr. Nishinakamura's team at the Institute of Molecular Embryology and Genetics (IMEG) at Kumamoto University, to induce two of the components (the nephron progenitor and the ureteric bud) from mouse ES cells.

In this, their most recent work, the IMEG team has developed a method to induce the third and final component, kidney-specific stromal progenitor, in mice. Furthermore, by combining these three components in vitro, the researchers were able to generate a kidney-like 3D tissue, consisting of extensively branched tubules and several other kidney-specific structures.

The researchers believe that this is the first ever report on the in-lab generation of such a complex kidney structure from scratch. The IMEG team has already succeeded in inducing the first two components from human iPS cells. If this last component can also be generated from human cells, a similarly complex human kidney should be achievable.

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Low volcanic temperature ushered in global cooling and the thriving of dinosaurs

Researchers in Japan, Sweden, and the US have unearthed evidence that low volcanic temperatures led to the fourth mass extinction, enabling dinosaurs to flourish during the Jurassic period.

Large volcanic eruptions create climatic fluctuations, ushering in evolutionary changes. Yet it is the volcanic temperature of the eruption that determines whether the climate cools or warms.

Since the emergence of early animals, five mass extinctions have taken place. The fourth mass extinction occurred at the end of the Triassic Period -- roughly 201 million years ago. This mass extinction saw many marine and land animals go extinct, especially large-body, crocodilian-line reptiles known as pseudosuchia. Approximately 60-70% of animal species disappeared. As a result, small bodied dinosaurs were able to grow and prosper.

Scientists think the fourth mass extinction was triggered by the eruptions in the Central Atlantic Magmatic Province -- one of the largest regions of volcanic rock. But the correlation between the eruption and mass extinction has not yet been clarified.

Using analysis of sedimentary organic molecules and a heating experiment, current professor emeritus at Tohoku University, Kunio Kaiho and his team demonstrated how low temperature magma slowly heated sedimentary rocks, causing high sulfur dioxide (SO2) and low carbon dioxide emissions (CO2).

The SO2 gas was distributed throughout the stratosphere, converting to sulfuric acid aerosols. The instantaneous increase of global albedo caused short-term cooling, which could have contributed to the mass extinction.

Kaiho and his team took marine sedimentary rock samples from Austria and the United Kingdom and analyzed the organic molecules and mercury (Hg) in them. They found four discrete benzo[e]pyrene + benzo[ghi]perylene + coronene -Hg enrichments.

The discovery of low coronene in the first enrichment was particularly revealing. The second, third, and fifth mass extinction had high coronene concentrations. A low concentration indicates that low temperature heating caused high SO2 release and global cooling.

"We believe the extinction was the product of large volcanic eruptions because the benzo[e]pyrene + benzo[ghi]perylene + coronene anomaly could only be seen around the time frame of the mass extinctions," said Kaiho.

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Locations of ancient Maya sacred groves of cacao trees discovered

For as much as modern society worships chocolate, cacao -- the plant chocolate comes from -- was believed to be even more divine to ancient Mayas. The Maya considered cacao beans to be a gift from the gods and even used them as currency because of their value.

As such, cacao bean production was carefully controlled by the Maya leaders of northern Yucatan, with cacao trees only grown in sacred groves. But no modern researcher has ever been able to pinpoint where these ancient sacred groves were located -- until now.

Researchers at Brigham Young University, including professor emeritus Richard Terry and graduate students Bryce Brown and Christopher Balzotti, worked closely with archaeologists from the U.S. and Mexico to identify locations the Maya used to provide the perfect blend of humidity, calm and shade required by cacao trees. While the drier climate of the Yucatan peninsula is inhospitable to cacao growth, the team realized the vast array of sinkholes common to the peninsula have microclimates with just the right conditions.

As detailed in a study newly published in the Journal of Archaeological Science Reports, the team conducted soil analyses on 11 of those sinkholes and found that the soil of nine of them contained evidence of theobromine and caffeine -- combined biomarkers unique to cacao. Archaeologists also found evidence of ancient ceremonial rituals -- such as staircase ramps for processions, stone carvings, altars and offerings like jade and ceramics (including tiny ceramic cacao pods) -- in several sinkholes.

