Gene editing extends lifespan in mouse model of prion disease

Broad Communications Eric Minikel and Sonia Vallabh run a lab with a singular focus: preventing and treating prion disease within their lifetime.
Photo Credit: Maria Nemchuk

Researchers at the Broad Institute of MIT and Harvard have developed a gene-editing treatment for prion disease that extends lifespan by about 50 percent in a mouse model of the fatal neurodegenerative condition. The treatment, which uses base editing to make a single-letter change in DNA, reduced levels of the disease-causing prion protein in the brain by as much as 60 percent. 

There is currently no cure for prion disease, and the new approach could be an important step towards treatments that prevent the disease or slow its progression in patients who have already developed symptoms. A base-editing approach could also likely be a one-time treatment for all prion disease patients regardless of the genetic mutation causing their disease. 

The work, led by Broad senior group leaders Sonia Vallabh and Eric Minikel, as well as Broad core institute member David Liu, is the first demonstration that lowering levels of the prion protein improves lifespan in animals that have been infected with a human version of the protein. The findings appear in Nature Medicine.

Chornobyl Dogs’ Genetic Differences Not Due to Mutation

Photo Credit: Norman Kleiman

Radiation-induced mutation is unlikely to have induced genetic differences between dog populations in Chornobyl City and the nearby Chornobyl Nuclear Power Plant (NPP), according to a new study in PLOS ONE from North Carolina State University and Columbia University Mailman School of Public Health. The study has implications for understanding the effects of environmental contamination on populations over time.

“We have been working with two dog populations that, while separated by just 16 kilometers, or about 10 miles, are genetically distinct,” says Matthew Breen, Oscar J. Fletcher Distinguished Professor of Comparative Oncology Genetics at NC State. “We are trying to determine if low-level exposure over many years to environmental toxins such as radiation, lead, etcetera, could explain some of those differences.” Breen is the corresponding author of the study.

Previously, the team had analyzed genetic variants distributed across the genome and identified 391 outlier regions in the dogs that differed between the two populations. Some of these regions contained genes associated specifically with repair of DNA damage. In this new study, the researchers conducted a deeper dive into the genomes of the dogs to detect evidence of mutations that may have accumulated over time.

First-of-its-kind integrated dataset enables genes-to-ecosystems research

DOE national laboratory scientists led by Oak Ridge National Laboratory have developed the first tree dataset of its kind, bridging molecular information about the poplar tree microbiome to ecosystem-level processes.
Illustration Credit: Andy Sproles/ORNL, U.S. Dept. of Energy

The first-ever dataset bridging molecular information about the poplar tree microbiome to ecosystem-level processes has been released by a team of Department of Energy scientists led by Oak Ridge National Laboratory. The project aims to inform research regarding how natural systems function, their vulnerability to a changing climate, and ultimately how plants might be engineered for better performance as sources of bioenergy and natural carbon storage.

The data, described in Nature Publishing Group’s Scientific Data, provides in-depth information on 27 genetically distinct variants, or genotypes, of Populus trichocarpa, a poplar tree of interest as a bioenergy crop. The genotypes are among those that the ORNL-led Center for Bioenergy Innovation previously included in a genome-wide association study linking genetic variations to the trees’ physical traits. ORNL researchers collected leaf, soil and root samples from poplar fields in two regions of Oregon — one in a wetter area subject to flooding and the other drier and susceptible to drought. 

Details in the newly integrated dataset range from the trees’ genetic makeup and gene expression to the chemistry of the soil environment, analysis of the microbes that live on and around the trees and compounds the plants and microbes produce.

The dataset “is unprecedented in its size and scope,” said ORNL Corporate Fellow Mitchel Doktycz, section head for Bioimaging and Analytics and project co-lead. “It is of value in answering many different scientific questions.” By mining the data with machine learning and statistical approaches, scientists can better understand how the genetic makeup, physical traits and chemical diversity of Populus relate to processes such as cycling of soil nitrogen and carbon, he said. 

Single genomic test could speed up diagnoses for rare genetic diseases

Image Credit: Sinousxl

A new approach to analyzing exome sequencing data reliably detects large-scale genetic changes and could reduce the number of genetic tests a child might need.

