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Neuroscience

Inner Speech, Internal Monologues and Hearing Voices: Exploring the Conversations Between Our Ears – Technology Networks

Its slightly strange that we talk to ourselves inside our own head. Its even stranger that we do it virtually the whole time we are awake. Whats strangest of all is that, despite coronavirus isolation making our internal chatter all the more apparent, we dont often outwardly discuss the conversation in our head.Similarly, our scientific investigation of inner speech has made surprisingly little headway. Charles Fernyhough is a professor in the Department of Psychology at Durham University and author of The Voices Within, a book focusing on inner speech. He suggests that the first challenge is defining exactly what to call the noises we make inside our head. A lot of people talk about the inner voice, which is a term I avoid, because it is very vague and fluffy and hard to pin down.Fernyhough says that people may associate the term inner voice with concepts like gut feeling or moments of inspiration, but what he and his team study is inner speech, a formal scientific term that involves the word-based conversations we have with ourselves inside our heads. Fernyhough has argued in hisresearch that inner speech is a distinct type of auditory thinking, separate from, for example, imagining a siren going off. As well see, inner speechs developmental origins and unique characteristics separate it from these other between-our-ears phenomena.

Researchers in Fernyhoughs field have not chosen an easy area of study. Whilst behavioural neuroscientists can mimic fear responses in a mouse and neuroimaging researchers can look at highly-conserved reward pathways in non-human primates, studying inner speech in humans really requires human volunteers. These test sujects often arent particularly cooperative: People find it very hard to reflect on their own inner speech. The reason it's had little attention, publicly, culturally, but also scientifically is that it's very hard to get a grip on ones own inner speech, says Fernyhough.Fernyhoughs quest to understand inner speech began by observing outer speech at the beginning of the brains development. His research began in developmental psychology, studying how young children behaved when playing alone. Fernyhough noticed that his subjects would spend a lot of their time talking to themselves out loud. This seemed to fulfil a function beyond just annoying nearby working-from-home parents. [The children] give a strong impression, and the research supports this, that they are doing it for a reason they're doing it because it's helpful. They're getting some sort of cognitive benefit from it, says Fernyhough.

As the children aged, this helpful out-loud speech gradually stopped. Had parents just asked them to keep quiet, or was there something more complicated involved? Fernyhough found an answer in the work of influential Soviet psychologist Lev Vygotsky. Vygotsky, Fernyhough tells me, believed that speech was something that began as a purely social instrument for communication between people that over the course of development became gradually internalized. This process of internalizing, Fernyhough says, gives us tools for thinking that benefits our development.

Not all aspects of our inner speech have obvious benefits to our behavior. Anyone who has anxiously spent hours internally processing worried thoughts about an exam, only to have no time to actually study for it, might wonder why such unhelpful examples of inner speech were not chopped out at an earlier point in evolution. Surely an early human would have been much fitter to their environment if they just threw a spear straight into a mammoth without ruminating on how they were going to extract the spear later, and whether this particular mammoth was going to be as delicious as the one they had caught last winter?

Jonny Smallwood, a professor in the Department of Psychology at the University of York, has made the study of one particularly aimless form of rumination, daydreaming, his own research niche. Things like daydreaming even though they might seem "purposeless must be having some kind of quite important role in how we guide our lives, says Smallwood.

But what is that role? Smallwoods studies have looked at how people from different countries and cultures daydream. All his participants had one thing in common they tended to think about the future. Smallwood reckons that this common finding hints at why internal states like daydreaming and inner speech have become so widespread. One of the ways that the internal representation system can be selected for is because you can prepare for an interaction with another person and you can think about the kind of things that they might be happy or unhappy for you to say. Then, when you get into that circumstance, you're less likely to say the wrong thing, which might make the interaction smoother, says Smallwood.

Internal processes like inner speech and daydreaming might give us an evolutionary advantage. But the most interesting thing about these processes isnt their function, but their prevalence. Fernyhough has noted that inner speech, despite perhaps seeming to many people like the most innate behavior of all, is not ubiquitous. You certainly find that private speech in children is pretty universal. You don't find many kids who are developing in a typical way that don't use private speech. But when it comes to adults, I came across people who clearly just weren't doing much inner speech, says Fernyhough.

These internally silent volunteers instead commonly relied on imagery in their day-to-day thoughts, with pictures replacing words as their thinking tool of choice. To my mind it says it's something that a lot of humans do because it's handy. But it's by no means an essential component of consciousness, says Fernyhough. We find different ways to get to the same outcome and I think that's one of the marvels of psychology.

Variation in how we think isnt limited to whether we use words or images. Sometimes, the very nature of our thinking can become disrupted. Fernyhough became acutely aware of this when he shared his developmental psychology findings with psychiatrist colleagues, who took his comments about inner speech to be referring to auditory hallucinations, or hearing voices.

Durham University's Palace Green Library hosted an exhibition titled Hearing Voices: suffering, inspiration and the everyday in 2016-17. Image credits from Durham exhibition: Andrew Cattermole Photography

These hallucinations are most commonly linked in popular culture to the mental health disorder schizophrenia. In reality, schizophrenia is a complex disorder, and auditory hallucinations are just part of an often complex range of symptoms. The idea that hearing voices is unique to schizophrenia is also misleading, suggests Fernyhough. The experience of hearing voices is involved in all sorts of different psychiatric diagnoses, everything from post-traumatic stress disorder (PTSD) to eating disorders. It is also experienced by quite a small but significant number of people who are not mentally ill who hear voices quite regularly, but don't seek help for them because they're not troubled by them.

Is there a fundamental difference between inner speech and auditory hallucinations? This question has been the target of a project Fernyhough is helping run at Durham, funded by the Wellcome Trust, called Hearing the Voice. The study is still ongoing, but some early conclusions are that the difference between these internal states is very simple. The idea is that when somebody hears a voice, what they're actually doing is some inner speech, but for some reason, they don't recognize that they themselves made that bit of language in their heads, says Fernyhough. Its experienced as coming from somewhere else or from someone else.

