Mount Sinai Neuroscience Student Earns NIH Fellowship to Study Substance Use Disorders

Oct 29, 2021 | Diversity and Inclusion, Featured, Research

Can the bacteria in your gut influence addictive behavior? That is the question that Katherine Meckel is studying and trying to answer. Currently a fifth-year PhD candidate in neuroscience at the Icahn School of Medicine at Mount Sinai, Ms. Meckel is one of 31 young scientists from across the country to be honored with the National Institutes of Health (NIH) Blueprint Diversity Specialized Predoctoral to Postdoctoral Advancement in Neuroscience (D-SPAN) Award.

The award will provide Ms. Meckel with a six-year, $447,000 fellowship to fund the remaining two years of her PhD studies, as well as four years of postdoctoral research. The D-SPAN Award recognizes outstanding trainees from historically underrepresented communities in the sciences.

Working in the lab of Drew D. Kiraly, MD, PhD, Ms. Meckel is drawing upon her background in gastroenterology and neuropharmacology to study the effects of the gut microbiome on gene expression and behavior in a rodent model of cocaine use disorder.

“When we look at human patients and also animal models of substance use disorders, we see highly altered gene expression in response to cocaine and other drugs of abuse,” she explains. “This seems to emerge from long-term adaptations or ‘molecular scars’ which affect the ability of gene sequences in the DNA to be accessed and expressed. My work seeks to understand how gut bacteria and the metabolites they produce regulate the structure and accessibility of the DNA, influencing gene expression and ultimately drug-seeking behaviors.”

Dr. Kiraly, her dissertation advisor, praises her tenacity in establishing a new line of research within the field of neuroscience. “Katherine has generated a tremendous amount of exciting data, which provides insight into the mechanisms of gut-brain communication,” says Dr. Kiraly, Assistant Professor of Psychiatry, and Neuroscience, at Icahn Mount Sinai. “Her work holds potential to uncover novel pathways for drug development, which may one day lead to much-needed treatments for patients with substance use disorders.”

Trusting Her Gut Intuition

As an undergraduate, Ms. Meckel pursued a rigorous five-year dual degree program in Voice Performance and Biochemistry at Lawrence University in Appleton, Wisconsin. There, she conducted neuropharmacology research under Bruce Hetzler, PhD, studying the effects of methylphenidate (Ritalin) on rodent behavior and visual processing.

After graduating, she joined the Section of Gastroenterology at the University of Chicago, working under Joel Pekow, MD, and Marc Bissonnette, MD, to study the effects of diet and metabolism on inflammatory bowel disease and colorectal cancer.

Ms. Meckel credits her time in gastroenterology for encouraging a more integrative physiological approach, which now informs her studies. “Often times in neuroscience, we study the brain in isolation,” she says. “But it’s important to consider that the brain exists in communication with the other peripheral organs throughout the body, and they influence each other’s activity.”

Building Community for Students With Disabilities

Ms. Meckel has also emerged as a leader in disability rights since joining Icahn Mount Sinai. Together with classmates Jessica Pintado Silva and Marisa Goff, she co-founded Disability Rights, Education, and Awareness at Mount Sinai (DREAMS), which provides peer mentoring and support to graduate students with visible and invisible disabilities.

“As a queer, disabled individual, I often compare living with invisible chronic illness to ‘being in the closet.’ If you didn’t know me well, you probably wouldn’t realize I am disabled,” she says. “But much of my life outside of lab is characterized by managing chronic health flares.”

Ms. Meckel expressed gratitude to her advisors and the National Institute of Neurological Disorders and Stroke for supporting her training. “I hope that my experience inspires disabled and chronically ill trainees to continue in the sciences,” she says. “So we can share our unique perspectives and bring new innovation to STEM.”

Mount Sinai Researchers Describe a Novel Approach to Harness Fecal Microbiota Transplantation That Could Be Safer and More Precise

Oct 8, 2021 | Featured, Research

In a study published in Nature Microbiology, researchers at the Icahn School of Medicine at Mount Sinai address unanswered questions about how fecal microbiota transplantation (FMT) can effectively restore a patient’s microbiome.

