Miriam Merad, MD, PhD: Overcoming Doubt and Redefining Immunology

Nov 30, 2023 | Featured, Research

Miriam Merad, MD, PhD: Overcoming Doubt and Redefining Immunology

About 17 years ago, when Miriam Merad, MD, PhD, had barely started her lab at the Icahn School of Medicine at Mount Sinai to research macrophage lineages, she was having trouble attracting grants from the National Institutes of Health (NIH).

Macrophages are a group of immune cells found in all organs, constantly surveying for potential threats and ensuring elimination of damaged cells and dead cells. During her fellowship at Stanford University, Dr. Merad discovered that in contrast to the dominant understanding that macrophages are recruited from blood circulation, some macrophages are independently renewed locally in tissues. She hypothesized that these self-renewing macrophages played a key role for the maintenance of tissue integrity.

But knowledge and awareness of the topic were too nascent at the time, and there weren’t sufficient experts on the grant committees who recognized the value of the research, said Dr. Merad, who is now the Mount Sinai Professor in Cancer Immunology, Chair of the Department of Immunology and Immunotherapy, and Director of the Marc and Jennifer Lipschultz Precision Immunology Institute at Icahn Mount Sinai. For years, it was difficult to convince scientists of the importance of this cell lineage and secure funding. “While I was projecting confidence, I was doubting, too, whether I was on the right path,” said Dr. Merad.

Fast forward to October 2023, and that perseverance paid off: Dr. Merad was elected to the National Academy of Medicine (NAM), making her one of the few scientists at Mount Sinai to hold dual membership with the National Academy of Sciences, which she was elected to in 2020. The appointments were for her discovery of this new lineage, and that body of work has ignited research around the world on revealing the key role of macrophages in many key physiological processes, including preserving the vascular tone, promoting neuronal function, and contributing to tissue regeneration and repair via stem cell niches.

“Miriam Merad is one of the most renowned immunologist of her generation and has made seminal discoveries in our understanding of the embryonic origin of tissue-resident macrophages and the crucial contribution of these and related cells to the tumor microenvironment,” said Eric Nestler, MD, PhD, Dean for Academic Affairs of Icahn Mount Sinai and Chief Scientific Officer of the Mount Sinai Health System.

“These advances are now driving highly novel clinical trials for lung and other cancers. Mount Sinai is enormously proud of her accomplishments and the leadership role that she serves on campus,” said Dr. Nestler.

Switching Tracks

Early in her medical career, in France during the late 90s, Dr. Merad trained in allogeneic bone marrow transplants and saw how they essentially cured leukemia for some patients. As she moved onto the subject of solid tumors, she noted that the treatment landscape was bleak—especially for metastatic patients, for whom chemotherapy and radiation therapy had limited effect.

As she was studying tumor stains of her patients, Dr. Merad realized that in some tumor lesions, there were more immune cells than cancer cells, which led her to conclude that solid tumors could also be targeted by immune cells. Having come from the hematological oncology field, where immunotherapy had seen success, she saw the potential of tapping the immune system in tackling solid tumor cancers. And so Dr. Merad pursued a PhD at Stanford University to deepen her understanding of immunology, and began a research career in cancer vaccines.

At the time, researchers knew that dendritic cells—responsible for initiating all antigen-specific immune responses—could mount a response against cancer cells, but not enough was known about dendritic cells to harness them. Nor was there great interest in the related lineage of macrophages.

“I thought if we wanted to be serious in harnessing dendritic cells and macrophages to destroy tumor cells, we had to understand everything about these cells, including where they came from and why they accumulated in cancer tissues,” Dr. Merad said.

Persevering Through a Rocky Start

Dr. Merad’s research brought her to Icahn Mount Sinai, where she established a lab to study the lineages of tissue-resident macrophages. That journey had a rough start.

“I managed to produce some nice papers with my seed funding from Mount Sinai, but I had no money otherwise, and I needed more funding to carry out these big experiments that were needed,” she said.

The next step—obtaining formal proof that macrophages had a lineage independent of circulating immune cells existed—required a gene tracing experiment that traces the origin of the cells in the embryo. “It’s very technical research that requires the building of many new expensive tools and experimental models. I was spending a lot of money and I was not getting any grants,” Dr. Merad said.