What complicates this idea are the many types of both inner speech and auditory hallucinations. Fernyhough thinks that his theory will apply to some types of both experiences, but not all. Some hallucinations have acoustic properties, as if the speaker is in the room with you. Sometimes the voice has an accent or a timbre or a pitch. It's very hard to pin down what it is that makes some people have an experience that feels alien, that is distressing, especially when some people have what seems to be the same experience, but don't find it distressing, says Fernyhough. I think the only thing you can really point to is that for some reason, that experience of hearing your voice doesn't feel like you. It comes from some other author or agency. And that's what can be, as you can imagine, very distressing.

Bringing relief to that distress will require research into both "normal" and pathological forms of inner speech. To do that, psychologists rely on imaging techniques like fMRI and PET scanning. Nevertheless, the biggest advances in the field have been less to do with the hardware used and more about the way in which researchers get their participants to do inner speech.

At the beginning of these neuroimaging studies, researchers noted that when they asked their participants to engage in inner speech, areas of the brains basic language system began to light up. For most people, Fernyhough tells me, that means activation of the left hemisphere, particularly in an area at the front of the brain called Brocas area.

As we talk, our respective Brocas areas will be lighting up. Given the developmental connections between outward and inner speech, it might make sense that the same brain areas would be activated. But Fernyhough tells me these initial studies had some serious flaws.

The problem is that when we do scanning experiments like this, what we tend to do is put people into a scanner, and we say to them, right, whilst you are lying there I want you to do some inner speech, and we tell them what inner speech to do, says Fernyhough. Volunteers would be asked to say a particular phrase, such as I like football, in repetition whilst they lay inside the scanner.

Fernyhough points out that, except for the most single-minded fan, few peoples inner speech consists of repetitive statements about their love for sports. Its more often complex and chopped up into smaller chunks of thought. To try and monitor this kind of natural inner speech, Fernyhoughs team took a different approach that made use of descriptive experience sampling, a technique where subjects are prompted to note down what their inner experience was just prior to the sounding of a beeper. The process is labor-intensive, as people often need to be coached to effectively capture the details of their inner experience.

Listen to a podcast by Hearing the Voice, in which we hear testimoniescollected by Elisabeth Svanholmer (voice-hearer and mental health trainer) of how people have shared their experience of hearing voices.

Over time, Fernyhough believes the end result is much more valuable. We were able to capture the moments in which they just happened to be doing inner speech spontaneously because it's what was in their head at that time. Not because we told them to, says Fernyhough.

So was there any difference in brains doing this more natural inner speech as opposed to the repetitive, proscribed type? Fernyhough says there was a stark contrast. Using descriptive experience sampling, we got a totally different pattern of brain activations. We found activations much further back in the brain, in areas that you would associate with speech perception and understanding, not speech production. Whilst the findings need to be replicated, Fernyhough believes that if peoples brains act differently depending on whether they perform tasks spontaneously or in response to instruction, there could be ramifications for all kinds of imaging-based neuroscience.

These fundamental findings about the nature of our inner experience will only be expanded upon if neuroscience makes changes to how experiments are conducted, says Fernyhough. These changes in practice will also need to be at a fundamental level. We've got fantastic machines and software for telling us what's going on in a particular cluster of neurons and a particular moment. We're not very good at the other thing, which is asking people about their experience, of getting at the subjective quality of experience. We really have to raise our game on that.

Going forward, Fernyhough will try and bring this alternative focus to the analysis of voices as part of Hearing the Voice. Fernyhough thinks that exploring the vast range of different types of voices people hear in health and disease will raise questions not only about the brain, but about the nature of language and the mind itself. Exploring these differences could be brain researchs greatest challenge yet. But its a challenge that Fernyhough, at least, relishes: So many people in psychology and cognitive science are kind of looking for the thing that makes us all the same. And I think that's a mistaken enterprise a lot of the time. I think we are so different in so many ways, in fascinating ways. And I think our minds are just one way in which we are very, very different.

Worried about hearing voices? Visit the resources at Understanding Voices to get more information.

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Inner Speech, Internal Monologues and Hearing Voices: Exploring the Conversations Between Our Ears - Technology Networks

Neuroscience

Frog brain discovery may pave the way for repairing birth defects in humans – News-Medical.Net

A new study on the frog brain may lead to innovative ways of repairing congenital disabilities in humans.

A team of researchers from Tufts University, Universitat de Valencia, and Harvard University has discovered that the brains of developing frog embryos damaged by nicotine exposure can be repaired by using ionoceuticals that can help in the recovery of bioelectric patterns in the embryo.

The study, which was published in the journal Frontiers of Cellular Neuroscience, highlights the possibility of treatment strategies based on restoring the bioelectric blueprint or map for embryonic development. The study may pave the way for developing drugs and therapies to help repair birth defects in the future.

Nicotine induced defects in the frog embryo brain (center) can be rescued by transplanting an HCN2 expressing patch on the embryo far from the brain. Treated embryos are observed to have normal brain morphology and function (right). View of normal embryo head is shown at left. Similar results are seen when nicotine-exposed embryos are treated with ionoceutical drugs. (FB = forebrain; MB = midbrain; HB = hindbrain) Image Credit: Vaibhav Pai, Tufts University

Bioelectrical signals among cells control and guide embryonic brain development. Previous studies have shown that manipulating these signals can repair genetic defects and induce the development of healthy brain tissue.

In a study published in the Journal of Neuroscience in 2015, the same scientists revealed that bioelectric signaling controls the activity of two cell reprogramming factors, which they tested on African clawed frog embryos.

The team found that cells communicate even in long distances in the embryo by using bioelectrical signals. The cells use this data to know where to form a brain and how big the brains should be.

The findings of their current study were based on their previous research on bioelectric signals.

Now, the team aimed to see how bioelectric signals can help repair the brain damaged by nicotine.

Nicotine is a stimulant and potent parasympathomimetic alkaloid that is naturally produced in the nightshade family of plants. Nicotine is highly addictive. It is one of the most commonly abused drugs. The primary therapeutic use of nicotine is treating nicotine dependence to eliminate smoking.

Earlier studies have shown that nicotine can disrupt the normal electrical patterns in the brain of a growing embryo. It was found that it can reduce the contrast of the bioelectric blueprint, which is a map of different voltage levels around the cells. This map aids and guides the pattern and growth of organs and tissues.