Ari Grinspan, MD

FMT involves transferring processed stool collected from a healthy donor into the intestinal tract of a patient in order to replace the existing microorganisms in the intestinal tract and treat Clostridioides difficile infection (CDI). FMT helps to restore the balance of “good” and “bad” bacteria in the colon, which can help patients fight off infections.

“This is big news for patients and providers. While FMT is effective for CDI, it is a crude treatment, fraught with challenges including access and safety concerns.  We have identified a select group of bacteria in a real-life human study that can serve as an ideal starting point for a synthetic FMT product–without the ‘fecal’ component,” says Ari Grinspan, MD, Associate Professor of Medicine, Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, a co-author of the study.

Studies have shown how a healthy patient’s gut microbiota after transplantation resembles that of a healthy donor. However, these studies have failed to answer a very basic question: Which individual bacterial strains are actually transferred to the recipient’s gut microbiota and for how long?

Jeremiah Faith, PhD

“Knowing which bacterial strains are transferred to the recipient gut microbiota is critical to our understanding of why some patients respond to FMT and others do not,” says Jeremiah Faith, PhD, Associate Professor, Precision Immunology Institute and the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, senior author of the study.

Dr. Faith and his team of researchers isolated and sequenced the whole genomes of 2,987 bacterial isolates representing 1,008 unique strains from 9 FMT healthy donors and 13 recurrent CDI FMT recipients, while also developing an algorithm to track sequenced bacterial strains and metagenome, thus allowing them to pinpoint strains that will be most effective in treatment.

They rigorously validated and benchmarked the algorithms and showed that most FMT donor strains (more than 70 percent) and a minority of recipient strains (less than 25 percent) are retained for at least five years after FMT in non- relapsing patients.

Several U.S. Food and Drug Administration (FDA) advisories have recently reported severe adverse events from FMT, increasing safety concerns around undefined FMT, which uses the entire stool. Isolating and identifying the strains that are transferred from FMT donors to recipients could lead to a potentially safer alternative to FMT, according to the researchers.

The study received funding support from the Crohn’s & Colitis Foundation; the National Institutes of Health; and a SUCCESS philanthropic award funded by the Bacchetta Foundation.

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Brain Researcher Ian Maze Has Upended Scientific Dogma and Forged New Areas for Therapeutic Discovery

Oct 7, 2021 | Featured, Research

Ian Maze, PhD

For decades, scientific dogma held that the chemicals dopamine and serotonin served as messengers within the central nervous system, allowing brain cells, or neurons, to communicate with each other. Known as neurotransmitters, dopamine and serotonin also contribute to drug addiction and depression.

But neuroscientist Ian Maze, PhD, had a nagging suspicion there was more to their story, and when he established his lab at the Icahn School of Medicine at Mount Sinai in 2014, he began to build tools that would enable him to explore the full range of their power.

Today, his research has upended the scientific dogma about dopamine and serotonin, showing that in addition to their role as messengers, the chemicals are able to change the fundamental biology and behavior of brain cells.

His significant discovery opens new avenues for research into other neurotransmitters in the human body, including histamine and norepinephrine, and new possibilities for treating a range of diseases. These include post-traumatic stress disorder, Parkinson’s disease, and even breast cancer and gastrointestinal disorders, which can be associated with a large buildup of serotonin in the cells.

In September, Dr. Maze, Associate Professor of Neuroscience, and Pharmacological Sciences, at Icahn Mount Sinai, was named a Howard Hughes Medical Institute Investigator (HHMI), a highly selective and prestigious award that will provide his lab with millions of dollars in funding and support for years to come.

“This is a tremendous honor,” says Dr. Maze, who received his doctoral degree at Mount Sinai under the mentorship of Eric J. Nestler, MD, PhD, Dean for Academic and Scientific Affairs, Director of The Friedman Brain Institute, and the Nash Family Professor of Neuroscience. “I received this award after running my lab for only seven years, so I feel pretty humbled to be in this position and to be able to tackle these high-risk high-reward types of projects.”

Recently, Icahn Mount Sinai launched the Center for Neural Epigenome Engineering, which will be led by Dr. Maze. The Center will investigate the mechanisms responsible for neurodevelopmental and neuropsychiatric illnesses using chemical-biology and protein-engineering technologies and facilitate the development of more targeted neurotherapeutics.

