Miriam Merad, MD, PhD

Miriam Merad, MD, PhD, a pioneering immunologist at the Icahn School of Medicine at Mount Sinai, has been elected to the National Academy of Science (NAS), an honor that recognizes her transformational contributions to the fields of myeloid cell biology and innate immunity. Dr. Merad, the Mount Sinai Professor in Cancer Immunology and Director of the Precision Immunology Institute, joins an elite group of international scientists with membership in the NAS.

In a landmark study published in Science in 2010, Dr. Merad showed that macrophages—large white blood cells—arise from embryonic precursors that take residence in tissues prior to life where they play a distinct role in organ physiology and pathophysiology. This study, cited several thousand times, has had important clinical implications. Dr. Merad and her team also established the contribution of this macrophage lineage to cancer progression and response to treatment, and to inflammatory bowel disease, in studies published in prominent journals such as Science, Cell, and Nature.

In addition to her work on macrophages, Dr. Merad is known for her work on dendritic cells, a group of cells that control adaptive immunity. She identified a new subset of dendritic cells, which is now considered a key target of antiviral and antitumor immunity. In a May 2020 study in Nature, she and her team revealed novel therapeutic targets to enhance dendritic cell-mediated antitumor immunity.

“I am thrilled to have been elected to the National Academy of Science and proud to represent Mount Sinai in immunology,” says Dr. Merad, who joined Mount Sinai’s faculty in 2004. She says her parents—both scientific and medical professionals who were educated in France and practiced in Algeria—raised her “to respect the transformational power of science.”

She adds that Mount Sinai helped foster her passion by giving her the freedom to grow and pursue her work. “Mount Sinai has a culture that empowers junior faculty. I tell junior scientists, ‘If you want to be transformative and innovate early in your career, this is the place to be,’” she says.

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, says, “Dr. Merad’s discoveries have helped changed the course of medical treatments and her work continues to shed light on the way the human immune system responds to disease.”

In May, after receiving word of her election to the NAS, Dr. Merad shared the news with all of the former and current postdoctoral fellows in her lab. Many of her original fellows, who continue to collaborate with her on research, are now established investigators in institutions that include Stanford University, the University of Massachusetts-Amherst, the University of Toronto, the University of Zurich, and Charité in Berlin. “I told them that this election recognizes the many hours they spent in my laboratory and I thanked them for everything we have done together,” she says.

A NEW COVID-19 RESEARCH EFFORT

Under Dr. Merad’s leadership, Mount Sinai has become an international hub for the study of the human immune system. She developed Mount Sinai’s Human Immune Monitoring Center (HIMC) as one of the world’s most sophisticated research centers; it uses cutting-edge single-cell technology to understand the contribution of immune cells to major human diseases or treatment responses. HIMC participates in several major consortia funded by the National Institutes of Health.

This center will now play a key role in helping Dr. Merad and her colleagues understand why some patients develop severe forms of COVID-19 and some do not. For the past six weeks, she has led a major effort at Mount Sinai with her colleague Alexander Charney, MD, PhD, Assistant Professor of Psychiatry, Genetics and Genomic Sciences, Neuroscience, and Neurosurgery, to collect blood samples from 500 hospitalized COVID-19 patients. The collection is still ongoing.

She says, “We will use the HIMC to analyze the inflammatory response that is triggered in our patients as a result of COVID-19, as well as the adaptive immune response to the virus.” Her goals for the project include the ability to predict which patients will develop a severe inflammatory response and then find ways to prevent and treat it.

Yet, she adds, even when some patients recover from the disease, they continue to have negative effects. “We do not know if it’s because inflammation persists and does not resolve. There is still a lot to learn. We will be following these patients for a long time because we need to monitor the resolution of inflammation and the quality of the immune response that these patients develop and see whether this response is protective.”

Photo Courtesy: National Institute of Allergy and Infectious Diseases

Did the SARS-CoV-2 virus emerge in the human population spontaneously or was it engineered in a laboratory? Several months into this pandemic, there are still many more questions than answers about this stealthy new coronavirus that has commandeered the world stage. Its ability to enter a human population for the first time and spread quickly and with such unpredictable outcomes has led to many conflicting theories and suspicions about its origins.

“People are hungry for basic information to dispel the rumors that are out there,” says Benhur Lee, MD, Professor of Microbiology and Ward-Coleman Chair in Microbiology at the Icahn School of Medicine at Mount Sinai.

In March, Jillian Carmichael, PhD, a postdoctoral fellow in Dr. Lee’s lab, created a blog to address the misinformation and confusion about the COVID-19 disease caused by the virus that she was seeing on social media. In addition, “I was getting so many questions about SARS-CoV-2 from friends and family that I couldn’t answer them all. I decided to reach out to my virology colleagues for help.”

Together with Christian Stevens, an MD/PhD student in the Lee lab, Dr. Carmichael launched a science-communications blog. Since then, they have worked with a team of graduate students and postdoctoral fellows to parse through reams of studies to create an ongoing series of posts that educate the public about what is plausible and what is not based on their knowledge of science and virology, in particular. Their posts have received traffic from more than 100 countries.

One persistent rumor they sought to demystify for the public was whether SARS-CoV-2 could have been deliberately engineered.

