Biochemical Pathway To Skin Darkening Holds Implications for Prevention of Skin Cancers (Medicine)

A skin pigmentation mechanism that can darken the color of human skin as a natural defense against ultraviolet (UV)-associated cancers has been discovered by scientists at Massachusetts General Hospital (MGH). Mediating the biological process is an enzyme, NNT, which plays a key role in the production of melanin (a pigment that protects the skin from harmful UV rays) and whose inhibition through a topical drug or ointment could potentially reduce the risk of skin cancers. The study was published online in Cell.

“Skin pigmentation and its regulation are critically important because pigments confer major protection against UV-related cancers of the skin, which are the most common malignancies found in humans,” says senior and co-corresponding author David Fisher, MD, PhD, chief of the Department of Dermatology at MGH. “Darker-pigmented individuals are better protected from cancer-causing UV radiation by the light-scattering and antioxidant properties of melanin, while people with the fairest and lightest skin are at highest risk of developing skin cancers.”

Through their laboratory work with skin from humans and animal models, the MGH researchers mimicked the natural protection that exists in people with dark pigments. In the process, they gained a fuller understanding of the biochemical mechanism involved along with their drivers, and how they might be influenced by a topical agent independent of UV radiation, sun exposure, or genetics.

“We had assumed that the enzymes that make melanin by oxidizing the amino acid tyrosine in the melanosome (the synthesis and storage compartment of the cell) are largely regulated by gene expression,” explains Fisher. They were surprised to learn, however, that the amount of melanin being produced is in large part regulated by a much different chemical mechanism, one that can ultimately be traced to an enzyme in the mitochondria, the inner chamber of the cell, with the ability to alter skin pigmentation.

That enzyme is nicotinamide nucleotide transhydrogenase, or NNT. Researchers found that topical application of small molecule inhibitors of NNT resulted in skin darkening in human skin, and that mice with decreased NNT function displayed increased fur pigmentation. To test their discovery, they challenged the skin with UV radiation and found that the skin with darker pigments was indeed protected from DNA damage inflicted by ultraviolet rays.

“We’re excited by the discovery of a distinct pigmentation mechanism because it could pave the way, after additional studies and safety assessments, for a new approach to skin darkening and protection by targeting NNT,” says Elisabeth Roider, MD, previously an investigator with MGH, and lead author and co-corresponding author of the study. “The overarching goal, of course, is to improve skin cancer prevention strategies and to offer effective new treatment options to the millions of people suffering from pigmentary disorders.”

Fisher is professor of Dermatology and Pediatrics, Harvard Medical School, and director of both the Cutaneous Biology Research Center and Melanoma Center at MGH. Roider is an attending physician in the Department of Dermatology at the University Hospital of Basel, Switzerland, and a visiting scientist at the Cutaneous Biology Research Center at MGH.


Provided by Massachusetts General Hospital

Researchers Analyze Statistically Small-scale Magnetic Reconnections (Cosmology)

Using the high-resolution data obtained by the 1-meter New Vacuum Solar Telescope (NVST) at the Fuxian Solar Observatory of Yunnan Observatories of the Chinese Academy of Sciences, Dr. XUE Zhike et al. study statistically six small-scale magnetic reconnections for the first time, and the results have been published recently in The Astrophysical Journal.

Magnetic reconnection plays a crucial role in determining the topology of magnetic fields in cosmic plasma and also provides an efficient way for the conversion of magnetic energy into kinetic energy. Actually, magnetic reconnection is not easy to be observed and confirmed, even though it is generally considered to be directly related to the solar eruptions, such as flares and coronal mass ejections. Previous observational reports on magnetic reconnection are often based on a single event. In addition, magnetic reconnection has not been studied statistically.

Researchers checked the high-resolution data of the NVST from 2012 to 2020 carefully. They found only six cases of magnetic reconnection with obvious inflows and outflows. It is interesting that all of these magnetic reconnections have large separatrix angles. Their morphological characteristics and magnetic field configurations are obtained by the NVST and the Solar Dynamics Observatory (SDO). Meanwhile, several physical parameters of each magnetic reconnection are calculated including the velocities of reconnection inflows, outflows, and separatrix jets, the angles between each pair of separatrices, and the width and length of current sheets and their ratio.

