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Category: genetics – Page 3

The Rise of Mechanobiology for Advanced Cell Engineering and Manufacturing

The rise of cell-based therapies, regenerative medicine, and synthetic biology, has created an urgent need for efficient cell engineering, which involves the manipulation of cells for specific purposes. This demand is driven by breakthroughs in cell manufacturing, from fundamental research to clinical therapies. These innovations have come with a deeper understanding of developmental biology, continued optimization of mechanobiological processes and platforms, and the deployment of advanced biotechnological approaches. Induced pluripotent stem cells and immunotherapies like chimeric antigen receptor T cells enable personalized, scalable treatments for regenerative medicine and diseases beyond oncology. But continued development of cell manufacturing and its concomitant clinical advances is hindered by limitations in the production, efficiency, safety, regulation, cost-effectiveness, and scalability of current manufacturing routes. Here, recent developments are examined in cell engineering, with particular emphasis on mechanical aspects, including biomaterial design, the use of mechanical confinement, and the application of micro-and nanotechnologies in the efficient production of enhanced cells. Emerging approaches are described along each of these avenues based on state-of-the-art fundamental mechanobiology. It is called on the field to consider mechanical cues, often overlooked in cell manufacturing, as key tools to augment or, at times, even to replace the use of traditional soluble factors.

Current manufacturing workflows for CAR-based immunotherapies, particularly CAR T, and the emerging CAR NK and CAR macrophage platforms, generally involve four key stages: (i) isolation of primary immune cells or their precursors, (ii) cell activation or differentiation, (iii) genetic modification with CAR constructs, most often via viral vectors or electroporation (EP), and (iv) expansion or preparation for reinfusion. Among these, transfection remains the most critical and technically challenging step, directly influencing the functionality, safety, and scalability of the final product.

In clinical-scale production, EP remains the most widely used non-viral method for gene delivery into immune cells, yet it is increasingly recognized as suboptimal, particularly when delivering large or complex CAR constructs. It suffers from inefficient nuclear delivery, high cell toxicity, and poor functional yields of viable, potent CAR-expressing cells.[ 113 ] These limitations are further exacerbated in more fragile or less permissive cell types, such as NK cells and macrophages, which show lower transfection efficiencies and greater sensitivity to electroporation-induced stress.[ 114 ] Viral vectors, while still dominant in clinical manufacturing, present their own challenges: they are constrained by limited cargo capacity, are costly to produce at scale, and raise regulatory and safety concerns, especially when applied to emerging CAR-NK and CAR macrophage therapies that require flexible, transient, or multiplexed genetic programs.[ 115 ]

In contrast to immune-cell engineering, stem cell-based approaches present a different set of challenges and engineering requirements. While immune cells are genetically modified to enhance cytotoxicity[ 116 ] and specificity or to mitigate excessive T-cell activation,[ 117 ] stem cells must be engineered to control self-renewal, lineage commitment, and functional integration, often requiring precise, non-integrative delivery of genetic or epigenetic modulators (e.g., mRNA, episomal vectors) to maintain cellular identity and safety.[ 118 ] Stem cells hold exceptional therapeutic promise due to their capacity for self-renewal and differentiation into specialized cell types, supporting applications in personalized disease modeling, tissue repair, and organ regeneration.[ 119 ] However, engineering stem cells in a safe, efficient, and clinically relevant manner remains a major challenge. Conventional delivery methods, such as viral vectors and EP, can compromise genomic integrity,[ 120 ] reduce viability,[ 118 ] and induce epigenetic instability,[ 121 ] limiting their translational potential.

Gene variant that protects against norovirus spread with arrival of agriculture, prehistoric DNA reveals

The arrival of agriculture coincided with a sharp rise in a gene variant that protected against the virus that causes winter vomiting, researchers from Karolinska Institutet and Linköping University report after analyzing DNA from over 4,300 prehistoric individuals and cultivating “mini guts.”

Winter vomiting disease is caused by the norovirus, which is most virulent during the colder half of the year. The infection clears up after a couple of days, but the protection it provides is short-lived, meaning that the same person can repeatedly fall sick in a short space of time. But some people cannot succumb to the virus, thanks to a particular gene variant.

“We wanted to trace the historical spread of the gene variant,” says Hugo Zeberg, senior lecturer in genetics at the Department of Physiology and Pharmacology, Karolinska Institutet, and researcher at the Max Planck Institute for Evolutionary Anthropology in Leipzig.

Psoriasis-linked gene mutation also impacts gut health, scientists discover

A mutation previously linked to skin disorders like psoriasis may also play a surprising role in gut health, according to new research published by scientists at VIB-UGent and colleagues from UGent, the University of Barcelona, and University College London. This mutation activates skin immune responses but also affects the intestine.

This finding, published in EMBO Molecular Medicine, reveals a new connection between genetics, the immune system, and the gut, which may have therapeutic implications.

Scientists under the leadership of Dr. Inna Afonina and Prof. Rudi Beyaert (VIB-UGent Center for Inflammation Research) have found that a mutation in the gene CARD14, known for activating skin immune responses in psoriasis patients, also affects the intestine. This mutation reduces gut motility, promotes mild inflammation, and increases vulnerability to bacterial infections.