In order to keep her lab aloft, Dr. Merad had to lay off two people in her group. “I was extremely saddened,” she said. “These people stuck with me through my research, and I kept saying what a fantastic job they were doing. And somehow I let them down.”

Thankfully, about a month later, the group had a big paper published in a leading scientific journal, and that recognition attracted two NIH grants, turning Dr. Merad’s lab around.

What kept Dr. Merad pushing forward was the belief in her research. “I knew the data was reproducible and would have an impact for sure. But new discoveries are always faced with some skepticism by the scientific community. I realized that I needed more successes to convince the community of the clinical relevance of the new discovery,” she said. Dr. Merad then examined the distribution and contribution of these new macrophages to different disease conditions, which gained traction, and now, nearly 15 years after the initial discovery, textbooks have been rewritten and graduate students are now taught about this lineage.

“But new discoveries are always faced with some skepticism by the scientific community. I realized that I needed more successes to convince the community of the clinical relevance of the new discovery.”

—Dr. Merad

“It had been an anxious three years of starting my journey. Despite all the anxiety and the doubts, I always felt strongly supported at Mount Sinai,” said Dr. Merad. In addition to the intellectual engagement she has received from her peers and lab group, she appreciated the support of Dennis Charney, MD, the Anne and Joel Ehrenkranz Dean of Icahn Mount Sinai, who emboldened her belief in her niche line of research.

“We’re from different fields,” she said of Dr. Charney, a psychiatrist, “and when I engaged him to explain my field and my research, he encouraged me to explore further.” Most deans usually don’t want to rock the boat, but Dr. Charney pushed me to find a way to bring the discovery to the clinic, Dr. Merad added.

That encouragement to keep probing despite uncertainty and doubt was why Dr. Merad stayed at Icahn Mount Sinai, even after her research took off, she said. “I came into science because I wanted to change medicine. Mount Sinai is exactly the environment that enables you to do so, aim big despite the uncertainty, and accomplish your dreams.”

A closer look at Dr. Merad's work

Brian Brown, PhD

Brian Brown, PhD, Professor of Genetics and Genomic Sciences, and Dermatology, and Associate Director of the Marc and Jennifer Lipschultz Precision Immunology Institute, explains why Dr. Merad’s body of work in immunology is so impactful.

“Dr. Merad’s work has transformed our understanding of an entire branch of the immune system, which is made up of cells called macrophages and dendritic cells,” said Dr. Brown.

These cells are found in all tissues of the body and influence virtually every disease. Macrophage and dendritic cells used to be thought of as having no variations, but Dr. Merad led the way in showing otherwise—they differ developmentally, reside in healthy and diseased tissues differently, and have different molecule programs, which also means they have different physiological functions.

Uncovering the diversity in these cells, especially at the molecular level, has had a profound impact in our thinking about what these cells do, including how they help fight infections, control tumor growth, or contribute to inflammation, Dr. Brown said. “She helped rewrite our textbook understanding of these cells and really about the immune system itself.”

Prominent papers from Dr. Merad include a 2010 Science study which revealed that adult microglia—primary immune cells of the central nervous system—derive from primitive macrophages, and the paper was cited nearly 3,000 times, according to the journal. Another 2010 Science paper on the development of monocytes, macrophages, and dendritic cells was cited nearly 2,000 times. Dr. Merad has published more than 250 articles, and her works have been cited over 82,000 times, according to Google Scholar.

Dr. Merad’s work on dendritic cells and macrophages has very broad implications for the treatment of many diseases, said Dr. Brown. In cancer, her work is helping therapies to be developed that can enhance immune responses in patient tumors, and clinical trials are running based on concepts and specific molecular pathways she has identified as being important. Similarly, in inflammatory diseases, Dr. Merad has been pioneering the use of single-cell analysis technologies to study disease, and this work has led to new ways to classify disease lesions and predict what types of drugs a patient might respond to, Dr. Brown noted.

The National Academy of Medicine (NAM) only admits 100 individuals each year, and membership is one of the highest honors for a scientist in health and medicine. NAM has more than 2,400 members, and Dr. Merad’s appointment brings Mount Sinai’s membership in this organization to 26 current and emeritus faculty members. Dr. Merad also holds joint membership in the National Academy of Sciences, which she was elected to in 2020.