It is found that the outflow velocity, the separatrix jet velocity, and the width and length of the current sheet are positively related to the inflow velocity. However, the separatrix angle does not depend on the inflow velocity, and it is related to the initial magnetic field configuration before magnetic reconnection. Furthermore, besides the inflow velocity, the magnetic diffusivity or the magnetic Reynolds number is also important to determine the width of the current sheet. The magnetic reconnection rates are different among the six reconnection events, and it decreases with the increase of the inflow velocity. The results obtained by the kinetic parameters and by the parameters of the current sheet are consistent. Meanwhile, when the separatrix angle is close to 90°, the jet and the outflow reach their maximum velocities.

These observations are consistent with the results of theoretical model and numerical simulation. However, researchers still do not know how the magnetic reconnection is triggered. They need to observe finer structures and more accurate magnetic fields to improve the observational and theoretical understanding of magnetic reconnection. Fortunately, there are already numerous high-resolution solar telescopes in operation or under development that will help researchers to further study small-scale magnetic reconnections.


Provided by Yunnan Observatories CAS

Inherited Memories Of A Chromosomal Site (Biology)

Two UNIGE teams have discovered that the location of a specific chromosomal site is transmitted between two generations, even if the part of the protein that initially defines that site is absent in the offspring.

Most biological traits are inherited through genes, but there are exceptions to this rule. Two teams from the University of Geneva (UNIGE) have been investigating the location of centromeres  – specific sites on chromosomes that are essential for cell division. They found that in the small worm Caenorhabiditis elegans, the transmission of the correct location of these sites to the offspring is not mediated by genes, but by an epigenetic memory mechanism. These results have been published in the journal PLOS Biology.

Living organisms, from humans to microscopic worms, inherit physical and sometimes behavioral traits from their parents. The transmission of biological traits is usually mediated by DNA which is replicated at each cell division and contains the genes. However, some characteristics can be transmitted from one generation to the next independently of genes: these are epigenetic phenomena.


A transparent organism to observe the segregation of chromosomes

By studying the physical separation of chromosomes into the two daughter cells during cell division, scientists at the UNIGE have been able to identify one such epigenetic process. The team of Florian Steiner, professor in the Department of Molecular Biology at the UNIGE Faculty of Science and last author of this study, is investigating centromeres in the nematode Caenorhabditis elegans. These specific chromosomal structures serve as anchors for the machinery responsible for the correct distribution of the chromosomes to the daughter cells: a defect in this distribution can result in cell death but is also frequently observed in cancerous cells. “Studying these processes is greatly facilitated in C. elegans, since this small worm is transparent and allows live observation of cell divisions and the fate of chromosomes from one generation to the next”, explains Reinier Prosée, researcher in the Department of Molecular Biology at the UNIGE Faculty of Science and first author of the study.


A memory transmitted only to the next generation

The location of the centromere on the chromosome is defined by a protein that biologists study in the group of both Florian Steiner and Monica Gotta, professor at the UNIGE Faculty of Medicine. These research groups together discovered that the protein finds its right location on the chromosome to define the centromere thanks to a particular region that serves as a guide. They then created a mutant whose DNA lacks the piece that codes for this ‘guide’ region of the protein. “The prediction was that this mutant would not be viable, since the position of the centromere could not be defined in the absence of the guide part of the protein. This, we expected, would lead to the incorrect distribution of chromosomes”, explains Florian Steiner. “However, we found that even in the absence of this ‘guide’ region, the truncated protein positions itself correctly and is functional. The worms are therefore perfectly viable!” Reinier Prosée continues. It turns out that once the centromeric sites are correctly defined in the mother, this information is transmitted to the next generation thanks to cells ‘remembering’ the correct location of these sites, even in the absence of the part of the gene that codes for the ‘guide’ region of the protein.