"We looked for theobromine for several years and found cacao in some places we didn't expect," said Terry, who recently retired from BYU. "We were also amazed to see the ceremonial artifacts. My students rappelled into one of these sinkholes and said, 'Wow! There is a structure in here!' It was a staircase that filled one-third of the sinkhole with stone."

To extract and analyze the sinkhole soil for cacao biomarkers -- specifically theobromine and caffeine -- the team developed a new method of soil extraction. This involved drying the soil samples and passing them through a sieve, covering them with hot water, having them centrifuged and passed through extraction disks, and analyzing the extracts by mass spectrometry. To increase the sensitivity of their testing, the research team compared the results of the soil samples to seven control samples with no history of exposure to the biomarkers.

The findings of the BYU study indicate that cacao groves played an important role in ancient rituals and trade routes of the ancient Maya, impacting the entirety of the Mesoamerican economy. A 70-mile Maya "highway" in the area that was the main artery for trade passes near hundreds of sinkholes, so it is likely that the leaders who commissioned the highway development also controlled cacao production. The evidence of cacao cultivation alongside archaeological findings also supports the idea that cacao was important in the ideological move from a maize god to a sun god.

In one sinkhole near Coba, Mexico, a village 45 minutes from modern day Tulum, the research team found the arm and bracelet of a figurine attached to an incense jar and several ceramic modeled cacao pods. They also found remnant cacao trees growing there, making it quite possible that this sinkhole, named "Dzadz Ion," was the location of a sacred cacao grove during the Late Postclassic period (About A.D. 1000 to 1400).

"Now we have these links between religious structures and the religious crops grown in these sinkholes," Terry said. "Knowing that the cacao beans were used as currency, it means the sinkholes were a place where the money could be grown and controlled. This new understanding creates a rich historical narrative of a highly charged Maya landscape with economic, political and spiritual value."

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2D material in three dimensions

The carbon material graphene has no well-defined thickness, it merely consists of one single layer of atoms. It is therefore often referred to as a "two-dimensional material." Trying to make a three-dimensional structure out of it may sound contradictory at first, but it is an important goal: if the properties of the graphene layer are to be exploited best, then as much active surface area as possible must be integrated within a limited volume.

The best way to achieve this goal is to produce graphene on complex branched nanostructures. This is exactly what a cooperation between CNR Nano in Pisa, TU Wien (Vienna) and the University of Antwerp has now achieved. This could help, for example, to increase the storage capability per volume for hydrogen or to build chemical sensors with higher sensitivity.

From solid to porous

In Prof. Ulrich Schmid's group (Institute for Sensor and Actuator Systems, TU Wien), research has been conducted for years on how to transform solid materials such as silicon carbide into extremely fine, porous structures in a precisely controlled way. "If you can control the porosity, then many different material properties can be influenced as a result," explains Georg Pfusterschmied, one of the authors of the current paper.

The technological procedures required to achieve this goal are challenging: "It is an electrochemical process that consists of several steps," says Markus Leitgeb, a chemist who also works in Ulrich Schmid's research group at TU Wien. "We work with very specific etching solutions, and apply tailored electric current characteristics in combination with UV irradiation." This allows to etch tiny holes and channels into certain materials.

Because of this expertise in the realization of porous structures, Stefan Heun's team from the Nanoscience Institute of the Italian National Research Council CNR turned to their colleagues at TU Wien. The Pisa team was looking for a method to produce graphene surfaces in branched nanostructures to enable larger graphene surface areas. And the technology developed at TU Wien is perfectly suited for this task.

"The starting material is silicon carbide -- a crystal of silicon and carbon," says Stefano Veronesi who performed the graphene growth at CNR Nano in Pisa. "If you heat this material, the silicon evaporates, the carbon remains and if you do it right, it can form a graphene layer on the surface."

