Scientific and Medical Breakthroughs
A New Tool for Exploring the Role of the Genetic On/Off Switch DNA Adenine Methylation in Health and Disease
(Science February 4, 2022) Gang Fang, PhD, Associate Professor of Genetics and Genomic Sciences
A small group of cutting-edge medical researchers has been trying to study whether a genetic on/off switch that is often studied in bacteria may also play role in human health and disease. The switch relies on a biochemical DNA tagging system called adenine methylation, or “6ma” for short. To help with this, the Fang Lab created 6maSCOPE: a new method for accurately measuring the levels and cell sources of 6ma. This involved the customization of an advanced gene-sequencing method and the development of a machine learning algorithm. Initial results suggested that 6maSCOPE accurately distinguished bacterial 6ma levels from that seen in human and other non-bacterial cells, including brain cancer cells. Overall the results could help scientists evaluate the role 6ma may play in a variety of diseases.
A Population-Based Approach to Assessing Pathogenic Genetic Variant Risk
(JAMA January 25, 2022) Ron Do, PhD, Associate Professor of Genetics and Genomic Sciences and a member of The Charles Bronfman Institute for Personalized Medicine
Over the past couple of decades, scientists have discovered hundreds of thousands of pathogenic genetic variants, or disease-causing mutations. However, due to the nature of these discoveries, it has been difficult to provide accurate statistics on the chances that a variant could cause a disease. To address this, the Do Lab analyzed the DNA sequences and electronic health record data of thousands of individuals stored in two massive biobanks. They found that the average chance a variant may cause a disease is relatively low—about 7 percent. Nevertheless, they also found that some variants, such as those associated with breast cancer, are linked to a wide range of risks for disease. The results could alter how variant risks are reported, and one day help physicians interpret genetic testing results.
Multi-Organ Gene Networks May Explain Many Cases of Arteriosclerosis
(Nature Cardiovascular Research, January 12, 2022) Johan L.M. Bjorkegren, MD, PhD, Professor of Genetics and Genomic Sciences, and Medicine (Cardiology)
Working with researchers in Sweden, Estonia, and Australia, the Bjorkegren Lab found that up to 60 percent of the risk associated with coronary arteriosclerosis may be explained by changes in the activity of hundreds of genes working together across the body in multi-organ networks that resemble air traffic maps. Fat processing hormones may play a central role in coordinating this activity. The study involved 850 Estonian patients who were part of the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) study. The researchers studied the gene activity across seven different tissues obtained during open breast surgery. The full results are publicly available for other researchers to explore. The Bjorkegren Lab hopes that these results may give researchers the tools they need to reduce the burden of coronary artery disease throughout the world.
How Wavy Extracellular Matrix Fibers May Keep Metastatic Cancer Cells Dormant
(Nature Cancer, December 13, 2021) Jose Javier Bravo-Cordero, PhD, Associate Professor of Medicine (Hematology and Medical Oncology) at The Tisch Cancer Institute at Mount Sinai
Most cancer deaths are caused by metastatic tumors, or cancer cells that spread to other parts of the body. These cells can remain dormant for many years before they reappear as tumors. The Bravo-Cordero Lab discovered a new biochemical pathway that may control this process. Initial results showed that secretion of the protein collagen III played a key role. High levels of collagen III were associated with dormancy and wavy shaped extracellular matrix (ECM) fibers whereas low levels were associated with cancer cell growth and strait ECM fibers. Further experiments suggested that secretion may be controlled by a positive feedback loop involving collagen III, the collagen III receptor DDR1, and the transcription factor STAT1. Understanding this pathway may help with the development of new treatments and diagnostics for metastatic cancers.
Our Brains May Use Forward Thinking to Persuade Others
(eLife, October 29, 2021) Xiaosi Gu, PhD, Director of the Center for Computational Psychiatry, and Associate Professor of Psychiatry, and Neuroscience
The Gu Lab showed for the first time that our brains may use forward thinking when trying to sway others. For years, scientists knew that forward thinking is used in non-social situations, such as navigating a new hiking trail or planning a vacation. This study showed that it may also be used in social situations, specifically when one tries to exert “social control.” The study relied on a bargaining game played both in person and online. Brain scans suggested that the ventromedial prefrontal cortex, a decision-making center known to be involved in forward thinking, may play a role in social control. Social control plays a role in mental health and well-being. The researchers plan to investigate whether forward thinking plays a role in depression, schizophrenia, and other psychiatric disorders.
The Long-Term Effects of Long COVID
(American Journal of Physical and Rehabilitation Medicine, October 21, 2021) David Putrino, PhD, Director of Rehabilitation Innovation for the Mount Sinai Health System, and Assistant Professor of Rehabilitation Medicine
In a study of 156 patients, Mount Sinai researchers found that patients experiencing post-acute COVID syndrome (PACS, also known as Long COVID) may have symptoms—including fatigue, headaches, and brain fog—for at least 12 months after initial COVID-19 infection. This appeared to disrupt their ability to work, think, and engage in physical activity. The results may help researchers better understand the full impact that long COVID could have on patients.