In contrast, the offspring of the mutant worms cannot divide their cells properly and therefore do not survive. This is because the offspring have not inherited information about the correct position of the centromeric sites from their mutant mother. This particular epigenetic memory only lasts for one generation and is not transmitted to the next. “We will now test our hypotheses to explain the epigenetic mechanism by which this memory is established and persists during development”, concludes Florian Steiner.

Featured image: A Caenorhabditis elegans nematode surrounded by offspring at different stages (eggs and larvae). © UNIGE


Reference: Prosée RF, Wenda JM, Özdemir I, Gabus C, Delaney K, Schwager F, et al. (2021) Transgenerational inheritance of centromere identity requires the CENP-A N-terminal tail in the C. elegans maternal germ line. PLoS Biol 19(7): e3000968. DOI: 10.1371/journal.pbio.3000968


Provided by University of Geneve

Fighting COVID with COVID (Medicine)

Researchers design new COVID-19 therapy that uses a defective version of the SARS-CoV-2 virus to drive the disease-causing version to extinction

What if the COVID-19 virus could be used against itself? Researchers at Penn State have designed a proof-of-concept therapeutic that may be able to do just that. The team designed a synthetic defective SARS-CoV-2 virus that is innocuous but interferes with the real virus’s growth, potentially causing the extinction of both the disease-causing virus and the synthetic virus.

“In our experiments, we show that the wild-type [disease-causing] SARS-CoV-2 virus actually enables the replication and spread of our synthetic virus, thereby effectively promoting its own decline,” said Marco Archetti, associate professor of biology, Penn State. “A version of this synthetic construct could be used as a self-promoting antiviral therapy for COVID-19.”

Archetti explained that when a virus attacks a cell, it attaches to the cell’s surface and injects its genetic material into the cell. The cell is then tricked into replicating the virus’s genetic material and packaging it into virions, which burst from the cell and go off to infect other cells.

‘Defective interfering (DI)’ viruses, which are common in nature, contain large deletions in their genomes that often affect their ability to replicate their genetic material and package it into virions. However, DI genomes can perform these functions if the cell they’ve infected also harbors genetic material from a wild-type virus. In this case, a DI genome can hijack a wild-type genome’s replication and packaging machinery.

“These defective genomes are like parasites of the wild-type virus,” said Archetti, explaining that when a DI genome utilizes of a wild-type genome’s machinery, it also can impair the wild-type genome growth.

In addition, he said, “given the shorter length of their genomes as a result of the deletions, DI genomes can replicate faster than wild-type genomes in coinfected cells and quickly outcompete the wild-type.”

Indeed, in their new study, which published today (July 1) in the journal PeerJ, Archetti and his colleagues found that their synthetic DI genome can replicate three times faster than the wild-type genome, resulting in a reduction of the wild-type viral load by half in 24 hours.

To conduct their study, the researchers engineered short synthetic DI genomes from parts of the wild-type SARS-CoV-2 genome and introduced them into African green monkey cells that were already infected with the wild-type SARS-CoV-2 virus. Next, they quantified the relative amounts of the DI and WT genomes in the cells over time points, which gave an indication of the amount of interference of the DI genome with the wild-type genome.

The team found that within 24 hours of infection, the DI genome reduced the amount of SARS-CoV-2 by approximately half compared to the amount of wild-type virus in control experiments. They also found that the the DI genome increases in quantity 3.3 times as fast than the wild-type virus.

Archetti said that while the 50% reduction in virus load that they observed over 24 hours is not enough for therapeutic purposes, presumably, as the DI genomes increase in frequency in the cell, the decline in the amount of wild-type virus would lead to the demise of both the virus and the DI genome, as the DI genome cannot persist once it has driven the wild-type virus to extinction.

