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Category: genetics – Page 13

Genetic atlas reveals how human liver cells divide their labor

If scientists could shrink themselves to microscopic size and take a journey through the human body—like the submarine crew in the 1966 science fiction classic “Fantastic Voyage”—one of their first stops would no doubt be the liver. The unique structure of our largest internal organ comprises small, hexagonal functional units called lobules, each carrying out more than 500 functions simultaneously. Studies from the 1970s and 1980s revealed that liver cells divide these many tasks among themselves according to their location within each subunit; however, the technology available at the time provided only a blurred picture of this division of labor.

In a new study published in Nature, scientists from the Weizmann Institute of Science, together with colleagues at Sheba Medical Center and the Mayo Clinic, present the first genetic atlas of a healthy human liver at a resolution of 2 microns. The findings show that the division of labor in the human liver differs from that of other mammals and is more extensive than previously recognized, helping explain why certain regions of the liver are particularly vulnerable to fatty liver disease.

In recent years, technological advances have made it possible to identify which genes are active in each individual cell while also mapping the cells’ precise spatial positions within the tissue. Still, a comprehensive map of functional division in the human liver remained elusive, largely due to the difficulty of obtaining tissue samples from healthy donors.

CRISPR Technology: Transforming the Future of Medicine and Diagnostics

Among the many promising possibilities of using CRISPR-based therapeutics, their translational use in monogenic human genetic diseases has the potential to provide long-term therapy after a single treatment. Genetic disorders can be treated with the help of CRISPR by editing the defective (disease-causing) gene or by editing the enhancer or regulator of the defective gene. Numerous studies, which are summarized in the table below (Table ), have shown promising results by using these two approaches.

3. Examples of CRISPR-Based Therapeuticsfor the Treatment of Genetic Disorders.

DiseaseCRISPR targetapproachmajor outcome of the studyreferenceDuchenne muscular dystrophydystrophin gene (DMD)single or multiplexed sgRNAs were developedto restore thedystrophin reading frame by targeting the mutational hotspot at exons45–55 and introducing shifts within exons or deleting one ormore exonsdystrophin expression is restored in vitroOusterout et al. Huntington’sdiseaseHuntingtin gene (HTT)HTT 5′ UTR was targetedimpropermaturation of the transcript and reducing the expressionof the disease-causing alleleKolli et al.a dual sgRNA approachwas used in vitro toexcise a 44kb promoter region upstream of a mutant HTT gene to silence its expressionexpression of the Huntington’sdisease-causing variant wasablatedShin et al.glaucomamyocilin gene (MYOC)Knocked down the expression of mutant MYOC in a mouse model of primary open-angle glaucomareductionof ER stress, lower intraocular pressure, and thepreventability of further glaucomatous damage in mouse eyes was observed. The authors also demonstrated the feasibility of utilizing CRISPR/Cas9in human eyes with glaucomaJain et al.hereditary tyrosinemiatype Ifumarylacetoacetate hydrolase gene (FAH)HDR-mediated point mutation correction in mouse hepatocytes.a significant proportion of alleles were correctedVanLith et al. Leber congenital amaurosis type 10 (LCA10)centrosomalprotein 290 gene (CEP290)AAV5-basedtherapy (EDIT-101) encapsulates Staphylococcusaureus Cas9 (SaCas9) and two sgRNAs targeting genomic locationsupstream and downstream of the intronic CEP290 pointmutation. The two sgRNAs enable cutting around the mutation to induceits removal or inversionnormal splicing of CEP290 pre-mRNA was restoredMaeder et al. Noonan syndromeleucine zipper like post translational regulator 1 gene (LZTR1)intron 16 of LZTR1 was targetedthe gene editing process could overcomethe disease phenotypeassociated with Noonan syndrome-associated cardiomyopathy in iPSC-derivedcardiomyocytes in vitroHanses et al. Angelman syndromeUBE3A-ATS Inc. RNAUBE3A-ATS Inc. RNA was targetedin cultured human neurons andin a mouse model of the diseasetargeting of UBE3A-ATSablated its function, leading to expressionof the paternal UBE3A gene and rescuing the diseasephenotypeWolter et al.congenital muscular dystrophy type 1A (MDC1A)laminin subunit alpha 1 gene (LAMA1)CRISPR activator mediated gene upregulation3.6-foldupregulation of LAMA1 was observedKemaladevi et al.genetic deafnesstransmembrane channel like 1gene (TMC1)non-homologous end joining(NHEJ)-mediated mutant Tmc alleledisruptiondeafness was prevented in mouse models upto one year postinjectionGyörgy et al.

“You Have To Iterate, You Have To Fail, You Have To Quickly Pick Yourself Up”: Genome Loaded Onto Quantum Computer For First Time

The achievement marks a milestone in the quest to use quantum computing to unlock the full complexity of human genetic diversity, with implications for cancer, drug design, and personalised medicine.

Iatrogenic Cerebral Amyloid Angiopathy After Cardiac SurgeryTwo Case Reports

Authors describe 2 cases of likely iatrogenic cerebral amyloid angiopathy after cadaveric dura mater use for cardiac surgery during infancy. Both are remarkable for their early age at onset, lack of genetic risk factor, and demonstration of brain amyloidosis.