“I think we need to put out the best data that we can and inspire people from all disciplines…I’m all about sharing our resources and tools to get people to help us move it forward. I want to see this grow and see what the implications are for improving human health.” — Ian Maze, PhD 

Training new scientists to think independently and follow their “gut” instinct is important to him. So is collaborating with other labs, which will help answer the many questions raised by his latest research.

Dr. Maze says his persistent investigation into dopamine, serotonin, and other monoamine neurotransmitters happened serendipitously, following a conversation he had with a former colleague, who mentioned a paper on the subject published a decade earlier that Dr. Maze had not seen.

That is when the “light bulbs went off,” he recalls. “So then it was an obsession. The initial years in the lab, the pursuit was so—you can’t describe it, it was so exciting. That’s how science goes. You build upon things that people have done and you put together connections that maybe other people weren’t putting together and then you test it.”

He believes his areas of expertise, in molecular neuroscience and chromatin biochemistry, provided him with a unique perspective from which he was able to view these chemicals from the inside out, and he integrated the latest biochemical approaches and techniques to analyze them in a way that had not been done before.

His lab extracts proteins from brain cells in animal models and postmortem tissues and examines how they are chemically modified or changed. By now, the team has characterized thousands of modified proteins using mass spectrometry and other approaches, and they continue to search for new protein modifications and how they affect brain cells.

“When scientists identify a new type of chemical modification they often characterize it on one or a handful of proteins, but think about all the proteins out there that could be modified, and they all have different functions and different outcomes depending on their regulation,” says Dr. Maze.

One of his goals is to build out large-scale genetic modeling systems that would allow him to organize and categorize all of these chemical modifications on proteins, something he says HHMI would also like to see. “Our challenge is trying to figure out how we tackle this in a more comprehensive way.”

Another avenue of research will be exploring specific categories of drugs that may also function by directly or indirectly modifying proteins in our cells. In a 2020 study on cocaine dependence in Science, Dr. Maze and his team showed that by manipulating these types of marks in the brain’s reward circuitry in animal models they could reduce the tendency to relapse into addiction.

Dr. Maze says the new Center for Neural Epigenome Engineering and his lab will “continue to work in the brain and collaborate with other neuroscientists to build out different disease and developmental models.” His lab will continue to focus on substance use disorder, depression and post-traumatic stress disorders and improving current treatments, which are ineffective for many people. But he hopes specialists in other areas of the body will join in this search, as well.

“I think we need to put out the best data that we can and inspire people from all disciplines,” he says. “I’m all about sharing our resources and tools to get people to help us move it forward. I want to see this grow and see what the implications are for improving human health.”

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Higher Risk of Autism Found in Babies Born Prematurely According to a Definitive New Mount Sinai Study

Sep 21, 2021 | Featured, Psychiatry, Research

Premature birth is linked to an increased risk of autism spectrum disorder (ASD) in both males and females, with those born earliest carrying the highest risk, according to a large and definitive new study in Pediatrics from the Icahn School of Medicine at Mount Sinai. ASD, a disability associated with social, behavioral, and communication challenges, affects nearly one in 54 children in the United States.

The research found that children born between 22 and 27 weeks gestation had nearly four times the risk of developing ASD than children born full-term, between 39 and 41 weeks. Even babies born early-term—at 37 to 38 weeks—carried a 10 percent to 15 percent higher risk of ASD when compared to full-term births.

According to the Centers for Disease Control and Prevention, most children are diagnosed with ASD after the age of four, and boys are more likely to be diagnosed than girls. But an important takeaway from the Mount Sinai study is the need for parents and pediatricians to carefully monitor all premature babies, says the study’s lead author, Casey Crump, MD, PhD, Vice Chair for Research in the Department of Family Medicine and Community Health, and Professor of Epidemiology, Department of Population Health Science and Policy, Icahn Mount Sinai.

Casey Crump, MD, PhD

“Both preterm and early-term births should now be recognized as independent risk factors for autism in both males and females,” say Dr. Crump. “Children born prematurely need early evaluation and long-term follow-up to facilitate early detection and treatment of autism. Hopefully, our findings will help raise awareness of that.”