A single genetic test could potentially replace the current two-step approach to diagnosing rare developmental disorders in children, enabling earlier diagnoses for families and saving the NHS vital resources.

Researchers from the University of Exeter, along with collaborators at the Wellcome Sanger Institute, and the University of Cambridge, reassessed genetic data from nearly 10,000 families from the Deciphering Developmental Disorders study.

In a new study, recently published in Genetics in Medicine, they show for the first time that using exome sequencing – which reads only protein-coding DNA – is as accurate, if not better, than standard microarrays at identifying disease-causing structural genetic variations.

Its adoption offers hope for faster and more accurate diagnoses of rare genetic diseases. It could also deliver substantial cost savings for the NHS, though more training is needed for specialists to generate and analyze the data, say researchers.

Cystic fibrosis: why infections persist despite therapy

The anchor points present on the surface of the airways in cystic fibrosis (left image, in red) decrease when the balance between the two cell signaling pathways is restored (right image).
Image Credit: Marc Chanson et al, 2024

Cystic fibrosis is a genetic disease that causes serious and sometimes fatal respiratory and digestive disorders. A new treatment, available since 2020, improves lung function and quality of life. However, it does not always eradicate the bacteria responsible for respiratory infections. By studying 3D models of human lung cells, scientists at the University of Geneva (UNIGE) discovered that this drug does not prevent the development on the surface of the respiratory tract of ''docking stations'' to which bacteria attach themselves to infect the body. These docking stations result from a disruption in the signals involved in cell development in the respiratory system. By combining the current treatment with other molecules, it may be possible to restore cell balance and thus better prevent bacterial infections. These results are published in the American Journal of Respiratory Cell and Molecular Biology.

Cystic fibrosis is the most common genetic disease. Each year, it affects one in every 3,300 newborns in Switzerland. Mutations in the gene responsible for the CFTR protein cause the secretion of excessively thick mucus, which obstructs the airways. Although a triple therapy, available in Switzerland since 2020, has improved the quality of life of people with cystic fibrosis, it is not suitable for all those affected and does not always prove effective.

New sunflower family tree reveals multiple origins of flower symmetry

A new sunflower family tree reveals that flower symmetry evolved multiple times independently. Chrysanthemum lavandulifolium, on the upper left, and Artemisia annua, upper right, are closely related species from the same tribe; the former has bilaterally symmetric flowers — the rays — and the latter does not. Rudbeckia hirta, lower left, from the sunflower tribe has bilaterally symmetric flowers, and Eupatorium chinense, lower right, from the Eupatorieae tribe does not; these two tribes are closely related groups. A sunflower, center, shows flowers with bilateral symmetry — the large petal-like flowers in the outer row — and without bilateral symmetry — the small flowers in the inner rows.
Photo Credits: Guojin Zhang, Ma laboratory / Pennsylvania State University
(CC BY-NC-ND 4.0 DEED)

The sunflower family tree revealed that flower symmetry evolved multiple times independently, a process called convergent evolution, among the members of this large plant family, according to a new analysis. The research team, led by a Penn State biologist, resolved more of the finer branches of the family tree, providing insight into how the sunflower family — which includes asters, daisies and food crops like lettuce and artichoke — evolved.

A paper describing the analysis and findings, which researchers said may help identify useful traits to selectively breed plants with more desirable characteristics is available online and will be published in an upcoming print edition of the journal Plant Communications.

“Convergent evolution describes the independent evolution of what appears to be the same trait in different species, like wings in birds and bats,” said Hong Ma, Huck Chair in Plant Reproductive Development and Evolution, professor of biology in the Eberly College of Science at Penn State and the leader of the research team. “This can make it difficult to determine how closely related two species are by comparing their traits, so having a detailed family tree based on DNA sequence is crucial to understanding how and when these traits evolved.”

Scientists discover potential treatment approaches for polycystic kidney disease

cientists would like to know how cysts form in polycystic kidney disease (PKD). Here, they compared two 3-D mini-kidney models. On the left, a model shows a mini kidney with a gene mutation that causes cysts to form. On the right, researchers used gene editing to correct a gene mutation, preventing the development of cysts.
Image Credit: Vishy, et al., Cell Stem Cell 2024

Researchers have shown that dangerous cysts, which form over time in polycystic kidney disease (PKD), can be prevented by a single normal copy of a defective gene. This means the potential exists that scientists could one day tailor a gene therapy to treat the disease. They also discovered that a type of drug, known as a glycoside, can sidestep the effects of the defective gene in PKD. The discoveries could set the stage for new therapeutic approaches to treating PKD, which affects millions worldwide. The study, partially funded by the National Institutes of Health (NIH), is published in Cell Stem Cell.

