Category Archives: Cell Biology

The Catalyst Reducing ImmuNe Ageing (CARINA) Network comprises more than 70 clinicians and researchers with compatible expertise in fields such as immunology, nutrition, and medicine.

CARINA is one of 11 networks fundedby the Medical Research Council (MRC) and Biotechnology and Biological Sciences Research Council (BBSRC)that aspire to transform ageing research in the UK.

The team of experts will identify priority areas for immunity and age research to advance the integrated understanding of the factors influencing the trajectory to an aged, compromised immune system and inspire new approaches to support ageing populations.

"The CARINA Network will facilitate large-scale collaboration between researchers from multiple disciplines who, for the first time, will work together to identify and better understand patterns and commonalities in the immunology of ageing, explains Professor Arne Akbar, Chair of CARINA Management Board.

As the ageing population grows, better understanding of immune mechanisms as we get older could help identify new methods to enhance quality of life and even improve life expectancy, say scientists.

Network member and chair of intestinal microbiome at the Technical University Munich, Professor Lindsay Hall, comments: It will be important to work with colleagues from a range of sectors to understand how further work in this area could be used to provide useful biomarkers of immune health.

Our immune system changes as we get older and responses to disease are unpredictable. Studies suggest that immunity declines with age, making it harder to fight off infections.

The COVID-19 pandemic has demonstrated the vulnerability of older people when confronted with a new pathogen, which can translate into severe outcomes for some, and highlights the utility of age-related research.

Professor Hall adds:We hope this new network will drive new interactions and new ways of thinking particularly around development of microbial and diet-based therapies that could also be used to boost beneficial immune responses, like after vaccination.

CARINA is supported by partners in industry and charities, as well as by public and patient groups.

TheBritish Society for Immunology (BSI) provides project management services for planning and delivery of important milestones, in addition to events support, communications expertise, and mediation of patient and public involvement (PPI).

Meanwhile, a Management Group, led by Chair Professor Akbar, formulates research strategies to ensure the Network facilitates a novel approach to ageing research. Professor Akbar is also Professor of Immunology at University College London, and President of the BSI.

Other members of the Management Group include: Professor Deborah Dunn-Walters (Professor of Immunology, University of Surrey); Professor Janet Lord (Professor of Immune Cell Biology, University of Birmingham); Dr Ed Chambers (Lecturer in Nutrition and Dietetics, Imperial College London), and Professor Neil Mabbott (Professor of Immunopathology, University of Edinburgh).

An independent Scientific Advisory Board of representatives from academia, clinicians, and public and patient groups has also been established to guide Network activity and make sure the research is sufficiently inclusive and interdisciplinary.

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A team of UK researchers transform ageing research - NutraIngredients-usa.com

Cell Biology

Dual delivery of BMP2 and IGF1 promotes cranial bone defect healing – EurekAlert

April 23, 2022 medical

image:Journal brings together scientific and medical experts in the fields of biomedical engineering, material science, molecular and cellular biology, and genetic engineering. view more

Credit: Mary Ann Liebert, Inc., publishers

A new dual delivery system designed to sequentially release BMP2 and IGF1 in microparticles in an injectable hydrogel successfully healed an 8-mm cranial defect in rats. The study design and results are reported in the peer-reviewed journal Tissue Engineering, Part A. Click hereto read the article now.Cranial bone defects of a critical size cannot repair spontaneously, and affected patients ultimately required surgical reconstruction of the cranial bone. Experiments have shown that bone morphogenetic protein2 (BMP2)-laden hydrogel can promote cranial bone defect healing after implantation in rats. Insulin-like growth factor1 (GF1) is another growth fact that exerts a cell proliferation and differentiation effect on bone cells.

In this study, Yunzhi Peter Yang, PhD, from Stanford University School of Medicine, and coauthors, examined the sequential release of BMP2 followed by IGF1 in microparticles in injectable hydrogels in a rat model of cranial bone defect healing.

The investigators reported that microparticles containing BMP2 (2 g) or a combination of BMP2 (1 g) and IGF1 in the hydrogel successfully restored the 8-mm diameter cranial defect as early as 4 weeks after implantation. It suggests that supplemental IFG1 (1 g) to the lower dose of BMP2 (1 g) could be as effective as higher dose of BMP2 (2 g), state the investigators. Considering possible side effects of BMP2 in high doses, a supplemental IFG-1 may reduce the use of BMP2, which helps in minimizing the risk of causing side effect.

Dr. Yang and colleagues beautifully demonstrate the utility of a dual release microparticle system as an emerging technique for cranial bone regeneration.Further, their results show that the use of two potent growth factors in a sequential delivery system allows for a reduction in dose, potentially mediating off-target effects a critical advance in the field of tissue engineering, says Tissue Engineering Co-Editor-in-ChiefJohn P. Fisher, PhD, Fischell Family Distinguished Professor & Department Chair, and Director of the NIH Center for Engineering Complex Tissues at the University of Maryland.

