Publisher Health

In a new study co-led by investigators at the United States Department of Veterans Affairs and Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, a global team of scientists conducted one of the largest genetic association studies on heart failure to date. Using genomic data from over 90,000 heart failure patients and more than a million controls, the team identified 39 genetic mutations associated with heart failure, 18 of which had not been reported previously.
The researchers also pinpointed seven druggable proteins that, when targeted with specially designed medications, may prevent heart failure’s onset. They say their overall findings, published today in Nature Communications, could one day help physicians identify and treat at-risk patients before heart failure occurs.
“Our study provides a better understanding of disease etiology, identifies causal pathways, and pinpoints potential drug targets for the primary prevention of heart failure,” said lead author Danielle Rasooly, PhD, a research associate in the Brigham’s Department of Medicine. Rasooly is also an investigator for the VA’s Million Veteran Program.
Heart failure affects over 60 million people worldwide and 6 million people in the United States, costing the American healthcare system over 30 billion dollars every year. Patients diagnosed with heart failure have an estimated five-year survival rate of 50%, which has pressed scientists to better understand the environmental and genetic risk factors associated with heart failure.
Although several studies in the past decade have used advanced computing techniques to identify genetic risk factors for heart failure, scientists have wondered if their limited sample sizes have allowed some unidentified mutations to slip through the cracks. Genome-Wide Association Studies (GWAS), which look for differences in the DNA of patients with diseases and healthy controls, are only as comprehensive as the datasets they’re built on. GWAS with larger sample sizes have more statistical power, meaning they’re able to find mutations that smaller-cohort studies may miss.
The team built their large cohort by gathering genomes from two established genomic research programs. The Million Veteran Program (MVP), a national effort launched in 2011 to examine the long-term health outcomes of United States Veterans, provided 302,287 genomes for the study. Heart failure is a particular concern for veterans, with some studies showing that they may be at a higher risk of developing heart disease. To date, over 950,000 veterans have enrolled in MVP.
“We want to thank all the veterans who have taken part in the MVP and allowed us to study how genes affect heart failure,” Rasooly said.

A bitter taste in the mouth is often a symptom or side effect of illness, which may be the result of how the body reacts to pathogens. A new study published in iScience, by Hong Wang, PhD, an Associate Member at the Monell Chemical Sense Center, and colleagues sheds light on the mechanisms involved in the complex interplay between taste perception and immune function. Their work also highlights the potential of a sequencing tool for investigating epigenetic mechanisms that affect taste-cell gene expression. Epigenetics is the study of how and when genes are expressed rather than alteration of the genetic code itself.
In addition to being unpleasant, a bitter taste in the mouth or from food can contribute to a loss of appetite, an effect associated with ailments from the common cold to cancer. Bitter taste can also affect patients’ willingness to take certain medications, especially when they are young children. Bitter receptors are encoded by Tas2r genes, which also provide an important defense against bacteria and parasites in the mouth and gut. However, this process is not well understood.
For this study, the team explored how inducing inflammation would affect gene regulation of these taste receptors. Using lipopolysaccharide (LPS), a compound that induces inflammation similar to that caused by bacterial infections, they found that mice showed a distinct elevated aversion to bitter tastes. The team used nerve-recording experiments to confirm that this aversion originates in the taste buds of mice, rather than in their brains.
“Our study had very clear data showing this is actually a change at the peripheral level, not deep in the brain,” said Wang, confirming that genes in taste cells govern bitter taste distortion to this type of inflammation.
This finding has interesting clinical implications for the study of behavioral aspects of illness, such as a loss of appetite. When people are sick they often do not feel like eating. This can affect even humans’ love for sugary treats, as other studies have noted. Mice also have a decreased preference for sweet tastes during illness and forced intake of sugar can make them sicker. These results potentially indicate a protective behavior with a biological or evolutionary basis.
To investigate the underlying gene expression mechanisms of the bitterness response, the team used several methods of analysis. Real-time quantitative reverse-transcription polymerase chain reaction (qRT-PCR) revealed a significantly increased response across the majority of the Tas2r taste-receptor genes, with peak gene expression ranging from three to five days during the sickness period.