An electrochemical etching process was therefore developed at TU Wien that turns solid silicon carbide into the desired porous nanostructure. About 42 % of the volume is removed in this process. The remaining nanostructure was then heated in high vacuum in Pisa so that graphene formed on the surface. The result was then examined in detail in Antwerp. This revealed the success of the new process: indeed, a large number of graphene flakes form on the intricately shaped surface of the 3D nanostructure.

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Small group of genetic variants found in extremely ill patients with COVID may help explain big differences in how sick people get

The search to better understand the tremendous range of responses to infection with the COVID-19 virus -- from symptom free to critically ill -- has uncovered in some of the sickest patients a handful of rare structural gene variants involved in body processes, like inflammation, which the virus needs to be successful.

"The virus has to attach to our cells, it has to get inside our cells and it has to multiply inside our cells. It also has to attract inflammation," says Dr. Ravindra Kolhe, director of the Georgia Esoteric and Molecular Laboratory at the Medical College of Georgia at Augusta University. "We have identified genes with structural changes in very sick individuals that are part of all four of these essential processes."

In apparently the first study of its kind, investigators used optical genome mapping, to get a thorough, three-dimensional assessment of the genome of 52 severally ill patients with COVID-19.

In nine of the sickest patients, they identified seven rare structural variants affecting a total of 31 genes involved in key pathways mediating the response between a person, or host, and a virus. These include innate immunity, our frontline immune defense against invaders like viruses; the inflammatory response, a key response to an infection that, gone awry, can also destroy the lungs of some of the sickest patients; and the ability of a virus to replicate and spread. As an example, one variant they identified can lead to overexpression of keratin genes. Keratins are proteins that are the structural components of things like our hair and nails, but that also have been identified as key to the transmission of both flu viruses and the COVID-19 virus between cells and are known to be upregulated in the respiratory tract during an infection.

"It's a hyperactivation of the normal systems," says Kolhe, corresponding author of the study, published by the international collaborative COVID-19 Host Genome Research consortium in the journal iScience.

"Millions of people get infected, and fortunately only a very small percentage become symptomatic, and a very small percentage of the symptomatic individuals require oxygen and a small percentage of those individuals are hospitalized and die," Kolhe says. "But even a small percentage amounts to millions of people and that is too many."

"Our data show that large (structural variants) identified using optical genome mapping might further explain the inter-individual clinical variability in response to COVID-19," the investigators write.

Large structural variants account for much of the genetic diversity among us, including changes that are just unique to the individual and those that can increase their risk of problems like cancer. Optical genome mapping is an emerging technology that can detect these larger variants with multiple changes, like deletion or insertion of genetic material and/or when a section of chromosome is reversed.

The investigators say that while more work needs to be done, their findings about the potential role of structural variants in the host-virus interaction point toward the need to look for genetic variations, ideally with a simple- to-use blood assay. Once identified, the goal would be to initiate proactive moves for these individuals like ensuring vaccination and boosting and potentially more aggressive treatment early on, like monoclonal antibody therapy, to help these individuals better combat COVID, Kolhe says.

Clinical studies have identified factors like older age, being male, hypertension, diabetes and other chronic conditions as risk factors associated with the degree of illness from COVID-19. The nine sickest patients in this study shared common comorbid conditions, 32 of the patients required mechanical ventilation to support their breathing and a total of 13 of the 52 patients died while in intensive care.

But in their studies, which also included individuals who were negative for the COVID-19 virus and those who were positive but asymptomatic, there were again outliers, including individuals with comorbid conditions who remained asymptomatic when infected with SARS-CoV-2 and those who were perfectly healthy but became extremely ill when infected, another indicator of a role for genetics in determining the degree of response, Kolhe says.

Kolhe notes that the large structural variants they found in the sickest patients were not caused by the virus rather used by the virus and may not increase susceptibility to other, even similar, conditions.

Overall, the individuals in this study had about 40 rare structural variants, which other studies have indicated is about average.

The COVID-19 Host Genome Research consortium currently has a membership of 34 institutions, including Duke and Columbia universities, the National Cancer Institute and the New York Genome Center, exploring different aspects of how structural variants impact the divergent individual responses to infection with the COVID-19 virus.

