Mice Share Each Other’s Pain and Fear

The animals adopt the emotional state of their cagemates, and the parts of the brain engaged during the process are different for pain and fear, according to a new study.

By Amanda Heidt

The ability to empathize with others stems from a long evolutionary history that includes empathy-like behaviors in animals beyond humans. Whales and primates grieve alongside members of their social groups, for example, while rodents are able to recognize and respond to the fear and pain of their neighbors. 

A study published January 8 in Science has found that the brain circuits engaged during empathetic behaviors in mice differ depending on the emotion they are experiencing. The social transmission of pain, for example, is mediated by a pathway involving the brain’s anterior cingulate cortex (ACC) and the nucleus accumbens (NAc), while empathy-based fear is dictated by projections leading from the ACC to a region called the basolateral amygdala (BLA). These results also show, for the first time, that observing a neighbor having its pain alleviated can make a mouse’s own pain more tolerable. 

“The authors were able to determine the specific inputs and outputs from the ACC to other regions of the brain, which hasn’t been done before, and show that they differ depending on what state you’re in,” Stephanie Preston, a neuroscientist and psychologist at the University of Michigan who studies empathy in humans, tells The Scientist. “This is a novel demonstration of the specific wiring that’s involved above and beyond the general idea of empathic pain and fear.”

Empathy is often studied in humans using MRI scans, during which a person must lie perfectly still within a noisy, enclosed space. As a result, “it’s much harder to get into a human brain and elucidate the mechanisms at the level of detail I think they need to be understood,” says Robert Malenka, a neuroscientist at Stanford University and the senior author on the study. 

Rodents, being social animals capable of reacting to the emotions of their neighbors, therefore provide a tractable model system for probing the neural circuits associated with empathetic behavior. A better understanding of the molecular and neurological basis of empathy is important not only for the study of social interactions in humans, but also for the development of noninvasive treatments for people with conditions that limit their ability to empathize with others, such as narcissistic personality disorder, borderline personality disorder, or psychopathy.  

To test the empathetic exchange of fear, Malenka’s team subjected a handful of mice to an electrical shock. The next day, these “bystanders” watched as a companion mouse was shocked repeatedly, causing it to freeze as part of a fight-or-flight response. A day later, when the bystander mouse was placed back into the experimental arena by itself, it too froze, supporting the idea that mice have an empathetic response to seeing others in distress.

During trials examining the same mice’s empathetic response to pain, the researchers injected 20 mice with a substance that causes inflammation. Then, a paired bystander mouse was put into the cage, and the two were able to interact with one another for an hour. Afterward, the bystander underwent a series of tests to determine its pain threshold. In each case, mice that had interacted with a cagemate registered a lower tolerance to pain for at least four hours after separation compared to a pair of control mice that interacted but neither received an inflammatory injection. 

Lastly, Malenka and his colleagues wanted to know if pain relief could be socially transferred in the same way as pain. This time, the team injected both mice with the inflammatory compound but gave one mouse morphine. Even though it had not received any morphine, the second mouse nevertheless registered a higher pain tolerance; being around an analgecized cagemate made the pain of the second mouse more bearable.  

“We think we have directly demonstrated that our mice are experiencing an empathic response,” says Malenka. “They are adopting the emotional state of another member of their species just by hanging out with that other animal for an hour or so.”

Having shown that mice can adopt the behavioral states of their neighbors, the team next used a neurological tracer and optogenetics to tease apart the individual pathways involved in each emotional state. 

For the tracer, they injected mice with a benign version of the rabies virus. “We did a clever experiment where we expressed the receptor for the rabies virus only in the neurons that were activated during the social experiments,” Malenka says. Following the path of the virus through the brain, they were able to show that the social transfer of pain and pain relief are mediated by different pathways.

The results, Malenka tells The Scientist, show that “there is some specificity to our empathic responses in terms of the brain mechanisms. Different parts of the brain are allowing us to be empathic for different experiences.” 

When the researchers used optogenetics to activate the pain circuit during the pain experiment, the response of the bystander became more pronounced, with the bystander experiencing a lower pain tolerance for 24 hours instead of four. Similarly, when they used optogenetics to turn off the link between the ACC and the NAc, the route empathic pain takes, the social transfer of the sensation stopped, demonstrating that communication between the two brain regions is necessary to prompt empathetic behaviors.

With respect to fear, the team blocked the flow of information from the ACC to the BLA and similarly mitigated a mouse’s fear response.

While mouse brains are not identical to our own, the results of this study do seem to align with some of what is known about empathy in humans, says Ewelina Knapska, a neurobiologist at the Nencki Institute of Experimental Biology in Poland. “I think it’s a very nice study because it shows the role of the cortex in controlling downstream structures in mice,” she tells The Scientist. “We know that the ACC is important in human subjects in controlling empathy-related behaviors, but here we see a very similar organization in mice. It gives us a good model to study the fine details of neuronal circuits and hope for the translatability of the research.”