Giving Thanks and Helping Kids Express Gratitude

Nov 21, 2023 | Featured, Your Health

With the holiday season upon us, it’s that time of year when we take a moment to reflect and give thanks for the wonderful blessings in our lives. We gather with family and friends to feast and celebrate, and we express our gratitude through acts of kindness and appreciation.

Children are excited for the big season ahead and the wonder of it all. But how do we encourage them to embrace and express gratitude—and not only now but all year round? It might be a bit of an abstract concept for some little ones.

There are many reasons why teaching kids gratitude is important, according to Aliza Pressman, PhD, co-Founding Director and Director of Clinical Programming for the Mount Sinai Parenting Center. She explains how practicing gratitude has been linked to many positive outcomes and ways to express gratitude.

“Gratitude is a value that your family can hold dear and practice together in various ways,” she says. “It can be a family tradition that is celebrated all year round. But it’s not just about teaching kids to say, ‘thank you.’ We all know that being grateful is about so much more than that. We need to ask kids ‘How did that make you feel?’ This way, they can start linking the emotion and the feeling of gratitude with the words.”

In addition, gratitude can have health benefits for kids—such as improved relationships, better physical health, reduced depression and anxiety, enhanced empathy, reduced aggression, better sleep, increased resilience, and improved performance at school or with chores at home.

Dr. Pressman suggests starting a “gratitude practice” in your own life, and modeling one for your children.

“Cultivating gratitude in our children balances the many challenges we all face, and helps to promote connected, grounded and involved citizens in our communities,” she says. “However, we sometimes fall into a trap of forcing a feeling of gratitude in our children and this is not something we can force.”

In fact, gratitude takes patience. “The benefits of a gratitude practice expand over time, unlike many of the quick fix or feel good solutions we usually turn to,” she says. “Effects of gratitude occur in the prefrontal cortex and make us more sensitive to emotional connectivity and relationships with others.”

Here are five ways we can help children learn to express gratitude:

Model saying “thank you” and help your child to thank others in whatever way they feel comfortable. Write thank you notes, make cards, or send videos to show others you are grateful for them. Sharing a message to say thank you means so much.

Use the phrase “I really appreciate” when noticing acts for which you are grateful.

Play the rose/thorn/bud game at the dinner table. For the rose, name one sweet part of the day. For the thorn, name one challenge. For the bud, name one thing you are excited for or are looking forward to.

Volunteer in your community. Find an opportunity to help others and discuss how that act adds value to your own life and a sense of purpose.

Create a gratitude journal that you fill out on holidays or special occasions. This can be a gratitude tree for Thanksgiving or a birthday gratitude journal. Have each family member participate and read the entries from the year before.

Consistency is the key to helping make lasting change in your family, so keep it simple and easy for you to work into everyday life. Avoid labels like “spoiled” in your own home, and focus instead on feeling appreciative for what you have and what surrounds you.

“Let your children feel grateful for whatever comes naturally to them, and don’t judge. Remember that your goal is to inspire your children into building this muscle, not force them into it,” says Dr. Pressman. All of your hard work, thoughtfulness, and efforts now will have an great impact on your children for years to come. This is a wonderful way of sharing gratitude and giving thanks full circle.”

Learn more about the Mount Sinai Parenting Center

Learn more about Pediatrics at Mount Sinai

Celebrating Nurse Practitioner Week: Advancing Care Through Collaboration

Updated on Nov 13, 2023 | Featured, Nursing

Since 1965, nurse practitioners have collaborated with interdisciplinary teams in addressing the growing health care needs of underserved populations. Today, nurse practitioners provide care via more than 1 billion patient visits each year across the nation.

Nearly 70 years since the inception of the profession, nurse practitioners continue to play a critical role within the health care system. Overall employment of advanced practice nurses is projected to grow 45 percent from 2020 to 2030, much faster than the average for all occupations.

Patients at Mount Sinai Health System are almost certain to receive care from an advanced practice nurse over the course of their care. Advanced practice nurses such as nurse practitioners, midwives, and certified registered nurse anesthetists, are valuable team members in nearly every clinical department. These providers continue to make tremendous contributions towards addressing areas such as improving access to care, adding efficiency to work flows, providing continuity of care, and providing specialty based expertise.

Beth Oliver, DNP, RN, FAAN, Chief Nursing Executive at Mount Sinai Health System, applauds how advanced practice nurses work collaboratively with their respective teams in expanding access, addressing social determinants of health, and increasing patient satisfaction across all Mount Sinai sites.