Nicotine in humans has been tied to various health effects, including intrauterine fetal death, attention deficit hypersensitivity disorder (ADHD), sudden infant death, and other cognitive function deficits. It can also affect the infants memory and learning abilities.

In the study, the researchers applied nicotine to developing frog embryos to generate neural defects. They want to determine the specific interventions that can reverse the harmful effects of the chemical. In the previous study, the team identified one specific element in the natural electric signaling that controls brain development the hyperpolarization-activated cyclic nucleotide-gated channel-2 (HCN2), which was able to restore the bioelectric patterns.

In 2015, the team tried to repair the defects by using a form of gene therapy that modifies the expression of HCN2. However, in the current study, no gene was used. Instead, the team has found that the same effects can be achieved by using small molecule drugs to stimulate the HCN2 channels that are already present inside the embryo. Next, the team has demonstrated that they can reset the electrical patterning information that oversees brain development from a distant location on the embryo.

Michael Levin, the study author, and a Vannevar Bush Professor of Biology at Tufts University said that the study is a breakthrough in preventing neural tube defects and birth defects in embryos. Further, he added that when the team boosted the expression of HCN2 at a distance from the brain, such as in non-neural regions, they were still able to prevent or repair the defects in the brain.

The instructions to build a fully grown animal, including organs as complex as the brain, are distributed among all the cells of the embryo. These results suggest that we might not have to target the damaged region directly, and we can use drugs instead of genetic manipulation, which opens a lot of opportunities for biomedical deployment, Levin added.

The findings of the study have led the scientists to think that there may be a drug that activated HCN2. They can use the drug to prevent defects in the embryo.

At present, two drugs can activate HCN2 gabapentin, and lamotrigine. They are already FDA-approved and are safe-to-use.

To test their hypothesis, the team exposed the embryos to nicotine and treated them with drugs during the various stages of embryonic development.

The team discovered that 68 percent of the tadpoles who were not treated with drugs had brain defects. On the other hand, the embryos that were treated with either of the drugs had a reduction of brain defects. About only 10 percent of the frogs treated with lamotrigine and 16 percent of those treated with gabapentin had brain defects.

Our results and quantitative model identify a powerful morphogenetic control mechanism that could be targeted by future regenerative medicine exploiting ion channel modulating drugs approved for human use, the team concluded in the study.

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Neuroscience

In the Inner Ear, UVA Finds an Essential Key to Hearing Sensitivity – University of Virginia

New research from theUniversity of Virginia School of Medicineis shedding light on the biological architecture that lets us hear and on a genetic disorder that causes both deafness and blindness.

Sihan Li, a graduate student in the lab of Jung-Bum Shin of UVAs Department of Neuroscience, has made a surprising discovery about how the hearing organ in mammals achieves its extraordinary sensitivity.

It was long suspected that tiny molecular motors maintain the proper tension in the so-called hair cell mechanoreceptors that are located in the inner ear. This tension is a key factor in how we detect sound, similar to how a taut fishing line indicates nibbling fish.

The research team led by Li and Shin demonstrated that maintaining this tension was the responsibility of a protein called Myosin-VIIa. They also found that there is not just one Myosin-VIIa, but several subtle variations that all play important roles. Problems with these protein isoforms, as the variations are known, lead to hearing loss, Shins team found. That speaks to the vital importance of these underappreciated variations in proteins.

Our sense of hearing is incredibly sensitive, and our study identified a very important component in the underlying mechanism, Shin said. Furthermore, we showed that the molecular machinery that enables hearing is much more complicated than we thought, with each protein having multiple sister forms that have distinct functions.

Myosin-VIIa is made by a genelabeled MYO7A. Mutations in that gene cause a rare genetic disorder, Usher syndrome type 1. Children with the syndrome typically are born deaf and then suffer progressive vision loss. The discovery by the Shin lab will contribute to a better understanding of this disease.

Shin and his team found that lab mice lacking proper Myosin-VIIa isoforms developed hearing loss. His work shows that the mice were able to develop hair cells, but their function was impaired and grew progressively worse. (Myosin-VIIa is also produced in the retina, the part of the eye that senses light. The Shin lab did not look at that, but his work might shed more light on how impairments in Myosin-VIIa affect vision as well.)

One of the great questions arising from the work, the researchers say, is exactly why the inner ear uses multiple isoforms of this protein. Finding those answers will help us understand an important aspect of our ability to hear, and it may one day help doctors develop new treatments for hearing loss.

After all, the flip side of the extreme sensitivity of our hearing organ is that it is also very vulnerable to stress factors, such as noise and age. We have found one important mechanism by which the ear achieves its sensitivity, Shin said. This will help us understand the harmful processes that lead to the loss of our hearing sensitivity with age or due to noise trauma, laying the foundation for the development of preventative and therapeutic strategies.

The researchers havepublished their findings in the scientific journal Nature Communications. The studys authors were Li, Andrew Mecca, Jeewoo Kim, Giusy A. Caprara, Elizabeth L. Wagner, Ting-Ting Du,Leonid Petrov, Wenhao Xu, Runjia Cui, Ivan T. Rebustini, Bechara Kachar, Anthony W. Peng and Shin.

The research was a collaboration with laboratories at the University of Colorado and the National Institute of Health, and was supported by the NIHs National Institute for Deafness and Other Communication Disorders, grants R01DC014254, R56DC017724 and R01DC016868, and by NIDCD Intramural Research Program Z01-DC000002.

To keep up with the latest medical research news from UVA, subscribe to theMaking of Medicineblog.

