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

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

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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High body fat is associated with sleeping problems - Sciworthy

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

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

Cell Biology

Shanghai Cell Therapy Group Launches Collaboration with USC researcher to Improve the ex vivo Expansion of Hematopoietic Stem Cells for Clinical…

SHANGHAI, May27, 2020 /PRNewswire/ -- Shanghai Cell Therapy Group (SHCell) recently entered intoa six-year research collaborative project with Professor Qi-Long Ying from the University of Southern California (USC). Through the project, sponsored by $3.6 million from the Baize Plan Fund, the Ying laboratory aims to develop conditions for the long-term ex vivo expansion of mouse and human hematopoietic stem and progenitor cells.

"Hematopoietic stem cells, or HSCs, are found in the bone marrow of adults," said Professor Qijun Qian, CEO of Shanghai Cell Therapy Group. "HSCs have the ability for long-term self-renewal and differentiation into various types of mature blood cells, and for rebuilding normal hematopoiesis and immune function in patients. They also have enormous potential to treat diseases, including tumors, autoimmune diseases, severe infectious disease, and inherited blood diseases, and to combat the effects of aging."

This research project will be conducted and supervised by Professor Qi-Long Ying, a Professor of Stem Cell Biology and Regenerative Medicine at the Keck School of Medicine of USC. Professor Ying's pioneering stem cell research has won international acclaim, including the 2016 McEwen Award for Innovation, the highest honor in the field.

"We'll develop and optimize culture conditions for the long-term ex vivo expansion of HSCs," said Professor Ying. "We'll also test combinations of basal media, small molecules, cytokines and growth factors, and characterize ex vivo expanded hematopoietic stem and progenitor cells. These cells will then be genetically modified and tested for their potential to treat different diseases, including blood disorders and cancers."

Professor Andrew P. McMahon, Director of Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research of USC, added: "Stem cell biology represents an exciting area in medicine with great therapeutic potential. I am delighted SHCell is supporting Professor Ying. A breakthrough in the ability to propagate and manipulate HSCs will have lasting clinical significance."

The project also plans to build animal models of different blood diseases and cancers and test the safety and effectiveness of genetically modified hematopoietic stem and progenitor cells before clinical translation. SHCell will actively explore clinical applications of hematopoietic stem and progenitor cells in the treatment of cancers or blood diseases.

As SHCell's first overseas collaboration, this project aims to advance the goals of the Baize Plan: to provide first-class cell treatments and cell therapies at an affordable price to cure cancer and increase life expectancy. SHCell hopes that this project will also accelerate original scientific breakthroughs in the stem cell field.

Shanghai Cell Therapy Group

Founded in 2013, Shanghai Cell Therapeutics Group Co., Ltd is located at the Shanghai Municipal Engineering and Technology Research Center, which was established by the Shanghai Science and Technology Commission. With a mission of "changing the length and abundance of life with cell therapy", SHCell has created a closed-loop industrial chain and an integrated platform for cell treatment and cell therapy. It comprises cell storage, cell drug research and cell clinical transformation with cell therapy as its core business.

The Baize Plan was proposed in 2016 by Wu Mengchao, an Academician of the Chinese Academy of Sciences (CAS) and initiated by Professor Qian, aiming to provide first-class cell treatments and cell therapies at an affordable price with the goal of curing cancers and increasing life expectancy. The Baize Plan Fund was created by the Shanghai Cell Therapy Group to realize the vision of the Baize Plan.

University of Southern California (USC)

Founded in 1880, the University of Southern California is one of the world's leading educational and research institutions, and also the oldest private research university in California. Located in the heart of Los Angeles, the University of Southern California comprises 23 schools and units, and students are encouraged to explore different fields of study. The University of Southern California ranked #22 in National Universities in the 2020 edition of Best Colleges, published by U.S. News & World Report.