Advanced practice providers have been successfully integrated into team-based models without compromising quality, safety, and patient satisfaction. The current landscape of health care has amplified the value these providers bring to the communities they serve, according to Dr. Oliver.

“The demand for these advanced practice nurses is reflected in the growth of the number of these providers within our own enterprise,” says Priscilla Samuel, DNP, FNP-BC, Vice President of Advanced Practice Nursing, Mount Sinai Heath System.

Mount Sinai first integrated nurse practitioners into the workforce in the late 1980s. Today the Health System employs more than 900 advanced practice nurses, including nurse practitioners, certified registered nurse anesthetists, and midwives across various subspecialties.

“We are fortunate to have a strong bench of NPs who are ensuring uninterrupted access to high-quality, safe, and equitable care within the Mount Sinai Health System,” says Dr. Samuel. “Nurse Practitioner Week is an excellent time to recognize the value nurse practitioners bring in advancing the mission, vision and values of our organization and highlight the important work they do each day for the communities we serve.”

Here are the thoughts of eight of Mount Sinai’s dedicated nurse practitioners on what inspires them, what fills them with pride, and what they wish people knew about their role:

“Working for Mount Sinai has strongly enhanced my clinical expertise as a nurse practitioner,” says Kelly Cash, MSN, AGPCNP-C, Senior Nurse Practitioner for Cardiology, Mount Sinai South Nassau. “With the rapidly expanding medical field and new innovations, Mount Sinai remains at the forefront and provides continuous growth and education to support staff. They truly stand by their core values.”

Claire Murphy, RN, Adult-Gerontology Acute Care Nurse Practitioner at The Mount Sinai Hospital, says there is a particular blend of nursing and medical expertise that is reflected in a nurse practitioner’s care. “The NP embodies and combines the best of the medical and nursing fields of thought,” she says. “NPs look at problems from two perspectives and become a resource that bridges nursing and medical concerns.”

“Nurse practitioners are uniquely positioned to help decrease the care gap by providing cost effective and high-quality comprehensive care,” says John Sexton, FNP-BC, Family Nurse Practitioner, Mount Sinai Brooklyn. “They also help ease the strain from the volume of patients a physician would ‘normally’ encounter. In the emergency room, for example, this means decreased wait times, improvements in the overall patient experience.”

Family Nurse Practitioner Bilikisu Bhadmus, MSN, APRN, FNP-BC, Advanced Practice Provider Manager at Mount Sinai Beth Israel, says the nurse practitioner’s background as a bedside nurse, along with an ability to diagnose and treat patients, allows them to bring a unique set of skills and perspective to the care model. “We’re positioned to address patients’ needs holistically and be great care coordinators, educators, and sources of support that our patients truly value,” she says.

“Clinical nurses excel in hands-on patient care, delivering treatments, and monitoring patient status, and physicians are experts in their respective fields with extensive training in diagnosing and treating patients,” says Mollie Aidasani, MSN, NP, a women’s health nurse practitioner and Clinical Program Director of Gynecologic Oncology, Mount Sinai Health System. “NPs perform advanced assessments, diagnose illnesses, order and interpret diagnostic tests, initiate and manage treatments including prescribing medications, while often taking more of a nursing-centric approach to care and treatment.”

Describing the nurse-provider hybrid perspective of the nurse practitioner, Jon Rockfeld, ANP-BC, Advanced Oncology Certified Nurse Practitioner at Mount Sinai West, says that nurse practitioners help augment the focus on a patient’s emotional, social, and mental well-being. “NPs spend additional time focusing on patient engagement and education to help promote ongoing well-being,” he says.

“Among the most important aspects of my NP role are educating and advocating for my patients,” says Peggy Trainor-O’Malley, NP, a dually certified acute and family nurse practitioner, who has been a nurse practitioner at Mount Sinai Morningside for 25 years. “Working in cardiac surgery, many times we’re the first and last clinician encounters during their stay. We’re addressing their pain, fears, and overall health. I try to convey to the patient and family that I am there for them even after discharge and encourage them to call me with any questions or concerns.”

“NPs are a vital liaison between all aspects of patient interaction,” says Joanna Toussaint, NP, Adult-Gerontology Primary Care Nurse Practitioner, Mount Sinai Queens, “From education to treatment, to assessment, and even outpatient as follow up, we help keep patients’ needs seen and heard. We’re able to offer a well-rounded approach to patient-centered care and a sense of constant presence and support for the patients.”