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Neuroscience

Schizophrenia: Is the Thalamus Misleading the Ear? – Technology Networks

There is an extremely high probability that individuals with 22q11.2 micro deletion syndrome a rare genetic disorder will develop schizophrenia together with one of its most common symptoms, auditory hallucinations. Scientists at the University of Geneva (UNIGE) and the Synapsy National Centre of Competence in Research (NCCR) have been studying this category of patients. They have succeeded in linking the onset of this hallucinatory phenomenon with the abnormal development of certain substructures of a region deep in the brain called the thalamus. These thalamic nuclei have been identified using a combination of functional and structural magnetic resonance imaging. They are involved in processing memory and hearing among other things. The authors suggest that there might be an explanation for these auditory hallucinations that is almost "mechanical": the immaturity of the axon connections that bind the thalamic nuclei to the cortex areas responsible for hearing. The results, published in the journal Biological Psychiatry: CNNI, pave the way for a new understanding of the pathophysiology and treatment of schizophrenia.Several studies in recent years have demonstrated a link between schizophrenia and abnormalities in the development of the thalamus, a deep brain region that processes a number of cognitive functions, including working memory and hearing. More specifically, the volume of the thalamus is smaller on average in schizophrenic patients. Accordingly, it has been possible to link the onset of auditory hallucinations with an overly-intense neuronal connectivity between the thalamus and auditory cortex. An auditory hallucination is defined as the perception of sound in the absence of an external sound source. It is one of the most characteristic symptoms of schizophrenia, a psychotic disorder that affects approximately 1% of the population.

"We used a cohort of patients that is unique in the world in an attempt to analyse the mechanism behind this hallucinatory phenomenon in more detail," begins Stephan Eliez, a professor in the Department of Psychiatry in UNIGE's Faculty of Medicine. "For the last 19 years, a program backed by the University of Geneva has helped us enlist and monitor individuals suffering from a rare neurogenetic syndrome: 22q11.2 micro deletion syndrome, which is caused by the absence of a small piece of DNA in chromosome 22. These patients are often prone to auditory hallucinations among other things. More importantly, 30 to 35% of them develop schizophrenia during their lifetime. This is the category with the highest risk of falling victim to the psychotic disorder."Monitoring from childhood to adulthoodThis cohort, made up of over 200 patients living in Switzerland, France, Belgium, Luxembourg and England, represents a unique opportunity to follow individuals from childhood to adulthood and submitting them to a regular battery of tests (medical imaging, genetic analyses, etc. ). It offers the chance to understand the neurodevelopmental processes involved in the onset of schizophrenia and possibly to determine potential treatments that could delay, slow down or even halt the progression of psychotic symptoms.

The study focused on 230 people aged 8 to 35 years: 120 from the cohort and 110 healthy individuals who served as controls. Participants underwent a brain scan every three years using functional and structural magnetic resonance imaging. They were not given any task to complete: the machine simply recorded the brain activity generated by floating thoughts activating the major neural networks by turns. The scientists focused in particular on the various sub-structures of the thalamus that each has its own functions.Unparalleled precision"We discovered that the thalamic nuclei involved in auditory and visual sensory processing and working memory are smaller in people with deletion syndrome than in others," explains Valentina Mancini, a researcher in UNIGE's Department of Psychiatry and the article's first author. "And among people with deletion syndrome, the volume of the medial geniculate nucleus (the MGN, one of the sub-parts of the thalamus involved in the auditory pathways) and that of the other nuclei used in memory are smaller in the group with auditory hallucinations relative to the group that doesn't experience any. The size of the MGN differs between the two groups from childhood with a divergent developmental trajectory".

The scientists made a further observation: in the patients suffering from auditory hallucinations, they noticed a hyper-connectivity between the thalamic nuclei and cortical areas devoted to the primary processing of hearing and Wernicke's area, which is highly significant for understanding language. This type of thalamo-cortical hyper-connection is normal during childhood, when the neural networks are being formed. The fact that it persists during adolescence and then into adulthood is the sign that the connections have never reached maturity.

"This characteristic could provide an almost mechanical explanation for the hallucinatory phenomenon in these patients," notes Eliez. "Our results also open up new perspectives for the more general understanding of the pathophysiology of schizophrenia. Identifying the markers that foreshadow the development of the disease in such detail gives us many new targets for action using specific neuroprotective drugs, for example, to prevent symptoms as much as possible."ReferenceMancini et al. (2020). Abnormal development and dysconnectivity of distinct thalamic nuclei in patients with 22q11.2 deletion syndrome experiencing auditory hallucinations. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging. DOI: https://doi.org/10.1016/j.bpsc.2020.04.015

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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Neuroscience

High body fat is associated with sleeping problems – Sciworthy

A worm study in PLOS Biology could hold the answer to what drives sleep deprivation. A research team from the University of Pennsylvania and the University of Nevada questioned how big of a role body fat plays in the sleep cycle. The researchers used C. elegans, a common worm model in neuroscience, for its simple biology. Unlike the complex sleep circuits in human brains, C. elegans only have one brain cell responsible for regulating sleep.

Body fat provides energy to the body. When we eat, our body converts the nutrients into energy and any excess into fat. To explore the energy levels of the worms during sleep, the scientists measured their ATP levels. ATP is a large molecule that stores energy from our food. When ATP is broken apart, that energy is released to drive bodily processes. Every cell needs energy to survive, so every cell works to get ATP and spend it as they need it.

While measuring ATP, the team found that ATP levels decreased during sleep. It was a chicken or the egg situation. Does a drop in energy cause sleep or does sleep cause a decrease in energy levels? To study this, the researchers chemically turned off the RIS neuron, a brain cell in worms thats important for sleep. When the team deactivated this neuron, the worms lost their ability to sleep. The difficulty sleeping was linked to a drop in ATP levels.

The next step was to find the biggest contributor to energy depletion: sleep or starvation. Oil Red O staining was used to show the presence of fat, and triglyceride measurements were used to calculate the amount of fat left in worms. They found the worms used up more fat in sleep compared to when they were starved for an hour. Taken together, the study suggests it was sleep that caused ATP levels to drop, and fat was used to conserve the bodys energy.

Building on their previous findings, the researchers genetically modified the worms to test if fat burning and sleep were genetically linked. They decided to turn off kin-29, a gene important in signaling the demand for sleep to the brain. When kin-29 was turned off, worms were unable to sleep and had low energy and energy production levels.

Interestingly, the kin-29 mutants gained a lot of weight and produced more lipid dropletscellular structures used to store fat. If the kin-29 gene was important in sleep, why did these worms get fat? Researchers found their answer when they genetically altered the worms to overproduce an enzyme used to break down fat. When the excess fat was metabolized, kin-29 mutant worms were finally able to sleep. Taken together, this suggests excess fat is linked to poor sleep and fat breakdown could help sleep problems.