Dr. Crump and researchers at Lund University in Sweden examined the population records of more than 4 million Swedish individuals across a 30-year period and found the prevalence of ASD was directly related to gestational age. While the risk of ASD in children born between 37 and 38 weeks gestation is relatively modest, he says, the high numbers of children born during that gestational window make it notable.

In reaching their conclusions, the researchers compared siblings within families and were able to control for genetic and environmental factors, which strengthened the link between prematurity and ASD. The researchers also paid attention to these patterns in premature females, a group that had not been studied as extensively as males.

According to Dr. Crump, the study is meant to raise awareness but not alarm parents of premature babies. “Most of these children do very well across their lifespans,” he says.

Yet, “Preterm birth can interrupt or delay the development of all organ systems, such as the cardiovascular system and kidneys, as well as the neurological system,” he adds. For example, the weight of the human brain increases by nearly one-third between 34 and 40 weeks gestation, with significant increases in the volume of white and grey matter. Additional research has shown that the preterm brain is exposed to an inflammatory environment, which could result in a cascade of neuronal injury and alterations that occur prior to birth.

“Parents of children born preterm should be extra careful that their children have close clinical follow-up with physicians who are aware of these issues and can refer them to specialists,” says Dr. Crump. “Earlier detection leads to earlier treatments, which can improve outcomes. Gestational age at birth should certainly be tracked in the medical records to facilitate identification of these people across their life course.”

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Pandemic’s Toll on Mount Sinai Front-Line Staff Is Surveyed, and Addressed

Updated on Jun 30, 2022 | COVID-19, Featured, Mental Health, Psychiatry, Research

Recharge rooms were created across the Health System in one of many initiatives informed by surveys of front-line staff.

Front-line staff who were already feeling burnout showed the most signs of mental distress during the height of the COVID-19 pandemic, while those who fared best had an active social network and felt supported by their supervisors. These were among the many lessons learned by a team of Mount Sinai researchers based on two surveys of front-line Mount Sinai staff in 2020.

“The main takeaway is what most people would expect—that if you’re involved in health care during a pandemic, it’s going to take its toll,” says Jonathan Ripp, MD, MPH, Dean for Well-Being and Resilience and Chief Wellness Officer at the Icahn School of Medicine at Mount Sinai. “But beyond that, we were able to identify what types of things may put you at greater or lesser risk of these mental health outcomes, and inform how we can try to mitigate them.”

The results were used in real time to develop programs to help Mount Sinai staff handle the pressures of the pandemic, Dr. Ripp says, and they are being shared with other institutions through journal publications and a Well-Being Toolkit developed by the Office of Well-Being and Resilience.

The three mental health outcomes studied were depression, anxiety, and post-traumatic stress disorder related to the COVID-19 pandemic. Among the more than 3,000 front-line staff members who responded to an initial survey in April and May 2020, 39 percent screened positive for at least one of these outcomes. The most significant factor predicting mental health symptoms was the presence of pre-pandemic burnout, according to studies published by the Mount Sinai team in The Journal of Clinical Psychiatry and Chronic Stress.

At the start of the pandemic, Mount Sinai focused on meeting the basic needs of front-line staff, such as providing free or subsidized food onsite.

“This means that if you already felt exhausted, fatigued, and detached from your work, you were more likely to develop these mental health symptoms during the pandemic,” says investigator Lauren Peccoralo, MD, MPH, Senior Associate Dean for Faculty Well-Being and Development, and Associate Professor of Medicine at the Icahn School of Medicine at Mount Sinai. The research team emphasized that burnout is distinct from other mental health issues in that it is more a function of the work environment, and can be remedied by strategies that support workers.

In the earliest days of the COVID-19 pandemic, the Office of Well-Being and Resilience assembled a group of researchers with backgrounds in psychology, psychiatry, survey design, and statistical analysis to examine its mental health consequences on the workforce, in an effort initiated by Dennis S. Charney, MD, Anne and Joel Ehrenkranz Dean, Icahn School of Medicine at Mount Sinai, and President for Academic Affairs, Mount Sinai Health System.