The researchers also used single-cell sequencing assay for transposase-accessible chromatin (scATAC-seq) to explore the expression of Tas2r genes in response to LPS — the first reported instance of this method to study taste receptor gene expression. LPS markedly increased the accessibility of many Tas2r genes, indicating that the bitter taste distortion in this experiment is caused by an epigenetic mechanism, similar to how disease-causing bacteria can affect those genes.
Finally, the study showed that LPS-induced inflammation globally affected gene expression in taste stem cells, suggesting a “remodeling” of the cells’ genome. This may leave an epigenetic memory, enabling the cells to respond faster to future infections, but may also contribute to long-lasting effects on taste responses. This finding sheds light on why cancer treatment and certain chronic illnesses can cause a lingering bitter taste in the mouth or alter the taste perception of certain foods.
This diverse response across taste receptors has potential implications for research on how to make more effective bitter blockers for medications and other edible health and wellness products. “The spectrum of the bitter taste receptor expression is not uniform,” Wang said. “If we want to look at a bitter blocker for an individual taste receptor, we may want to take these factors into consideration, such as whether it’s for after a sickness, during a sickness, or which of the taste receptor genes is most prominently expressed.”

Researchers from the Center for Regenerative Medicine (CReM), a joint venture between Boston University and Boston Medical Center, have discovered a novel approach for engrafting engineered cells into injured lung tissue. These findings may lead to new ways for treating lung diseases, such as emphysema, pulmonary fibrosis and COVID-19. The two studies describing the methodologies for engineering lung stem cells and transplanting them into injured experimental lungs without immunosuppression appear online in Cell Stem Cell.
For more than 20 years, the scientists leading this work have pursued a way to engraft cells into injured lung tissues with the goal of regenerating lung airways or alveoli. They suspected that for engraftment to be long-lived and functional it would be important to reconstitute the stem or progenitor “compartments” of the lung, also sometimes known as stem cell niches. They concentrated on first developing methods for engineering each of the lung’s stem or progenitor cells in the laboratory using pluripotent stem cells, and then developed methods for transplanting these cells into experimental mouse models with injured lungs.
In their study “Airway Stem Cell Reconstitution by Transplantation of Primary or Pluripotent Stem Cell-Derived Basal Cells,” the CReM researchers focus on the lung airways. These airways are lined by an epithelium that has well described stem cells called “basal cells,” which are responsible for maintaining these airways throughout life.
“By differentiating experimental model and human pluripotent stem cells into airway basal cells in the laboratory dish, we were then able to use these cells to reconstitute the stem cell compartment of the injured model airways in vivo (in living tissue). This resulted in life-long engraftment of the engineered basal cells in an immunocompetent model. Because the cells engrafted as basal cells, the normal stem cell of the airways, they were able to self-renew or make copies of themselves by dividing and also giving rise to other cell types that together make a functional airway epithelium,” explained corresponding author Darrell Kotton, MD, the David C. Seldin Professor of Medicine at Boston University Chobanian & Avedisian School of Medicine and director of the CReM.
In their second paper, “Durable alveolar engraftment of PSC-derived lung epithelial cells into immunocompetent mice,” CReM researchers targeted the lung air sacks, known as alveoli. Kotton and his team developed methods for engrafting engineered cells into the alveoli, the region of the lung responsible for gas exchange. The engrafted cells formed both types of alveolar cells, called type 1 and type 2 pneumocytes. Since type 2 pneumocytes act as progenitors of lung alveoli throughout life, forming new type 2 pneumocytes out of their transplanted engineered cells ensured the cells would self-renew and differentiate to maintain lung alveoli for a long time.
The researchers believe the reconstitution of lung stem and progenitor cells in the airways and alveoli using cells engineered from pluripotent stem cells is an important finding with many implications for the future treatment of lung diseases that involve injury, degeneration or mutations. “Since induced pluripotent stem cells (iPSCs) can be generated from the blood or skin of any individual through a technology called reprogramming, we hope this work will help to pave the way towards developing new therapeutic approaches where iPSCs can be made from any patient with lung disease, differentiated into lung stem cells in the laboratory, and used for transplantation to reconstitute the healthy airway and alveolar epithelial tissues in a way that is durable and functional,” said Martin Ma, first author of the first paper and a BU MD/PhD student in the Kotton lab.