About the JournalTissue Engineeringis an authoritative peer-reviewed journal published monthly online and in print in three parts: Part A, the flagship journal published 24 times per year; Part B: Reviews, published bimonthly, and Part C: Methods, published 12 times per year. Led by Co-Editors-in-ChiefAntonios G. Mikos, PhD, Louis Calder Professor at Rice University, Houston, TX, and John P. Fisher, PhD, Fischell Family Distinguished Professor & Department Chair, and Director of the NIH Center for Engineering Complex Tissues at the University of Maryland, the Journal brings together scientific and medical experts in the fields of biomedical engineering, material science, molecular and cellular biology, and genetic engineering. Leadership of Tissue Engineering Parts B (Reviews) and Part C (Methods) is provided by Katja Schenke-Layland, PhD, Eberhard Karls University, Tbingen and John A. Jansen, DDS, PhD, Radboud University, respectively. Complete tables of content and a sample issue may be viewed online at theTissue Engineering website. Tissue Engineering is the official journal of theTissue Engineering& Regenerative Medicine International Society (TERMIS). Complete tables of content and a sample issue may be viewed on theTissue Engineering website.

About the PublisherMary Ann Liebert, Inc., publishersis known for establishing authoritative peer-reviewed journals in many promising areas of science and biomedical research. Its biotechnology trade magazine,GEN (Genetic Engineering & Biotechnology News), was the first in its field and is today the industrys most widely read publication worldwide. A complete list of the firms more than 100 journals, books, and newsmagazines is available on theMary Ann Liebert, Inc., publisherswebsite.

Experimental study

Animals

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Dual delivery of BMP2 and IGF1 promotes cranial bone defect healing - EurekAlert

Cell Biology

Learning from RNA’s Mistakes Along the Way – University of Colorado Anschutz Medical Campus

April 23, 2022 medical

Sujatha Jagannathan, PhD, chases RNA for a living and the pursuit often takes her in directions she didnt expect to go.

It turns out that the detours are the journeys reward.

Anytime nature breaks things, Jagannathan says, you can swoop in and understand exactly how the pathway works. Why is it broken? And what happens if you break a pathway like that?

Its the mistakes that provide the opportunity to learn, she says.

I study how mistakes in these molecules called RNA are handled by cells, basically, she says. We all have a genome in which genes are encoded. Its sort of like this big cookbook, where you have every recipe possible. Each cell in our body makes a subset of those genes that gives them their identity.

Messenger RNA, or mRNA, transfer information from the cookbook to other parts of the cell, where they are key ingredients to making proteins.

To end up running a laboratory focused on mRNA at the University of Colorado School of Medicine, Jagannathan herself took her own detour. I went to Duke to do my PhD in microbiology, and I came across this lab that did RNA biology and I said, That sounds cool, lets give it a shot, she says. And I fell in love.

Jagannathan had planned to study bacteria microscopic single-celled bugs that can sometimes make people sick but turned her attention to those microscopic messengers hauling the instructions for life itself.

Theres just something about the idea of this chancy and unstable molecule orchestrator thing, you know, she says. How it affects everything from how humans are made, embryogenesis, all the way to diseases and aging and this whole plethora of functions, just fascinated me. And I thought, Okay, studying bacteria was nice, but this is what Im going to do.

Jagannathan had completed a bachelors degree in industrial biotechnology at Anna University in Chennai, India, in 2006 before heading to Duke University, where she earned a PhD in cell biology.

I specifically studied how RNA molecules go to different places in the cell, she says. Because putting the same molecule in different parts of the cell can give it different properties, exactly the same molecule in different places has different properties. Its really amazing.

From Duke, Jagannathan went Fred Hutchinson Cancer Research Center in Seattle for a four-year postdoctoral fellowship.

I knew coming off of my PhD that I wanted training in computational biology, because thats where biology was heading, she says. I wanted to be able to do these high-throughput approaches, analyze my own data, really take advantage of computation as a tool to understand the intricacies of biology.

In Seattle, Jagannathan worked on research of facioscapulohumeral muscular dystrophy (FSHD), a debilitating disease that slowly consumes skeletal muscle in the face, scapula (shoulder blade), and humerus (upper arm).

Combining her interests in RNA biology and computational biology, Jagannathan collected data measuring RNA and protein levels in cells that express the protein DUX4. That protein induces changes in hundreds of genes that affect dozens of interconnected pathways. With so many connections, specific causes of FSHD are hard to discern. Her studies helped identify patterns for more targeted research.

Normally, this protein is expressed in early development, she says. But in people who have this disease, the protein turns on in this skeletal muscle, and turns on genes that should have no business being expressed in skeletal muscle.

Such research is a step-by-methodical-step process.