He added that further experiments are needed to verify the potential of SARS-CoV-2 DIs as an antiviral treatment, suggesting that the experiments could be repeated in human lung cell lines, and against some of the newer variants of SARS-CoV-2. Furthermore, he said, an efficient delivery method should be devised. In further work that is still unpublished, the team has now used nanoparticles as a delivery vector and observed that the virus declines by more than 95% in 12 hours.

“With some additional research and finetuning, a version of this synthetic DI could be used as a self-sustaining therapeutic for COVID-19.”

Other Penn State authors on the paper include Shun Yao, postdoctoral scholar in biology; Anoop Narayanan, associate research professor of biochemistry and molecular biology; Sydney Majowicz, graduate student in molecular, cellular, and integrative biosciences; and Joyce Jose, assistant professor of biochemistry and molecular biology.

The Huck Institutes of the Life Sciences at Penn State supported this research.


Reference: Yao S, Narayanan A, Majowicz SA, Jose J, Archetti M. 2021. A synthetic defective interfering SARS-CoV-2. PeerJ 9:e11686 https://doi.org/10.7717/peerj.11686


Provided by Penn State

Sodium Solid Electrolyte Combining High Conductivity With Electrochemical Stability (Chemistry)

For the development of all-solid-state sodium-ion batteries with long-term stability

Overview:

A research team from the Department of Electrical and Electronic Information Engineering at Toyohashi University of Technology developed a chlorine (Cl) substituted Na3SbS4 solid electrolyte for use in all-solid-state sodium (Na) ion batteries. Compared to the sample without a Cl substitution, the ionic conductivity of the Na3SbS4 solid electrolyte where sulfur (S) was partially substituted with Cl improved by up to three times. The team also demonstrated that the Cl-substituted Na3SbS4 has a crystal structure framework that allows Na ions to move easier in three dimensions, and they discovered that the Cl substitution showed superior stability with Na metal anodes.

Details:

Due to increases in demand for large-scale energy storage, research into all-solid-state sodium (Na) ion batteries using low-cost and abundantly available Na resources is accelerating. In order to use all-solid-state Na-ion batteries in practical applications, a solid electrolyte with high ionic conductivity at room temperature must be developed. Among various Na solid electrolytes, Na3SbS4 solid electrolytes have a high conductivity of 1 mS cm-1 or higher at room temperature and are therefore widely researched around the world. However, in order to achieve the high conductivity, post processing is required through ball milling, and achieving high ion conductivity through a simpler synthetic process has been notably problematic.

Therefore, the research group used a liquid-phase synthesis method suitable for mass production to develop a Cl-substituted Na3SbS4 solid electrolyte. By partially substituting S in the Na3SbS4 solid electrolyte with Cl, they increased ionic conductivity at room temperature by three times (0.9 mS cm-1) compared to the sample without substitution (0.3 mS cm-1). Also, they visualized the ion-conduction pathway in order to clarify the effect on conduction characteristics by the structural change that occurs due to the Cl substitution. As a result, they demonstrated that partially substituting S in Na3SbS4 with Cl resulted in loose local bonding of Na ions with S (or Cl), forming a crystal structure framework with a weak electrostatic interaction between Na and S (or Cl) and promoting ion diffusion particularly along the crystallographic c-axis. The increase in ionic conductivity by Cl substitution is caused by the formation of a crystal structure with a three-dimensional ion diffusion pathway.

Additionally, the team discovered that the Cl-substituted Na3SbS4 solid electrolytes showed superior stability with Na metal anodes compared to the sample without a Cl substitution. They demonstrated that this improvement in electrochemical stability was linked to a reduction in interfacial resistance between the anode and the solid electrolyte and that heavy Cl doping was effective in improving stability with the anode.

Future Outlook:

The research team uncovered an important design principle for developing an ideal solid electrolyte with desirable characteristics such as high ionic conductivity and superior electrochemical stability. They believe that the solid electrolyte from this research could be combined with liquid-phase coating technology to achieve a high storage capacity and stable cycling for all-solid-state Na-ion batteries.