For more information, visit http://www.shcell.com/

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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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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

Alpacas and antibodies: How scientists hope to stop coronavirus in its tracks – Horizon magazine

Researchers at the Karolinska Institute in Stockholm, Sweden, are optimistic that at least one of the 124 vaccines in the pipeline will succeed. However, a vaccine needs to be delivered to everyone, and scaling to more than 7 billion doses is extremely challenging. So they have set their research sights on a more accessible goal: neutralising antibodies that kill an infection after it has taken hold.

The project CoroNAb was established in mid-February when there were 1,000 known deaths from Covid-19 in the world. Containing the spread of the virus is not our primary objective that ship has sailed, said Dr Benjamin Murrell, assistant professor at the Department of Microbiology, Tumor and Cell Biology at the Karolinska Institute. Our aim is to find therapeutics to stop the progression of disease within a patient.

Therapeutics

These therapeutics will take the form of antibodies that are infused into a patient through a syringe. When someone is infected with the new SARS-CoV-2 coronavirus, they typically mount an antibody response against it, and in most cases these antibodies contribute to clearing the virus. However, infection-fighting antibodies produced in a lab can also be introduced into the body, resulting in passive immunisation.

So what differentiates a vaccine from imported antibodies?

Vaccines are given to people when they are well, prompting them to develop their own antibodies, whereas antibody therapy is administered when an infection has taken hold and a patient is struggling to mount their own immune response.

Monoclonal antibodies (mAbs) that is, antibodies that are identical clones of one another have emerged over the past few decades as effective therapies for various medical conditions, including cancers and autoimmune disorders. Increasingly, they are also considered a major medical tool to fight severe viral infections such as Covid-19 though to date, only one mAb been approved for this purpose. Many more are in clinical trials, including one that Dr Murrell has been working on.

At what stage of an infection, exactly, a coronavirus patient would be treated with mAbs remains to be seen. This will need to be studied in animal models, or directly in human trials, said Dr Murrell, who is coordinating the CoroNAb project together with partners in Denmark, Switzerland, and the UK.

Maybe you can treat someone with monoclonal antibody therapy late in infection and still stop deterioration, but perhaps not, he said.

The CoroNAb team at the Karolinska Institute is creating mAbs from animals. An animal is given a specific viral antigen (the molecules that interact with a bodys antibodies) and an immune response is provoked, leading to some of the animals immune cells producing antibodies. The cells harbouring these antibodies are then isolated and the genetic sequence of the antibody is cloned from each cell into a circular form of DNA that allows the antibodies to be produced in the lab.

Since the potency of the antibodies discovered is at least partly down to chance, it makes sense for many groups to be going after the same goal.

Dr Benjamin Murrell, Karolinska Institute in Stockholm, Sweden

Alpacas

The Stockholm team is focusing its research efforts on mice, rhesus macaques and alpacas. Alpacas are camelids (like camels and llamas) producing particularly interesting antibody fragments, known as single domain antibodies, which allow for fast antibody discovery and large-scale antibody production, which is why they are favoured by the CoroNAb team.

One month into the project, these mammals have been injected with lab-created variants of the coronaviruss spike proteins, and preliminary indications suggest that all animal groups are responding well. Mining the alpaca antibody repertoire is currently underway. Over the next few weeks, the researchers will be testing the neutralising activity of the produced antibodies against SARS-CoV-2.

Dr Murrell said: The coming weeks are both critical and uncertain. Depending on these first results, well either get lucky, or we might have to take a few steps back and repeat.

Despite all the unknowns, Dr Murrell is confident that neutralising antibodies will emerge from this research. We will make something work, he said. The question is, will an effective antibody discovered by the CoroNAb team become a useful addition to Europes arsenal of SARS-CoV-2 treatments? Labs around the world are chasing the same prize, working night and day to identify effective antibodies against Covid-19, with some early results already emerging.

To make a contribution in this climate, an antibody will need to have a strong edge over its competition. If one groups antibody turns out to be 10 times more potent than the next best, you might have to produce far less of it for an effective therapy, reducing the manufacturing burden, explained Dr Murrell. He added, Since the potency of the antibodies discovered is at least partly down to chance, it makes sense for many groups to be going after the same goal.