When you think of science, its sort of like climbing a mountain, she says. Every day, youre putting your head down, and youre just climbing. That can be hard, right? And then when you have a team of people that youre doing it with, you are cheerleading, helping, facilitating, seeing them go up the mountain too.

The reward is really when you can go to a height and you can see a new vista, something you didnt know existed, something thats going to now open up so many new opportunities. I think thats the joy. Seeing it myself, but also helping other people see it too.

For Jagannathan, the RNA Bioscience Initiative at the University of Colorado School of Medicine provided an opportunity to work in a community of scientists with similarly focused research.

I came to CU because of this group, she says. I had other offers, but this was the place that made me feel that as an RNA person, I couldnt be in a better place.

Jagannathan, an assistant professor of biochemistry and molecular genetics, and other RNA Bioscience Initiative scientists are clustered in offices and laboratories on the same floor of one of the research towers on the CU Anschutz Medical Campus.

If I just step out into the corridor, I can run into any colleague and I can ask, Hey, you know, I have this idea, what do you think? And they can shut it down or they can say, Heres another way of thinking about it, or heres the reagent I have, go do the experiment,or I can do the experiment for you. These are the opportunities of being here. Its the community, its just enabled science that I did not think I would be doing four years ago.

When the COVID pandemic disrupted operations for several months in 2020, scientists worked from home to review studies and analyze previously collected data. But getting back to the labs was a high priority. Jagannathan served on a working group to help the campus explore childcare opportunities so that working parents could return to campus sooner.

The kind of basic research conducted by the RNA Bioscience Initiative members is fundamental for future scientific advances. Jagannathan notes that vaccines for COVID-19 were developed quickly because of decades of research.

We wouldnt have a COVID vaccine if the basic science hadnt been done for the past 30 years, she says. There are people who say, Oh, this vaccine just came out of nowhere. No, it did not come out of nowhere. It came out of the work of basic scientists for decades. You have to have that foundation. You cant build therapies overnight like that if you dont have people putting in the time.

The dedication to knowledge is necessary, but not the sole purpose of the scientific endeavor, Jagannathan says.

It doesnt make sense for me to say, Heres the science I want to do, heres the person who can do that. Its more than that. Its really about who do I want to come out of the lab. What kind of scientists are we putting out into the world? Are they good citizens? Are they kind people? I want my lab to be a place that can produce really good quality scientists who go out and are a positive presence in the world.

Cell Biology

New insights about ‘bad news’ breast cancer mutation point to treatment opportunities – EurekAlert

April 23, 2022 medical

image:Steffi Oesterreich, Ph.D., co-leader of the Cancer Biology Program at UPMC Hillman Cancer Center, professor in the University of Pittsburgh School of Medicine Department of Pharmacology & Chemical Biology, and co-director of the Womens Cancer Research Center, a collaboration between UPMC Hillman and Magee-Womens Research Institute. view more

Credit: UPMC

A mutated gene found in more than 20% to 30% of breast cancer recurrences may help tumors become more aggressive and promote metastasis, according to a pair of new studies that uncover mechanisms behind these processes and point to new therapy targets.

Were excited about this research because it addresses an important clinical problem: A huge number of deaths in breast cancer patients are the result of mutations in estrogen receptor genes, said senior author Steffi Oesterreich, Ph.D., co-leader of the Cancer Biology Program at UPMC Hillman Cancer Center and professor in the University of Pittsburgh School of Medicine Department of Pharmacology & Chemical Biology. Our study provides a deeper understanding of how these mutations contribute to disease progression and also identifies potential vulnerabilities, which we hope will lead to development of personalized treatment approaches.

More than 40,000 women die each year from breast cancer in the United States. About two-thirds of tumors express estrogen receptor genes. Hormone therapy can be very effective for these estrogen receptor-positive (ER+) tumors, but in about one-third of cases, the receptor becomes mutated and no longer responds to this treatment.

As a first step toward developing new therapies for these patients, the multi-institutional team led by Dr. Zheqi (Vaciry) Li, who was a postdoctoral associate in Oesterreichs lab, took a closer look at tumors harboring estrogen receptor gene ESR1 with a mutation at one of several hotspots in the genetic code.

In a new Cancer Research study, the researchers show that these hotspot mutations not only drive resistance to hormone therapy but also promote metastasis, helping breast cancer cells move to other parts of the body.

According to Oesterreich, ESR1 is a master regulator of several molecular pathways, including a type of interaction between cells called cell-cell attachment. When the researchers took liquid biopsies from patients with mutated ESR1, they found clusters of tumor cells circulating in the blood.

We think that this mutation makes tumor cells sticky, so they clump together, said Oesterreich, who is also co-director of the Womens Cancer Research Center, a collaboration between UPMC Hillman and Magee-Womens Research Institute. This is a novel finding and somewhat unexpected.