Featured image: Visualization of three-dimensional ion diffusion pathway (yellow section) and crystal structure of Cl-substituted Na3SbS4 © COPYRIGHT (C) TOYOHASHI UNIVERSITY OF TECHNOLOGY. ALL RIGHTS RESERVED.


Reference:

Hirotada Gamo, Nguyen Huu Huy Phuc, Hiroyuki Muto, and Atsunori Matsuda, Effects of Substituting S with Cl on the Structural and Electrochemical Characteristics of Na3SbS4 Solid Electrolytes, ACS Applied Energy Materials, (2021). doi.org/10.1021/acsaem.1c00927


Provided by Toyohashi University of Technology

Satellite Galaxies Can Carry On Forming Stars When They Pass Close to Their Parent Galaxies (Cosmology)

Historically most scientists thought that once a satellite galaxy has passed close by its higher mass parent galaxy its star formation would stop because the larger galaxy would remove the gas from it, leaving it shorn of the material it would need to make new stars. However, for the first time, a team led by the researcher at the Instituto de Astrofísica de Canarias (IAC), Arianna di Cintio, has shown using numerical simulations that this is not always the case. The results of the study were recently published in the journal Monthly Notices of the Royal Astronomical Society (MNRAS).

Using sophisticated simulations of the whole of the Local Group of galaxies, including the Milky Way, the Andromeda galaxy and their respective satellite galaxies, the researchers have shown that the satellites not only can retain their gas but can also experience many new episodes of star formation just after passing close to the pericentre of their parent galaxy (the mínimum distance they reach from its centre).

The satellite galaxies of the Local Group show a wide variety of star formation histories, whose origin has not previously been fully understood. Using hydrodynamic simulations within the project Constrained Local UniversE (CLUES) the authors studied the star formation histories of satellite galaxies similar to those of the Milky Way in a cosmological context.

While in the majority of the cases the gas of the satellite is sucked out by the parent galaxy due to gravitational action and transfers itself to the larger galaxy, interrupting star formation in the satellite, in a process known as accretion; in some 25% of the sample they found that star formation was clearly enhanced by this interactive process.

The results show that the peaks of star formation are correlated with the close pass of the satellite around the parent galaxy, and occasionally by the interaction of two satellites. The researchers identified two key features to the star formation: the satellite must enter the parent galaxy with a large reserve of cold gas, and a minimum distance not too small, so that stars may form due to compression of the gas. On the contrary, galaxies which pass too close to the parent galaxy, or to a parent galaxy with little gas, are stripped of their gas and thereby lose the possibility of forming new stars.

“The passage of satellites also coincide with peaks in the star formation of their parent galaxies, which suggests that this mechanism causes bursts of stars equally in both parent galaxies and satellites, in agreement with recent studies of the history of star formation in our own Galaxy”, explains Arianna di Cintio, the lead author on the paper.

“This is very important when we try to understand how star formation is produced in the smaller dwarf galaxies of our Local Group, an unresolved question”, she adds.

This finding will shed light on the episodes of star formation which are observed in the dwarf galaxies of the Local Group, such as Carina and Fornax, giving an attractive explanation of their existence. It also requires a revision of the theoretical models used to explain the formation of stars in dwarf galaxies.

Featured image: Image of the simulated local group used for the article. Left, image of dark matter; on the right, gas distribution. The three main galaxies of the Local Group (MW, M31 and M33) are indicated. Credit: CLUES simulation team.


Article: Arianna Di Cintio, et al. “Pericentric passage-driven star formation in satellite galaxies and their hosts: CLUES from Local Group simulations”. Monthly Notices of the Royal Astronomical Society, June 12, 2021. DOI: https://doi.org/10.1093/mnras/stab1682


Provided by IAC

Counting Sheep And Still Awake? Mindfulness Therapy May Help Bring On The ZZZ’s (Neuroscience)

Researchers from the Centre for Sleep and Cognition at the NUS Yong Loo Lin School of Medicine found mindfulness-based therapy to be more effective than an active sleep hygiene programme in improving sleep quality. This study is the first preregistered and adequately powered trial to test sleep-targeted mindfulness-based therapy as a treatment for insomnia.

