Stem Cell Clinic

Researchers chart the contents of human bone marrow – Science Daily

A team at Weill Cornell Medicine has mapped the location and spatial features of blood-forming cells within human bone marrow. Their findings confirm hypotheses about the anatomy of this tissue and provide a powerful new means to study diseases, ranging from noncancerous conditions, such as sickle cell anemia, to malignant conditions, such as acute leukemia, that affect bone marrow.

For the research described Sept. 29 in Blood, the investigators retrieved deidentified archival bone marrow samples from 29 patients at NewYork-Presbyterian/Weill Cornell Medical Center, generating a vast amount of data about the spatial relationships among their contents.

Creating images of bone marrow has been difficult historically, according to senior author Dr. Sanjay Patel, director of the Multiparametric In Situ Imaging (MISI) Laboratory in the Department of Pathology and Laboratory Medicine and an assistant professor of pathology and laboratory medicine at Weill Cornell Medicine. He and his colleagues overcame these challenges by devising a method for visualizing whole pieces of the tissue, then analyzing them with artificial intelligence (AI).

"We have been able to apply our approach to archival samples in a way that wasn't possible before," said Dr. Patel, who is also a hematopathologist at NewYork-Presbyterian/Weill Cornell Medical Center and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. He noted that they succeeded in identifying and determining the positions of about 1.5 million cells in all.

Visualizing the Elusive Birthplace of Blood

Our blood cells get their start in the bone marrow, where stem cells produce the progenitors that in turn generate red and white blood cells, as well as the wound-sealing fragments known as platelets. Errors in these processes can give rise to acquired diseases including cancers, such as leukemia, lymphoma, and multiple myeloma, and those, such as sickle cell anemia, present from birth.

Studying the birth of blood cells within their native environment in human tissues, however, has proven challenging. What's more, when bone marrow samples are collected, the preservation technique can degrade some nucleic acids and proteins within the cells they contain. And, to avoid bias, researchers need to capture images of an entire piece of tissue, generating a daunting amount of data.

Dr. Patel's team came up with a series of solutions. They started by gathering samples from the tissue archive within Weill Cornell Medicine's Department of Pathology and Laboratory Medicine. These one-to-two-centimeter-long pieces of tissue came from patients who had received biopsies, but who had turned out to be disease free. Researchers in the MISI lab tested a variety of immune proteins known as antibodies, selecting from a catalog of thoroughly-vetted markers used in routine clinical diagnostics, to see which most effectively tagged the contents of bone marrow to make them visible with their fluorescence-based imaging instrumentation.

Their collaborators at BostonGene Corporation, a medical bioinformatics company, then used AI to analyze the resulting images, picking out individual cells, such as stem cells and the platelet-producing megakaryocytes, as well as bone, fat and blood vessels. This technology allowed the team to wrangle an otherwise unmanageable amount of information into a sophisticated analysis, according to Dr. Patel.

A New Way to Investigate Diseases

Previous studies have suggested that, during normal blood cell development, stem and progenitor cells inhabit certain locations, near bone and blood vessels, where surrounding cells create environments critical for their normal function. More recently, some research has suggested that these cells also gather around megakaryocytes, large cells that give rise to platelets. The team's analysis confirmed these patterns, including for megakaryocytes, in human samples. However, when they took patients' age into account, they found the cells were no longer as closely associated with megakaryocytes, which also tended to be smaller in older patients.

While these findings contribute to scientists' understanding of normal bone marrow, Dr. Patel sees the new method's greatest potential in investigating diseases, particularly along the course of their evolution. For a few conditions, such as acute myeloid leukemia, researchers already have evidence that the spatial arrangement of stem and progenitor cells may be disrupted. This new method could open the door to studies that specifically explore such changes -- and to those testing new treatments and evaluating existing ones, according to Dr. Patel.

"I hope our work unlocks the imagination of people who study diseases related to the bone marrow," he said.

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Researchers chart the contents of human bone marrow - Science Daily

New study reveals the critical role of microglia in human brain … – EurekAlert

image:

Super-resolution image of human stem cell-derived Microglia cells with labeled mitochondria (yellow), nucleus (magenta), and actin filaments (cyan). These Microglia cells help in the maturation of neurons in human brain organoid models. Photo credit: A*STAR's SIgN

Credit: A*STAR's SIgN

An international team of scientists has uncovered the vital role of microglia, the immune cells in the brain that acts as its dedicated defense team, in early human brain development. By incorporating microglia into lab-grown brain organoids, scientists were able mimic the complex environment within the developing human brain to understand how microglia influence brain cell growth and development. This research represents a significant leap forward in the development of human brain organoids and has the potential to significantly impact our understanding of brain development and disorders. The study, iPS-cell-derived microglia promote brain organoid maturation via cholesterol transfer was published in Nature on 1 November 2023.

To investigate microglia's crucial role in early human brain development, scientists from A*STAR's Singapore Immunology Network (SIgN) led by Professor Florent Ginhoux, utilised cutting-edge technology to create brain-like structures called organoids, also known as mini-brains in the laboratory. These brain organoids closely resemble the development of the human brain. However, previous models were lacking in microglia, a key component of early brain development.

To bridge this gap, A*STAR researchers designed a unique protocol to introduce microglia-like cells generated from the same human stem cells used to create the brain organoids. These introduced cells not only behaved like real microglia but also influenced the development of other brain cells within the organoids.

A*STAR's Institute of Molecular and Cell Biology (IMCB)'s Dr Radoslaw Sobota and his team at the SingMass National Laboratory for Mass Spectrometry applied cutting edge quantitative proteomics approach to uncover changes in protein. Their analysis provided crucial insights into the protein composition of the organoids, further confirming the studys findings.

What sets this study apart is the discovery of a unique pathway through which microglia interact with other brain cells. The study found that microglia play a crucial role in regulating cholesterol levels in the brain.The microglia-like cells were found to contain lipid droplets containing cholesterol, which were released and taken up by other developing brain cells in the organoids. This cholesterol exchange was shown to significantly enhance the growth and development of these brain cells, especially their progenitors.