Learn more about Nursing at Mount Sinai

A New Fellowship Program at Mount Sinai Will Help Shape the Next Generation of Health Care Leaders

Updated on Oct 25, 2023 | Community, Featured, School

The Graduate Medical Education (GME) program at the Icahn School of Medicine and the Graduate School of Biomedical Sciences have announced the launch of the Health Care Administration, Leadership, and Management Fellowship for early career stage physicians.

This ACGME-accredited fellowship program is designed to offer physicians a comprehensive experience combining the academic rigor of the school’s Masters of Health Administration (MHA) program with hands-on training in Graduate Medical Education. This collaboration will provide fellows with a well-rounded education encompassing leadership development, health care administration, quality improvement, and patient safety, among other critical areas.

“I want to grow as a leader in the next three to five years. I see myself as a physician executive who can help make decisions on how to make health care better and create new health care delivery models that are equitable.” — Shantheri Shenoy, MBBS

“The fellowship is unique because it brings together excellent classroom-based learning and unique rotations across the Mount Sinai Health System, which makes for a physician who is poised to lead,” said Brijen Shah, MD, Fellowship Director, Associate Dean for Graduate Medical Education, and Professor, Medicine (Gastroenterology) at Icahn Mount Sinai. “This program provides a unique chance to get a peek behind the curtain of how health care is delivered and to advance and be part of diverse teams to solve health care problems.”

Shantheri Shenoy, MBBS

The MHA program provides the academic and curricular side of the fellowship requirements, while GME provides experience on the clinical side through rotations in various departments within the Health System.

The fellow will gain practical insights into the operational aspects of managing a health care organization while collaborating with a diverse team of health care professionals. Additionally, the fellow will have access to a network of faculty members, accomplished alumni, and industry experts, who will provide mentorship and guidance. Upon completing the program, the fellow will receive a Masters in Health Administration degree.

The inaugural fellow is Shantheri Shenoy, MBBS, who started the fellowship in September and will be in the program for two years. Dr. Shenoy is the Associate Division Chief of Hospital Medicine at Mount Sinai West and Assistant Professor, Medicine (Hospital Medicine, Nephrology) at Icahn Mount Sinai. She completed her internal medicine internship and residency at Maimonides Medical Center followed by a fellowship in nephrology at New York Medical College – Westchester Medical Center. Dr. Shenoy completed the Greater New York Hospital Association Clinical Quality Fellowship Program in 2019. She has planned and implemented several projects on high-value care and patient safety, and she has presented them at national and international conferences.

“I want to grow as a leader in the next three to five years. I see myself as a physician executive who can help make decisions on how to make health care better and create new health care delivery models that are equitable” she said. “Addressing the social determinants of health and patient safety are focus areas for me.”

Dr. Shenoy said the fellowship offers valuable experience. “I’ve been meeting leaders in my hospital and throughout the Health System,” she said. “My experience was at the hospital level, so this is giving me a good sense of the health care industry overall. The courses are easy to accommodate with my schedule. The fellowship gives me a hands-on experience for what I’m learning in my courses. You get to see what you have learned in theory.”

The fellowship is the result of the Graduate School’s partnering with GME on this first-of-its kind, ACGME-accredited program, according to Brian Nickerson, PhD, JD, who is the MHA Program Director and Senior Associate Dean for Master’s Programs. “It is a truly unique collaboration reflecting Mount Sinai’s commitment to building leadership for tackling today’s complex health care issues,” he said.

“This fellowship will serve as a stepping stone for aspiring physician leaders who seek to make a significant impact in the health care industry,” he added. “By fostering a deeper understanding of health care management principles and fostering strong clinical acumen, fellows will be uniquely positioned to address the challenges and opportunities that lie ahead in health care delivery.”

To learn more about the Health Care Administration, Leadership, and Management Fellowship for early career stage physicians, contact Fellowship Director Brijen Shah, MD, Fellowship Director, or Brian Nickerson, PhD, MHA Program Director.