The group began to emerge after more commonplace gene sequencing studies, which essentially lay out the DNA in a straight line to look for problematic and smaller variations in the usual order of its four base pairs -- adenine, thymine, guanine and cytosine -- on thousands of patients have yielded little information to help explain -- and ideally predict -- the wide variations in how sick people will get. Better than 30% of the known disease-causing variants are larger than the single base pair changes sequencing can identify, according to the Human Gene Mutation Database.

Even the amount of virus in an individual does not directly correlate with how sick the individual gets, Kolhe says. "We had individuals with very high viral loads who did not even know they were positive," he says. "It is something in the host genome that is different."

Some studies have found that blood type might be a factor in predicting risk, specifically type A, and there have been some specific gene findings as well that predispose to immune deficiencies that may make people more susceptible.

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Climate change in the Early Holocene

New insight into how our early ancestors dealt with major shifts in climate is revealed in research, published today [27 Jan] in Nature Ecology & Evolution, by an international team, led by Professor Rick Schulting from Oxford University's School of Archaeology.

It reveals, new radiocarbon dates show the large Early Holocene cemetery of Yuzhniy Oleniy Ostrov, at Lake Onega, some 500 miles north of Moscow, previously thought to have been in use for many centuries, was, in fact, used for only one to two centuries. Moreover, this seems to be in response to a period of climate stress.

The team believes the creation of the cemetery reveals a social response to the stresses caused by regional resource depression. At a time of climate change, Lake Onega, as the second largest lake in Europe, had its own ecologically resilient microclimate. This would have attracted game, including elk, to its shores while the lake itself would have provided a productive fishery. Because of the fall in temperature, many of the region's shallower lakes could have been susceptible to the well-known phenomenon of winter fish kills, caused by depleted oxygen levels under the ice.

The creation of the cemetery at the site would have helped define group membership for what would have been previously dispersed bands of hunter-gatherers -- mitigating potential conflict over access to the lake's resources.

But when the climate improved, the team found, the cemetery largely went out of use, as the people presumably returned to a more mobile way of life and the lake became less central.

The behavioural changes -- to what could be seen as a more 'complex' social system, with abundant grave offerings -- were situation-dependent. But they suggest the presence of important decision makers and, say the team, the findings also imply that early hunting and gathering communities were highly flexible and resilient.

The results have implications for understanding the context for the emergence and dissolution of socioeconomic inequality and territoriality under conditions of socio-ecological stress.

Radiocarbon dating of the human remains and associated animal remains at the site reveals that the main use of the cemetery spanned between 100-300 years, centring on ca. 8250 to 8,000 BP. This coincides remarkably closely with the 8.2 ka dramatic cooling event, so this site could provide evidence for how these humans responded to a climate-driven environmental change.

The Holocene (the current geological epoch which began approximately 11,700 years before present) has been relatively stable in comparison to current events. But there are a number of climate fluctuations recorded in the Greenland ice cores. The best known of these is the 8,200 years ago cooling event, the largest climatic downturn in the Holocene, lasting lasted one to two centuries. But there is little evidence that the hunter-gatherers, who occupied most of Europe at this time, were much affected, and if they were, in what specific ways.

Yuzhniy Oleniy Ostrov is one of the largest Early Holocene cemeteries in northern Eurasia, with up to 400 possible graves, 177 of which were excavated in the 1930s by a team of Russian archaeologists. Based on their work, the cemetery site has an important position in European Mesolithic studies, in part because of the variation in the accompanying grave offerings. Some graves lack these entirely, to those with abundant and elaborate offerings.

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Scientists regrow frog's lost leg

For millions of patients who have lost limbs for reasons ranging from diabetes to trauma, the possibility of regaining function through natural regeneration remains out of reach. Regrowth of legs and arms remains the province of salamanders and superheroes.

But in a study published in the journal Science Advances, scientists at Tufts University and Harvard University's Wyss Institute have brought us a step closer to the goal of regenerative medicine.