The Warrior Watch Study and the Utility of Wearable Devices in Combating COVID-19
(Journal of Medical Internet Research, February 23, 2021; Journal of Medical Internet Research, September 13, 2021) Robert P. Hirten, MD, Assistant Professor of Medicine (Gastroenterology); Zahi Fayad, PhD, Director of the BioMedical Engineering and Imaging Institute and the Lucy G. Moses Professor of Medical Imaging and Bioengineering
With the help of a new heart-beat monitoring smartwatch app, Mount Sinai researchers were able to diagnose COVID-19 infections earlier than currently used methods. It also helped determine that factors such as resilience and strong emotional support may have protected some health care workers from the stress they experienced during intense periods of COVID-19 hospitalizations. These findings and the development of the app are part of Mount Sinai’s Warrior Watch Study. The study involves Mount Sinai Health System health care workers who were given an Apple Watch loaded with a custom-made app, designed by Mount Sinai researchers to take a wearer’s pulse. In one study, changes in pulses were found to be a hallmark of whether a worker was infected. Similarly, the other study used changes in heart rates as marker for stress levels. Overall, the results supported the utility of wearable device technology in medical research.
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A Labor-Saving Algorithm for Electronic Health Records Research
(Patterns, September 2, 2021) Benjamin S. Glicksberg, PhD, Assistant Professor of Genetics and Genomic Sciences, a member of the Hasso Plattner Institute for Digital Health at Mount Sinai
The Glicksberg Lab created a new, automated, artificial intelligence-based algorithm that can learn to read patient data from electronic health records. In a side-by-side comparison, Mount Sinai researchers found that their method, called Phe2vec (FEE-to-vek), accurately identified patients with certain diseases as well as the traditional, more labor-intensive “gold-standard” method. The method relied on unsupervised machine-learning algorithms. The results suggested that this and other automated architectures for disease phenotyping may help researchers use electronic health records to study disease complexity and improve clinical practice and medical research.
Unraveling the Early Stages of Dementia in Cerebral Organoids
(Cell, July 26, 2021) Alison M. Goate, DPhil, Director, Ronald M. Loeb Center for Alzheimer’s disease at Mount Sinai, and Chair of Genetics and Genomic Sciences
By growing special types of genetically engineered cerebral organoids in petri dishes, scientists in the Goate Lab were able recreate much of the damage seen in a form of frontotemporal dementia (FTD). This form of the disease is caused by a mutation in the gene for tau, a protein that is a hallmark of Alzheimer’s disease and other dementias. The scientists not only discovered how the mutant protein may trigger the death of a specific class of neurons but also how an experimental Crohn’s disease drug may prevent cell death. This is just one of the many ways that the Goate Lab is trying to use genetics as a guide to studying the biochemical pathways that may underlie the damage caused by Alzheimer’s disease and other forms of dementia.
Discovery of a Candidate Enzyme for Combating Optic Nerve-Based Vision Disorders
(Cell, July 22, 2021) Bo Chen, PhD, Associate Professor of Ophthalmology, and Neuroscience, and Director of the Ocular Stem Cell Program
The Chen Lab found that the activity of an enzyme called calcium calmodulin II (CaMKII) and its downstream biochemical reactions may play a critical role in the survival of retinal ganglion cells. These cells relay signals from the eye to brain via the optic nerve. In experiments on mice, the researchers found that genetic activation of CaMKII prevented the type of cell death and vision loss that is often seen in glaucoma and other vision robbing injuries. The results may one day lead to the development of novel therapies for combating optic nerve-based vision disorders.
The Merad lab found that immune cells in the lung may be tricked into helping tumors attack. The researchers used single cell sequencing to study the role that immune cells known as macrophages may play in human and mouse non-small cell lung carcinoma lesions. The results suggested that during the early stages of lung cancer, the tumors recruit macrophages to help with the invasion, including allowing harm to lung tissue and hiding the cancer cells from the rest of the immune system. The results highlight the importance that the surrounding tumor microenvironment may play in cancer cell growth and may provide new avenues for treatment.
Scientists in the Kenny Lab showed how ancestral genes may be used to obtain a more accurate picture of ethnicity and locate the groups of patients who are most susceptible to certain diseases. The study involved searching the data of 30,000 patients stored in the Mount Sinai Health System’s BioMe™ BioBank program for ancestral stretches of the genome, or “long haplotypes,” which were shared among the patients. The results suggested that this approach produced a more accurate picture of a person’s background than traditional racial and ethnic classifications—such as Hispanic or South Asian—and that about 96 percent of the patients came from 17 different ethnic backgrounds. The team then used these results to remap the health risks of each group of patients. This led to the discovery of new risks for some groups of patients.
Development of a Low-Cost, COVID-19 Vaccine That Can Be Manufactured in Low- and Middle-Income Countries
(EBioMedicine, November 21, 2020; Vaccines, December 17, 2020) Peter Palese, PhD, the Horace W. Goldsmith Professor and Chair of Microbiology; Florian Krammer, PhD, Professor in Vaccinology; Adolfo Garcia-Sastre, PhD, the Irene and Dr. Arthur M. Fishberg Professor of Medicine and Director of the Global Health and Emerging Pathogens Institute at Mount Sinai
Mount Sinai researchers are developing a low-cost COVID-19 vaccine that could help low- and middle-income countries. The vaccine they created works very much like those made by AstraZeneca and Johnson & Johnson, in that it uses a harmless viral vector to deliver genetic, cDNA instructions for the antigen spike proteins to cells. However, unlike the other ones, this vaccine employs the Newcastle disease viral vector system that is also used for manufacturing influenza viruses in the developing world. Stage III clinical trials are currently being conducted in Mexico, Thailand, Brazil, and Vietnam. The hope is these vaccines will help combat coronaviruses worldwide.
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