Sleep problems are common in the general population with up to half of Singaporean adults reporting insufficient or unsatisfying sleep. Sleep quality tends to worsen with age and poor sleep is a modifiable risk factor for multiple disorders, including cardiovascular disease and cognitive impairment.

Currently, insomnia is treated with either medication or psychological interventions. However, even frontline treatments such as cognitive-behavioural therapy have limitations – up to 40% of patients do not get relief from their insomnia symptoms after undergoing this treatment. Furthermore, in Singapore, the waiting time to receive such treatment is long, as it is typically delivered as individual therapy and there are limited available local providers.

To search for alternative approaches to treat insomnia, Principal Investigator Assistant Professor Julian Lim from the Centre for Sleep and Cognition at the National University of Singapore’s (NUS) Yong Loo Lin School of Medicine, together with the Singapore General Hospital’s Department of Psychology, looked towards mindfulness-based treatment. Mindfulness is the awareness of moment-to-moment thoughts, feelings, and bodily sensations, and the practice of accepting these experiences without judging or reacting to them. Backed by scientific evidence.¹ ², practicing mindfulness is becoming increasingly popular as a means to reduce stress, treat mental health problems, and improve general well-being.

The randomised controlled study compared a Mindfulness-Based Therapy for Insomnia (MBTI) with an active Sleep Hygiene, Education, and Exercise Programme (SHEEP) to see if the former could improve sleep outcomes in older adults with sleep complaints. A total of 127 participants, aged 50-80, were randomised and allocated between the two programmes – 65 received MBTI while 62 went through SHEEP. Both interventions consisted of eight weekly sessions which were of two hours duration each.

The MBTI course included formal mindfulness exercises such as mindful eating, sitting meditation, mindful movement and body scans. This was followed by a group discussion of their experiences during the past week, as well as the application of practices and principles of mindfulness which directly addressed their sleep difficulties. In addition, participants were taught good sleep habits and behavioural strategies that they could use to improve their sleep.

On the other hand, the SHEEP course provided participants with information about sleep biology, self-monitoring of sleep behavior and taught changes to make in their habits and environment that could improve sleep quality. Participants also learned and practised sleeppromoting exercises such as diaphragmatic breathing, morning and evening stretching movements, and progressive muscle relaxation.

Although sleep quality improved across the board, the study found MBTI to be more effective in reducing insomnia symptoms than SHEEP. Additionally, MBTI led to observable improvements when sleep was measured objectively – using wrist-worn activity monitors, and by recording electrical brain activity while participants slept at home. These objective measurements showed that MBTI participants took less time to fall asleep, and spent less time awake during the night, while this was not seen among SHEEP participants.

Explaining the study’s findings, Assistant Professor Julian Lim said: “Insomnia is strongly linked to hyperarousal, or a failure to switch off the “fight-or-flight” system when it’s time to sleep. It typically starts because of a triggering stressful event, and persists because some individuals go on to develop bad sleep habits and dysfunctional thoughts about sleep. MBTI uses behavioural strategies to address the bad sleep habits directly, such as encouraging people to get out of bed if they have difficulty sleeping to rebuild the association between the bed and good sleep, and mindfulness techniques to equip people with more flexible strategies to deal with the dysfunctional or arousing thoughts.”

Assistant Professor Lim added, “The demonstration of the Mindfulness-Based Therapy as a viable treatment for insomnia presents possible valid alternatives for people who have failed or have no access to standard frontline therapies. Such treatment can be delivered in groups within and outside of a medical setting, providing members of the public with sleep issues easier and more efficient access to seek help.”

The study has been reported in the journal Psychological Medicine on 1 July 2021, and was funded by the Singapore Millennium Foundation, the Far East Organization, and start-up funding from Duke-NUS Medical School and NUS.

The Centre for Sleep and Cognition at the NUS Yong Loo Lin School of Medicine studies the scientific underpinnings of human behavior and ways to improve sleep. Through research and advocacy efforts, the Centre seeks to enhance human cognitive potential as well as to reduce the impact of lifestyle factors and neurodegenerative diseases on cognition and well-being.