Cholesterol, makes up about 25% of the body's total cholesterol content, is abundantly present in the brain and is essential for the structure and function of neurons. Abnormal cholesterol metabolism has been linked to various neurological disorders, including Alzheimer's and Parkinson's Disease.

To investigate the roles of lipids in brain development and disease, researchers from the Department of Biochemistry at the Yong Loo Lin School of Medicine (NUS Medicine), led by Professor Markus Wenk, took on the crucial task of data acquisition, particularly in the field of lipidomics to draw valuable insights into the lipid composition and dynamics within the brain organoids containing microglia.

Using this information, another team from the Department of Microbiology and Immunology at NUS Medicine and led by Associate Professor Veronique Angeli, found that cholesterol affects the growth and development of young brain cells in human brain models. Microglia use a specific protein to release cholesterol, and when this process is blocked, it causes the organoid cells to grow more, leading to larger brain models. It has always been known that the microglia is key to brain development, however their precise role remains poorly understood. This finding from our team at the Department of Microbiology and Immunology is particularly impactful because we finally understand how cholesterol is transported. Our next focus will be finding out how we can regulate cholesterol release to optimise brain development and slow down, or prevent, the onset of neurological conditions, added Assoc Prof Veronique, who is also Director of the Immunology Translational Research Programme at NUS Medicine.

Moreover, Dr Olivier Cexus from the University of Surrey and formely at A*STAR, progressively deciphered the complex molecular interactions within the brain organoids using proteomic and lipidomic analysis. This provided valuable insights into the metabolic cross-talks involved in brain development and potential implications for diseases.

Together, these collective efforts were instrumental in deepening our understanding of the roles of microglia and the molecular components within brain organoids and its implications for human health.

Prof Florent Ginhoux, Senior Principal Investigator at A*STARs SIgN and Senior author of the study said, "Understanding the complex roles of microglia in brain development and function is an active area of research. Our findings not only advance our understanding of human brain development but also have the potential to impact our knowledge of brain disorders. This opens up new possibilities for future research into neurodevelopmental conditions and potential therapies."

Co-author of the study, Professor Jerry Chan, Senior Consultant, Department of Reproductive Medicine, KK Womens and Childrens Hospital, and Senior National Medical Research Council Clinician Scientist, added, There is currently a lack of tools to study how microglia interacts with the developing brain. This has hampered the understanding of microglia-associated diseases that play an important role during the early development of conditions such as autism, schizophrenia, and neurodegenerative diseases such as Alzheimers and Parkinsons disease.

The development of these novel microglia-associated brain organoids with same-donor pluripotent stem cells gives us an opportunity to study the complex interactions between microglia and neurons during early brain development. Consequentially, this may enable us to study the role of microglia in the setting of diseases and suggest ways to develop new therapies in time.

iPS-cell-derived microglia promote brain organoid maturation via cholesterol transfer

1-Nov-2023

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

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New study reveals the critical role of microglia in human brain ... - EurekAlert

Anti-aging molecule extends lifespan by improving cellular health – Earth.com

Researchers at the Buck Institute have made a significant breakthrough in the field of aging and disease with the discovery of a new drug-like molecule.

This molecule, known as MIC (Mitophagy-inducing compound), has been shown to extend lifespan and improve health in a variety of ways.

MIC operates by promoting healthy mitochondria through a process called mitophagy, which removes and recycles damaged mitochondria.

Mitochondria are crucial organelles in cells that produce energy, and their health is directly linked to overall cellular health and longevity.

The study demonstrated that this molecule extended the lifespan of C. elegans, a nematode worm frequently used in aging research.

MIC also improved mitochondrial function in mouse muscle cells and showed promise in ameliorating pathology in neurodegenerative disease models.

Mitochondrial dysfunction is known to play a role in various age-related diseases, including neurodegenerative disorders like Parkinsons and Alzheimers, cardiovascular diseases, metabolic disorders, muscle wasting, and cancer progression.

Despite the potential of treatments targeting mitochondrial dysfunction, none have been approved for human use to date.

The mitophagy-inducing compound is a coumarin, a type of naturally bioactive compound found in many plants and certain types of cinnamon.

Coumarins are known for their diverse health benefits, including anticoagulant, antibacterial, antifungal, antiviral, anticancer, antihyperglycemic properties, and neuroprotective effects.

The discovery of the effects of MIC originated from a study on Parkinsons disease. A team of experts including Dr. Julie Andersen and Dr. Shankar Chinta were examining known enhancers of mitophagy in a mouse model.

The mitophagy-inducing compound emerged as a significant find in their research. Instead of immediately testing MIC in mice, the researchers opted to study its impact on overall aging and its mechanism of action using the C. elegans model.

This approach led to the discovery that MIC belongs to a different class of molecules that enhance the expression of a key protein in autophagy and lysosomal functions (TFEB).

The study, led by Dr. Andersen and research scientist Dr. Manish Chamoli, revealed that MIC activates the transcription factor TFEB, a master regulator of genes involved in autophagy and lysosomal functions. Autophagy is an intracellular recycling process vital for cellular health.

The research findings are significant as they show MICs potential in not only extending lifespan but also preventing mitochondrial dysfunction in mammalian cells, offering new avenues for treating various age-related diseases.

Theres a bottleneck in efforts to develop potential therapeutics in the field of geroscience, and the bottleneck is that we dont have enough molecules in the pipeline, said study senior co-author Dr. Gordon Lithgow.

MIC is a great candidate to bring forward given its therapeutic effect across multiple models and the fact that it is a naturally occurring molecule.

Anti-aging strategies encompass a variety of practices and research areas focused on slowing down or reversing the aging process. Here are some key areas:

This includes a balanced diet rich in antioxidants, regular physical activity, adequate sleep, and stress management. Avoiding smoking and excessive alcohol consumption also plays a critical role.

Using sunscreen to protect the skin from UV damage, along with regular use of moisturizers and anti-aging products like retinoids and peptides, can help maintain skin health.

These include hormone replacement therapies, cosmetic procedures like Botox or fillers, and plastic surgery. These methods should be approached cautiously and under medical supervision.