For those suffering from genetic lung diseases, like cystic fibrosis and primary ciliary dyskinesia, it is possible to gene-edit the iPSCs in the laboratory prior to transplantation, meaning the newly engrafted cells will have had their gene mutation corrected and should be free of disease. “Since these cells will be the patient’s own cells, differing only in the corrected gene, in theory they should not be rejected after transplantation back into that patient, thus avoiding any need for immunosuppression, as we have demonstrated in our two proof-of-concept syngeneic transplantation studies in immunocompetent experimental models” added Michael Herriges, PhD, first author of the second paper and a postdoctoral fellow in the Kotton lab.
According to Kotton, these papers represent the culmination of 20 years of research. “While treatment of lung diseases like emphysema, pulmonary fibrosis and COVID-19 will take a lot more research, we are hopeful that those with gene mutations that cause damage to lung airways or alveoli, such as children or adults with familial forms of lung disease, might be treatable in the future with this type of approach.”

Duchenne muscular dystrophy (DMD) is a muscle degeneration disorder caused by mutations affecting the dystrophin gene. On August 24th in the journal Stem Cell Reports, researchers show how a dual CRISPR RNA method restored dystrophin protein function in induced pluripotent stem cells derived from DMD patients. The approach worked by removing large sections of the dystrophin gene, allowing the cells to skip faulty or misaligned sections of the genetic code. This yields truncated but still functional proteins for a wide variety of mutation patterns associated with DMD.
“Dual CRISPR-Cas3 is a promising tool to induce a gigantic genomic deletion and restore dystrophin protein via multi-exon skipping induction,” says senior author Akitsu Hotta of Kyoto University. “We expect this study to enlighten new ways to treat DMD patients and other genetic disorders that require extensive deletions.”
Due to significant variations in the mutation patterns affecting the dystrophin gene, deleting a small section of the gene can only be used for a limited number of DMD patients. For example, the most common mono-exon skipping of exons 51, 53, and 45 can be applied to 13%, 8%, and 8% of DMD patients, respectively.
Multi-exon skipping (MES) has broad applicability to various DMD mutation patterns. By targeting the mutation hotspots in the dystrophin gene, MES from exon 45 to 55 was estimated to benefit more than 60% of DMD patients. Unfortunately, few techniques are available to induce a large deletion to cover the target exons spread over several hundred kilobases.
To overcome this hurdle, Hotta and his team used CRISPR-Cas3 to induce a deletion of up to 340 kilobases at the dystrophin exon 45-55 region in various DMD mutation patterns. Because it was rare to observe a deletion of more than a hundred kilobases using a single CRISPR RNA — which helps to locate the correct segment of DNA — the researchers used a pair of CRISPR RNAs inwardly sandwiching the target genomic region.
The authors note potential limitations of the dual CRISPR RNA system. First, there is variation in the deletion pattern, and the precise start and end points of the deletion cannot be fully controlled. This could be a drawback when a large but precise deletion is required. Second, the study did not demonstrate the functionality of the recovered dystrophin protein. Third, other methods should be developed to improve the overall genome editing efficiency of the Cas3 system.
“Our dual-Cas3 system might apply to future gene therapies once we’re able to deliver the dual-Cas3 components in vivo to skeletal muscle tissues safely and efficiently,” says Hotta. “The ability to induce several hundred kilobases of DNA deletion itself also has broad applicability for basic research when a large deletion is needed.”
This study was partly supported by the Japan Agency for Medical Research and Development, the Japan Society for the Promotion of Science, the iPS Cell Research Fund, and the National Center of Neurology and Psychiatry. Akitsu Hotta is a scientific adviser of C4U, and several co-authors have submitted a patent regarding this study.

Researchers at The University of Texas MD Anderson Cancer Center have uncovered a functional role for KRAS mutations in pancreatic cancer and rapidly translated these findings into a novel therapeutic approach combining a KRAS G12D inhibitor with immune checkpoint inhibitors for early- and late-stage KRAS G12D-mutant pancreatic cancer. The combination therapy led to durable tumor elimination and significantly improved survival outcomes in preclinical models, leading to the launch of a Phase I clinical trial.