At its most basic level, the results could inform new, socially mediated ways of treating pain or fear in humans, such as group therapy for those with post-traumatic stress disorder (PTSD) or changing the organization of hospital wards. Placing patients recovering from surgery in a room with others further along in their process, Preston says, could speed the healing of all. 

“Hospitals try really hard to maintain this controlled environment because they believe it’s important to the recovery of the individual,” Preston says. “We need to be aware about the distinction between controlling the environment and making it seem more scientific versus actually loosening some of these restrictions and promoting togetherness in these environments where people are trying to recover.”

Moving beyond, Malenka says that a better understanding of the pathways associated with empathy could spur conversations about drugs used to treat empathy-related disorders. While more study is needed to be sure the pathways are conserved between rodent and human, he says, this is work that is already underway. In his lab, Malenka is studying how the empathetic response of rodents is affected by MDMA, the “empathogenic drug” known as ecstasy. 

“This is not crazy stuff,” Malenka tells The Scientist, pointing out that clinical trials are currently testing the efficacy of MDMA in individuals with PTSD. “I almost can’t imagine a more important topic to study, whether you’re a psychologist or a neuroscientist, than what in our brains allows us to be empathetic and compassionate.”

Scientists Are Figuring Out Why Some People Can ‘Hear’ The Voices of The Dead


Scientists have identified the traits that may make a person more likely to claim they hear the voices of the dead.

According to new research, a predisposition to high levels of absorption in tasks, unusual auditory experiences in childhood, and a high susceptibility to auditory hallucinations all occur more strongly in self-described clairaudient mediums than the general population.

The finding could help us to better understand the upsetting auditory hallucinations that accompany mental illnesses such as schizophrenia, the researchers say.

The Spiritualist experiences of clairvoyance and clairaudience – the experience of seeing or hearing something in the absence of an external stimulus, and attributed to the spirits of the dead – is of great scientific interest, both for anthropologists studying religious and spiritual experiences, and scientists studying pathological hallucinatory experiences.

In particular, researchers would like to better understand why some people with auditory experiences report a Spiritualist experience, while others find them more distressing, and receive a mental health diagnosis.

“Spiritualists tend to report unusual auditory experiences which are positive, start early in life and which they are often then able to control,” explained psychologist Peter Moseley of Northumbria University in the UK.

“Understanding how these develop is important because it could help us understand more about distressing or non-controllable experiences of hearing voices too.”

He and his colleague psychologist Adam Powell of Durham University in the UK recruited and surveyed 65 clairaudient mediums from the UK’s Spiritualists’ National Union, and 143 members of the general population recruited through social media, to determine what differentiated Spiritualists from the general public, who don’t (usually) report hearing the voices of the dead.

Overall, 44.6 percent of the Spiritualists reported hearing voices daily, and 79 percent said the experiences were part of their daily lives. And while most reported hearing the voices inside their head, 31.7 percent reported that the voices were external, too.

The results of the survey were striking.

Compared to the general population, the Spiritualists reported much higher belief in the paranormal, and were less likely to care what other people thought of them.

The Spiritualists on the whole had their first auditory experience young, at an average age of 21.7 years, and reported a high level of absorption. That’s a term that describes total immersion in mental tasks and activities or altered states, and how effective the individual is at tuning out the world around them.

In addition, they reported that they were more prone to hallucination-like experiences. The researchers noted that they hadn’t usually heard of Spiritualism prior to their experiences; rather, they had come across it while looking for answers.

In the general population, high levels of absorption were also strongly correlated with belief in the paranormal – but little or no susceptibility to auditory hallucinations. And in both groups, there were no differences in the levels of belief in the paranormal and susceptibility to visual hallucinations.

These results, the researchers say, suggest that experiencing the ‘voices of the dead’ is therefore unlikely to be a result of peer pressure, a positive social context, or suggestibility due to belief in the paranormal. Instead, these individuals adopt Spiritualism because it aligns with their experience and is personally meaningful to them.

“Our findings say a lot about ‘learning and yearning’. For our participants, the tenets of Spiritualism seem to make sense of both extraordinary childhood experiences as well as the frequent auditory phenomena they experience as practising mediums,” Powell said.

“But all of those experiences may result more from having certain tendencies or early abilities than from simply believing in the possibility of contacting the dead if one tries hard enough.”

Future research, they concluded, should explore a variety of cultural context to better understand the relationship between absorption, belief, and the strange, spiritual experience of ghosts whispering in one’s ear.

The research has been published in Mental Health, Religion and Culture.