Scientists used gene editing and 3-D human cell models known as organoids to study the genetics of PKD, which is a life-threatening, inherited kidney disorder in which a gene defect causes microscopic tubes in the kidneys to expand like water balloons, forming cysts over decades. The cysts can crowd out healthy tissue, leading to kidney function problems and kidney failure. Most people with PKD are born with one healthy gene copy and one defective gene copy in their cells.

“Human PKD has been so difficult to study because cysts take years and decades to form,” said senior study author Benjamin Freedman, Ph.D., at the University of Washington, Seattle. “This new platform finally gives us a model to study the genetics of the disease and hopefully start to provide answers to the millions affected by this disease.”

Scientists identify rare gene variants which confer up to 6-fold increase in risk of obesity

Photo Credit: Mart Production

The discovery of rare variants in the genes BSN and APBA1 are some of the first obesity-related genes identified for which the increased risk of obesity is not observed until adulthood.

The study, published in Nature Genetics, was led by researchers at the Medical Research Council (MRC) Epidemiology Unit and the MRC Metabolic Diseases Unit at the Institute of Metabolic Science, both based at the University of Cambridge.

The researchers used UK Biobank and other data to perform whole exome sequencing of body mass index (BMI) in over 500,000 individuals.

They found that genetic variants in the gene BSN, also known as Bassoon, can raise the risk of obesity as much as six times and was also associated with an increased risk of non-alcoholic fatty liver disease and of type 2 diabetes.

The Bassoon gene variants were found to affect 1 in 6,500 adults, so could affect about 10,000 people in the UK.

‘Exhausted’ immune cells in healthy women could be target for breast cancer prevention

Photo Credit: Angiola Harry

Everyone has BRCA1 and BRCA2 genes, but mutations in these genes - which can be inherited - increase the risk of breast and ovarian cancer.

The study found that the immune cells in breast tissue of healthy women carrying BRCA1 or BRCA2 gene mutations show signs of malfunction known as ‘exhaustion’. This suggests that the immune cells can’t clear out damaged breast cells, which can eventually develop into breast cancer.

This is the first time that ‘exhausted’ immune cells have been reported in non-cancerous breast tissues at such scale - normally these cells are only found in late-stage tumors.

The results raise the possibility of using existing immunotherapy drugs as early intervention to prevent breast cancer developing, in carriers of BRCA1 and BRCA2 gene mutations.

The researchers have received a ‘Biology to Prevention Award’ from Cancer Research UK to trial this preventative approach in mice. If effective, this will pave the way to a pilot clinical trial in women carrying BRCA gene mutations.

“Our results suggest that in carriers of BRCA mutations, the immune system is failing to kill off damaged breast cells - which in turn seem to be working to keep these immune cells at bay,” said Professor Walid Khaled in the University of Cambridge’s Department of Pharmacology and Wellcome-MRC Cambridge Stem Cell Institute, senior author of the report.

New Genetic Analysis Tool Tracks Risks Tied to CRISPR Edits

UC San Diego researchers have created a new system that reveals specific categories of potentially risky mutations resulting from CRISPR edits. This high magnification image reveals CRISPR-based DNA transcription of the homothorax gene in fruit fly embryos.
Image Credit: Bier Lab, UC San Diego

Since its breakthrough development more than a decade ago, CRISPR has revolutionized DNA editing across a broad range of fields. Now scientists are applying the technology’s immense potential to human health and disease, targeting new therapies for an array of disorders spanning cancers, blood conditions and diabetes.

In some designed treatments, patients are injected with CRISPR-treated cells or with packaged CRISPR components with a goal of repairing diseased cells with precision gene edits. Yet, while CRISPR has shown immense promise as a next-generation therapeutic tool, the technology’s edits are still imperfect. CRISPR-based gene therapies can cause unintended but harmful “bystander” edits to parts of the genome, at times leading to new cancers or other diseases.