Two studies, published today in Developmental Cell and Cancer Cell, describe why KRAS-targeted monotherapy likely is not enough to completely eliminate tumors, suggesting that engaging the immune system is needed to prevent relapse. The comprehensive models generated for this investigation more accurately reflect the tumor microenvironment found in patients with metastatic disease, allowing for rigorous testing that provided unique insights into how oncogenic KRAS allows tumors to escape cancer cell death.
The studies were the result of collaborative work led by Krishnan Mahadevan, Ph.D., postdoctoral fellow in Cancer Biology, Kathleen McAndrews, Ph.D., instructor of Cancer Biology, and co-corresponding authors Raghu Kalluri, M.D., Ph.D., chair of Cancer Biology, Anirban Maitra, M.B.B.S., professor of Pathology and Translational Molecular Pathology, and Timothy Heffernan, Ph.D., vice president of Oncology Research for MD Anderson’s Translational Research to AdvanCe Therapeutics and Innovation in ONcology (TRACTION) platform.
“By extensively testing the functional role of KRAS, we gained important insights into how better to prime the tumor microenvironment in advanced pancreatic cancer to improve treatment responses,” Kalluri said. “These results are a testament to the value of team science and to the incredible research environment at MD Anderson, which enables the accelerated and seamless translation from genetic models to clinical application. We are encouraged that these results could lead to meaningful benefits for patients.”
Pancreatic cancer is the third leading cause of cancer death in the United States and often is diagnosed at a late stage, when treatment options are limited and the prognosis is poor. KRAS G12D mutations occur in over 40% of pancreatic cancer cases, but KRAS inhibitors alone have not yielded durable responses for patients. Immunotherapy treatments also have not benefitted patients, partly due to an immunosuppressive tumor microenvironment in pancreatic tumors.
New models more accurately reflect tumor microenvironment, providing insights into molecular function of oncogenic KRAS In the Developmental Cell study, researchers examined the functional role of KRAS by generating mouse models with various genetic alterations known to accompany KRAS mutations. Genetic suppression of KRAS in these models activated the Fas pathway, which is required for cancer cell death, and resulted in a greater number of T cells and fewer myeloid cells in the tumors.
This demonstrated that oncogenic KRAS epigenetically blocks expression of the Fas protein, silencing the pathway and allowing cancer cells to avoid an anti-tumor immune response. Suppressing KRAS led to complete tumor regression and significantly improved survival in these models, suggesting the potential for KRAS inhibition to improve immunotherapy responses and prevent relapse.

For many patients, the internet serves as a powerful tool for self-education on medical topics. With ChatGPT now at patients’ fingertips, researchers from Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, assessed how consistently the artificial intelligence chatbot provides recommendations for cancer treatment that align with National Comprehensive Cancer Network (NCCN) guidelines. Their findings, published in JAMA Oncology, show that in approximately one-third of cases, ChatGPT 3.5 provided an inappropriate (“non-concordant”) recommendation, highlighting the need for awareness of the technology’s limitations.
“Patients should feel empowered to educate themselves about their medical conditions, but they should always discuss with a clinician, and resources on the Internet should not be consulted in isolation,” said corresponding author Danielle Bitterman, MD, of the Department of Radiation Oncology and the Artificial Intelligence in Medicine (AIM) Program of Mass General Brigham. “ChatGPT responses can sound a lot like a human and can be quite convincing. But, when it comes to clinical decision-making, there are so many subtleties for every patient’s unique situation. A right answer can be very nuanced, and not necessarily something ChatGPT or another large language model can provide.”
The emergence of artificial intelligence tools in health has been groundbreaking and has the potential to positively reshape the continuum of care. Mass General Brigham, as one of the nation’s top integrated academic health systems and largest innovation enterprises, is leading the way in conducting rigorous research on new and emerging technologies to inform the responsible incorporation of AI into care delivery, workforce support, and administrative processes.
Although medical decision-making can be influenced by many factors, Bitterman and colleagues chose to evaluate the extent to which ChatGPT’s recommendations aligned with the NCCN guidelines, which are used by physicians at institutions across the country. They focused on the three most common cancers (breast, prostate and lung cancer) and prompted ChatGPT to provide a treatment approach for each cancer based on the severity of the disease. In total, the researchers included 26 unique diagnosis descriptions and used four, slightly different prompts to ask ChatGPT to provide a treatment approach, generating a total of 104 prompts.