Mount Sinai Researchers Share Thoughts on the Promise of mRNA Technology, a Nobel Prize-Winning Science

Updated on Oct 27, 2023 | Cancer, Featured, Research, Vaccines

Miriam Merad, MD, PhD, the Mount Sinai Professor in Cancer Immunology (left), and Nina Bhardwaj, MD, PhD, Ward-Coleman Chair in Cancer Research (right), lead some of the most cutting edge research in mRNA technology at the Icahn School of Medicine at Mount Sinai.

The 2023 Nobel Prize in Medicine was awarded jointly to two researchers, Katalin Karikó, PhD, and Drew Weissman, MD, PhD, for their decades-long work on messenger RNA (mRNA), which ultimately led to the successful development of COVID-19 vaccines that made a huge difference during the pandemic.

The concept of using mRNA to deliver genetic instructions was met with a lot of skepticism in the beginning, says Nina Bhardwaj, MD, PhD, Ward-Coleman Chair in Cancer Research at the Icahn School of Medicine at Mount Sinai. Because these molecules were rapidly degraded by the immune system, they were thought to be too transient to be used to express anything therapeutic, such as antigens or other molecules in immune cells, she added.

“It’s really through the two researchers’ sheer hard work and determination and validation, both in the lab and in the clinic, that this became a technology that can be harnessed for patient benefit,” says Dr. Bhardwaj, who is also Director of Immunotherapy and Medical Director of the Vaccine and Cell Therapy Laboratory.

The validation of mRNA as a delivery mechanism has opened the doors to vaccines in many other diseases, including cancer, says Miriam Merad, MD, PhD, the Mount Sinai Professor in Cancer Immunology, and Director of the Marc and Jennifer Lipschultz Precision Immunology Institute (PrIISM) at Icahn Mount Sinai.

“We’ve been quite interested in the mRNA for some time—not only this type but also another called the micro RNA,” says Dr. Merad. Even prior to COVID-19, Mount Sinai researchers have recognized the potential of various RNA for use in vaccines, such as for cancer, she adds.

Read more from Drs. Bhardwaj and Merad on their thoughts on mRNA technology, and learn how Mount Sinai is leading this field with its research.

Katalin Karikó, PhD (left), and Drew Weissman, MD, PhD, were the joint winners of the 2023 Nobel Prize in Medicine. Dr. Karikó, a Hungarian-American biochemist who worked at the University of Pennsylvania, continues her research as a professor at the University of Szeged in Hungary. Dr. Weissman, an immunologist, advances vaccine work at his laboratory at the Perelman School of Medicine at UPenn.

What’s the history of mRNA technology development been like?

Dr. Bhardwaj: There was a lot of skepticism in the beginning about how exogenously-delivered RNA—which we usually think of as these transient molecules that are rapidly degraded—can be utilized to express antigens and other molecules in immune cells. So the concept that could happen was not well accepted initially.

Dr. Merad: Also, much of the early focus was on cancer, and researchers were not obtaining fantastic results. Cancer vaccines are still yielding anecdotal responses, and it might not have anything to do with the technology.

What do you feel was a turning point for that skepticism?

Dr. Bhardwaj: I think, in especially the last decade, this technology was being used a good deal at the National Institutes of Health’s Vaccine Research Center as a platform for developing vaccines against other infectious agents, not COVID-19 at the time. What had been generated from the platform showed promise, in preclinical models.

When the COVID-19 pandemic came along, there were highly immunogenic modified “cassettes” generated wherein one could just plug in antigens—such as the spike protein of the COVID-19 virus—which could be rapidly formulated into vaccines and tested.

But even prior to that, there were ongoing efforts to use this technology as platforms for cancer vaccines, which are now being tested in the clinic with encouraging preliminary results in randomized studies in melanoma.

Dr. Merad: I think the big two were the lipid nanoparticle (LNP) as a delivery mechanism, and of course, a disease that somehow was the perfect case to try this new therapeutic strategy.

Drs. Karikó and Weissman were able to change up the RNA prior to the injections so that the molecules persisted longer. They were making clear advances in the way the proteins were being made. But, still, the real fixes started when they learned to encapsulate the mRNA in nanoparticles.

In fact, Dr. Karikó went to BioNTech (which partnered with Pfizer to produce the COVID-19 vaccine) and Moderna also licensed mRNA technology, and what happened was that two companies developed a way of delivering mRNA. This extra component—the delivery mechanism—was what made therapeutics possible.