Next-generation solutions are needed to help scientists unravel the complex biological dynamics behind both on- and off-target CRISPR edits. But the landscape for such novel tools is daunting, since intricate bodily tissues feature thousands of different cell types and CRISPR edits can depend on many different biological pathways.

Blood analysis predicts sepsis and organ failure in children

Photo Credit: Edward Jenner

University of Queensland researchers have developed a method to predict if a child is likely to develop sepsis and go into organ failure.

Associate Professor Lachlan Coin from UQ’s Institute for Molecular Bioscience said sepsis was a life-threatening condition where a severe immune response to infection causes organ damage.

“Our research involved more than 900 critically ill children in the emergency departments and intensive care units of four Queensland hospitals,” Dr Coin said.

“Blood samples were taken from these patients at the acute stage of their infection, and we analyzed which genes were activated or deactivated.

“We were able to identify patterns of gene expression which could predict whether the child would develop organ failure within the next 24 hours, as well as whether the child had a bacterial or viral infection or a non-infectious inflammatory syndrome.”

Professor Luregn Schlapbach from UQ’s Child Health Research Centre said sepsis is best treated when recognized early, so the finding could help clinicians in the future.

Mystery of unexplained kidney disease revealed to patients

Professor John Sayer
“What we are now able to do is give some patients a precise diagnosis, which allows their investigations, treatment and management to be tailored to their needs for the best possible outcomes.”
Photo Credit: Courtesy of Newcastle University

Scientists have identified a new method of analyzing genomic data in a major discovery that means patients with unexplained kidney failure are finally getting a diagnosis.

Experts at Newcastle University have worked with data from Genomics England 100,000 Genomes Project to establish a diagnosis in patients with unexplained kidney failure.

There are numerous reasons for kidney failure, which if left untreated is life-threatening, but often patients do not get a precise diagnosis which can make their best course of treatment unclear.

Missing genetic data

Research, published in the Genetics in Medicine Open, has now revealed that for these patients areas in their genome are missing so are not detected as faulty when using the routine genetic pipelines to analyze data. 

Scientists say that as this missing gene has now been identified, and mutations within it found, they have been able to classify this as NPHP1-related kidney failure.

Researchers roll out a more accurate way to estimate genetic risks of disease

Illustration Credit: Ricardo Job-Reese, Broad Communications.

Researchers have developed statistical tools called polygenic risk scores (PRSs) that can estimate individuals’ risk for certain diseases with strong genetic components, such as heart disease or diabetes. However, the data on which PRSs are built is often limited in diversity and scope. As a result, PRSs are less accurate when applied to populations that differ demographically from the PRS training data.

A new scoring approach featured in Cell Genomics and developed by researchers at the Broad Institute of MIT and Harvard and Massachusetts General Hospital (MGH) uses a comprehensive approach to generate more accurate and informative PRSs. Aptly named PRSmix due to its ability to “mix” all previously developed PRSs for a given trait, the approach generates scores that estimate a patient’s genetic disease risk more accurately than PRSs generated from individual studies.

“A major challenge with PRSs is that they’re derived in one population and then unleashed broadly with the assumption that the scores can be generalized,” explained Pradeep Natarajan, the study’s corresponding author. Natarajan is an associate member in Broad's Cardiovascular Disease Initiative and director of preventive cardiology at MGH. “The overall motivation for this work is to better identify individuals who are prematurely at high risk for heritable conditions.”

Cells harvested from urine may have diagnostic potential for kidney disease, find scientists

Image Credit: AI generated / Gemini Advance

Genes expressed in human cells harvested from urine are remarkably similar to those of the kidney itself, suggesting they could be an important non-invasive source of information on the kidney.

The news offers hope that doctors may one day be able to investigate suspected kidney pathologies without carrying out invasive procedures such as biopsies, raising the tantalizing prospect of earlier and simpler disease detection.

The impact of late detection of kidney disease can be severe and can lead to serious and sometimes life-threatening complications.

The team led by University of Manchester scientists measured the levels of approximately 20,000 genes in each cellular sediment sample of urine using a technique called transcriptomics.

The British Heart Foundation-funded study benefited from access to the world's largest collection of human kidney samples collected after surgery or kidney biopsy conducted before transplantation, known as the Human Kidney Tissue Resource, at The University of Manchester.