The researchers suspect that these sticky clumps of cells are transported throughout the blood and adhere to healthy tissues, promoting new tumors, or metastases, in other parts of the body.

This mutation is bad news for cancer prognosis, but the good news is that there are drugs that target cell-cell attachment, said Oesterreich. We hope that this study lays the foundation to test drugs that prevent or treat metastatic breast cancer driven by estrogen receptor mutations.

In the second study, published today in Nature Communications, the researchers found that tumors with ESR1 mutations also had high expression of so-called basal features, which make breast cancers aggressive and difficult to treat.

But this study also offered a silver lining. Mutant tumors had high expression of genes associated with tumor infiltration by macrophages, a type of immune cell that cleans up dead cells and destroys bacteria and other pathogens.

Previously, it was thought that ER+ tumors are cold, or impenetrable by immune cells, meaning that they dont respond to immunotherapy, explained Oesterreich. But these findings give us a potential new target for patients with the ESR1 mutant breast cancer: Targeting macrophages could kill the tumor.

In ongoing work, Oesterreich and her team seek to confirm immune infiltration in ESR1 mutant tumors collected at other research centers. They are also collaborating with investigators from other institutions to test whether cell-cell attachment involved in metastasis can be blocked with drugs.

Additional authors on the Cancer Research and Nature Communications studies are listed in the papers.

Nature Communications

Experimental study

Human tissue samples

ESR1 mutant breast cancers show elevated basal cytokeratins and immune activation

19-Apr-2022

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New insights about 'bad news' breast cancer mutation point to treatment opportunities - EurekAlert

Cell Biology

InGeneron Publishes Overview on Current State and Potential of Regenerative Cell Therapy in Orthopedics – Yahoo Finance

January 25, 2022 medical

Concise review outlines key concepts behind using a patients own regenerative cells for point-of-care treatment of orthopedic indications and the advantages of this approach compared with other methods.

HOUSTON, January 24, 2022--(BUSINESS WIRE)--InGeneron, Inc., a clinical stage biotechnology company, announced the publication of a succinct scientific review of regenerative cell therapy, commonly called "stem cell therapy", to treat orthopedic indications. This newly released paper, titled "Why and how to use the bodys own stem cells for regeneration in musculoskeletal disorders: a primer", was published in the Journal of Orthopaedic Surgery and Research (J Orthop Surg Res 17, 36 (2022): https://doi.org/10.1186/s13018-022-02918-8). The publication provides an approachable overview of stem cell biology and clarifies common misconceptions about adipose-derived regenerative cells (ADRCs) including vascular-associated pluripotent stem cells (vaPS cells). The authors emphasize the ability of therapies using ADRCs to readily fit into modern orthopedic treatment concepts and reference InGenerons proprietary cell therapy platform, currently under evaluation in ongoing FDA-approved trials.

Summarizing 20 years of both basic and clinical research, the review aims to provide a straightforward look at the current state of orthopedic regenerative cell therapies and clarifies the role of different regenerative cells, such as vaPS cells, in tissue regeneration. The publication highlights the advantages of InGenerons therapeutic approach utilizing ADRCs to develop point-of-care therapies compared to other types of "stem cell therapy", including techniques requiring cells to be cultured in a lab. Dr. Eckhard Alt, Director of Stem Cell Research at Tulane University (New Orleans, LA, USA), Executive Chairman of InGeneron and co-author of the paper explains: "Using unmodified, uncultured, autologous cells allows for true point-of-care treatment, which can be performed within a short time on the same day in an outpatient facility. Culturing and modifying cells before treatment increases the complexity and cost for patients and physicians and also increases the possibility for contamination of the cells and other health concerns, such as autoimmune rejection, that are not an issue when using ADRCs."

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Pointing out another advantage of InGenerons therapeutic approach, Dr. Christoph Schmitz, Head of the Department of Anatomy II at Ludwig-Maximilians University of Munich (Munich, Germany), Advisory Medical Director of InGeneron and co-author of the paper adds, "We realized early on that stem cells were important but that they benefitted from other cells contained in ADRCs such as progenitor cells, pericytes, endothelial cells and fibroblasts, which we collect from patients adipose tissue along with their stem cells. All of these cell types play an essential role in tissue regeneration and work synergistically, each affecting the other to promote healing in specific ways that we are still working to fully understand. Therapies that isolate stem cells for culturing in the lab lack these other cell types."

The publication concludes that utilizing ADRCs offers the most attractive therapeutic approach for providing safe and effective treatments, which can be integrated into the modern orthopedic clinical paradigm.

Building on the insights obtained from years of research studying regenerative cells, InGeneron is currently conducting three actively enrolling FDA-approved clinical trials to evaluate its cell therapy platform for the treatment of musculoskeletal indications such as partial-thickness rotator cuff tear, wrist osteoarthritis, and facet joint syndrome.