Access the full paper here: https://www.cambridge.org/core/journals/psychological-medicine/article/mindfulnessbased-therapy-for-insomnia-for-older-adults-with-sleep-difficulties-a-randomized-clinical-trial/B7FB38A61EA1DA64EBF9C91CFCC3B20A


References: (1) Goldberg et al. (2018) Mindfulness-based interventions for psychiatric disorders: A systematic T review and meta-analysis. Clinical Psychology Review 59:52-60 (2) Van Agteren et al. (2021) A systematic review and meta-analysis of psychological interventions to improve mental wellbeing. Nature Human Behaviour, 5: 631-652


Provided by National University of Singapore

Engineered Cells Successfully Treat Cardiovascular and Pulmonary Disease (Medicine)

UCSF proof-of-concept study shows possibilities of more cost-effective cell therapy using “universal” stem cells

Scientists at UC San Francisco have shown that gene-edited cellular therapeutics can be used to successfully treat cardiovascular and pulmonary diseases, potentially paving the way for developing less expensive cellular therapies to treat diseases for which there are currently few viable options.

The study, in mice, is the first in the emerging field of regenerative cell therapy to show that products from specially engineered induced pluripotent stem cells called “HIP” cells can successfully be employed to treat major diseases while evading the immune system. The findings subvert the immune response that is a major cause of transplant failure and poses a barrier to using engineered cells as therapy.

“We showed that immune-engineered HIP cells reliably evade immune rejection in mice with different tissue types, a situation similar to the transplantation between unrelated human individuals. This immune evasion was maintained in diseased tissue and tissue with poor blood supply without the use of any immunosuppressive drugs.” said Tobias Deuse, MD, the Julien I.E. Hoffman, M.D. Endowed Chair in Cardiac Surgery and a first author of the study.

Deuse’s research is an example of “living therapeutics,” an emerging pillar of medicine in which treatments are broadly defined as living human and microbial cells that are selected, modified, or engineered to treat or cure disease.

The study appears in PNAS (Proceedings of the National Academy of Science of the United States of America).

“Universal Stem Cells” Avoid Immune Detection

The prospects of generating specialized cells in a dish that can be transplanted into patients to treat various diseases are encouraging, the scientists report. However, the immune system would immediately recognize cells that were recovered from another individual and would reject the cells. Hence, some scientists believe that custom cell therapeutics need to be generated from scratch using a blood sample from every individual patient as starting material.

The research group at UCSF followed a different approach, using gene editing to create ‘universal stem cells’ (named HIP cells) that are not recognized by the immune system and can be used to make “universal cell therapeutics.”

The team tested the ability of these cells to treat three major diseases affecting different organ systems: Peripheral artery disease; chronic obstructive pulmonary disease from alpha1-antitrypsin deficiency; and heart failure, increasingly a global epidemic with more than 5.7 million patients in the United States alone and some 870,000 new cases annually.

The scientists transplanted specialized, immune-engineered HIP cells into mice with each of these conditions and were able to show that the cell therapeutics could alleviate peripheral artery disease in hindlimbs, prevent the development of lung disease in mice with alpha1-antitrypsin deficiency, and alleviate heart failure in mice after myocardial infarction.

To enhance the translational aspect of this proof-of-concept study, the researchers assessed the treatment’s efficacy using standard parameters for human clinical trials focusing on outcome and organ function.

The Promise of an Affordable Option

Deuse, who is also surgical director of the Transcatheter Valve Program and directs Minimally Invasive Cardiac Surgery, plans to explore the potential of these universal stems cells for treating other endocrine and cardiovascular conditions. He noted that, because of the novelty of the approach, a careful and measured introduction into clinical trials will be crucial. Once more is known about human safety, he said, it will be easier to estimate when treatments using HIP cells might be approved and available for patients.