Scientists Just Discovered 3 New Kinds of Carnivorous Sponge in The Deep Ocean


Even though we know the deep sea is weird, ‘carnivorous sea sponges’ still sound like something from a sci-fi movie. And yet, researchers just announced the discovery of three new such species off the coast of Australia.

Go a few hundred metres deep into the ocean, and it starts to look like you’re in a whole new world: From a creature that looks like a sea star crossed with an octopus, to shark-devouring fish, to carnivorous sponges we’ve never seen before.

“It just goes to show how much of our deep oceans are yet to be explored – these particular sponges are quite unique in that they are only found in this particular region of The Great Australian Bight – a region that was slated for deep sea oil exploration,” said one of the researchers, Queensland Museum Sessile Marine Invertebrates Collection manager Merrick Ekins.

Typically, sea sponges are multicellular filter feeders – they have holey tissues for flowing water, from which their cells extract oxygen and food. They’re pretty simple creatures, with no nervous, digestive, or circulatory system, but have existed in some form for over 500 million years.

But carnivorous sponges are a bit different. Some carnivorous sponges still use the water flow system, while others (like the three newly discovered species) have lost this ability altogether, and nab small crustaceans and other prey using filaments or hooks.

The researchers in this study found three new species of carnivorous sponges – Nullarbora heptaxiaAbyssocladia oxyasters and Lycopodina hystrix, which are also all new genera, as well as a closely related species of sponge that isn’t carnivorous, Guitarra davidconryi. All these species were found at depths of between 163 and over 3,000 metres (535 to 9,842 feet) deep.

“Here we report on an additional four new species of sponges discovered from the Great Australian Bight, South Australia. This area has recently been surveyed, using a Smith-McIntyre Grab and a Remotely Operated Vehicle (ROV) to photograph and harvest the marine biota,” the researchers write in their new paper.

“These new species are the first recorded carnivorous species from South Australia and increase the number of species recorded from around Australia to 25.”

The sponges are also prettier than you would imagine, looking a little like flowers with their spiky protrusions, but not a lot like sponges. 

Carnivorous sponges are having a bit of a moment. We’ve known about them since 1995, but many more have recently been discovered around the world.

“Over the past two decades, our knowledge of carnivorous sponge diversity has almost doubled,” the same team explains in an earlier paper, where they described their discovery of 17 new species of carnivorous sponges.

“[This is] due in part to rapid advances in deep sea technology including ROVs and submersibles able to photograph and harvest carnivorous sponges intact, and also to the herculean efforts of a number of contemporary taxonomists redescribing many of the older species described in the 19th and 20th centuries.”

Nearly every species of carnivorous sponge found in Australia was discovered during a CSIRO RV Investigator Voyage in 2017, showing just how important these deep-sea investigations are.

With the bottom of the ocean still mostly unexplored, we imagine we’ll see plenty more species of carnivorous sponges, and other weird and wonderful sea creatures. 

The research has been published in Zootaxa.


Disagreement creates cognitive disharmony

By Bill Hathaway

Yale researchers have devised a way to peer into the brains of two people simultaneously while are engaged in discussion. What they found will not surprise anyone who has found themselves arguing about politics or social issues.

When two people agree, their brains exhibit a calm synchronicity of activity focused on sensory areas of the brain. When they disagree, however, many other regions of the brain involved in higher cognitive functions become mobilized as each individual combats the other’s argument, a Yale-led research team reports Jan. 13 in the journal Frontiers in Human Neuroscience.

“Our entire brain is a social processing network,” said senior author Joy Hirsch, the Elizabeth Mears and House Jameson Professor of Psychiatry and professor of comparative medicine and neuroscience. “However, it just takes a lot more brain real estate to disagree than to agree.”

For the study, the researchers from Yale and the University College London recruited 38 adults who were asked to say whether they agreed or disagreed with a series of statements such as “same-sex marriage is a civil right” or “marijuana should be legalized.”  After matching up pairs based on their responses the researchers used an imaging technology called functional near-infrared spectroscopy to record their brain activity while they engaged in face-to-face discussions.

When the people were in agreement, brain activity was harmonious and tended to be concentrated on sensory areas of the brain such as the visual system, presumably in response to social cues from their partner. However, during disputes these areas of the brain were less active. Meanwhile, activity increased in the brain’s frontal lobes, home of higher order executive functions.

“There is a synchronicity between the brains when we agree,” Hirsch said. “But when we disagree, the neural coupling disconnects.”

Understanding how our brains function while disagreeing or agreeing is particularly important in a polarized political environment, Hirsch noted.

In discord, she said, two brains engage many emotional and cognitive resources “like a symphony orchestra playing different music.” In agreement, there “is less cognitive engagement and more social interaction between brains of the talkers, similar to a musical duet.” 