Some people use supplements like omega-3 fatty acids, vitamin D, coenzyme Q10, and others believed to have anti-aging effects. However, their effectiveness can vary and should be used judiciously.

Areas like telomere therapy, stem cell research, and gene editing are being explored for potential anti-aging benefits. While promising, many of these are still in the experimental stages.

Maintaining mental health and active social life is essential. Activities that stimulate the mind, like puzzles, reading, and learning new skills, along with regular social interaction, can contribute to longevity and quality of life.

Regular visits to healthcare professionals for check-ups can help in early detection and management of age-related diseases.

Certain foods are known for their potential anti-aging benefits, mainly due to their high antioxidant content and other beneficial nutrients. Heres a list of some of these foods:

Incorporating these foods into a balanced diet can contribute to overall health and potentially slow some aspects of the aging process. Its also important to maintain a diverse diet and consult with a healthcare professional, especially when making significant dietary changes.

The research is published in the journal Nature Aging.

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Pancreas gene finding gives new insights into human development … – EurekAlert

Understanding how the human pancreas develops is crucial to allow scientists to make insulin producingbeta cells in the quest to cure Type 1 diabetes. Now, scientists have made a unique and surprising discovery - a gene that is essential for making the pancreas in humans is not present in almost all other animals.

Beta cells within the pancreas produce insulin that regulate blood sugar. Every mammal needs the pancreatic beta-cells to survive. In established Type 1 diabetes there are no, or very few, working beta-cells.

The new finding, published in Nature Genetics, challenges assumptions about how the regulation of development evolves. Until now, scientists had assumed that genes essential for development of key organs and functions were highly conserved through evolution, meaning the genetic pathway remains the same between different species, from fish to humans. However, the gene, called ZNF808, is only found in humans, other apes such as chimpanzees and gorillas, and in some monkeys, such as macaques.

This Wellcome Trust-funded research was carried out by researchers at the University of Exeter Medical School, the University of Cambridge and the University of Helsinki in Finland. The study shows just how different humans can be to other animals often used in research, such as mice, emphasising the importance of studying the human pancreas.

Lead author Dr Elisa De Franco, of the University of Exeter Medical School, said: Our finding is really surprising this is the only example we know of where a gene that is fundamental to the development of an organ in humans and primates is not present in other animals. Youd expect a gene only found in primates to regulate a feature that is specific to primates, such as brain size, but it is not the case for this gene, which instead is involved in development of an organ shared by all vertebrates! We think this shows that there must have been an evolutionary shift in higher primates to serve a purpose.

Senior author Professor Andrew Hattersley, of the University of Exeter Medical School, said: One hypothesis that we are exploring is that the evolutionary benefit is to the pancreas in the fetus. Human babies are born through the pelvis, so they cannot stay in the uterus for a longtime as they would grow too large for birth. Instead to cope with being born early and needing to survive without continual feeding they need to be born with more fat than any other animal. This fat is laid down when the fetus pancreas produces more insulin. Our research has shown that human fetuses have more insulin-related growth than other animals.

Dr Nick Owens, of the University of Exeter Medical School, remarked This research really emphasises the importance of studying the human pancreas in order to understand and find new treatments for diabetes. Animal research is important, but it can only tell us so much. We know there are fundamental differences between humans and other animals, such as mice which are often the subject of research in this field. The human pancreas is different in how it looks, works and develops. Our genetic finding could help us understand why thats the case.

ZNF808 belongs to a family of recently evolved proteins which bind and switch off specific regions of the DNA which have also developed recently in evolutionary terms. These DNA regions were among the regions considered junk DNA with no meaningful purpose for decades, but new technology have recently allowed us to discover their functions. Our findings confirm that these regions of our DNA are playing important roles during human development.

Dr Michael Imbeault, from the University of Cambridge, said These findings show that genes like ZNF808, even if relatively recent in evolution, can have a crucial role in human development. ZNF808 is a member of the largest, but also least studied family of proteins that regulate our genome. There are hundreds of genes like ZNF808 in our DNA, many primate or even human specific, and our results demonstrate how these can be key players in human health..

The identification of ZNF808 as being involved in human pancreas development occurred after researchers at the University of Exeter examined genetic samples from patients recruited across the world who were born without a pancreas and found that they all had genetic changes resulting in loss of ZNF808. They then teamed up with colleagues at the University of Cambridge and Helsinki University to study the effect of ZNF808 loss using stem cells in the lab. The results showed that ZNF808 plays an important function early during human development when cells need to decide whether to become pancreas or liver.

Among those who shared their genetic samples was Tania Bashir, aged 12, from Luton. Her father Imran Bashir welcomed the Exeter teams progress. Having an answer to why this happened is important. Weve always wanted to know now we do. The next important step is to understand what this means to the future of science. My dream is that one day, scientists will be able to genetically modify a stem cell and grow a human pancreas, and implant that into Tania, and potentially cure her. I dont know if that will ever be possible, but I do know that this understanding is a crucial step forward.

Professor Timo Otonkoski from University of Helsinki remarked The input of people born without a pancreas was fundamental to this discovery. Nobody would have ever thought that ZNF808 played a role in pancreatic development if we hadnt found the changes in this gene in these patients. The ultimate goal of our research is for this knowledge to be translated into being able to manipulate stem cells to produce beta cells that can produce insulin in the laboratory. That could be the key to curing type 1 diabetes. Our finding is a significant step in understanding what makes the human pancreas unique, which could help progress this area.

The research was supported by the Wellcome Trust, Diabetes UK, and by the Exeter NIHR Biomedical Research Centre. The paper is entitled Primate-specific ZNF808 is essential for pancreatic development in humans and is published in Nature Genetics.

Tanias story

Tania Bashir, Twin 2, weighed just 1.1kg when she was born, via emergency caesarean section, five weeks premature, without a pancreas.

Her mother Saiqa said: From week 20 onwards the weekly scans were stressful. We were told there was a high chance that the smaller twin wouldnt make it, so we kept the fact we had a twin a secret from friends, family and even her other three siblings.