The kin-29 gene in C. elegans is similar to a gene in humans, called SIK3, which also tells our brain that its time to sleep. However, the study showed that when the kin-29 gene was turned off, the worms stored excess fat and had trouble sleeping. These findings are similar to sleeping problems seen in obese individuals that have a variation of the SIK3 gene. Although human studies are needed, the researchers conclude that breaking down body fat is important in promoting sleep.

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Neuroscience

Reversing SHANK3 mutations in mice mitigates autism-like traits – Spectrum

Double dose: Mice with mutations in both copies of SHANK3 have more behavioral differences than animals with mutations in one copy of the gene.

tiripero / iStock

Correcting a mutation in the autism gene SHANK3 in fetal mice lessens some autism-like behaviors after birth, according to a new study1. The work adds to evidence that gene therapy may help some people with SHANK3 mutations.

In people, mutations in SHANK3 can lead to Phelan-McDermid syndrome, a condition that causes developmental delays and often autism. Up to 2 percent of people with autism have a mutation in SHANK32.

Our findings imply that early genetic correction of SHANK3 has the potential to provide therapeutic benefit for patients, lead investigator Craig Powell, professor of neurobiology at the University of Alabama at Birmingham, wrote in an email.

A 2016 study showed that correcting mutations in SHANK3 in both young and adult mice can decrease excessive grooming, which is thought to correspond to repetitive behaviors in people with autism.

Last year, Powell and his team also showed that correcting SHANK3 mutations in adult mice eliminates some autism-like behaviors3. But the results were difficult to interpret. The team reversed the mutation using an enzyme called Cre-recombinase that could edit SHANK3 if the animals were given a drug called tamoxifen. Control mice in that study that did not receive tamoxifen but had the gene for Cre still showed behavior changes, raising the possibility that the enzyme affected their brains.

In the new work, Powells team used a different approach. They engineered mice with a mutation in both or only one copy of SHANK3 the latter more closely mirrors what happens in people. Some animals had the Cre gene, but some also had another gene for a Cre-activating protein that is naturally expressed when the animals are in utero. By using this protein, the researchers could avoid using tamoxifen, which some studies have shown may also cause behavioral changes in mice4.

The control mice had either the gene for Cre-recombinase or fortheCre-activating protein, but not both, allowing the researchers to isolate any effects from the method itself.

They found that correcting the mutation lowers some but not all of the animals autism-like behaviors, a finding Powell says is surprising. The mice groom less and are more social by some measures, but they still prefer interacting with an object than with another mouse.

We dont really know why some behaviors are affected and not others, Powell says.

Mice with one mutated copy of SHANK3 have fewer behavioral differences than mice with two, they also found, which indicates the value of using both kinds of animals in gene-reversal studies, experts say.

The fact that they did analyze both side by side, and they did see some differences, I find quite intriguing, says Gaia Novarino, professor of neuroscience at the Institute of Science and Technology in Klosterneuburg, Austria.

The team originally planned to consider when and where in the brain SHANK3 was corrected. But the Cre-activating protein involved in the study was expressed throughout the brain, preventing region-specific findings.

The team gave some mice the antibiotic doxycycline to suppress Cre expression, in hopes of also testing the effects of correcting SHANK3 in adulthood. But the method failed, for unknown reasons.

It is also important to publish experiments that do not work out exactly as planned, Powell says.

The teams openness about the studys shortcomings could help others design their own studies or re-evaluate previous work, says Yong-Hui Jiang, chief of medical genetics at Yale University.

People will learn from the difficulties and the experience, Jiang says.

It would still be helpful to test whether correcting SHANK3 mutations can reverse autism-like behaviors in adult mice without using tamoxifen, other researchers say.

Its beneficial to do experiments in such a way where you leave very little room for alternative interpretations, says Gavin Rumbaugh, professor of neuroscience at the Scripps Research Institute in Jupiter, Florida. He suggests using a mouse that does not express Cre until the animal is administered doxycycline, rather than trying to suppress Cre with the drug.

The work lends credence to the idea that gene therapy might alleviate some difficulties associated with autism in people with SHANK3 mutations, researchers say. Further studies could also investigate in how many cells the gene needs to be restored to change behavior, and what would be the safest and most effective stage of development to intervene with a gene therapy.

The impression is you have a quite large window, Novarino says. Thats quite positive.

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Cell Biology

New liver cancer research targets non-cancer cells to blunt tumor growth – Penn: Office of University Communications

Senotherapy, a treatment that uses small molecule drugs to target senescent cells, or those cells that no longer undergo cell division, blunts liver tumor progression in animal models according to new research from a team led byCeleste Simon, a professor of cell and developmental biology in the Perelman School of Medicine, and scientific director of the Abramson Family Cancer Research Institute. The study was published inNature Cell Biology.

This kind of therapy is not something that has been tried before with liver cancer, Simon says. And in our models, so-called senolytic therapy greatly reduced disease burden, even in cases with advanced disease.

Loss of the enzyme FBP1 in human liver cells significantly increases tumor growth. Previous research has shown FBP1 levels are decreased in stage 1 tumors, and further reduced as the disease progresses. In this study, Simon and her team used RNA-sequencing data to identify FBP1 as universally under-expressed in the most common form of liver cancer, hepatocelluar carcinoma, regardless of underlying causes like obesity, alcoholism, and hepatitis.

This story is by Melissa Moody. Read more at Penn Medicine News.

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Cell Biology

Tracking the physics of biological cells using nanodevices (video) – Lab News

For the first time, scientists have introduced minuscule tracking devices directly into the interior of mammalian cells, giving an unprecedented peek into the processes that govern the beginning of development. This work on one-cell embryos is set to shift our understanding of the mechanisms that underpin cellular behaviour in general, and may ultimately provide insights into what goes wrong in ageing and disease.

The research, led by Professor Tony Perry from the Department of Biology and Biochemistry at the University of Bath, involved injecting a silicon-based nanodevice together with sperm into the egg cell of a mouse. The result was a healthy, fertilised egg containing a tracking device.