On adult frogs, which are naturally unable to regenerate limbs, the researchers were able to trigger regrowth of a lost leg using a five-drug cocktail applied in a silicone wearable bioreactor dome that seals in the elixir over the stump for just 24 hours. That brief treatment sets in motion an 18-month period of regrowth that restores a functional leg.

Many creatures have the capability of full regeneration of at least some limbs, including salamanders, starfish, crabs, and lizards. Flatworms can even be cut up into pieces, with each piece reconstructing an entire organism. Humans are capable of closing wounds with new tissue growth, and our livers have a remarkable, almost flatworm-like capability of regenerating to full size after a 50% loss.

But loss of a large and structurally complex limb -- an arm or leg -- cannot be restored by any natural process of regeneration in humans or mammals. In fact, we tend to cover major injuries with an amorphous mass of scar tissue, protecting it from further blood loss and infection and preventing further growth.

Kickstarting Regeneration

The Tufts researchers triggered the regenerative process in African clawed frogs by enclosing the wound in a silicone cap, which they call a BioDome, containing a silk protein gel loaded with the five-drug cocktail.

Each drug fulfilled a different purpose, including tamping down inflammation, inhibiting the production of collagen which would lead to scarring, and encouraging the new growth of nerve fibers, blood vessels, and muscle. The combination and the bioreactor provided a local environment and signals that tipped the scales away from the natural tendency to close off the stump, and toward the regenerative process.

The researchers observed dramatic growth of tissue in many of the treated frogs, re-creating an almost fully functional leg. The new limbs had bone structure extended with features similar to a natural limb's bone structure, a richer complement of internal tissues (including neurons), and several "toes" grew from the end of the limb, although without the support of underlying bone.

The regrown limb moved and responded to stimuli such as a touch from a stiff fiber, and the frogs were able to make use of it for swimming through water, moving much like a normal frog would.

"It's exciting to see that the drugs we selected were helping to create an almost complete limb," said Nirosha Murugan, research affiliate at the Allen Discovery Center at Tufts and first author of the paper. "The fact that it required only a brief exposure to the drugs to set in motion a months-long regeneration process suggests that frogs and perhaps other animals may have dormant regenerative capabilities that can be triggered into action."

The researchers explored the mechanisms by which the brief intervention could lead to long-term growth. Within the first few days after treatment, they detected the activation of known molecular pathways that are normally used in a developing embryo to help the body take shape.

Activation of these pathways could allow the burden of growth and organization of tissue to be handled by the limb itself, similar to how it occurs in an embryo, rather than require ongoing therapeutic intervention over the many months it takes to grow the limb.

How the BioDome Works

Animals naturally capable of regeneration live mostly in an aquatic environment. The first stage of growth after loss of a limb is the formation of a mass of stem cells at the end of the stump called a blastema, which is used to gradually reconstruct the lost body part. The wound is rapidly covered by skin cells within the first 24 hours after the injury, protecting the reconstructing tissue underneath.

"Mammals and other regenerating animals will usually have their injuries exposed to air or making contact with the ground, and they can take days to weeks to close up with scar tissue," said David Kaplan, Stern Family Professor of Engineering at Tufts and co-author of the study. "Using the BioDome cap in the first 24 hours helps mimic an amniotic-like environment which, along with the right drugs, allows the rebuilding process to proceed without the interference of scar tissue."

Next Steps in Frogs and Mammals

Previous work by the Tufts team showed a significant degree of limb growth triggered by a single drug, progesterone, with the BioDome. However, the resulting limb grew as a spike and was far from the more normally shaped, functional limb achieved in the current study.

The five-drug cocktail represents a significant milestone toward the restoration of fully functional frog limbs and suggests further exploration of drug and growth factor combinations could lead to regrown limbs that are even more functionally complete, with normal digits, webbing, and more detailed skeletal and muscular features.

"We'll be testing how this treatment could apply to mammals next," said corresponding author Michael Levin, Vannevar Bush Professor of Biology in the School of Arts & Sciences, director of the Allen Discovery Center at Tufts, and associate faculty member of the Wyss Institute.

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