Tanias father Imran, a chartered hardware engineer in Luton, recalled: Tania weighed about as much as a bag of sugar; you could quite easily fit her in the palm of your hand They immediately realised she had neonatal diabetes, but she was also not growing or gaining weight. It took eight weeks of investigations, tests and scans to figure out she had no pancreas. Our lives have never been the same since.

As well as producing no insulin to control her blood sugar, Tania, now 12, does not produce the enzymes that break down fats, proteins and carbohydrates into smaller molecules such as triglycerides, amino acids, and sugars so they can pass through the intestine into the bloodstream. Today, with the support of her parents, she lives a relatively normal life, despite still needing a special liquid feed via a tube at night and permanently using an insulin pump. But her dad recalls the dark days of fear and uncertainty when she was small.

First, we were told she wouldnt survive till birth, then that she wouldnt survive the next few weeks I remember consciously thinking that I didnt want to get too attached, because one of us would have to be strong when she died. In the end, we stopped asking. You normally look to the medical professionals for answers, but because the condition was so rare, there just is not the experience in the UK or across the world. We were learning along with the medical professionals, pushing each other to find better solutions for Tania. We are really lucky to have a fantastic team at the Luton and Dunstable hospital.

Imran found a small network of families globally via Facebook, which provided some shared experience. When Tania was six months old, the family was connected to the research team at the University of Exeter, who specialise in genetic causes of diabetes. They visited the lab and Imran said: I remember thinking, I like what theyre trying to do here we could get an answer.

A decade later, through sequencing all the genes in Tanias DNA (a technique called whole exome sequencing) the Exeter team has identified a gene which is crucial to the development of the human pancreas and is only present in humans and some monkeys, but not in other mammals. Tanias genetic sample was one of just 13 of children born without a pancreas to enable this discovery.

Imran welcomed the progress. Having an answer is important. It draws a line under the question of why, but the journey is far from over. Unlike people with type 1 diabetes, Tanias immune system didnt attack her pancreas so a pancreas could function in her body. I believe that it might be possible to use this research to modify stem cells and grow a pancreas using Tanias own cells, which could be implanted into her. I know it sounds like science fiction, but 40 years ago, there was no such thing as the internet. Now we can share moments instantly across the world. Theres some amazing scientific progress going on in the world, and the work done by Exeter has brought us one step closer to making my dream possible.

Dr Elisa de Franco, of the University of Exeter Medical School, said: Our findings really show the importance of studying the DNA of people with rare diseases to understand how organs develop and function. We are immensely grateful to people like Tania and her family, without them none of this would be possible.

Case study

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Primate-specific ZNF808 is essential for pancreatic development in humans

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Pancreas gene finding gives new insights into human development ... - EurekAlert

Study Provides Clues to Developing Better Treatments for Lung … – Duke University School of Medicine

Scientists and clinicians at the Duke University School of Medicine have discovered new details about how lung tissue heals after injury caused by toxins such as air pollution or cigarette smoke.

The researchers found that a cascade of interacting steps involving two different cell types is crucial for healing. An imbalance in these steps can lead to damage that resembles emphysema or lung fibrosis, the study found.

The study, published November 2, 2023, in the journal Cell Stem Cell, paves the way for future investigations to identify possible new treatments to prevent or reverse these diseases.

"A long-standing question in the field of wound healing is how our body organs know to regrow and build the same structure after a wound," said co-senior author Purushothama Rao Tata, PhD, assistant professor of cell biology and medicine, and co-director of the Duke Regeneration Center. The study's other senior author was Aleksandra Tata, PhD, assistant research professor of cell biology.

Tata explained that lung tissue is like a big balloon draped by a structure akin to a fishnet: the extracellular matrix scaffold, which creates multiple compartments with strong, flexible walls that expand and contract as we breathe. This study focused on how the lungs rebuild this scaffold after injury.

To study this question, the scientists used a variety of methods, including single cell transcriptome analysis and other computational tools, to build "time-lapse molecular circuits" to reconstruct wound repair in mouse lungs.

"We refer to it as molecular circuits because we are not looking at one or two genes, but a collection of genes associated with a particular cell state or phenotype," Tata said. "These are like electrical circuits that all come together to switch on a light, for example. All of these genes together exert a collective function."

"Disruption of these circuits revealed key druggable molecules to target two currently incurable lung diseases emphysema and fibrosis," he said. "These diseases are like two sides of the same coin. In a lung with emphysema, we lose the walls of the scaffold. In the case of fibrosis, the wall thickness increases so they are no longer flexible."

The study revealed that after a healing "program" is activated, a cascade of events ensues, involving both epithelial cells (cells that line the lungs) and mesenchymal cells (support cells).

The researchers outlined three crucial steps or "transitional states" that happen during this process. If certain transitional states involving epithelial cells persist too long, the result is fibrosis (buildup of scar tissue). "If there is a blockade in the transition of these cell states, the result is loss of tissue that resembles emphysema," Tata said.

In a preview article highlighting the work, scientists not affiliated with the Duke study pointed out that one of the intermediate cell states identified as crucial in the healing process has previously been termed a "bad actor" in lung fibrosis research. Two drugs currently approved for fibrosis (nintedanib and pirfenodone) actually kill this cell state, Tata said. "Our study shows that treating with these drugs may actually be a bad thing," he said.

Other authors of the study are: Arvind Konkimalla, MD, PhD, currently a resident at Duke University Hospital; postdoctoral associate Satoshi Konishi, MD, PhD; laboratory research analyst Lauren Macadlo; PhD candidates Jeremy Morowitz and Zachary Farino; postdoctoral fellow Naoya Miyashita, PhD; and bioinformatician Pankaj Agarwal, all in the Duke Department of Cell Biology; Department of Pediatrics postdoctoral research associate Lea El Haddad, MD, PhD; Mai K. ElMallah, MD, associate professor of pediatrics; Christina E. Barkauskas, MD, associate professor of medicine; and Tomokazu Souma, MD, PhD, assistant professor in medicine; and Yoshihiko Kobayashi, PhD, now an assistant professor at Kyoto University in Japan.