Nearly all responses (98 percent) included at least one treatment approach that agreed with NCCN guidelines. However, the researchers found that 34 percent of these responses also included one or more non-concordant recommendations, which were sometimes difficult to detect amidst otherwise sound guidance. A non-concordant treatment recommendation was defined as one that was only partially correct; for example, for a locally advanced breast cancer, a recommendation of surgery alone, without mention of another therapy modality. Notably, complete agreement in scoring only occurred in 62 percent of cases, underscoring both the complexity of the NCCN guidelines themselves and the extent to which ChatGPT’s output could be vague or difficult to interpret.
In 12.5 percent of cases, ChatGPT produced “hallucinations,” or a treatment recommendation entirely absent from NCCN guidelines. These included recommendations of novel therapies, or curative therapies for non-curative cancers. The authors emphasized that this form of misinformation can incorrectly set patients’ expectations about treatment and potentially impact the clinician-patient relationship.
Going forward, the researchers are exploring how well both patients and clinicians can distinguish between medical advice written by a clinician versus a large language model (LLM) like ChatGPT. They are also prompting ChatGPT with more detailed clinical cases to further evaluate its clinical knowledge.
The authors used GPT-3.5-turbo-0301, one of the largest models available at the time they conducted the study and the model class that is currently used in the open-access version of ChatGPT (a newer version, GPT-4, is only available with the paid subscription). They also used the 2021 NCCN guidelines, because GPT-3.5-turbo-0301 was developed using data up to September 2021. While results may vary if other LLMs and/or clinical guidelines are used, the researchers emphasize that many LLMs are similar in the way they are built and the limitations they possess.
“It is an open research question as to the extent LLMs provide consistent logical responses as oftentimes ‘hallucinations’ are observed,” said first author Shan Chen, MS, of the AIM Program. “Users are likely to seek answers from the LLMs to educate themselves on health-related topics — similarly to how Google searches have been used. At the same time, we need to raise awareness that LLMs are not the equivalent of trained medical professionals.”

Researchers at the University of California San Diego have uncovered a connection between the topography of the human genome and the presence of mutations in human cancer. They found that certain regions of the genome, which exhibit unique features, act as hotspots for the accumulation of mutations.
The findings, published recently in Cell Reports, shed light on how the 3D architecture of the human genome may play a role in the development of various forms of cancer.
The human genome is often visualized as the iconic DNA double helix, composed of long sequences of the letters A, C, G and T. “However, the genome is far more than that,” explained study senior author Ludmil Alexandrov, professor of bioengineering and cellular and molecular medicine at UC San Diego. “Like Earth with its diverse landscapes, the genome has a rich topography made up of different structures, shapes and features.”
For example, the genome contains sections where DNA tightly coils, as well as sections where it coils more loosely. Some sections are looped. The genome also possesses various features, such as one called replication timing, where certain regions of the genome are copied early during cell division, while other regions are copied much later.
Alexandrov’s team performed a comprehensive study of how this genomic topography influences where mutations in cancer arise across the human genome. Just as different terrains on Earth foster distinct ecosystems, certain topographic features in the genome seem to provide an environment for specific mutations to thrive.
“When studying the genome of a cancer, we usually assume that mutations accumulate randomly across that genome. However, this is not the case as different parts of the genome have different features,” said Alexandrov.
“With our topographic analysis, we show that certain mutations in cancer preferentially accumulate in certain regions of the genome,” said study first author Burçak Otlu, a former postdoctoral researcher in Alexandrov’s lab.

Gene therapy that induces the body to create microRNA-22 (miR-22), a naturally occurring molecule, successfully treated mice with hepatocellular carcinoma, the most common form of liver cancer.
The miR-22 treatment also reduced liver inflammation and produced better survival outcomes with no observable toxicity compared to the FDA-approved liver cancer treatment lenvatinib.
Those are the findings of a new study from the UC Davis Comprehensive Cancer Center published in Molecular Therapy.