Also, the pandemic is kind of a boost for mRNA technology. Because, first, of the number of patients available, and second, we are in a bit of a risk-taking mode. These vaccines were already developed against pathogens, so they just had to be pivoted to COVID-19.

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One solution that companies like Pfizer/BioNTech and Moderna used to protect the mRNA instructions in their vaccines from being degraded by the immune system was loading them into tiny fat particles known as lipid nanoparticles (LNPs). These delivery vehicles are also able to find the targeted cells, which mRNA molecules alone cannot achieve. Icahn School of Medicine at Mount Sinai honored the efforts of the BioNTech executives during its 54th Commencement in May 2023, conferring upon them honorary Doctor of Science degrees.

Learn more about LNPs and mRNA technology in a Q&A with BioNTech executives

What research is Mount Sinai doing with mRNA?

Dr. Bhardwaj: One exciting line of research includes work from Yizhou Dong, PhD, Professor of Oncological Sciences at Icahn Mount Sinai, who works with the Icahn Genomics Institute and PrIISM. He is one of our newly recruited faculty members, who has been working in this space for quite a while. He has demonstrated that RNA can be used as a platform to introduce various kinds of immune modulators into cells, including dendritic cells, a key cellular potentiator of the immune system.

Dr. Dong uses RNA-LNPs to introduce various types of immune modulators into immune cells and even cancer cells to enhance antitumor immunity. My team is using RNA-LNPs to encode newly identified antigens, such as neoantigens, which arise from mutations in cancer cells, and then use those within vaccine constructs.

In preclinical models, we have shown that such RNA-lipid constructs, developed in-house in The Tisch Cancer Institute, are immunogenic and can have therapeutic benefit in treating cancers. Our goal is to take that to the next level: develop our own vaccine constructs and deliver them into humans.

Dr. Merad: We’ve been interested in exploiting mRNA to translate into specific proteins. We have been very much interested in using mRNA to change the immunosuppressive environment of tumors, where we use mRNA to go into the tumor and start making it look like an infection to induce an antitumor immune response. There is a lot of effort in using mRNA to transform cancer lesions—which can suppress and evade the immune system—into something very inflamed that can be recognized by the immune system and lead to tumor clearance.

One of my colleagues, Brian Brown, PhD, Director of the Icahn Genomics Institute, and Professor of Genetics and Genomic Sciences at Icahn Mount Sinai, is quite interested in using mRNA in different types of disease settings. My lab is mostly looking at inflaming regions in cancer, or reducing inflammation in inflammatory diseases—in this case we use mRNA as cargo to deliver proteins that will dampen inflammation and enable inflammatory lesions to heal.

What do you see as the future of mRNA technology?

Dr. Bhardwaj: I think the breadth is enormous. We can add many different types of immune-enhancing modulators into these particles—not just antigens—including homing receptors and cytokines. RNA platforms have been given intramuscularly and intravenously, and it’s possible you may be able to deliver it intranasally and into the skin, as well as directly into tumors.

The scope of what we can do, what we can encode and add, and the potential combinations with other immunomodulatory agents is vast. I think the field is moving really fast, especially with new companies coming into the field and startups accelerating rapidly.

Dr. Merad: Right now, the big conundrum that we have is: how can we raise an immune response against cancer that is beneficial, without inducing a harmful response against other tissue? I think the answer is delivery.

With mRNA, it provides all the instruction needed for therapeutic effect, but what we are still working on is enhancing that cell-specific delivery system. If we were allowed to bring that instruction to the right compartment, then we can afford to do so much more.

Patient Recovers From Two Brain Surgeries With Help From “Wonderful” Mount Sinai Team

Updated on Oct 24, 2023 | Featured, Stories of Excellence

Shannon Hickey, patient, right, with her occupational therapist, Aura Weltman

Shannon Hickey, 29, never imagined a case of double vision shortly before Valentine’s Day in February would lead to an Emergency Department visit, two brain surgeries, and months of rehabilitation therapy. It has been a long journey, made easier by her medical team, and on one memorable day, by an unexpected word of kindness and cheer.