Algorithm maps genetic connection between Alzheimer’s and specific neurons

The number of people living with dementia worldwide was estimated at 57 million in 2021 with nearly 10 million new cases recorded each year. In the U.S., dementia impacts more than 6 million lives, and the number of new cases is expected to double over the next few decades, according to a 2025 study. Despite advancements in the field, a full understanding of disease-causing mechanisms is still lacking.

To address this gap, Rice University researchers and collaborators at Boston University have developed a that can help identify which specific types of cells in the body are genetically linked to complex human traits and diseases, including in forms of dementia such as Alzheimer’s and Parkinson’s.

Known as “Single-cell Expression Integration System for Mapping genetically implicated Cell types,” or seismic, the tool helped the team hone in on genetic vulnerabilities in memory-making brain cells that link them to Alzheimer’s ⎯ the first to establish an association based on a genetic link between the disease and these specific neurons. The algorithm outperforms existing tools for identifying that are potentially relevant in complex diseases and is applicable in disease contexts beyond dementia.

Study unveils mechanisms driving axonal accumulation of TDP-43 and associated nerve damage in ALS

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive muscle wasting and limb paralysis. This neurodegenerative condition results from the gradual destruction of motor neurons, the nerve cells that control muscles.

Past neuroscience studies have identified a TAR DNA-binding protein that plays a key role in ALS, known as TDP-43. This protein, which generally regulates RNA processing (i.e., how genetic information is managed inside cells), was found to abnormally accumulate in the axons (i.e., nerve fibers) of patients diagnosed with ALS.

Researchers at Tel Aviv University, Sheba Medical Center and other institutes carried out a study aimed at further exploring the mechanisms that underpin this local aggregation of TDP-43 in axons.

Toxic Salton Sea dust triggers changes in lung microbiome after just one week

Dust from California’s drying Salton Sea doesn’t just smell bad. Scientists from UC Riverside found that breathing the dust can quickly re-shape the microscopic world inside the lungs.

Genetic or have previously been shown to have an effect on lung microbes. However, this discovery marks the first time scientists have observed such changes from environmental exposure rather than a disease.

Published in the journal mSphere, the study shows that inhalation of airborne dust collected close to the shallow, landlocked lake alters both the microbial landscape and immune responses in mice that were otherwise healthy.

Ectopic expression of a mechanosensitive channel confers spatiotemporal resolution to ultrasound stimulations of neurons for visual restoration

Cadoni et al. show that expression of the bacterial sonogenetic ion channel MscL(G22S) allows focused ultrasound (FUS) neuromodulation of the mouse visual cortex. They even provide evidence for possible induction of a visual percept in mice via this approach, though much more work is needed to make this into a useful visual restoration method. It should be noted that some of the FUS frequencies used in Cadoni et al.’s experiments were quite high (15 MHz), so a surgically implanted cranial window was needed. I personally think that it would be better to focus on frequencies that can be employed in a transcranial fashion to minimize invasiveness. That said, there is still merit to moderately invasive methods as seen here. #sonogenetics [ https://www.nature.com/articles/s41565-023-01359-6](https://www.nature.com/articles/s41565-023-01359-6)

Sonogenetics provides neuron-specific activation at high spatiotemporal resolution ex vivo in retina and in vivo deep in the visual cortex using the AAV gene delivery of a mechanosensitive ion channel and low-intensity ultrasound stimulations.

Decoding the T cell burst: Signature genes predict T cell expansion in cancer immunotherapy

The ability of immune cells—particularly CD8+ T cells—to launch a rapid burst of proliferation inside tumors is key to the success of modern day cancer immunotherapies. However, the factors and mechanisms that drive this burst in proliferation remain poorly understood, making it difficult to predict which patients will benefit from treatment. A deeper understanding of this T cell burst could also guide the development of new therapies that enhance T cell proliferation and improve treatment outcomes.

To tackle this challenge, an international team of researchers led by Associate Professor Satoshi Ueha and Professor Kouji Matsushima from the Research Institute for Biomedical Sciences, Tokyo University of Science (TUS), Japan, developed a novel approach to monitor CD8⁺ T cell activity over time. Their findings, published in the journal Nature Communications on October 20, 2025, sheds new light on how T cells expand in the tumor—and how their expansion can be predicted, and ultimately, therapeutically reactivated.

“The development of immunotherapies has been hindered by our inability to comprehensively monitor their effects on —particularly cancer-fighting T cells—over time,” explains Dr. Ueha. “Building on our previous work, we developed a method to track these cells longitudinally in the tumor, allowing us to gain deeper insights into the burst of that drives effective anti-tumor responses.”

Gene deficiency that causes obesity also protects from heart disease, finds new study

Deficiency of the gene melanocortin 4 receptor (MC4R) is linked with obesity among adults. A recent study has found that the same deficiency also leads to surprising outcomes such as reduced risk of heart disease, lower cholesterol, and triglycerides. These results contradict the well-established correlation between obesity and cardiovascular diseases.

The researchers scanned the of 7,719 children from the Genetics of Obesity Study (GOOS) cohort. They identified 316 probands—first person in a family to draw medical attention to a —and 144 adult family members with obesity due to loss-of-function (LoF) MC4R mutations.

Even after adjusting for weight, these individuals showed better blood pressure profiles and when compared to 336,728 controls from the UK Biobank.

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