“This research introduces miR-22 gene therapy as a promising and innovative approach for treating hepatocellular carcinoma,” said Yu-Jui Yvonne Wan, senior author of the study. Wan is a distinguished professor and vice chair for research in the UC Davis Department of Pathology and Laboratory Medicine. “The study’s findings suggest that miR-22 therapy could provide better survival outcomes, enhance anti-tumor immunity, improve metabolism and reduce inflammation.”
The University of California filed a patent application for Wan’s discovery of miR-22 for treating hepatic and metabolic diseases. The patent is currently pending.
MicroRNAs’ role in health and disease
MicroRNAs are small molecules that contain ribonucleic acid (RNA), a type of genetic material. MicroRNAs are widely found in plants and animals. They are “non-coding,” meaning they do not make proteins like some other RNA molecules.

Scientists from Nanyang Technological University, Singapore (NTU Singapore) have developed a flexible battery as thin as a human cornea, which stores electricity when it is immersed in saline solution, and which could one day power smart contact lenses.
Smart contact lenses are high-tech contact lenses capable of displaying visible information on our corneas and can be used to access augmented reality. Current uses include helping to correct vision, monitoring wearers’ health, and flagging and treating diseases for people with chronic health conditions such as diabetes and glaucoma. In the future, smart contact lenses could be developed to record and transmit everything a wearer sees and hears to cloud-based data storage.
However, to reach this future potential a safe and suitable battery needs to be developed to power them. Existing rechargeable batteries rely on wires or induction coils that contain metal and are unsuitable for use in the human eye, as they are uncomfortable and present risks to the user.
The NTU-developed battery is made of biocompatible materials and does not contain wires or toxic heavy metals, such as those in lithium-ion batteries or wireless charging systems. It has a glucose-based coating that reacts with the sodium and chloride ions in the saline solution surrounding it, while the water the battery contains serves as the ‘wire’ or ‘circuitry’ for electricity to be generated.
The battery could also be powered by human tears as they contain sodium and potassium ions, at a lower concentration. Testing the current battery with a simulated tear solution, the researchers showed that the battery’s life would be extended an additional hour for every twelve-hour wearing cycle it is used. The battery can also be charged conventionally by an external power supply.
Associate Professor Lee Seok Woo, from NTU’s School of Electrical and Electronic Engineering (EEE), who led the study, said: “This research began with a simple question: could contact lens batteries be recharged with our tears? There were similar examples for self-charging batteries, such as those for wearable technology that are powered by human perspiration.
“However, previous techniques for lens batteries were not perfect as one side of the battery electrode was charged and the other was not. Our approach can charge both electrodes of a battery through a unique combination of enzymatic reaction and self-reduction reaction. Besides the charging mechanism, it relies on just glucose and water to generate electricity, both of which are safe to humans and would be less harmful to the environment when disposed, compared to conventional batteries.”
Co-first author Dr Yun Jeonghun, a research fellow from NTU’s EEE said: “The most common battery charging system for smart contact lenses requires metal electrodes in the lens, which are harmful if they are exposed to the naked human eye. Meanwhile, another mode of powering lenses, induction charging, requires a coil to be in the lens to transmit power, much like wireless charging pad for a smartphone. Our tear-based battery eliminates the two potential concerns that these two methods pose, while also freeing up space for further innovation in the development smart contact lenses.”

Women with ME/CFS tend to have more symptoms and co-occurring conditions than men, according to initial results from the world’s largest study of the disease.
It has long been known that women are more likely to have ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome) but the DecodeME study has shown for the first time how their experience differs from men.
The study reveals that women who have ME/CFS — a long-term neurological condition where an excessive increase in symptoms can be triggered by normal levels of exertion — for more than 10 years are more likely to experience increasingly severe symptoms as they age.
Experts say that gaining a better understanding of how ME/CFS affects people is the first step to developing effective treatment options.
To aid their efforts, the study team from the University of Edinburgh are calling on more people with ME/CFS, aged 16 and over and based in the UK to take part in the study.
Experts analysed anonymous survey questionnaires from more than 17,000 people with ME/CFS. They included information on how long the respondent has had ME/CFS symptoms, when they were diagnosed, and whether they had any co-occurring conditions.
The study confirmed the well-established sex bias amongst ME/CFS patients, with women making up 83.5 per cent of respondents.