The lead investigator of the paper is Alex Salama-Manteau, a former graduate student of economics at Yale and now a data scientist at Airbnb. Mark Tiede, a research scientist at the Haskins Laboratory at Yale, is second author of the paper.


Scientists identify brain cells most vulnerable to Alzheimer’s disease

A major mystery in Alzheimer’s disease research is why some brain cells succumb to the creeping pathology of the disease years before symptoms first appear, while others seem impervious to the degeneration surrounding them until the disease’s final stages.

Now, in a study published January 10, 2021 in Nature Neuroscience, a team of molecular biologists and neuropathologists from the UC San Francisco Weill Institute for Neurosciences have joined forces to identify for the first time the neurons that are among the first victims of the disease—accumulating toxic “tangles” and dying off earlier than neighboring cells.

“We know which neurons are first to die in other neurodegenerative diseases like Parkinson’s disease and ALS, but not Alzheimer’s,” said co-senior author Martin Kampmann, Ph.D., an associate professor in the UCSF Institute for Neurodegenerative Diseases and Chan Zuckerberg Biohub Investigator. “If we understood why these neurons are so vulnerable, maybe we could identify interventions that could make them, and the brain as a whole, more resilient to the disease.”

Alzheimer’s researchers have long studied why certain cells are more prone to producing the toxic tangles of the protein known as tau, whose spread through the brain drives widespread cell death and the resulting progressive memory loss, dementia, and other symptoms. But researchers have not looked closely at whether all cells are equally vulnerable to the toxic effects of these protein accumulations.

“The belief in the field has been that once these trash proteins are there, it’s always ‘game over’ for the cell, but our lab has been finding that that is not the case,” said Lea Grinberg, MD, the study’s other senior author, an associate professor and John Douglas French Alzheimer’s Foundation Endowed Professor in the UCSF Memory and Aging Center. “Some cells end up with high levels of tau tangles well into the progression of the disease, but for some reason don’t die. It has become a pressing question for us to understand the specific factors that make some cells selectively vulnerable to Alzheimer’s pathology, while other cells appear able to resist it for years, if not decades.”

To identify selectively vulnerable neurons, the researchers studied brain tissue from people who had died at different stages of Alzheimer’s disease, obtained from the UCSF Neurodegenerative Disease Brain Bank and the Brazilian BioBank for Aging Studies, a unique resource co-founded by Grinberg. The São Paulo-based biobank collects tissue samples from a broad population of deceased individuals, including many without a neurological diagnosis whose brains nevertheless show signs of very early-stage neurodegenerative disease, which is otherwise very difficult to study in humans.

First, led by Kampmann lab MD/Ph.D. student Kun Leng and Ph.D. student Emmi Li, the study’s co-first authors, the team studied tissue from 10 donor brains using a technique called single-nucleus RNA sequencing, which let them group neurons based on patterns of gene activity. In a brain region called the entorhinal cortex, one of the first areas attacked by Alzheimer’s, the researchers identified a particular subset of neurons that began to disappear very early on in the disease. Later on in the course of the disease, the researchers found, a similar group of neurons were also first to die off when degeneration reached the brain’s superior frontal gyrus.

In both regions, these vulnerable cells were distinguished by their expression of a protein called RORB. This allowed researchers in Grinberg’s neuropathology lab, led by former lab manager Rana Eser, to examine RORB-expressing neurons in more detail in brain tissue from a larger cohort of 26 donors. They used histological staining techniques to examine the fate of cells from both healthy individuals and those with early and late stage Alzheimer’s. This work validated that RORB-expressing neurons do in fact die off early on in the disease and also accumulate tau tangles earlier than neighboring, non-RORB-expressing neurons.

“These findings support the view that tau buildup is a critical driver of neurodegeneration, but we also know from other data from the Grinberg lab that not every cell that builds up these aggregates is equally susceptible,” said Leng, who plans continue to study factors underlying RORB neurons’ selective vulnerability using CRISPR-based technology the Kampmann lab has developed.

It’s not clear whether RORB itself causes the cells’ selective vulnerability, the researchers said, but the protein provides a valuable new molecular “handle” for future studies to understand what makes these cells succumb to Alzheimer’s pathology, and how their vulnerability could potentially be reversed.

“Our discovery of a molecular identifier for these selectively vulnerable cells gives us the opportunity to study in detail exactly why they succumb to tau pathology, and what could be done to make them more resilient,” Leng said. “This would be a totally new and much more targeted approach to developing therapies to slow or prevent the spread of Alzheimer’s disease.”