They extracted both DNA and RNA from each sample and connected information from their analysis, together with data from previous large-scale analyses of blood pressure (called genome-wide association studies), using sophisticated computational methods.

Inflammatory bowel disease after a stem cell transplant

Additional genetic testing could make bone marrow donations even safer.
Image Credit: Gerd Altmann

A stem cell donation saves a leukemia sufferer’s life. Five years later, the patient develops a chronic inflammatory bowel disease that occurs very rarely following a transplant. Researchers from the University of Basel and University Hospital Basel have studied the case and are calling for more extensive genetic analyses in bone marrow donors.

In many forms of blood cancer, a transplant of blood stem cells is the only chance of a cure. This procedure involves first eliminating the patient’s degenerated blood stem cells and then building up their immune system again with stem cells from a donor.

So that the new immune system doesn’t turn against the recipient’s body, a series of tissue markers must match the recipient and donor. This criterion is investigated as standard. Now, a research team led by Professors Petr Hrúz from Clarunis (University Digestive Health Care Center Basel) and Mike Recher from the University of Basel and University Hospital Basel has shown that it would also be sensible to carry out a more extensive genetic analysis.

Writing in the Journal of Clinical Immunology, the team describes the case of a man who developed a chronic inflammatory bowel disease (Crohn’s disease) five years after receiving a blood stem cell transplant for leukemia. Genetic analysis revealed that a mutation had been transplanted along with the blood stem cells from the donor. This mutation affected the operation of a factor called TIM-3, a key regulator of the immune system. The donor, on the other hand, was and remains in apparently good health.

UC Irvine-led research team discovers role of key enzymes that drive cancer mutations

“Both APOBEC3A and APOBEC3B were known to generate mutations in many kinds of tumors, but until now we did not know how to identify the specific type caused by each,” says the study’s corresponding author, Rémi Buisson (center), UCI assistant professor of biological chemistry. He’s flanked by postdoctoral fellow Pedro Ortega (left) and graduate student Ambrocio Sanchez, UCI researchers who developed a new method to characterize the particular kind of DNA modified by the enzymes.
Photo Credit: UCI School of Medicine

A research team led by the University of California, Irvine has discovered the key role that the APOBEC3A and APOBEC3B enzymes play in driving cancer mutations by modifying the DNA in tumor genomes, offering potential new targets for intervention strategies.

The study, published today online in the journal Nature Communications, describes how the researchers identified the process by which APOBEC3A and APOBEC3B detect specific DNA structures, resulting in mutations at distinct positions within the tumor genome.

“It’s critical to understand how cancer cells accumulate mutations leading to hot spots that contribute to disease progression, drug resistance and metastasis,” said corresponding author Rémi Buisson, UCI assistant professor of biological chemistry. “Both APOBEC3A and APOBEC3B were known to generate mutations in many kinds of tumors, but until now we did not know how to identify the specific type caused by each. This finding will allow us to develop novel therapies to suppress mutation formation by directly targeting each enzyme accordingly.”

All creatures great and small: Sequencing the blue whale and Etruscan shrew genomes

Prompts by Scientific Frontline
Image Credit: AI Generated by Copilot / Designer / DALL-E 3

The blue whale genome was published in the journal Molecular Biology and Evolution, and the Etruscan shrew genome was published in the journal Scientific Data.

Research models using animal cell cultures can help navigate big biological questions, but these tools are only useful when following the right map.

“The genome is a blueprint of an organism,” says Yury Bukhman, first author of the published research and a computational biologist in the Ron Stewart Computational Group at the Morgridge Institute, an independent research organization that works in affiliation with the University of Wisconsin–Madison in emerging fields such as regenerative biology, metabolism, virology and biomedical imaging. “In order to manipulate cell cultures or measure things like gene expression, you need to know the genome of the species — it makes more research possible.”

The Morgridge team’s interest in the blue whale and the Etruscan shrew began with research on the biological mechanisms behind the “developmental clock” from James Thomson, emeritus director of regenerative biology at Morgridge and longtime professor of cell and regenerative bBiology in the UW School of Medicine and Public Health.  It’s generally understood that larger organisms take longer to develop from a fertilized egg to a full-grown adult than smaller creatures, but the reason why remains unknown.