The group sent surveys to more than 6,000 physicians, nurses, social workers, chaplains, and other front-line staff at The Mount Sinai Hospital during the height of the pandemic’s first wave in April and May 2020 and again seven months later. In the first survey, more than 3,000 respondents answered questions from three diagnostic series: the General Anxiety Disorder 7, the Personal Health Questionnaire 8, and the Post Traumatic Stress Disorder checklist. In the self-screening for depression, for example, about 26 percent of respondents reported that on more than half the days of the week, they felt such symptoms as taking little interest or pleasure in doing things, feeling hopeless, losing their appetite, having trouble staying or falling asleep, or difficulty concentrating.

The survey also asked open-ended questions about the respondents’ concerns. “There were a lot of infection-related worries. People were worried about PPE, about infecting colleagues or bringing COVID-19 home to their family members,” says Jordyn Feingold, MD, an investigator in the study, who graduated from Icahn Mount Sinai in May 2020 and is now a psychiatry resident. “There were worries about basic needs like getting food at work, and existential worries like ‘When is this going to end?’ and ‘When is life going to return back to normal?’”

The aid facilitated by the research team fell into three categories: providing basic needs like food and the proper personal protective equipment (PPE) and other materials; providing up-to-date information through channels including web sites and system-wide email broadcasts; and creating well-being spaces and onsite mental health and peer support to reduce the stress experienced by health care workers.

A Second Survey Finds an Increase in Burnout

The surveys also asked questions related to resilience, Dr. Ripp says. Specific factors that were found to be protective against mental health symptoms included getting enough sleep and exercise, having social emotional support, not using substances to cope, having sufficient PPE, and feeling supported by hospital leadership and valued by supervisors.

Simply feeling heard was also important, Dr. Feingold says. “Whether or not we have it in our control to fix all of these things right away,” she says, “just validating the concerns and letting people know that they’re not experiencing this in isolation, I think was really powerful.”

In the second survey, conducted from November 2020 to January 2021, more than 1,600 responded and of those, 786 staff provided follow-up responses on their mental health and well-being. The results indicate that mental health symptoms have declined, but the prevalence of burnout has increased, Dr. Peccoralo says. “We are still analyzing the data, but one thought is that the traumatic situation has largely gone away, but the work hasn’t. We’re all still working really hard, maybe even harder than we have ever worked before,” she says. “So we have to think about how we can tell if we are pushing people too much, and what we can do about it.”

The surveys have served an important role in helping Mount Sinai take care of its own, and in advancing knowledge of the mental health consequences of responding to a pandemic, Dr. Ripp says.

The needs identified in the surveys have informed the development of new initiatives, including the launch of the Center for Stress, Resilience, and Personal Growth, says its Clinical and Research Director, Jonathan DePierro, PhD, Assistant Professor of Psychiatry at the Icahn School of Medicine at Mount Sinai. The Center is an innovative service supporting the resilience and psychological health of all Mount Sinai faculty, staff, and trainees through a series of evidence-based resilience workshops, a resilience-promoting app available for download on Sinai Central, ongoing outreach efforts, and up to 14 treatment sessions in its confidential faculty practice.

“Let’s hope that it’s a very long time before something like this pandemic happens again, but should it happen, I think the lessons that we’ve learned can apply,” Dr. Ripp says. “And then of course we can share those lessons, so that other institutions that haven’t had the opportunity to study this trajectory can learn from our experience.”

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Mount Sinai Creates COVID-19 Vaccine for Low- and Middle-lncome Countries

Updated on Jun 30, 2022 | Featured, Research, School

An effective COVID-19 vaccine developed by scientists, from left, Florian Krammer, PhD; Adolfo García-Sastre, PhD; and Peter Palese, PhD, could help ease the shortage of vaccines available to low-and-middle-income countries.

The development of a safe, effective, and inexpensive COVID-19 vaccine that can easily be produced and distributed in low- and middle-income countries is underway at the Icahn School of Medicine at Mount Sinai, where early phase 1 clinical testing in Vietnam and Thailand has shown positive results.