More information: Molecular characterization of selectively vulnerable neurons in Alzheimer’s disease, Nature Neuroscience (2021). DOI: 10.1038/s41593-020-00764-7 , www.nature.com/articles/s41593-020-00764-7


Alzheimer’s brain tissue study uncovers three distinct disease subtypes

Researchers analyzed more than 1,500 postmortem brain tissue samples to distinguish the molecular differences between various cases of Alzheimer’s disease

Despite decades of rigorous research, scientists are still struggling to crack the mystery of Alzheimer’s disease. Promising preclinical research has consistently led to frustrating clinical trial failures and some have started to question whether we are even targeting the correct pathological mechanisms.

One possible explanation for why we can’t crack the Alzheimer’s code is that we are mistakenly considering the disease as a single homogeneous entity. Currently Alzheimer’s disease (AD) is only really separated into two types, either early-onset Alzheimer’s or late-onset Alzheimer’s, depending on what stage of a person’s life they begin displaying symptoms.

A robust 2018 study investigated the cognitive and genomic characteristics of several thousand patients diagnosed with late-onset Alzheimer’s and concluded Alzheimer’s should be considered six distinctly different conditions instead of one single disease.

This new study arose from a similar foundation, trying to understand why the disease manifests with such a variety of clinical symptoms from patient to patient. One third of patients displaying clinical characteristics of Alzheimer’s, for example, show no toxic accumulation of amyloid proteins in their brain. And the opposite is also seen, with postmortem brain tissue biopsies revealing comprehensive pathological signs of Alzheimer’s despite no indication of cognitive decline during the person’s life.

Such differences strongly suggest there are subtypes of AD with different biological and molecular factors driving disease progression,” says lead author on the new study, Bin Zhang.

The new research set out to understand the specific molecular characteristics of different Alzheimer’s cases. Using RNA sequencing the research analyzed over 1,500 brain tissue samples, spanning five different brain regions.

Three major molecular subtypes of Alzheimer’s were identified based on factors including synaptic signaling, immune activity, mitochondria organization, myelination and specific gene activity. Only one third of the cases studied displayed “typical” Alzheimer’s hallmarks, such as decreased synaptic signaling and increased immune response. This subtype was dubbed “class C.”


mportantly, the study suggests the other two identified subtypes (class A and B) showed unique and distinct characteristics. In some instances the subtypes displayed opposite gene regulation, leading the researchers to hypothesize their findings as potentially helping explain previous clinical trial failures.

“This may partially explain how many existing clinical trials that showed promising efficacy in one particular mouse model later do not align with human trial results, assuming that study participants had consisted of a heterogeneous group of participants across many AD subtypes,” the researchers write in the study.

The challenge moving forward will be to find ways to detect these disease subtypes easily in living patients. The comprehensive brain tissue analysis in the study cannot translate into a diagnostic tool, so more work is needed to find biomarkers that correspond with these three subtypes.

“These findings lay down a foundation for determining more effective biomarkers for early prediction of AD, studying causal mechanisms of AD, developing next-generation therapeutics for AD and designing more effective and targeted clinical trials, ultimately leading to precision medicine for AD,” explains Zhang. “The remaining challenges for future research include replication of the findings in larger cohorts, validation of subtype specific targets and mechanisms, identification of peripheral biomarkers and clinical features associated with these molecular subtypes.”

The new study was published in the journal Science Advances.


Hydrogen sulfide could guard against Alzheimer’s disease

Dr. Bindu Paul, M.S., Ph.D., and lead corresponding author on the discovery of the role of H2S in Alzheimer’s disease.

Typically characterized as poisonous, corrosive and smelling of rotten eggs, hydrogen sulfide’s reputation may soon get a facelift. In experiments in mice, researchers have shown the foul-smelling gas may help protect aging brain cells against Alzheimer’s disease. The discovery of the biochemical reactions that make this possible opens doors to the development of new drugs to combat neurodegenerative disease.

The study was led by John Hopkins Medicine, working with the University of Exeter. The findings are reported in The Proceedings of the National Academies of Science.

“Our new data firmly link aging, neurodegeneration and cell signaling using hydrogen sulfide and other gaseous molecules within the cell,” says Bindu Paul, M.Sc., Ph.D., Faculty Research Instructor in neuroscience in the Solomon H. Snyder Department of Neuroscience at the Johns Hopkins University School of Medicine and lead corresponding author on the study.

The human body naturally creates small amounts of hydrogen sulfide to help regulate functions across the body from cell metabolism to dilating blood vessels. The rapidly burgeoning field of gasotransmission shows that gases are major cellular messenger molecules, with particular importance in the brain. However, unlike conventional neurotransmitters, gases can’t be stored in vesicles. Thus, gases act through very different mechanisms to rapidly facilitate cellular messaging. In the case of hydrogen sulfide, this entails the modification of target proteins by a process called chemical sulfhydration, which modulates their activity, says Solomon Snyder, D.Phil., D.Sc., M.D., professor of neuroscience at the Johns Hopkins University School of Medicine and co-corresponding author on the study.