To alert on the risk of interhuman transmission of β-amyloid (Aβ) pathology leading to cerebral amyloid angiopathy (CAA) after non-neurosurgical procedures, here cardiovascular procedures, using cadaveric dura mater (DM) patches.

Unlocking secrets of human development: How early nerve cell choices shape the peripheral nervous system

Millions of neurons branch throughout our bodies, keeping them in close communication with our brains. This peripheral network begins to take shape long before birth, as the cells of a growing embryo move into position and adopt their specialized roles. This crucial stage of human development can’t be monitored directly, but by examining genetic clues that linger in adult cells, scientists have now gained surprising insights into the developmental origins of the peripheral nervous system.

Researchers led by Xiaoxu Yang, Ph.D., at University of Utah Health, and Keng Ioi Vong, Ph.D., and Joseph Gleeson, M.D., at the University of California San Diego, have discovered that within the first few weeks of development, some of an embryo’s cells have already been selected to take on particular roles in the peripheral nervous system. Their findings, recently reported in the journal Nature, overturn longstanding assumptions in biology.

Their discovery could change the way scientists think about treatments for a variety of childhood diseases that begin in the cells of the peripheral nervous system.

Heart Rate Variability Moderates the Association Between Trait Anxiety and Sympathetic Nerve Activity in Humans

A new study challenges the long-standing view that Alzheimer’s is driven primarily by amyloid plaques, instead pointing to a subtle but critical competition inside neurons.

New research led by the University of California, Riverside, suggests Alzheimer’s disease may not be driven solely by plaque buildup in the brain, as widely believed. Instead, it may result from one protein disrupting the normal function of another.

For years, scientists have focused on amyloid beta (a-beta) as the main cause of Alzheimer’s. Clusters of this protein are commonly found in patients, and genetic mutations that raise a-beta levels are known to trigger early-onset Alzheimer’s.

CRISPR takes a bold leap toward silencing Down syndrome’s extra chromosome

Scientists have taken an important step toward a gene therapy that could one day turn off the extra genetic material that causes Down syndrome (DS). Down syndrome is a genetic condition caused by an extra chromosome 21 (and consequently hundreds of triplicate genes) that leads to developmental and neurological issues. According to the Washington-based National Down Syndrome Society, approximately 1 in every 640 babies in the United States is born with DS. That makes it the most common chromosomal condition.

Traditional gene therapy targets one or two genes, but in this approach, scientists at Beth Israel Deaconess Medical Center and Harvard Medical School found a way to silence much of the extra chromosome’s activity in the cell at once.

Details of their research are published in a paper in the journal Proceedings of the National Academy of Sciences.

Sibling Stem Cell Transplant Leads to Rare HIV Remission in ‘Oslo Patient’

After receiving a stem cell transplant from his brother, a 63-year-old Norwegian man known as the “Oslo patient” has become one of only a handful of people to see their HIV (human immunodeficiency virus) go into long-term remission.

While HIV can now be controlled with medication that stops the virus from replicating, the virus remains in the body, rebounding when the drugs are stopped. So case studies like this one are invaluable for researchers working towards a full cure.

The Oslo man was given a bone marrow stem cell transplant to treat a rare type of blood cancer. Discovering at the last minute that his brother carried a rare genetic mutation previously shown to resist HIV, researchers led by a team from Oslo University Hospital closely tracked the operation’s impact on the virus.

APOE4, the Alzheimer’s risk gene, silently undermines bone quality in women

Scientists at the Buck Institute for Research on Aging, along with collaborators at UC San Francisco, have discovered that APOE4, the most common genetic risk factor for Alzheimer’s disease, causes bone quality deficits specifically in female mice, through a mechanism that is invisible to standard imaging and can emerge as early as midlife. The findings, published in Advanced Science, reveal an unexpected biological link between Alzheimer’s risk and skeletal health, and identify a new molecular pathway that could one day inform earlier diagnosis of cognitive decline or guide treatment for bone quality loss in women who carry the APOE4 gene.

“What makes this finding so striking is that bone quality is being compromised at a molecular level that a standard bone scan simply will not catch,” says Buck professor Birgit Schilling, Ph.D., a senior author of the study. “APOE4 is quietly disrupting the very cells responsible for keeping bone strong, and it is doing this specifically in females, which mirrors what we see with Alzheimer’s disease risk.”

Physicians have long observed that people with Alzheimer’s disease suffer bone fractures at higher rates, and that a diagnosis of osteoporosis in women is actually the earliest known predictor of Alzheimer’s. But the underlying mechanism connecting brain and bone health has remained elusive.

Compact CRISPR system unlocks targeted in-body gene editing, with up to 90% efficiency

A research team has discovered an enhanced CRISPR gene-editing system that could enable targeted delivery inside the human body—a key step toward broader clinical use. Researchers identified a naturally occurring enzyme, Al3Cas12f, that is small enough to fit into adeno-associated virus vectors, a leading targeted delivery method for gene therapies. They then engineered an enhanced version that dramatically improved gene-editing performance in human cells.

The advance addresses a major limitation in CRISPR technology. Commonly used gene-editing proteins are too large for targeted delivery systems, restricting clinical applications to cells modified outside the body, such as blood and bone marrow.

“Smart delivery of gene editing systems is a powerful notion with broad clinical implications, and this basic science finding takes us a significant step toward that future,” said Erica Brown, Ph.D., acting director of NIH’s National Institute of General Medical Sciences (NIGMS).

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