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Study Provides Clues to Developing Better Treatments for Lung ... - Duke University School of Medicine

Mutation in Brain’s Immune Cells Linked to Alzheimer’s Risk – Neuroscience News

Summary: A genetic mutation affecting microglia, the brains immune cells, can increase the risk of Alzheimers disease up to threefold.

The mutation, known as TREM2 R47H/+, impairs microglia function and contributes to Alzheimers pathology. It causes inflammation, reduces debris clearance, impairs response to neuronal injury, and leads to excessive synapse pruning.

The study highlights the complex impact of this mutation, offering insights for potential therapeutic interventions in Alzheimers disease.

Key Facts:

Source: MIT

A rare but potent genetic mutation that alters a protein in the brains immune cells, known as microglia, can give people as much as a three-fold greater risk of developing Alzheimers disease.

A new study by researchers in The Picower Institute for Learning and Memory at MIT details how the mutation undermines microglia function, explaining how it seems to generate that higher risk.

This TREM2 R47H/+ mutation is a pretty important risk factor for Alzheimers disease, said study lead author Jay Penney, a former postdoc in the MIT lab of Picower ProfessorLi-Huei Tsai. Penney is now an incoming assistant professor at the University of Prince Edward Island.

This study adds clear evidence that microglia dysfunction contributes to Alzheimers disease risk.

In the study in the journalGLIA, Tsai and Penneys team shows that human microglia with the R47H/+ mutation in the TREM2 protein exhibit several deficits related to Alzheimers pathology. Mutant microglia are prone to inflammation yet are worse at responding to neuron injury and less able to clear harmful debris including the Alzheimers hallmark protein amyloid beta.

When the scientists transferred TREM2 mutant human microglia into the brains of mice, the mice suffered a significant decline in the number of synapses, or connections between their neurons, which can impair the circuits that enable brain functions such as memory.

The study is not the first to ask how the TREM2 R47H/+ mutation contributes to Alzheimers, but it may advance scientists emerging understanding, Penney said. Early studies suggested that the mutation simply robbed the protein of its function, but the new evidence paints a deeper and more nuanced picture.

While the microglia do exhibit reduced debris clearance and injury response, they become overactive in other ways, such as their overzealous inflammation and synapse pruning.

There is a partial loss of function but also a gain of function for certain things, Penney said.

Misbehaving microglia

Rather than rely on mouse models of TREM2 R47H/+ mutation, Penney, Tsai and their co-authors focused their work on human microglia cell cultures. To do this they used a stem cell line derived from skin cells donated by a healthy 75-year-old woman.

In some of the stem cells they then used CRISPR gene editing to insert the R47H/+ mutation and then cultured both edited and unedited stem cells to become microglia. This strategy gave them a supply of mutated microglia and healthy microglia, to act as experimental controls, that were otherwise genetically identical.

The team then looked to see how harboring the mutation affected each cell lines expression of its genes. The scientists measured more than 1,000 differences but an especially noticeable finding was that microglia with the mutation increased their expression of genes associated with inflammation and immune responses.

Then, when they exposed microglia in culture to chemicals that simulate infection, the mutant microglia demonstrated a significantly more pronounced response than normal microglia, suggesting that the mutation makes microglia much more inflammation-prone.

In further experiments with the cells, the team exposed them to three kinds of the debris microglia typically clear away in the brain: myelin, synaptic proteins and amyloid beta. The mutant microglia cleared less than the healthy ones.

Another job of microglia is to respond when cells, such as neurons, are injured. Penney and Tsais team co-cultured microglia and neurons and then zapped the neurons with a laser.

For the next 90 minutes after the injury the team tracked the movement of surrounding microglia. Compared to normal microglia, those with the mutation proved less likely to head toward the injured cell.

Finally, to test how the mutant microglia act in a living brain, the scientists transplanted mutant or healthy control microglia into mice in a memory-focused region of the brain called the hippocampus. The scientists then stained that region to highlight various proteins of interest.

Having mutant or normal human microglia didnt matter for some measures, but proteins associated with synapses were greatly reduced in mice where the mutated microglia were implanted.

By combining evidence from the gene expression measurements and the evidence from microglia function experiments, the researchers were able to formulate new ideas about what drives at least some of the microglial misbehavior. For instance, Penney and Tsais team noticed a decline in the expression of a purinergic receptor protein involving sensing neuronal injury perhaps explaining why mutant microglia struggled with that task.

They also noted that mice with the mutation overexpressed complement proteins used to tag synapses for removal. That might explain why mutant microglia were overzealous about clearing away synapses in the mice, Penney said, though increased inflammation might also cause that by harming neurons overall.

As the molecular mechanisms underlying microglial dysfunction become clearer, Penney said, drug developers will gain critical insights into ways to target the higher disease risk associated with the TREM2 R47H/+ mutation.

Our findings highlight multiple effects of the TREM2 R47H/+ mutation likely to underlie its association with Alzheimers disease risk and suggest new nodes that could be exploited for therapeutic intervention, the authors conclude.

In addition to Penney and Tsai, the papers other authors are William Ralvenius, Anjanet Loon, Oyku Cerit, Vishnu Dileep, Blerta Milo, Ping-Chieh Pao, and Hannah Woolf.

Funding: The Robert A. and Renee Belfer Family Foundation, The Cure Alzheimers Fund, the National Institutes of Health, The JPB Foundation, The Picower Institute for Learning and Memory and the Human Frontier Science Program provided funding for the study.

Author: David Orenstein Source: MIT Contact: David Orenstein MIT Image: The image is credited to Neuroscience News

Original Research: Open access. iPSC-derived microglia carrying the TREM2 R47H/+ mutation are proinflammatory and promote synapse loss by Jay Penney et al. Glia

Abstract

iPSC-derived microglia carrying the TREM2 R47H/+ mutation are proinflammatory and promote synapse loss

Genetic findings have highlighted key roles for microglia in the pathology of neurodegenerative conditions such as Alzheimers disease (AD). A number of mutations in the microglial protein triggering receptor expressed on myeloid cells 2 (TREM2) have been associated with increased risk for developing AD, most notably the R47H/+ substitution.