Publication Details

DOI: https://doi.org/10.1186/s13018-022-02918-8

Citation: Furia, J.P., Lundeen, M.A., Hurd, J.L. et al. Why and how to use the body's own stem cells for regeneration in musculoskeletal disorders: a primer. J Orthop Surg Res 17, 36 (2022).

About the Transpose RT System and Current Clinical Trials

InGenerons Transpose RT cell therapy platform consists of a processing unit, a set of disposables, and Matrase, a proprietary enzyme mixture. The platform allows the isolation of regenerative cells from the patients' own adipose tissue at point-of-care in less than 90 minutes for same-day treatment. The cells are re-administered into the patients damaged tissue by injection under ultrasound or fluoroscopic guidance.

The Transpose RT System is being investigated in several FDA-approved clinical trials and is currently available in the U.S. for research use only. More information on InGenerons actively enrolling clinical trials can be found at http://www.clinicaltrials.gov under the identifiers NCT03752827, NCT03513731, and NCT03503305.

About InGeneron

InGeneron is a clinical-stage biotechnology company developing novel, safe, and evidence-based cell therapies. We are setting new therapeutic standards by enabling minimally invasive treatments that unlock the healing potential of each patients own regenerative cells processed at the point of care for same-day treatment. We currently focus on helping patients impacted by orthopedic conditions and are conducting several clinical trials to validate our technology as a disease-modifying treatment. Based on more than 20 years of research, InGeneron is dedicated to developing therapies supported by clinical evidence and approved by the FDA.

http://www.ingeneron.com

View source version on businesswire.com: https://www.businesswire.com/news/home/20220124005479/en/

Contacts

InGeneron, Inc. Eckhard Alt, MD, PhDExecutive Chairman of InGeneron+1 (713) 440 9900press@ingeneron.com

Media Inquiries Jon StoneStone Communications Consulting+1 (612) 475 5955jon@stonecommunications.net

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InGeneron Publishes Overview on Current State and Potential of Regenerative Cell Therapy in Orthopedics - Yahoo Finance

Cell Biology

Landing Therapeutic Genes Safely in the Human Genome Improving Gene and Cell Therapies – SciTechDaily

January 25, 2022 medical

By Wyss Institute for Biologically Inspired Engineering at HarvardJanuary 24, 2022

A collaborative research team at Harvards Wyss Institute and the ETH Zurich in Switzerland has identified genomic safe harbors (GSHs) in the tumultuous sea of human genome sequence to land therapeutic genes in. As part of their validation, they inserted a fluorescent GFP reporter gene into candidate GSHs and followed its expression over time. The GSHs could enable safer and longer-lasting expression of genes in future gene and cellular therapies. This illustration won the team the cover of the Cell Reports Methods issue the study is published in. Credit: Erik Aznauryan

Researchers at Harvards Wyss Institute, Harvard Medical School, and the ETH Zurich predict and validate genomic safe harbors for therapeutic genes, enabling safer, more efficient, and predictable gene and cell therapies.

Many future gene and cell therapies to treat diseases like cancer, rare genetic and other conditions could be enhanced in their efficacy, persistence, and predictability by so-called genomic safe harbors (GSHs). These are landing sites in the human genome able to safely accommodate new therapeutic genes without causing other, unintended changes in a cells genome that could pose a risk to patients.

However, finding GSHs with potential for clinical translation has been as difficult as finding a lunar landing site for a spacecraft which has to be in smooth and approachable territory, not too steep and surrounded by large hills or cliffs, provide good visibility, and enable a safe return. A GSH, similarly, needs to be accessible by genome editing technologies, free of physical obstacles like genes and other functional sequences, and allow high, stable, and safe expression of a landed therapeutic gene.

Thus far, only few candidate GSHs have been explored and they all come with certain caveats. Either they are located in genomic regions that are relatively dense with genes, which means that one or several of them could be compromised in their function by a therapeutic gene inserted in their vicinity, or they contain genes with roles in cancer development that could be inadvertently activated. In addition, candidate GSHs have not been analyzed for the presence of regulatory elements that, although not being genes themselves, can regulate the expression of genes from afar, nor whether inserted genes change global gene expression patterns in cells across the entire genome.

Now, a collaboration of researchers at Harvards Wyss Institute for Biologically Inspired Engineering, Harvard Medical School (HMS), and the ETH Zurich in Switzerland, has developed a computational approach to identify GSH sites with significantly higher potential for the safe insertion of therapeutic genes and their durable expression across many cell types. For two out of 2,000 predicted GSH sites, the team provided an in-depth validation with adoptive T cell therapies and in vivo gene therapies for skin diseases in mind. By engineering the identified GSH sites to carry a reporter gene in T cells, and a therapeutic gene in skin cells, respectively, they demonstrated safe and long-lasting expression of the newly introduced genes. The study is published in Cell Reports Methods.