One of the great benefits of this approach, said Deuse, is that the strategy of immune engineering comes with a reasonable price tag. It would make the manufacturing of universal, high-quality cell therapeutics more cost effective, could allow future treatment of larger patient populations, and facilitate access for patients from underserved communities.

“In order for a therapeutic to have a broad impact, it needs to be affordable,” said Deuse. “That’s why we focus so much on immune-engineering and the development of universal cells. Once the costs come down, the access for all patients in need increases.”

Sonja Schrepfer, MD, PhD © UCSF

Sonja Schrepfer, MD, PhD, a senior author on the paper, is a UCSF professor who has joined Sana Biotechnology, Inc. for the translation of the HIP technology into human therapeutics. She is a pioneer of immune engineering and co-inventor of the HIP cells The other co-senior author of the paper is Lewis L. Lanier, PhD, a UCSF professor of Microbiology and Immunology, and co-leader of the Cancer Immunology & Immunotherapy Program at the UCSF Helen Diller Family Comprehensive Cancer Center.

Featured image: Immune fluorescence of HIP cardiomyocytes in a dish. Credit: UCSF


Reference: Tobias Deuse el al., “Hypoimmune induced pluripotent stem cell–derived cell products treat cardiovascular and pulmonary diseases in immunocompetent allogeneic mice,” PNAS (2021). www.pnas.org/cgi/doi/10.1073/pnas.2022091118


Provided by UCSF

Study Uncovered New Signaling Pathway That Could Shed Light On Damage Repair During Brain Injury (Neuroscience)

The study has uncovered a signaling pathway that causes neural cells to enter divisions after damage

Most human cells are able to repair damage by dividing at wounds.

But mature nerve cells (neurons) in our brain are different. If they attempt division, they will likely die – and this is what happens during brain injury, or in conditions such as Alzheimer’s Disease (AD). Now new research led by the University of Plymouth has uncovered a pathway that has shed new light on how these divisions may be triggered.

The research, published today in Cell Reports, has focused on intracellular structures called microtubules – which are found in most animal cells, and can be damaged by a build-up of a protein called Tau in the brain during AD.

The study was conducted in fruit flies, with comparison to postmortem brain samples of AD patients.

The paper shows that when the microtubules of neural cells in fruit flies are damaged, division is triggered via activating the small signalling kinases, Tak1 and Ik2. Strikingly, activation of these molecules can also be seen in AD brains.

Why is this important?

By understanding how the damaged microtubules behave, scientists have a valuable opportunity to potentially prevent neuronal death following brain injury, or upon neurodegeneration, such as in Alzheimer’s Disease.

The research took place in fruit flies, but the team tested the applicability of their results by making fly neural cells express human Tau, and also examining post mortem human brain samples from AD patients.

Abnormal human Tau destroys microtubules in both flies’ and Alzheimer’s brains, and interestingly can trigger the same signalling cascade as discovered in fly neural cells after microtubule damage.

The reseachers also found that higher levels of Tau accumulation correlated to a greater frequency of neurons attempting to divide and neuronal death, but have not yet established a direct link or cause.

What needs to happen next?

The work took place in the Plymouth Institute of Health and Care Research (PIHR) and was led by Dr Torsten Bossing.

He said of the current research and future plans: “While other scientists are exploring Tau and how it builds up, we’re looking more at what happens to the cell after it has been damaged.

“The fact that the identified two signalling kinases are found alongside a build-up of Tau in post mortem brains of Alzheimer’s Disease patients suggests that the mechanism identified using fruit flies may act similarly in humans. So we want to further our studies by using cultured human neurons next. Ultimately we want to prevent this abnormal cell division entry process from happening in the first place. It’s an exciting piece of work, which we look forward to progressing.”

The full paper, entitled Microtubule disruption upon CNS damage triggers mitotic entry via TNF signalling activation is available to view now in Cell Reports (doi: 10.1016/j.celrep.2021.109325).

Featured image: Fruit fly neurons © Torsten Bossing, University of Plymouth


Provided by University of Plymouth