Bacterium

Professor Luis Serrano from the Centre for Genomic Regulation (CRG) in Spain leads another team engaged in the race against Covid-19. His lab is both supporting global vaccine efforts and probing novel, non-vaccine mechanisms to limit the death toll.

Until two months ago, Prof. Serrano was engaged in the MycoSynVac project, which investigated ways to enlist cellular hosts to transport vaccines around the body. Cellular hosts (known in the field of synthetic biology as chassis) hold great promise as low-cost, scalable and potentially game-changing systems for the targeted delivery of life-saving vaccines.

The chosen chassis in Serranos five-year project was a modified form of the bacterium Mycoplasma pneumoniae, which causes respiratory infections. By the projects conclusion, the researchers were able to show that Mycoplasma makes an excellent universal chassis meaning all manner of vaccines can safely hitch a ride off it.

Prof. Serrano is optimistic that a vaccine for Covid-19, when it arises, will be among the ingredients that can be safely delivered by his Mycoplasma chassis. The team is in the early stages of testing this hypothesis. Over the next month or so, they will insert synthetic copies of key coronavirus genes into bacterial cells, in the hope that those surface proteins belonging to the virus will trigger a protective immune response from the human body.

As it is engineered from a bacterium that targets the lungs, the chassis may be capable of even more than vaccine transportation, according to Prof. Serrano. We think it can deliver therapeutic molecules directly to receptors in the lungs, he said.

These molecules would either counteract inflammation or stop the virus from binding to the alveoli (the cells through which oxygen flows from lungs to bloodstream) by blocking the viral cell receptors, he explains.

With the virus blocked or lung damage repaired, a patient who is not responding to conventional treatments might be spared the worst symptoms of a Covid-19 infection, such as a devastating cytokine storm, where the body mounts a massive, and potentially deadly, immune response an overreaction triggered by pneumonia.

Spray

The idea is to create a spray to deliver our engineered bacteria directly to the lungs, where it will express locally what is needed the active molecules and later it will be washed away naturally, explained Prof. Serrano.

He added: There are clear advantages to this direct approach. If you apply a drug systemically (affecting the whole body), it might be beneficial where its needed but it might also have dangerous effects on other tissue.

Price is another major benefit to recruiting bacteria to deliver life-saving medications. Producing therapeutic molecules synthetically is expensive. For a fraction of the cost, a host cell can be cloned to produce vast populations of cells containing the same therapeutic molecules.

In the labs of their spin-off company Pulmobiotics, Prof. Serranos team is exposing coronavirus proteins to molecules with known anti-inflammatory qualities, to test the molecules effectiveness against the virus. They are also engineering mutations of these molecules, hoping to increase the affinity between molecule and human receptor proteins. Data from these experiments is expected by mid-summer.

Prof Serrano is hopeful that his research will yield positive results, however these may not come in time to save lives during the current outbreak. By the time we get (regulatory) approval, the Covid situation may have been resolved, he said. But this research will open the way for future therapies during future pandemics.

The research in this article was funded by the EU. If you liked this article, please consider sharing it on social media.

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Alpacas and antibodies: How scientists hope to stop coronavirus in its tracks - Horizon magazine

Cell Biology

Research at MDI Biological Laboratory explores novel pathways of regeneration and tumorigenesis – Bangor Daily News

BAR HARBOR Research by scientists at the MDI Biological Laboratoryis opening up new approaches to promoting tissue regeneration in organs damaged by disease or injury.

In recent years, research in regenerative biology has focused on stem cell therapies that reprogram the bodys own cells to replace damaged tissue, which is a complicated process because it involves turning genes in the cells nucleus on and off.

A recent paper in the journal Genetics by MDI Biological Laboratory scientist Elisabeth Marnik, Ph.D., a postdoctoral fellow in the laboratory of Dustin Updike, Ph.D., offers insight into an alternate pathway to regeneration: by recreating the properties of germ cells.