While GSHs could be utilized as universal landing platforms for gene targeting, and thus expedite the clinical development of gene and cell therapies, so far no site of the human genome has been fully validated and all of them are only acceptable for research applications, said Wyss Core Faculty member George Church, Ph.D., a senior author on the study. This makes the collaborative approach that we took toward highly-validated GSHs an important step forward. Together with more effective targeted gene integration tools that we develop in the lab, these GSHs could empower a variety of future clinical translation efforts. Church is a leader of the Wyss Institutes Synthetic Biology Platform, and also the Robert Winthrop Professor of Genetics at HMS and Professor of Health Sciences and Technology at Harvard University and the Massachusetts Institute of Technology (MIT).

The researchers first set up a computational pipeline that allowed them to predict regions in the genome with potential for use as GSHs by harnessing the wealth of available sequencing data from human cell lines and tissues. In this step-by-step whole-genome scan we computationally excluded regions encoding proteins, including proteins that have been involved in the formation of tumors, and regions encoding certain types of RNAs with functions in gene expression and other cellular processes. We also eliminated regions that contain so-called enhancer elements, which activate the expression of genes, often from afar, and regions that comprise the centers and ends of chromosomes to avoid mistakes in the replication and segregation of chromosomes during cell division, said first-author Erik Aznauryan, Ph.D. This left us with around 2,000 candidate loci all to be further investigated for clinical and biotechnological purposes.

Aznauryan started the project as a graduate student with other members of Sai Reddys lab at ETH Zurichs Department of Biosystems Science and Engineering before he visited the Church lab as part of his graduate work, where he teamed up with Wyss Technology Development Fellow Denitsa Milanova, Ph.D. He since has joined Churchs group as a Postdoctoral Fellow. Reddy, senior and lead author of the collaborative study, is an Associate Professor of Systems and Synthetic Immunology at ETH Zurich and focuses on developing new methods in systems and synthetic biology to engineer immune cells for diverse research and clinical applications.

Out of the 2,000 identified GSH sites, the team randomly selected five and investigated them in common human cell lines by inserting reporter genes into each of them using a rapid and efficient CRISPR-Cas9-based genome editing strategy. Two of the GSH sites allowed particularly high expression of the inserted reporter gene in fact, significantly higher than expression levels achieved by the team with the same reporter gene engineered into two earlier-generation GSHs. Importantly, the reporter genes harbored by the two GSH sites did not upregulate any cancer-related genes, said Aznauryan. This also can become possible because regions in the genome distant from one another in the linear DNA sequence of chromosomes, but near in the three-dimensional genome, in which different regions of folded chromosomes touch each other, can become jointly affected when an additional gene is inserted.

To evaluate the two most compelling GSH sites in human cell types with interest for cell and gene therapies, the team investigated them in immune T cells and skin cells, respectively. T cells are used in a number of adoptive cell therapies for the treatment of cancer and autoimmune diseases that could be safer if the receptor-encoding gene was stably inserted into a GSH. Also, skin diseases caused by harmful mutations in genes controlling the function of cells in different skin layers could potentially be cured by insertion and long-term expression of a healthy copy of the mutated gene into a GSH of dividing skin cells that replenish those layers.

We introduced a fluorescent reporter gene into two new GSHs in primary human T cells obtained from blood, and a fully functional LAMB3 gene, an extracellular protein in the skin, into the same GSHs in primary human dermal fibroblasts, and observed long-lasting activity, said Milanova. While these GSHs are uniquely positioned to improve on levels and persistence of gene expression in parent and daughter cells for therapeutics, I am particularly excited about emerging gain-of-function cellular enhancements that could augment the normal function of cells and organs. The safety aspect is then of paramount importance. With an entrepreneurial team at the Wyss, Milanova is developing a platform for genetic rejuvenation and enhancements with a focus on skin rejuvenation.

An extensive sequencing analysis that we undertook in GSH-engineered primary human T cells clearly demonstrated that the insertion has minimal potential for causing tumor-promoting effects, which always is a main concern when genetically modifying cells for therapeutic use, said Reddy. The identification of multiple GSH sites, as we have done here, also supports the potential to build more advanced cellular therapies that use multiple transgenes to program sophisticated cellular responses, this is especially relevant in T cell engineering for cancer immunotherapy.

This collaborative interdisciplinary effort demonstrates the power of integrating computational approaches with genome engineering while maintaining a focus on clinical translation. The identification of GSHs in the human genome will greatly augment future developmental therapeutics efforts focused on the engineering of more effective and safer gene and cellular therapies, said Wyss Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at HMS and Boston Childrens Hospital, and Professor of Bioengineering at the Harvard John A. Paulson School of Engineering and Applied Sciences.