We employed gene editing and stem cell models to gain insight into the effects of the TREM2 R47H/+ mutation on human-induced pluripotent stem cell-derived microglia. We found transcriptional changes affecting numerous cellular processes, with R47H/+ cells exhibiting a proinflammatory gene expression signature.

TREM2 R47H/+ also caused impairments in microglial movement and the uptake of multiple substrates, as well as rendering microglia hyperresponsive to inflammatory stimuli. We developed an in vitro laser-induced injury model in neuronmicroglia cocultures, finding an impaired injury response by TREM2 R47H/+ microglia.

Furthermore, mouse brains transplanted with TREM2 R47H/+ microglia exhibited reduced synaptic density, with upregulation of multiple complement cascade components in TREM2 R47H/+ microglia suggesting inappropriate synaptic pruning as one potential mechanism.

These findings identify a number of potentially detrimental effects of the TREM2 R47H/+ mutation on microglial gene expression and function likely to underlie its association with AD.

Link:
Mutation in Brain's Immune Cells Linked to Alzheimer's Risk - Neuroscience News

The largest biotech city in Europe will soon be built, with an … – BioPharma Dive

VILNIUS, Lithuania

The largest biotech city in Europe will soon be built, with an investment amounting to 7 billion euros

Northway Group is embarking on a project to establish Europes largest biotechnology hub, BIO CITY, in Vilnius, the capital of Lithuania. It includes 6 large biotechnological complexes 4 state-of-the-art GMP manufacturing plants and 2 advanced scientific research centres that will be built in an area equivalent to 10 football fields.The total investment for this biotech campus is projected to reach approximately 7 billion euros over the next decade.

A science-based economy, supported by bright minds and intelligent entrepreneurs, is the foundation for Lithuanias long-term economic prosperity. In the past, our growth was constrained by a lack of fossil resources, but today, we are boldly moving forward, relying on modern technologies. The new biotechnology hub embodies the direction of Lithuanias innovative economy. It also promises new inventions that will enable people with serious illnesses to become full members of society, thereby reducing exclusion, says the President of the Republic of Lithuania, Gitanas Nausda.

Prof. Vladas Algirdas Bumelis, founder and CEO of Northway Biotech and Celltechna, key components of the Northway Group, highlighted Lithuanias strong global standing in biotechnology. The aim of the BIO CITY project is to further solidify this position with four advanced biomanufacturing facilities and two innovative research centres, significantly boosting Lithuania's prominence in the international biotech sphere.

The Speaker of the Seimas, parliament of Lithuania, states that the new biotech city being developed in Vilnius will strengthen the competitiveness of our country. Lithuanian life sciences industry has ambitions and potential to become a global leader in this field: a leader who will significantly contribute to the development of scientific research for the well-being of man, nature and planet, and will facilitate new opportunities to deal with global health, sustainable development and other challenges, says Viktorija milyt-Nielsen.

Vision of BIO CITY: A European Biotechnology Leader

We envision BIO CITY as a frontrunner in the European biotechnology, by uniquely integrating various biotech segments into a single, synergistic ecosystem. This multifunctional complex will catalyse interdisciplinary collaborations, the quick realisation of ideas and technological advancements. Our unique model, which brings together diverse biotechnology fields in one location, is set to revolutionise the European biotech landscape, said Prof. V. A. Bumelis.

Gene Therapy Centre will Open in 2024

The first facility to open its doors in the biotech hub BIO CITY will be the Gene Therapy Centre, which is currently under construction and is being built by Northway Groups subsidiary, Celltechna. This centre, the first and so far the only one of its kind in the Baltic States, will bolster Lithuania's role in gene therapy, addressing the needs of the 280 million individuals worldwide who are affected by genetic diseases.

Our state-of-the-art facility will be instrumental in both research and production, offering new treatments for previously incurable diseases. This will not only augment our CDMO (Contract Development and Manufacturing Organisation) capabilities, but also position us for global competition and collaborations, added Prof. V. A. Bumelis.

The Gene Therapy Centre, which is expected to become operational in the second quarter of 2024, will specialise in gene therapy research and GMP manufacturing. Representing an investment of 50 million euros, the facility will span 8,000 square metres and is anticipated to create over 100 high-value jobs. The centre will work in synergy with Northway Biotech. Established in 2004, Northway Biotech is a leading provider of CDMO services in the field of biologics, with a focus on the development and manufacturing of recombinant proteins and antibodies.

A Comprehensive Lithuanian Biotech Hub

By 2030, BIO CITY will see the inauguration of five additional complexes, including centres for R&D and Virology, Life Sciences Industry Smart Services, Stem Cell Research and 3D Bioprinting, as well as two large-scale production centres for mammalian and microbial products. The entire BIO CITY complex will span an area equivalent to 10 football fields, with the total investment expected to reach around 7 billion euros over the next decade.

We will not only focus on contract development and manufacturing services, but will also invest significantly in the operation of scientific research centres. Scientific activity enhances a countrys competitiveness and generates value in various forms, beyond just the economic aspect. Modern biotechnologies, such as gene editing and cell therapies, are advancing rapidly. Lithuania can pride itself on having some of the most talented scientists and robust expertise in these areas. The development of the biotech campus in Vilnius means we are poised to foster new partnerships with innovative startups, research institutions and pharmaceutical companies on a global scale. We are actively seeking partnerships and offer a warm invitation to investors who are enthusiastic about joining this exciting venture, said Prof. V. A. Bumelis.

Upon its completion, BIO CITY is expected to offer employment to approximately 2,100 highly skilled professionals, including scientists, biotechnologists, and medical engineers.

Lithuania is Among the Leaders in the Global Biotechnology Market

The global biotechnology market, currently valued at over 1,130 billion euros, is anticipated to grow to be worth more than 2,775 billion euros by 2030. Lithuania holds a strong position in this market, ranking among the Top 35 innovative countries in the biotechnology field, according to Scientific American Worldview.