The tiny devices are a little like spiders, complete with eight highly flexible 'legs'. The legs measure the 'pulling and pushing' forces exerted in the cell interior to a very high level of precision, thereby revealing the cellular forces at play and showing how intracellular matter rearranged itself over time.

The nanodevices are incredibly thin - similar to some of the cell's structural components, and measuring 22 nanometres, making them approximately 100,000 times thinner than a pound coin. This means they have the flexibility to register the movement of the cell's cytoplasm as the one-cell embryo embarks on its voyage towards becoming a two-cell embryo.

"This is the first glimpse of the physics of any cell on this scale from within," said Professor Perry. "It's the first time anyone has seen from the inside how cell material moves around and organises itself."

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Caption: Five mouse embryos, each containing a nanodevice that is 22-millionths of a metre long. The film begins when the embryos are 2-hours old and continues for 5 hours. Each embryo is about 100-millionths of a metre in diameter. via @uniofbath,http://www.bath.ac.uk

Why probe a cells mechanical behaviour?

The activity within a cell determines how that cell functions, explains Professor Perry. "The behaviour of intracellular matter is probably as influential to cell behaviour as gene expression," he said. Until now, however, this complex dance of cellular material has remained largely unstudied. As a result, scientists have been able to identify the elements that make up a cell, but not how the cell interior behaves as a whole.

"From studies in biology and embryology, we know about certain molecules and cellular phenomena, and we have woven this information into a reductionist narrative of how things work, but now this narrative is changing," said Professor Perry. The narrative was written largely by biologists, who brought with them the questions and tools of biology. What was missing was physics. Physics asks about the forces driving a cell's behaviour and provides a top-down approach to finding the answer.

"We can now look at the cell as a whole, not just the nuts and bolts that make it."

Mouse embryos were chosen for the study because of their relatively large size (they measure 100 microns, or 100-millionths of a metre, in diameter, compared to a regular cell which is only 10 microns [10-millionths of a metre] in diameter). This meant that inside each embryo, there was space for a tracking device.

The researchers made their measurements by examining video recordings taken through a microscope as the embryo developed. "Sometimes the devices were pitched and twisted by forces that were even greater than those inside muscle cells," said Professor Perry. "At other times, the devices moved very little, showing the cell interior had become calm. There was nothing random about these processes - from the moment you have a one-cell embryo, everything is done in a predictable way. The physics is programmed."

The results add to an emerging picture of biology that suggests material inside a living cell is not static, but instead changes its properties in a pre-ordained way as the cell performs its function or responds to the environment. The work may one day have implications for our understanding of how cells age or stop working as they should, which is what happens in disease.

The study is titled; Tracking intracellular forces and mechanical property changes in mouse one-cell embryo development was published inNature Materialsand involved a trans-disciplinary partnership between biologists, materials scientists and physicists based in the UK, Spain and the USA.

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Cell Biology

On the Origins of Modern Biology and the Fantastic: Part 19 Nalo Hopkinson and Stem Cell Research – tor.com

She just wanted to be somewhere safe, somewhere familiar, where people looked and spoke like her and she could stand to eat the food. Midnight Robber by Nalo Hopkinson

Midnight Robber (2000) is about a woman, divided. Raised on the high-tech utopian planet of Touissant, Tan-Tan grows up on a planet populated by the descendants of a Caribbean diaspora, where all labor is performed by an all-seeing AI. But when she is exiled to Touissants parallel universe twin planet, the no-tech New Half-Way Tree, with her sexually abusive father, she becomes divided between good and evil Tan-Tans. To make herself and New Half-Way Tree whole, she adopts the persona of the legendary Robber Queen and becomes a legend herself. It is a wondrous blend of science fictional tropes and Caribbean mythology written in a Caribbean vernacular which vividly recalls the history of slavery and imperialism that shaped Touissant and its people, published at a time when diverse voices and perspectives within science fiction were blossoming.

Science fiction has long been dominated by white, Western perspectives. Vernes tech-forward adventures and Wells sociological allegories established two distinctive styles, but still centered on white imperialism and class struggle. Subsequent futures depicted in Verne-like pulp and Golden Age stories, where lone white heroes conquered evil powers or alien planets, mirrored colonialist history and the subjugation of non-white races. The civil rights era saw the incorporation of more Wellsian sociological concerns, and an increase in the number of non-white faces in the future, but they were often tokensparts of a dominant white monoculture. Important figures that presaged modern diversity included Star Treks Lieutenant Uhura, played by Nichelle Nichols. Nichols was the first black woman to play a non-servant character on TV; though her glorified secretary role frustrated Nichols, her presence was a political act, showing there was space for black people in the future.

Another key figure was the musician and poet Sun Ra, who laid the aesthetic foundation for what would become known as the Afrofuturist movement (the term coined by Mark Dery in a 1994 essay), which showed pride in black history and imagined the future through a black cultural lens. Within science fiction, the foundational work of Samuel Delany and Octavia Butler painted realistic futures in which the histories and cultural differences of people of color had a place. Finally, an important modern figure in the decentralization of the dominant Western perspective is Nalo Hopkinson.

A similarly long-standing paradigm lies at the heart of biology, extending back to Darwins theoretical and Mendels practical frameworks for the evolution of genetic traits via natural selection. Our natures werent determined by experience, as Lamarck posited, but by genes. Therefore, genes determine our reproductive fitness, and if we can understand genes, we might take our futures into our own hands to better treat disease and ease human suffering. This theory was tragically over-applied, even by Darwin, who in Descent of Man (1871) conflated culture with biology, assuming the Wests conquest of indigenous cultures meant white people were genetically superior. After the Nazis committed genocide in the name of an all-white future, ideas and practices based in eugenics declined, as biological understanding of genes matured. The Central Dogma of the 60s maintained the idea of a mechanistic meaning of life, as advances in genetic engineering and the age of genomics enabled our greatest understanding yet of how genes and disease work. The last major barrier between us and our transhumanist future therefore involved understanding how genes determine cellular identity, and as well see, key figures in answering that question are stem cells.