Previous studies using a new method have shown that sulfhydration levels in the brain decrease with age, a trend that is amplified in patients with Alzheimer’s disease. “Here, using the same method, we now confirm a decrease in sulfhydration in the AD brain,” says collaborator Milos Filipovic, Ph.D., Principal Investigator, Leibniz-Institut für Analytische Wissenschaften—ISAS.

For the current research, the Johns Hopkins Medicine scientists studied mice genetically engineered to mimic human Alzheimer’s disease. They injected the mice with a hydrogen sulfide-carrying compound, called NaGYY, developed by their collaborators at University of Exeter, that slowly releases the passenger hydrogen sulfide molecules while traveling throughout the body. The researchers then tested the mice for changes in memory and motor function over a 12-week period.

Behavioral tests on the mice showed that hydrogen sulfide improved cognitive and motor function by 50per cent compared with mice that did not receive the injections of NaGYY. Treated mice were able to better remember the locations of platform exits and appeared more physically active than their untreated counterparts with simulated Alzheimer’s disease.

“Up until recently, researchers lacked the pharmacological tools to mimic how the body slowly makes tiny quantities of H2S inside cells. “The compound used in this study does just that and shows by correcting brain levels of H2S, we could successfully reverse some aspects of Alzheimer’s disease,” says collaborator on the study, Matt Whiteman, Ph.D., Professor of Experimental Therapeutics at the University of Exeter Medical School.

The results showed that the behavioral outcomes of Alzheimer’s disease could be reversed by introducing hydrogen sulfide, but the researchers wanted to investigate how the brain chemically reacted to the gaseous molecule.

A series of biochemical experiments revealed a change to a common enzyme, called glycogen synthase β (GSK3β). In the presence of healthy levels of hydrogen sulfide, GSK3β typically acts as a signaling molecule, adding chemical markers to other proteins & altering their function. However, the researchers observed that in the absence of hydrogen sulfide, GSK3β is over-attracted to another protein in the brain, called Tau.

When GSK3β interacts with Tau, Tau changes into a form that tangles and clumps inside nerve cells. As Tau clumps grow, the tangled proteins block communication between nerves, eventually causing them to die. This leads to the deterioration and eventual loss of cognition, memory and motor function that is characteristic of Alzheimer’s disease.

“Understanding the cascade of events is important to designing therapies that can block this interaction like natural hydrogen sulfide is able to do,” says Daniel Giovinazzo, M.D./Ph.D. student, the first author of the study.

The Johns Hopkins Medicine team and their international collaborators plan to continue studying how sulfur groups interact with GSK3β and other proteins involved in the pathogenesis of Alzheimer’s disease in other cell and organ systems. The team also plans to test novel hydrogen sulfide delivery molecules as part of their ongoing venture.

More information: Daniel Giovinazzo et al. Hydrogen sulfide is neuroprotective in Alzheimer’s disease by sulfhydrating GSK3β and inhibiting Tau hyperphosphorylation, Proceedings of the National Academy of Sciences (2021). DOI: 10.1073/pnas.2017225118


Sleep evolved before the brain

By Chrissy Sexton

While it is known that sleep is critical for healthy brain function, it is not known when animals started to require sleep. A surprising new study from Kyushu University suggests that animals needed sleep before they even had brains. 

The investigation was focused on hydras – tiny freshwater organisms that lack a central nervous system. The researchers discovered that not only do hydras show signs of a sleep-like state despite having no brain, but also respond to molecules associated with sleep in more evolved animals.

“We now have strong evidence that animals must have acquired the need to sleep before acquiring a brain,” said study lead author Professor Taichi Q. Itoh.

Three years ago, scientists at Caltech were the first to document sleeping behavior in a brainless animal, the Cassiopea jellyfish, a relative of hydras that is also known as the upside-down jellyfish.

In collaboration with experts at the Ulsan National Institute of Science and Technology in Korea, the Kyushu team found that several chemicals which cause drowsiness even in humans had similar effects on the species Hydra vulgaris.

“Based on our findings and previous reports regarding jellyfish, we can say that sleep evolution is independent of brain evolution,” said Professor Itoh.

“Many questions still remain regarding how sleep emerged in animals, but hydras provide an easy-to-handle creature for further investigating the detailed mechanisms producing sleep in brainless animals to help possibly one day answer these questions.”

To monitor resting behavior among hydras, the researchers used a video system to track their movement and determine when hydras they were in a sleep-like state. 

The hydras displayed four-hour cycles of active and sleep-like states. The researchers uncovered many aspects of sleep regulation that were similar to that of animals who do possess a brain on a molecular and genetic level.