“It’s important just for fundamental biological knowledge from that perspective. How do you build such a large animal? How can it function?” says Bukhman.

Scientists develop a rapid gene-editing screen to find effects of cancer mutations

Using a variant of CRISPR genome-editing known as prime editing, MIT researchers have developed a method to screen cancer-associated genetic mutations much more easily and quickly than any existing approach. This illustration, by Samuel Gould’s brother Owen Gould, is an artistic interpretation of the research and the idea of “rewriting the genome,” explains Samuel.
Illustration Credit: Owen Gould
(CC BY-NC-ND 4.0 DEED)

Tumors can carry mutations in hundreds of different genes, and each of those genes may be mutated in different ways — some mutations simply replace one DNA nucleotide with another, while others insert or delete larger sections of DNA.

Until now, there has been no way to quickly and easily screen each of those mutations in their natural setting to see what role they may play in the development, progression, and treatment response of a tumor. Using a variant of CRISPR genome-editing known as prime editing, MIT researchers have now come up with a way to screen those mutations much more easily.

The researchers demonstrated their technique by screening cells with more than 1,000 different mutations of the tumor suppressor gene p53, all of which have been seen in cancer patients. This method, which is easier and faster than any existing approach, and edits the genome rather than introducing an artificial version of the mutant gene, revealed that some p53 mutations are more harmful than previously thought.

The researchers say this technique could also be applied to many other cancer genes, and could eventually be used for precision medicine, to determine how an individual patient’s tumor will respond to a particular treatment.

“In one experiment, you can generate thousands of genotypes that are seen in cancer patients, and immediately test whether one or more of those genotypes are sensitive or resistant to any type of therapy that you’re interested in using,” says Francisco Sanchez-Rivera, an MIT assistant professor of biology, a member of the Koch Institute for Integrative Cancer Research, and the senior author of the study.

MIT graduate student Samuel Gould is the lead author of the paper, which appears today in Nature Biotechnology.

AI research gives unprecedented insight into heart genetics and structure

Image Credit Copilot AI Generated

A ground-breaking research study has used AI to understand the genetic underpinning of the heart’s left ventricle, using three-dimensional images of the organ. It was led by scientists at the University of Manchester, with collaborators from the University of Leeds (UK), the National Scientific and Technical Research Council (Santa Fe, Argentina), and IBM Research (Almaden, CA).

The highly interdisciplinary team used cutting-edge unsupervised deep learning to analyze over 50,000 three-dimensional Magnetic Resonance images of the heart from UK Biobank, a world-leading biomedical database and research resource.

The study, published in the leading journal Nature Machine Intelligence, focused on uncovering the intricate genetic underpinnings of cardiovascular traits. The research team conducted comprehensive genome-wide association studies (GWAS) and transcriptome-wide association studies (TWAS), resulting in the discovery of 49 novel genetic locations showing an association with morphological cardiac traits with high statistical significance, as well as 25 additional loci with suggestive evidence.  

The study's findings have significant implications for cardiology and precision medicine. By elucidating the genetic basis of cardiovascular traits, the research paves the way for the development of targeted therapies and interventions for individuals at risk of heart disease.

How Proteins Control Genes to Prevent our Cells from Maldevelopment

Ole Nørregaard Jensen is a professor and head of research at the Department of Biochemistry and Molecular Biology.
Photo Credit: Stefan Kristensen

Every time a cell in our body prepares to divide, an extremely complex process begins to ensure that the mother cell's DNA is copied into a new daughter cell along with all the correct instructions for which genes on the DNA strand should be turned off and which should be activated.

If errors occur in this process and the new cell is not identical to the mother cell, damage and disease may occur.

Researchers are therefore interested in learning more about these processes and why the copying of DNA and instructions sometimes goes wrong.

Constant DNA replication of the cell

All humans have a unique DNA strand, originating from a single cell: the fertilized egg cell, which has divided and created the billions of cells that make up the whole human being. They all contain a copy of the DNA strand created at fertilization. However, different cells decode the DNA in different ways, allowing for the formation of more than 200 different cell types. Some cell types die quickly and need to be replaced many times during life; for example, skin cells and intestinal cells are renewed every few days. Each time a new cell is created, a copy of the unique DNA strand is made for the new cell.