Reference: Discovery and validation of human genomic safe harbor sites for gene and cell therapies by Erik Aznauryan, Alexander Yermanos, Elvira Kinzina, Anna Devaux, Edo Kapetanovic, Denitsa Milanova, George M. Church and Sai T.Reddy, 14 January 2022, Cell Reports Methods.DOI: 10.1016/j.crmeth.2021.100154

Additional authors on the study are Alexander Yermanos, Ph.D, and Edo Kapetanovic, members of Reddys group; Anna Devaux at the University of Basel, Switzerland; and, Elvira Kinzina at the McGovern Institute for Brain Research at MIT. The study was supported by ETH Research Grants, the Helmut Horten Stiftung and Aging and Longevity-Related Research Fund at HMS, as well as a Genome Engineer Innovation Grant 2019 from Synthego to Aznauryan.

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Landing Therapeutic Genes Safely in the Human Genome Improving Gene and Cell Therapies - SciTechDaily

Cell Biology

Global Cloud Computing in Cell Biology, Genomics and Drug Development Market Scope 2021 Growth Rate and Major Players are Google Inc., Amazon Web…

January 25, 2022 medical

The current MarketsandResearch.biz research report focuses on the Global Cloud Computing in Cell Biology, Genomics and Drug Development Market growth rate from 2021 to 2027 and the elements that will drive the industrys development. The paper investigates past market performance, current growth factors, and anticipated emerging technologies. The report explores the industrys origins and future growth prospects, and noteworthy traders who have succeeded in this market.

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Cell Biology

Revealing the mysterious biology of a fundamental process: reproduction | Penn Today – Penn Today

January 25, 2022 medical

Reproduction is a complex process, requiring a huge variety of molecular and cellular interactions, many aspects of which remain a mystery to science.

Solving some of these mysteries drives the curiosity and research of P. Jeremy Wang, professor of developmental biology in the School of Veterinary Medicines Department of Biomedical Sciences. Wang also directs the Center for Animal Transgenesis and Germ Cell Research. For the last two decades, his lab has focused on understanding the process of meiosis, the special type of cell division that gives rise to germ cells: sperm and eggs.

Three recently published studies illuminate some of the diverse strands of the Wang labs research.

By whipping their tails, known as flagella, sperm propel themselves through the female reproductive tract. Interacting with and moving through the zona pellucida, the thick coating that shrouds eggs, is energetically demanding. That stage of fertilization is powered by the activity of a calcium ion channel formed by a protein complex known as CatSper.

In the journal Development, Wang and colleagues describe a newly identified component of CatSper, a protein called C2CD6. Wangs team found that inactivating C2CD6 did not affect females but rendered males sterile. Their sperm count is normal, their sperm look normal, but they werent able to produce pups, Wang says.

The proteins location in the flagellum suggested a possible role in sperm motility.

And, indeed, the team found that C2CD6-deficient sperm were unable to enter what's known as hyperactivation, where a ramping up in calcium channel signaling gives sperm the burst of energy required to penetrate the zona pellucida. The work underscores the essential nature of this component of the CatSper complex; C2CD6 is in fact so essential, Wang says, that it could facilitate a drug screening system to find a male contraceptive.

A lot of people have thought about targeting the CatSper complex for a contraceptive, Wang says. Knowing this component of the complex might help scientists test which compounds would effectively stop sperm from being able to fertilize an egg.

A second recent study, described in Biology of Reproduction, looks at the female side of the reproductive process, specifically, what happens when it goes awry. In studying the CCNB3 gene, located on the X chromosome and believed to function in meiosis, Wang and colleagues found that male mice lacking CCNB3 appeared normal. But females, while they could become pregnant, lost the pregnancy at an early stage.

Detailed analysis by Wang and his team uncovered why these miscarriages arise. They found that CCNB3mutations which occur in humans as wellnormally helps meiosis progress. When the gene is not functioning normally, eggs that should have only one set of chromosomes wind up with two sets. That means a fertilized egg, with a set contributed from a sperm, would wind up with three sets of chromosomes, a genetic scenario incompatible with life.

The finding has translational value, Wang says.

With personalized or precision medicine, if a woman gets their genome sequenced and knows they have this mutation, doctors could take their egg, add a functional version of CCNB3 to rescue the defect, and then perform in vitro fertilization and end up with a normal embryo.

A third publication returns to the bread and butter of Wangs research: the intricacies of meiosis. In the journal Cell Reports, Wang and his team uncovered a new way in which YTHDC2, an RNA-binding protein, operates during the cell division process.

Other research groups had previously studied this protein, conducting genetic knockout experiments, where the gene was fully inactivated, to show that it acted during the early stages of meiosis.

Wangs lab, however, employed a different technique whereby they could allow YTHDC2 to function until meiosis had already begun. By doing so, they found that the protein had a second role later in meiosis, acting to maintain whats known as the pachytene stage, the lengthiest meiosis stage, lasting six full days.