***

Hopkinson was born December 20, 1960 in Kingston, Jamaica. Her mother was a library technician and her father wrote, taught, and acted. Growing up, Hopkinson was immersed in the Caribbean literary scene, fed on a steady diet of theater, dance, readings, and visual arts exhibitions. She loved to readfrom folklore, to classical literature, to Kurt Vonnegutand loved science fiction, from Spock and Uhura on Star Trek, to Le Guin, James Tiptree Jr., and Delany. Despite being surrounded by a vibrant writing community, it didnt occur to her to become a writer herself. What they were writing was poetry and mimetic fiction, Hopkinson said, whereas I was reading science fiction and fantasy. It wasnt until I was 16 and stumbled upon an anthology of stories written at the Clarion Science Fiction Workshop that I realized there were places where you could be taught how to write fiction. Growing up, her family moved often, from Jamaica to Guyana to Trinidad and back, but in 1977, they moved to Toronto to get treatment for her fathers chronic kidney disease, and Hopkinson suddenly became a minority, thousands of miles from home.

Development can be described as an orderly alienation. In mammals, zygotes divide and subsets of cells become functionally specialized into, say, neurons or liver cells. Following the discovery of DNA as the genetic material in the 1950s, a question arose: did dividing cells retain all genes from the zygote, or were genes lost as it specialized? British embryologist John Gurdon addressed this question in a series of experiments in the 60s using frogs. Gurdon transplanted nuclei from varyingly differentiated cells into oocytes stripped of their genetic material to see if a new frog was made. He found the more differentiated a cell was, the lower the chance of success, but the successes confirmed that no genetic material was lost. Meanwhile, Canadian biologists Ernest McCulloch and James Till were transplanting bone marrow to treat irradiated mice when they noticed it caused lumps in the mices spleens, and the number of lumps correlated with the cellular dosage. Their lab subsequently demonstrated that each lump was a clonal colony from a single donor cell, and a subset of those cells was self-renewing and could form further colonies of any blood cell type. They had discovered hematopoietic stem cells. In 1981 the first embryonic stem cells (ESCs) from mice were successfully propagated in culture by British biologist Martin Evans, winning him the Nobel Prize in 2007. This breakthrough allowed biologists to alter genes in ESCs, then use Gurdons technique to create transgenic mice with that alteration in every cellcreating the first animal models of disease.

In 1982, one year after Evans discovery, Hopkinson graduated with honors from York University. She worked in the arts, as a library clerk, government culture research officer, and grants officer for the Toronto Arts Council, but wouldnt begin publishing her own fiction until she was 34. [I had been] politicized by feminist and Caribbean literature into valuing writing that spoke of particular cultural experiences of living under colonialism/patriarchy, and also of writing in ones own vernacular speech, Hopkinson said. In other words, I had models for strong fiction, and I knew intimately the body of work to which I would be responding. Then I discovered that Delany was a black man, which opened up a space for me in SF/F that I hadnt known I needed. She sought out more science fiction by black authors and found Butler, Charles Saunders, and Steven Barnes. Then the famous feminist science fiction author and editor Judy Merril offered an evening course in writing science fiction through a Toronto college, Hopkinson said. The course never ran, but it prompted me to write my first adult attempt at a science fiction story. Judy met once with the handful of us she would have accepted into the course and showed us how to run our own writing workshop without her. Hopkinsons dream of attending Clarion came true in 1995, with Delany as an instructor. Her early short stories channeled her love of myth and folklore, and her first book, written in Caribbean dialect, married Caribbean myth to the science fictional trappings of black market organ harvesting. Brown Girl in the Ring (1998) follows a young single mother as shes torn between her ancestral culture and modern life in a post-economic collapse Toronto. It won the Aspect and Locus Awards for Best First Novel, and Hopkinson was awarded the John W. Campbell Award for Best New Writer.

In 1996, Dolly the Sheep was created using Gurdons technique to determine if mammalian cells also could revert to more a more primitive, pluripotent state. Widespread animal cloning attempts soon followed, (something Hopkinson used as a science fictional element in Brown Girl) but it was inefficient, and often produced abnormal animals. Ideas of human cloning captured the public imagination as stem cell research exploded onto the scene. One ready source for human ESC (hESC) materials was from embryos which would otherwise be destroyed following in vitro fertilization (IVF) but the U.S. passed the Dickey-Wicker Amendment prohibited federal funding of research that destroyed such embryos. Nevertheless, in 1998 Wisconsin researcher James Thomson, using private funding, successfully isolated and cultured hESCs. Soon after, researchers around the world figured out how to nudge cells down different lineages, with ideas that transplant rejection and genetic disease would soon become things of the past, sliding neatly into the hole that the failure of genetic engineering techniques had left behind. But another blow to the stem cell research community came in 2001, when President Bushs stem cell ban limited research in the U.S. to nineteen existing cell lines.

In the late 1990s, another piece of technology capturing the public imagination was the internet, which promised to bring the world together in unprecedented ways. One such way was through private listservs, the kind used by writer and academic Alondra Nelson to create a space for students and artists to explore Afrofuturist ideas about technology, space, freedom, culture and art with science fiction at the center. It was wonderful, Hopkinson said. It gave me a place to talk and debate with like-minded people about the conjunction of blackness and science fiction without being shouted down by white men or having to teach Racism 101. Connections create communities, which in turn create movements, and in 1999, Delanys essay, Racism and Science Fiction, prompted a call for more meaningful discussions around race in the SF community. In response, Hopkinson became a co-founder of the Carl Brandon society, which works to increase awareness and representation of people of color in the community.