The vaccine is the brainchild of three renowned scientists at Mount Sinai—Peter Palese, PhD, Horace W. Goldsmith Professor and Chair of the Department of Microbiology; Adolfo García-Sastre, PhD, Irene and Dr. Arthur M. Fishberg Professor of Medicine and Director of the Global Health and Emerging Pathogens Institute; and Florian Krammer, PhD, Mount Sinai Professor in Vaccinology. By combining their expertise, the scientists—who previously developed a universal influenza vaccine—hope to bring closure to this deadly pandemic by providing less affluent countries with an accessible and cost-effective COVID-19 vaccine they can manufacture themselves.

To date, the World Health Organization has distributed only 90 million vaccine doses to 131 countries, far short of the number needed to stop the spread of SARS-CoV-2, the virus that leads to COVID-19. More contagious variants of the virus will continue to evolve and plague countries around the world as long as their populations remain unvaccinated. “When we protect other countries we protect ourselves, as well,” says Dr. Palese.

Dr. Krammer says, “In North America and Europe many people are getting vaccinated and the virus circulation is going down. But that is not the case in countries in Asia or Latin America, for example. Their COVID-19 case numbers are going up quickly. They need a vaccine and they don’t have access.”

Anticipating this need, Dr. Palese and his colleagues designed Mount Sinai’s COVID-19 vaccine to use the avian Newcastle virus (NDV), and constructed it similarly to an influenza virus vaccine, which can be manufactured in embryonated or fertilized chicken eggs.

Mount Sinai’s COVID-19 vaccine, which would require two doses, could be made using the same influenza vaccine production facilities that many countries already have in place.

The NDV-based vaccine is engineered to express the spike protein of SARS-CoV-2. The construct is injected into an embryonated egg, the virus replicates, and the amplified vaccine virus is then collected, purified, and inactivated. According to Dr. Palese, the resulting vaccine is stable, extraordinarily immunogenic, and induces highly protective immune responses against SARS-CoV-2. Immunogenicity is a measure of the type of immune responses that a vaccine generates and their magnitude over time.

“The beauty of this vaccine is that it can be made using the same influenza vaccine production facilities that many countries already have” in place, Dr. Krammer says. Approximately three billion doses of flu vaccine are produced each year using embryonated eggs.

There are other advantages, as well. Mount Sinai’s Newcastle vector vaccine does not appear to cause any side effects, such as the low-grade fevers, headaches, or pain and swelling at the injection site that are associated with the Moderna and Pfizer-BioNTech mRNA vaccines. The vaccine can also be stored at the same temperature as a home refrigerator, whereas both mRNA vaccines require extra-cold temperatures found only in commercial-grade freezers.

Mount Sinai’s vaccine, says Dr. Palese, can “probably be produced for under one dollar per dose,” and will require two doses spread over 21 days. By comparison, the mRNA vaccines, which also require two doses spread over three to four weeks, cost roughly $50 per dose. To keep costs down, Mount Sinai has agreed to grant licenses for its intellectual property to low- and middle-income countries that produce the vaccine and forgo any royalties on its use.

Dr. Garcia-Sastre says, “Prior to COVID-19, we realized the potential of NDV-based vaccines and for several years optimized this vaccine vector to achieve optimal immunogenicity of the delivered antigen (or toxin). NDV-based vaccines not only have the potential to stop COVID-19 in countries that have no access to the existing SARS-CoV-2 vaccines, but  could be easily tailored to stop future pandemics caused by novel pathogens.”

As phase 2 testing for the vaccine ramps up in Thailand and Vietnam, accelerated phase 1 trials are ongoing in Mexico and Brazil. The trial designs used in these countries should lead to rapid phase 3 results. So far, the scientists say they have been pleased with their phase 1 results and with the tests that have been conducted in animal models.

“You can say that in animals, the vaccine protects beautifully,” says Dr. Krammer. “There is preliminary immunogenicity data that suggests the vaccine induces very good neutralizing titers.”

It is not yet clear whether the current vaccine will need to be updated to protect against aggressive new variants, according to Dr. Krammer. “But if it’s needed, we can change and move quickly to a variant vaccine. It would not be complicated.”

With regard to safety, which is top priority in a phase 1 trial, Dr. Palese says, “We are passing with flying colors.”

 

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