Melatonin moderately increased the amount and frequency of sleep among hydras, while the inhibitory neurotransmitter GABA greatly increased sleeping activity.

When the hydras were exposed to dopamine, they also slept more. In humans and other animals, dopamine typically causes arousal. “While some sleep mechanisms appear to have been conserved, others may have switched function during evolution of the brain,” explained Professor Itoh.

The researchers used vibrations and temperature changes to disturb the hydras’ sleep and induce signs of sleep deprivation. This caused the hydras to sleep longer during the following day and even suppressed cell proliferation.

Upon further analysis, the experts found that sleep deprivation led to changes in the expression of 212 genes. One of these genes in particular is related to PRKG, a protein involved in sleep regulation in a wide range of animals.

“Taken all together, these experiments provide strong evidence that animals acquired sleep-related mechanisms before the evolutional development of the central nervous system and that many of these mechanisms were conserved as brains evolved,” said Professor Itoh.

The study is published in the journal Science Advances.

Women May Transmit Cancer to Infants in Childbirth

by Dennis Thompson

In extremely rare instances, newborns can contract cancer from their pregnant moms during delivery, a new case report suggests.

Two boys, a 23-month-old and a 6-year-old, developed lung cancers that proved an exact genetic match to cervical cancers within their mothers at the time of birth, Japanese researchers report.

It appears that the boys breathed in cancer cells from their mothers’ tumors while they were being born, cancer experts say.

“In our cases, we think that tumors arose from mother-to-infant vaginal transmission through aspiration of tumor-contaminated vaginal fluids during birth,” said lead researcher Dr. Ayumu Arakawa, a pediatric oncologist with the National Cancer Center Hospital in Tokyo.

Transmission of cancer from a mom to her offspring is a very rare event, occurring in only 1 infant for every 500,000 mothers with cancer, researchers said in background notes. By comparison, about 1 in every 1,000 live births involves a mother with cancer.

The small number of previously observed cases typically have involved cancer cells traveling across the placenta and into the still-developing fetus, researchers said. Leukemia, lymphoma and melanoma are the most common cancers that children contract through suspected transplacental transmission.

These are the first cases in which newborns appear to have contracted lung cancer by breathing in cancer cells from cervical tumors, cancer experts said.

“I found it fascinating, personally. I didn’t know this was possible,” said Debbie Saslow, senior director of HPV-related and women’s cancers at the American Cancer Society.

Most cervical cancers are caused by human papillomavirus (HPV), a virus against which there is an effective vaccine. Cases like this will become even rarer as more boys and girls are vaccinated against HPV, Saslow said.

“I think it’s interesting that this study was from Japan, where they’ve had a lot of backlash against the HPV vaccine and they saw vaccination rates plummet because of unfounded concerns,” Saslow said. “I also know Japan has had particularly low cervical screening rates.”

Doctors discovered cancer in both lungs of the 23-month-old boy after his family took him to the hospital for a cough that had gone on for two weeks. His mother had received a diagnosis of cervical cancer three months after the infant’s birth.

The 6-year-old boy went to a local hospital with chest pain on his left side, and a CT scan revealed a 6-centimeter mass in his left lung. His mother had a cervical tumor that was thought to be benign at the time of delivery; she died from cervical cancer two years after his birth.

“Neither mother was known to have a cervical cancer. The first patient had a negative pap smear, and the second had a cervical mass but it was thought to be benign. I don’t know the obstetricians would have done anything differently based on the information they had,” said Dr. Shannon Neville Westin, a gynecologic oncologist with the University of Texas MD Anderson Cancer Center.

In both cases, doctors used genetic testing to positively link the mothers’ cervical cancers to the lung cancers in their sons.

“If we hadn’t been able to test the tumors from the mother and the infant, you never would have known those were truly related,” Westin said. “Because they determined that they were, they were able to direct therapy in a way that was very successful for the infants.”

Both boys still are alive following successful cancer treatment, the Japanese researchers said. The findings were reported Jan. 7 in the New England Journal of Medicine.

Arakawa and his colleagues suggest that pregnant women with cervical cancers consider having a C-section, to avoid the risk of passing cancer to their newborn.

“Mother-to-infant transmission of tumor may be a risk of vaginal delivery among women with cervical cancers,” Arakawa said. “Cesarean section should be recommended for mothers with uterine cervical cancer.”

Westin and Saslow both disagree, arguing that too little is known to immediately change recommendations around this specific and rare situation.

“If we are diligent about testing more of these infants with cancer, we may be able to move forward and change practice and say every patient with cervical cancer should have a cesarean section,” said Westin, an expert with the American Society of Clinical Oncology. “We just need to gather up that data to be able to change the practice.”