Hopkinsons second novel, Robber, was a breakthrough success and was nominated for Hugo, Nebula, and Tiptree Awards. She would also release Skin Folk (2001), a collection of stories in which mythical figures of West African and Afro-Caribbean culture walk among us, which would win the World Fantasy Award and was selected as one ofThe New York Times Best Books of the Year. Hopkinson also obtained masters degree in fiction writing (which helped alleviate U.S. border hassles when traveling for speaking engagements) during which she wrote The Salt Roads (2003). I knew it would take a level of research, focus and concentration I was struggling to maintain, Hopkinson said. I figured it would help to have a mentor to coach me through it. That turned out to be James Morrow, and he did so admirably. Roads is a masterful work of slipstream literary fantasy that follows the lives of women scattered through time, bound together by the salt uniting all black life. It was nominated for a Nebula and won the Gaylactic Spectrum Award. Hopkinson also edited anthologies centering around different cultures and perspectives, including Whispers from the Cotton Tree Root: Caribbean Fabulist Fiction (2000), Mojo: Conjure Stories (2003), and So Long, Been Dreaming: Postcolonial Science Fiction & Fantasy (2004). She also came out with the award-winning novelThe New Moons Arms in 2007, in which a peri-menopausal woman in a fictional Caribbean town is confronted by her past and the changes she must make to keep her family in her life.

While the stem cell ban hamstrung hESC work, Gurdons research facilitated yet another scientific breakthrough. Researchers began untangling how gene expression changed as stem cells differentiated, and in 2006, Shinya Yamanaka of Kyoto University reported the successful creation of mouse stem cells from differentiated cells. Using a list of 24 pluripotency-associated genes, Yamanaka systematically tested different gene combinations on terminally differentiated cells. He found four genesthereafter known as Yamanaka factorsthat could turn them into induced-pluripotent stem cells (iPSCs), and he and Gurdon would share a 2012 Nobel prize. In 2009, President Obama lifted restrictions on hESC research, and the first clinical trial involving products made using stem cells happened that year. The first human trials using hESCs to treat spinal injuries happened in 2014, and the first iPSC clinical trials for blindness began this past December.

Hopkinson, too, encountered complications and delays at points in her career. For years, Hopkinson suffered escalating symptoms from fibromyalgia, a chronic disease that runs in her family, which interfered with her writing, causing Hopkinson and her partner to struggle with poverty and homelessness. But in 2011, Hopkinson applied to become a professor of Creative Writing at the University of California, Riverside. It seemed in many ways tailor-made for me, Hopkinson said. They specifically wanted a science fiction writer (unheard of in North American Creative Writing departments); they wanted someone with expertise working with a diverse range of people; they were willing to hire someone without a PhD, if their publications were sufficient; they were offering the security of tenure. She got the job, and thanks to a steady paycheck and the benefits of the mild California climate, she got back to writing. Her YA novel, The Chaos (2012), coming-of-age novelSister Mine (2013), and another short story collection, Falling in Love with Hominids (2015) soon followed. Her recent work includes House of Whispers (2018-present), a series in DC Comics Sandman Universe, the final collected volume of which is due out this June. Hopkinson also received an honorary doctorate in 2016 from Anglia Ruskin University in the U.K., and was Guest of Honor at 2017 Worldcon, a year in which women and people of color dominated the historically white, male ballot.

While the Yamanaka factors meant that iPSCs became a standard lab technique, iPSCs are not identical to hESCs. Fascinatingly, two of these factors act together to maintain the silencing of large swaths of DNA. Back in the 1980s, researchers discovered that some regions of DNA are modified by small methyl groups, which can be passed down through cell division. Different cell types have different DNA methylation patterns, and their distribution is far from random; they accumulate in the promoter regions just upstream of genes where their on/off switches are, and the greater the number of methyl groups, the lesser the genes expression. Furthermore, epigenetic modifications, like methylation, can be laid down by our environments (via diet, or stress) which can also be passed down through generations. Even some diseases, like fibromyalgia, have recently been implicated as such an epigenetic disease. Turns out that the long-standing biological paradigm that rejected Lamarck also missed the bigger picture: Nature is, in fact, intimately informed by nurture and environment.

In the past 150 years, we have seen ideas of community grow and expand as the world became more connected, so that they now encompass the globe. The histories of science fiction and biology are full of stories of pioneers opening new doorsbe they doors of greater representation or greater understanding, or bothand others following. If evolution has taught us anything, its that nature abhors a monoculture, and the universe tends towards diversification; healthy communities are ones which understand that we are not apart from the world, but of it, and that diversity of types, be they cells or perspectives, is a strength.

Kelly Lagor is a scientist by day and a science fiction writer by night. Her work has appeared at Tor.com and other places, and you can find her tweeting about all kinds of nonsense @klagor

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On the Origins of Modern Biology and the Fantastic: Part 19 Nalo Hopkinson and Stem Cell Research - tor.com

Cell Biology

Campbell First Prof From Undergraduate Institution Elected to ASCB Leadership Post – Davidson News

Campbell was elected treasurer, the No. 2 post, in the American Society for Cell Biology. He is the first faculty member, not just from Davidson, but from any undergraduate institution to serve on the executive council for the organization. The society provides national leadership in science policy and in science advocacy in Washingtona critical need right now. The organization also leads in global research and policy, with a quarter of its members outside the United States. Its newly elected president, Columbia Biology Professor Martin Chalfie, is a Nobel laureate, who visited Davidson at Campbells request in 2015.

Campbell founded the James G. Martin Genomics Program at Davidson, and his influence already extended well beyond campus. He teamed up with Mathematics Professor Laurie Heyer and Environmental Studies Professor Chris Paradiseto write a textbook now used in high schools and colleges across the country that upended conventional teaching of biology. Traditional textbooks present information for students to digest and then repeat on a test. Campbells book presents each topic as a question and offers data sets so student can do what scientists doanalyze, interpret and reach a conclusion.

A Michigan State professor who uses the book saw a dramatic rise in students Medical College Admission Test scores. The National Association of Biology Teachers presented Campbell with its highest teaching honor two years ago.

Campbells election to the national post also helps put Davidson in a position of unprecedented national leadership in the sciences and across all academic professional organizations. Last year, R. Stuart Dickson Professor of Psychology Julio Ramirez wasvoted treasurer-elect for the Society for Neuroscience, the worlds largest and most prestigious organization representing the interests of neuroscientists. He is only the second professor from a liberal arts college to hold a leadership post in the groups 50-year history. Gerardo Marti, professor and chair of sociology, recently waselected president of the Association for the Sociology of Religion, an international organization that publishes the leading journal in the field.

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Campbell First Prof From Undergraduate Institution Elected to ASCB Leadership Post - Davidson News