It looks like YTHDC2 is a master regulator, says Wang. It appears to bind to RNA and help degrade or silence transcripts that are not supposed to be there, helping the cell commit to meiosis and allow the process to progress. While no YTHDC2 mutations have been found in humans linked with infertility, Wang says, its just a matter of time.

Future work in the Wang lab will pick up where some of these findings left off, continuing to uncover the workings of these fundamental processes.

These studies were supported by the National Institutes of Health (grants HD069592, HD068157, HD038082, HD088571, GM108556, HD03185, HD069592, and GM118052), China Scholarship Council fellowship, Swiss National Science Foundation, National Key Research & Development Program of China, Howard Hughes Medical Institute, and Human Frontier Science Program.

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Revealing the mysterious biology of a fundamental process: reproduction | Penn Today - Penn Today

Cell Biology

Senior Specialist Technician job with KINGS COLLEGE LONDON | 278848 – Times Higher Education (THE)

January 25, 2022 medical

We are seeking high-quality technical support to work on different biology-related projects within the Biological Physics and Soft Matter (BPSM) research group in the Department of Physics. We are seeking a talented, organized, friendly person who can assist with the molecular and cell biology aspects of the research agenda, and be able to assist the work of several laboratories. We especially need someone who is gifted in molecular biology skills and has vast knowledge in the latest cloning methods, as well as having expertise on cell culture and cell transfection.

The position will be temporarily held at the Francis Crick Institute, although it will be managed by Kings College London, within the framework of the seconded laboratory that Prof Garcia-Manyes has established at the Francis Crick Institute, although it will also assist other groups within the BPSM group.

Within Kings, the position will be managed from the department of Physics, with belongs to the Faculty of Natural, Mathematical & Engineering Sciences (NMES). NMES comprises Chemistry, Engineering, Informatics, Mathematics, and Physics with all departments highly rated in research activities and a wide-ranging portfolio of taught and research programmes. Supporting our staff is important to us and we offer a range of provision including flexible working, caring support, training, and promotion opportunities.

The university is making significant investment in the Faculty and both student and staff numbers are growing. Our staff come from over 45 countries and around 56% of our students are from outside the UK.

Further details available at http://www.kcl.ac.uk/nms

The study of Physics at King's dates back to the foundation of the College in 1829. The Department is currently undergoing significant growth with substantial investment in new appointments, research infrastructure and laboratory space refurbishment. We offer a range of BSc (three-year) and MSci (four-year) undergraduate courses as well as MSc and PhD programmes.

Further information may be found at:http://www.kcl.ac.uk/physics

This post will be offered on an a fixed-term contract for 18 months, with the possibility of becoming permanent

This is a full-time post

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Senior Specialist Technician job with KINGS COLLEGE LONDON | 278848 - Times Higher Education (THE)

Cell Biology

Research Fellow, Neurodevelopment and Degeneration Lab job with NATIONAL UNIVERSITY OF SINGAPORE | 278305 – Times Higher Education (THE)

January 25, 2022 medical

Job Description

A Postdoctoral Fellow position is available for PhD holders with experience in neuroscience and stem cell biology research. The successful candidate will manage and execute research projects (including design, conduct, collection of experiments and data analyses) and provide support to the Principal Investigator and his team.

Qualifications

Candidates should possess strong background and working knowledge of molecular biology, cell biology and biochemical techniques such as cell culture, cloning, real-time PCR, western blotting, immunoprecipitation, immunofluorescence-based microscopy. Candidates with familiarity in the handling of viral vectors and stem cells are highly desirable. Experience in animal handling, breeding and behavioural studies would be an advantage.

Candidates are expected to be able to work both independently and in team-based projects, be able to effectively communicate in written and spoken English. Applications should include full curriculum vitae, publication list, information on years of experience in research and laboratory work, and names and contact information (email and telephone numbers) of 3 referees.

Please send applications to: Assistant Prof John Chua (email: phsjcje@nus.edu.sg).

Only shortlisted candidates will be contacted.

Additional Information

At NUS, the health and safety of our staff and students is one of our utmost priorities and COVID-vaccination supports our commitment to ensure the safety of our community and to make NUS as safe and welcoming as possible. Many of our roles require significant amount of physical interactions with student / staff / public members. Even for job roles that can be performed remotely, there will be instances where on-campus presence is required.

With effect from 15 January 2022, based on Singapores legal requirements, unvaccinated workers will not be able work at the NUS premises. As such, we regret to inform that job applicants need to be fully COVID-19 vaccinated for successful employment with NUS.

More Information

Location: Kent Ridge CampusOrganization: Yong Loo Lin School of MedicineDepartment : PhysiologyEmployee Referral Eligible: NoJob requisition ID : 11735

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Research Fellow, Neurodevelopment and Degeneration Lab job with NATIONAL UNIVERSITY OF SINGAPORE | 278305 - Times Higher Education (THE)