Germ cells, which are the precursors to the sperm and egg, are considered immortal because they are the only cells in the body with the potential to create an entirely new organism. The stem cell-like ability of germ cells to turn into any type of cell is called totipotency.

By getting a handle on what makes germ cells totipotent, we can promote regeneration by unlocking the stem cell-like properties of other cell types, said Updike. Our research shows that such cells can be reprogrammed by manipulating their cytoplasmic composition and chemistry, which would seem to be safer and easier than changing the DNA within a cells nucleus.

Using the tiny, soil-dwelling nematode worm, C. elegans, as a model, the Updike lab studies organelles called germ granules that reside in the cytoplasm (the contents of the cell outside of the nucleus) of germ cells. These organelles, which are conserved from nematodes to humans, are one of the keys to the remarkable attributes of germ cells, including the ability to differentiate into other types of cells.

In their recent paper entitled Germline Maintenance Through the Multifaceted Activities of GLH/Vasa in Caenorhabditis elegans P Granules, Updike and his team describe the intriguing and elusive role of Vasa proteins within germ granules in determining whether a cell is destined to become a germ cell with totipotent capabilities or a specific type of cell, like those that comprise muscle, nerves or skin.

Because of the role of Vasa proteins in preserving totipotency, an increased understanding of how such proteins work could lead to unprecedented approaches to de-differentiating cell types to promote regeneration; or alternatively, to new methods to turn off totipotency when it is no longer desirable, as in the case of cancer.

The increase in chronic and degenerative diseases caused by the aging of the population is driving demand for new therapies, said MDI Biological Laboratory President Hermann Haller, M.D. Dustins research on germ granules offers another route to repairing damaged tissues and organs in cases where therapeutic options are limited or non-existent, as well as an increased understanding of cancer.

Because of the complexity of the cellular chemistry, research on Vasa and other proteins found in germ granules is often overlooked, but that is rapidly changing especially among pharmaceutical companies as more scientists realize the impact and potential of such research, not only for regenerative medicine but also for an understanding of tumorigenesis, or cancer development, Updike said.

Recent research has found that some cancers are accompanied by the mis-expression of germ granule proteins, which are normally found only in germ cells. The mis-expression of these germ-granule proteins seems to promote the immortal properties of germ cells, and consequently tumorigenesis, with some germ-granule proteins now serving as prognosis markers for different types of cancer, Updike said.

Updike is a former postdoctoral researcher in the laboratory of Susan Strome, Ph.D., at University of California, Santa Cruz. Strome, who was inducted into the National Academy of Sciences last year, first discovered P granules more than 30 years ago. She credits Updike, who has published several seminal papers on the subject, with great imagination, determination and excellent technical skill in the pursuit of his goal of elucidating the function and biochemistry of these tiny organelles.

The lead author of the new study from the Updike laboratory, Elisabeth A. Marnik, Ph.D., will be launching her own laboratory at Husson University in Bangor, Maine, this fall. Other contributors include J. Heath Fuqua, Catherine S. Sharp, Jesse D. Rochester, Emily L. Xu and Sarah E. Holbrook. Their research was conducted at the Kathryn W. Davis Center for Regenerative Biology and Medicine at the MDI Biological Laboratory.

Updikes research is supported by a grant (R01 GM-113933) from the National Institute of General Medical Sciences (NIGMS), an institute of the National Institutes of Health (NIH). The equipment and cores used for part of the study were supported by NIGMS-NIH Centers of Biomedical Research Excellence and IDeA Networks of Biomedical Research Excellence grants P20 GM-104318 and P20 GM-203423, respectively.

We aim to improve human health and healthspan by uncovering basic mechanisms of tissue repair, aging and regeneration, translating our discoveries for the benefit of society and developing the next generation of scientific leaders. For more information, please visitmdibl.org.

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Research at MDI Biological Laboratory explores novel pathways of regeneration and tumorigenesis - Bangor Daily News