“Only about 1% to 3% of all women with cervical cancer are pregnant or postpartum at the time of diagnosis. The incidence of cervical cancer ranges, but it’s around 12,000 a year,” Westin said. “You’re really selecting out such a tiny group of patients to even begin with.”


New DNA-editing method effectively treats mouse model of progeria

Progeria is caused by a mutation in the nuclear lamin A gene in which one DNA base C is changed to a T. Researchers used the base editing method, which substitutes a single DNA letter for another without damaging the DNA, to reverse that change. Credit: Ernesto del Aguila III, NHGRI

Researchers have successfully used a DNA-editing technique to extend the lifespan of mice with the genetic variation associated with progeria, a rare genetic disease that causes extreme premature aging in children and can significantly shorten their life expectancy. The study was published in the journal Nature, and was a collaboration between the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health; Broad Institute of Harvard and MIT, Boston; and the Vanderbilt University Medical Center, Nashville, Tennessee.

DNA is made up of four chemical bases—A, C, G and T. Progeria, which is also known as Hutchinson-Gilford progeria syndrome, is caused by a mutation in the nuclear lamin A (LMNA) gene in which one DNA base C is changed to a T. This change increases the production of the toxic protein progerin, which causes the rapid aging process.

Approximately 1 in 4 million children are diagnosed with progeria within the first two years of birth, and virtually all of these children develop health issues in childhood and adolescence that are normally associated with old age, including cardiovascular disease (heart attacks and strokes), hair loss, skeletal problems, subcutaneous fat loss and hardened skin.

For this study, researchers used a breakthrough DNA-editing technique called base editing, which substitutes a single DNA letter for another without damaging the DNA, to study how changing this mutation might affect progeria-like symptoms in mice.

“The toll of this devastating illness on affected children and their families cannot be overstated,” said Francis S. Collins, M.D., Ph.D., a senior investigator in NHGRI’s Medical Genomics and Metabolic Genetics Branch, NIH director and a corresponding author on the paper. “The fact that a single specific mutation causes the disease in nearly all affected children made us realize that we might have tools to fix the root cause. These tools could only be developed thanks to long-term investments in basic genomics research.”

The study follows another recent milestone for progeria research, as the U.S. Food and Drug Administration approved the first treatment for progeria in November 2020, a drug called lonafarnib. The drug therapy provides some life extension, but it is not a cure. The DNA-editing method may provide an additional and even more dramatic treatment option in the future.

David Liu, Ph.D., and his lab at the Broad Institute developed the base-editing method in 2016, funded in part by NHGRI.

“CRISPR editing, while revolutionary, cannot yet make precise DNA changes in many kinds of cells,” said Dr. Liu, a senior author on the paper. “The base-editing technique we’ve developed is like a find-and-replace function in a word processor. It is extremely efficient in converting one base pair to another, which we believed would be powerful in treating a disease like progeria.”

To test the effectiveness of their base-editing method, the team initially collaborated with the Progeria Research Foundation to obtain connective tissue cells from progeria patients. The team used the base editor on the LMNA gene within the patients’ cells in a laboratory setting. The treatment fixed the mutation in 90% of the cells.

“The Progeria Research Foundation was thrilled to collaborate on this seminal study with Dr. Collins’s group at the NIH and Dr. Liu’s group at Broad Institute,” said Leslie Gordon, M.D., Ph.D., a co-author and medical director of The Progeria Research Foundation, which partially funded the study. “These study results present an exciting new pathway for investigation into new treatments and the cure for children with progeria.”

Following this success, the researchers tested the gene-editing technique by delivering a single intravenous injection of the DNA-editing mix into nearly a dozen mice with the progeria-causing mutation soon after birth. The gene editor successfully restored the normal DNA sequence of the LMNA gene in a significant percentage of cells in various organs, including the heart and aorta.

Many of the mice cell types still maintained the corrected DNA sequence six months after the treatment. In the aorta, the results were even better than expected, as the edited cells seemed to have replaced those that carried the progeria mutation and dropped out from early deterioration. Most dramatically, the treated mice’s lifespan increased from seven months to almost 1.5 years. The average normal lifespan of the mice used in the study is two years.

“As a physician-scientist, it’s incredibly exciting to think that an idea you’ve been working on in the laboratory might actually have therapeutic benefit,” said Jonathan D. Brown, M.D., assistant professor of medicine in the Division of Cardiovascular Medicine at Vanderbilt University Medical Center. “Ultimately our goal will be to try to develop this for humans, but there are additional key questions that we need to first address in these model systems.”

More information: In vivo base editing rescues Hutchinson–Gilford progeria syndrome in mice, Nature (2021). DOI: 10.1038/s41586-020-03086-7 , www.nature.com/articles/s41586-020-03086-7