Every year, Lithuania is mentioned in the field of Life Sciences more often, and the ambitious BIO CITY project will contribute to our leadership. Our vision is coming to life we are talking about world-class Life Sciences infrastructure and a competitive sector capable of building innovative products. In 2022, companies in the sector posted combined revenues of 1.5 billion euros, while exporting their goods to more than 100 countries. Overall, Life Sciences is a leading sector in Lithuania, when it comes to creating and implementing innovative solutions, states Aurin Armonait, the Minister of the Economy and Innovation.

Over 80 life science companies operate in Lithuania, contributing about 2.5% to the countrys GDP. The Northway group, a key player in Lithuanias biotech sector, manages seven companies: five in Lithuania and one each in the UK and the US, with the US entity being recognised as the largest biotech investor from the Baltic region in recent years. Employing more than 200 specialists, these companies provide services to a diverse array of international biopharmaceutical firms, ranging from small to large enterprises, predominantly operating in both Europe and the US.

BIO CITY Contacts:

Vladas Algirdas Bumelis

CEO and Chairman of the Board

[emailprotected]

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The largest biotech city in Europe will soon be built, with an ... - BioPharma Dive

The Song of the Cell: An exploration of medicine and the new human – Reformed Journal

The Song of the Cell: An exploration of medicine and the new human

Siddhartha Mukherjee

Published by Scribner in 2022

496pp / $$17.89 / 978-1982117351

Ive spent more than thirty years studying cells of various types. First cells like those that make up human bodies (and their misbehaving counterpartscancer cells) and now bacterial cells. Its not at all difficult for me to tap my inner Miss Frizzle, hop on the Magic School Bus, and take a ride to the inside a cell. Its easy for me to picture ribosomes translating mRNA in the cytosol above my head, imagine importins carrying proteins through nuclear pores, and signal transduction cascades activating one protein after another like dominos falling. While I am familiar with the vivid molecular details, I know that visualizing those molecular details, much less cells, is not easy for most non-scientists. I believe that in spite of this, many people carry some curiosity about how cells work. Perhaps this curiosity arises when they encounter a disease or diagnosis, when something goes wrong with their bodies, or simply when they ponder the wonders of the natural world. At least I hope this is true. If you are someone who wonders about cells but thinks it would take too much time and effort to learn about them, The Song of the Cell: An Exploration of Medicine and the New Human is a book for you.

The author, Siddhartha Mukherjee, is an Associate Professor of Medicine in the Division of Hematology and Oncology at Columbia University where he is an oncologist and researcher, specializing in the physiology of cancer cells, stem cells in bone, and immunological therapy for cancers of the blood, such as leukemia and lymphoma. He is a prolific author with scientific publications in Nature and The New England Journal of Medicine, as well as the author of this and three other books for lay audiences. Mukherjees first book, The Emperor of All Maladies: A Biography of Cancer, won the Pulitzer Prize in 2011. His second book, The Gene: An Intimate History, was a New York Times bestseller. Mukherjees success as a popular nonfiction writer is not surprising. He has an uncanny ability to make complicated scientific processes accessible without sacrificing beauty, complexity, or accuracy. He is a master storyteller, especially gifted at using metaphors to help non-scientists picture and understand the inner workings of cells and other complicated biological processes.

What made this book especially compelling for me (and for my Cell Biology students, to whom I assigned the book last semester) was how Mukherjee was able to weave together basic cell biology with touching stories of patients who were dealing with cellular diseases as well as how our current understanding of how cells work was being used and applied to treat his patientssometimes with seemingly miraculous outcomes and sometimes with heartbreaking disappointment. He explores cancer, infertility, heart disease, bacterial and viral infections, autoimmune disease, depression, and organ/tissue transplantation in this nearly 400-page book. Despite its length, it reads quicklyperhaps because Mukherjee carefully intersperses history and complex science with personal stories of researchers, patients, and his own research.

In Emperor of All Maladies and The Gene, I found Mukherjees presentation of the science a bit too linear, giving the impression that one discovery led neatly to the next and then the next. As a scientist who spent ten years studying cancer cell biology and genetics, I know too well that the path to understanding how cells, cancer cells in particular, is laden with failures, misinterpretations, and mistakes. We zig-zag toward understanding much more than we take a straight path to it. In this book, Mukherjee makes more room for the missteps, arguments, and biases that shape scientific advances as much as the successes and collaborations, presenting what seemed to me a truer picture of how science actually works.

I didnt need much encouragement to read this book but why should a non-scientist pick it up? think this book helps a non-scientist to better appreciate the crooked path science takes toward understanding whatever it is they are studying. Readers will come away with a better understanding of how cells work and why sometimes the cells in our bodies fail. A deeper understanding of cells generates better questions when faced with health issues, greater appreciation of the available treatments and those who work to develop those treatments. Most importantly, I think readers will come away with a new level of awe at the wonder of Gods good creation and a deeper reason to worship the author of these wonder-filled, smallest units of life we call cells.

Sara Sybesma Tolsma, PhD is Professor of Biology at Northwestern College, Orange City, IA. She is currently working to discover novel bacteriophages (viruses that infect bacteria) and characterize their genomes.

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The Song of the Cell: An exploration of medicine and the new human - Reformed Journal

Ethics education among obstetrics and gynecologists in Saudi … – BMC Medical Education

Descriptions of the characteristics of the respondents

A total of 391 out of 1,000 OB/GYN practitioners responded to the survey questions by email; therefore, the response rate was 39.1%. Participants responded from all provinces of Saudi Arabia. Female respondents totaled 257 (66.4%), which was almost double the rate of male respondents. The married respondents totaled 291 (75.6%), whereas 94 (24.4%) were unmarried.

The study included participants of all ages, with approximate percentages of the participants between 30 and 50years is more than 60%.

Saudi physicians accounted for 213 (55.9%) participants and 371 (94.8%) Muslims. Approximately 247(63.1%) of the respondents were working in a tertiary government teaching hospital, whereas government non-teaching and private hospitals accounted for 107 (27%) of the participants.