Shannon had always been very healthy, and only a week before her symptoms began, she was sightseeing in Paris with her best friend. At most, Shannon thought her symptoms might simply be due to a vitamin deficiency. Imaging revealed that was not the case. She had a brainstem brain tumor, and on February 14, Shannon underwent surgery to remove the tumor at The Mount Sinai Hospital, performed by a team headed by Isabelle Germano, MD, MBA, Director of the Mount Sinai Comprehensive Brain Tumor Center. When she awoke, her double-blind vision was much improved but she developed a new difficulty with her peripheral vision on the right. She also had difficulty recalling words and moving the right side of her body, as consequence of a small stroke that occurred during surgery. After a few days in the Intensive Care Unit, Shannon spent two weeks as an inpatient in the Rehabilitation Unit at the hospital.

Shannon describes herself as extraordinarily positive, and says she never felt the severity of all she was going through. “A right-sided deficit was fortunate,” she says. “I am left -handed.” And she gives a lot of credit to her “wonderful” team of therapists. Shannon praises Emily Teitelbaum, MS, OTD, Senior Occupational Therapy Rehabilitation Specialist, “Emily was my inpatient OT. She had been a professional ballet dancer before becoming an OT, and I was a volunteer dance instructor, so Emily designed my exercises based on ballet moves, which clearly were personalized for me. It was just so nice.”

“My physical therapist, Will Long PT, DPT, was such a happy and positive person,” Shannon continues. “He made everything fun. I had to learn all the basics, basically how to walk again, but it never felt like work.”

“It was an amazing meeting, to have all of these professionals, in one room, in person and virtually, supporting me in this way.”

Shannon returned home in late March, but needed to continue physical and speech rehabilitation therapy. She still required a brace to walk and had challenges reading. As the spring progressed, Shannon was eager to return to work despite her limitations, as she had taken a three-month leave and wanted to meet her self-imposed deadline. At that point, my wonderful outpatient occupational therapist, Aura Weltman, MS, Senior Occupational Therapy Rehabilitation Specialist was instrumental in my emotional recovery as well as my progress physically. Shannon says. “She set up an interdisciplinary meeting with my team, including my therapists, social worker, and Aveniel Klein, MD, PhD, Associate Professor, Rehabilitation and Human Performance. They helped me understand that I was doing all the work I needed to do to recover, but there was no timeline I could measure myself against. I needed to be patient. It was an amazing meeting, to have all of these professionals, in one room, in person and virtually, supporting me in this way.”

Unfortunately, the tumor had formed another cyst in her thalamus, so a second surgery was scheduled for June. Shannon admits she was nervous this time. “I had so many changes after the first surgery, I was scared.” But she says, she felt incredibly supported by the Mount Sinai team she had come to consider family. She recounts a small, but meaningful gesture by Dr. Germano. “I gave Dr. Germano a valentine on the day of my first surgery. For the second surgery, she was wearing a Snoopy surgical cap and told me she knew I liked Snoopy. I was confused, but a few minutes later, I recalled I had given her a Peanuts valentine featuring Snoopy. It was incredibly sweet of her.”

During this surgery, a biopsy confirmed that Shannon had pilocytic astrocytoma, a type of brain tumor that originates from glial (brain) cells called astrocytes and seen primarily in children. Most cases are benign, as was Shannon’s. Shannon says the day she was informed of her diagnosis was “the best day of my life.” She explains, “It was my lucky day to learn this tumor does not multiply. Literally, I can thank my stars, because these glial cells are star-shaped.”

Shannon is taking oral targeted-therapy specific for her tumor’s molecular signature and may have long-term decreased peripheral vision on the right side. But she remains upbeat and unfazed. “I have adapted to my vision deficit. I no longer need speech therapy and will cut back on OT soon,” she says. “And, I am so lucky, the hospital is near my home so I get to practice walking on my way to PT.”

Shannon with Prince Allah, parking attendant

Shannon is grateful to another special Mount Sinai staff member: On her walks back home along Fifth Avenue after therapy, she says she had to be hyper-focused to avoid falling. “I could not really pay attention to my surroundings or people.” But one day, she heard someone say to her: “Oh, progress.” The voice was that of Prince Allah, a parking attendant at 1176 Fifth Avenue. Shannon introduced herself, and thanked Prince for his interest and support. Prince says he had seen Shannon walk by for months, first on crutches, and then on her own, and noted how she worked at her gait, but still had her smile.

“I could not hold back, I had to tell her she was so impressive,” he says. “And when she came up and introduced herself, it made my day.” Mount Sinai is his first hospital work experience. “I love working at The Mount Sinai Hospital,” he says, “helping people in any way I can.”