Fifty-five percent of the participants were OB/GYN Board certified under different types of boards. Most of the physicians were certified by the Saudi Arabian board (18.2%), followed by the Arab board and Egyptian board (10.5%) and (6.9%) respectively; however, physicians holding Western certificates from Canada, England, US, or Indian boards were minimal in numbers.

The participants had equal percentages in relation to their tier position. The consultants and registrars in the sample numbers were 119 (30.4%) and 126 (32.23%), respectively; the remaining were residents.

Around 192 (49%) physicians had more than 10years of experience in the field of OB/GYN. Currently, 61 (15.6%) of the practitioners face 110 ethical issues monthly in their practice, while the majority 309 (79.03%) face less than one issue per month (Table 1).

Approximately 85 (21.7%) of the participants received mixed ethics education (formal ethics education and informal bioethics education), whereas 74 (18.9%) received only formal ethics education and 85 (21.7%) received only informal ethics education. In addition, 78 (19.95%) did not have any type of bioethics education.

Approximately 75% of the respondents received different types of formal and informal bioethics education. Of the respondents, 25% had no bioethics education; 137(35%) of physicians received a formal education during medical school; however, only 46 (11.8%) throughout residency programs. Self-learning was the method used for informal bioethics education in 124 (31.7%) cohorts (see Table 2 & Fig.1).

Modes of formal and informal bioethics education

No differences relatedto genderor the type of ethics education received in medical school during residency programs, postgraduate programs, conferences, courses and workshops and daily practice were detected. However, male respondents, more so than female respondents, agreed to have received ethics education in sub-specialty programs. The same finding was true regarding self-learning and online training.

Regarding marital statusand type of ethics education, no significant differences during residency programs, sub-specialty programs, in conferences, online training, in courses and workshops were found. Single respondents agreed to receive an ethics education in medical school compared to married people. Married respondents received a greater degree of informal bioethics education through daily practice and self-learning, while others received it through self-learning. There exists a significant difference between marital status and medical school (P=0.00), postgraduate programs (P=0.009), daily practice (P=0.007) and self-learning (P=0.002).

Regarding age,no significant differences were found in ethics education,except in medical schools. Respondents under 30yearsof age showed higher results (57.9%), followed by people between 3039years old (37.1%) and people aged between 4049years (28.8%). Participants>50years of age received minimum ethics education at medical school (19.4%).

No significant statistical differences regarding nationality and the type of ethics education were found except in medical schools, whereSaudi Arabian physicians (41.3%) had a significant statistical difference (P=0.007) compared to non-Saudi Arabians (28%). However, in postgraduate programs, there was a significant statistical difference (P=0.002) between non-Saudi Arabians (11.9%) and Saudi Arabians (3.8%).

There was no significant statistical difference inrelation to positionor the type of ethics education, except that residents showed the highest agreement in relation to education in medical school (P=0.00), followed by registrar/specialists and then consultants. The statement is correct regarding ethics education during sub-specialty programs (P=0.00) too.

No significant statistical difference was found between thetype of board certificateandbioethics education, except for online training (P=0.029) and daily practice (P=0.01). The participants that received Westernsub-specialist certificateshad the highest agreement to learning from daily practice, while Saudi Arabian physicians had the least (Table 1).

Significant statistical difference was found in relation tothe current workplaceand bioethics education during residency programs (P=0.015), during sub-specialty programs (P=0.04), in postgraduate programs (P=0.025) and Online learning (P=0.004). Online learning had a higher percentage of physicians who worked in private hospitals.

There was no significant statistical difference in relationto experienceand the type of ethics education, except for education in medical schools (P=0.00) and during sub-specialty programs (P=0.005). Physicians having experience of<5years showed the highest positive agreement followed by participants of 510years, and then>10years. A high percentage of less experienced physicians had bioethics education in medical college, while those with more than 10years' experience were found to have a significant statistical difference from those who had bioethics education through subspecialty training.

There was a significant statistical difference between the number of ethical challenges per month and bioethics education in medical school (P=0.007), in courses and workshops (P=0.009) and daily practice (P=0.00). Most of the respondents with ethics education from medical school and in courses and workshops had faced more than 10 challenges per month (47.60% and 28.60% respectively), whereas respondents with ethics education from daily practice had a maximum of 110 challenges per month (39%) (Table 1).

There was no significant statistical difference in relationto sub-specialtyand the type of ethics education except for the general OB/GYN, which showed the least agreement compared to other types of subspecialties. The same finding is true regarding online training too.

No significant statistical difference was observed between the type of ethics education and ethical principles. Irrespective of the mode of ethics education, most of the respondents had a positive attitude towards various ethical principles. The highest positive attitude was towards respecting privacy of people and respecting confidentiality. Solidarity And Cooperation had the least positive attitude across all modes of ethics education (see Table 3).

The attitude of the OB/GYNs towards various ethical challenges in their daily practice were investigated. No statistical significance was observed between various forms of formal ethics education and ethical challenges, except there exists a significant statistical difference between post-graduate program and termination of pregnancy for non-medical (P=0.05) and between residency program and contraception issues (P=0.021). The respondents with postgraduate ethics education had a high positive response (agreed and strongly agreed, 31%) to the ethical challenge "Termination of pregnancy for a non-medical reason," and the respondents without residency program ethics education had a high positive response (agreed and strongly agreed, 46%) to the ethical challenge "contraception issues."

Pertaining to the informal mode of ethics education, significant statistical difference was observed between courses and workshops and paternity issues (P=0.006); female consent (P=0.004); breach of confidentiality (P=0.007). There also exists a significant difference between breach of confidentiality and conference and workshop (P=0.007) and daily practice (P=0.023). The respondents without courses and workshop mode of ethics education had agreed to the ethical challenges of paternity issues (33.92%), female consent (58%), and breach of confidentiality (33.6%). The respondents who did not have ethics education through conference (33%) and daily practice (33.8%) also agreed to the ethical challenge breach of confidentiality (Table 4).

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Ethics education among obstetrics and gynecologists in Saudi ... - BMC Medical Education