“While nothing is impossible in science, there are some things we do know, and it is very unlikely that SARS-CoV-2 could have been designed in a lab,” says Mr. Stevens, who helps engineer viruses in Dr. Lee’s lab. “We have a natural hypothesis that fits all the evidence so far.”

There are two ways to engineer something in biology, Mr. Stevens says. You take what you know works and piece it together so that it works in a new way. Or, you simulate the way nature does it and tweak it in order to make improvements.

“When the exact parts of the SARS-CoV-2 virus are plugged into a computer model, they look like they’re going to perform really badly,” he says. “The computer would tell you this is a terrible idea, try something better. A human would have been unlikely to rationally design this.”

In January, when the Chinese government released the virus’ genome, which showed its similarity to a virus from a horseshoe bat, researchers gained a better understanding of its makeup. They found that no prior studies existed to explain the way in which this new virus worked, and two distinct features made the theory supporting its natural evolution more likely.

First, a piece of the virus’ spike protein—called the receptor-binding domain (RBD)—provides the virus with an exceptional ability to attach to the ACE2 protein located on the outer surface of cells in various organs. Second, the backbone of the virus—its overall molecular structure—differed substantially from other coronaviruses and mostly resembled related viruses found in bats. If SARS-CoV-2 had been deliberately engineered in a laboratory it would have been constructed from a virus that was known to cause disease, and these did not.

In addition, the SARS-CoV-2 virus has features that would make it difficult to engineer in a lab. The RBD on the spike protein closely resembles that found in a coronavirus in pangolins—an animal also called a “scaly anteater” that is one of the world’s most trafficked. The theory that a bat virus mixed with, potentially, a pangolin virus, mutated, and then jumped to humans continues to make the most sense.

Then, he says, there is the virus’ biological makeup. It has a polybasic cleavage site, which appears to give it the ability to connect to many different tissue types in the human body. While additional testing is needed, early indications are that SARS-CoV-2 does hit many areas of the body in addition to the lungs. By comparison, previous coronaviruses all had monobasic cleavage sites that connected to fewer tissue types. And last, but not least, the virus has O-linked glycans, which may function to shield the virus from the immune system. This means that in order to develop, the virus probably would have needed a human immune system, something unlikely to have been engineered in cell culture.

On the flip side, says Mr. Stevens, there is plenty of evidence to support the premise that the virus emerged naturally and jumped into humans either already possessing the tools it needed to mutate and begin infecting them quickly, or acquiring these tools soon after landing in the human population.

To learn more about SARS-CoV-2, please go to the Lee lab’s science blog and subscribe for updates.

Benhur Lee, MD, Professor of Microbiology and Ward-Coleman Chair in Microbiology

As governments make plans to reopen their economies and seek reliable ways to ensure their populations can get back to work safely, high-quality antibody testing has emerged as the only way to truly determine which individuals may be protected against the SARS-CoV-2 virus that causes COVID-19. Microbiologists at the Icahn School of Medicine at Mount Sinai have created tests that are answering that need.

A team of scientists led by Benhur Lee, MD, Professor of Microbiology and Ward-Coleman Chair in Microbiology, has developed an assay that tests the quality of an individual’s antibodies to see whether they strongly neutralize the SARS-CoV-2 virus.

Using technology that differs from the more commonly used ELISA method of testing for antibodies, Dr. Lee’s lab has built an identical replica of the outer portion of the SARS-CoV-2 virus, or a pseudo virus. This replica allows researchers to see how well the antibodies from recovered patients actually block SARS-CoV-2 from entering into cells and effectively stop the infection in its tracks. Such neutralizing action provides confirmation that an individual is protected against the virus.

Using the ELISA test and the pseudo virus test together shows how well antibodies that bind to the spike protein also correlate with virus neutralization, says Dr. Lee. The two-step process can provide governments and institutions with a critically important starting point in effectively determining which individuals have been exposed to the virus and carry neutralizing protection.

There are still many unknowns. While the scientific community at large agrees that immunity to the SARS-CoV-2 virus offers protection from re-infection, there is no firm understanding of how long that immunity will last. In addition, researchers do not know whether there is a threshold or level at which antibodies correlate with immunity.

“The gold standard in determining whether someone carries neutralizing antibodies is by using a live virus to test their serum after it has been drawn,” says Dr. Lee. “But this is not scalable for the hundreds of thousands of samples that will need to be tested. So what we developed is a safe surrogate that represents the real virus and can be automated with high-throughput testing in scientific facilities used by many governments and universities around the world.”

Dr. Lee says his pseudo virus assay is essentially a bridge between the binding capability of the ELISA test and the “gold standard” of live-virus neutralization, which requires laboratories to carry a higher, biosafety-level-3 (BSL 3) designation, allowing them to work with dangerous or potentially lethal agents. The pseudo virus can be handled in more commonplace biosafety-level-2 (BSL 2) laboratories that are designated for working with milder agents.

The new pseudo virus can serve as a platform for creating and optimizing potential vaccine designs, generating monoclonal antibodies, and screening anti-viral peptides—all of which would be used to treat or prevent COVID-19.

Government health agencies and universities in the United States and around the world have been sending formal requests to use Dr. Lee’s assay, and he says he will look to them for feedback on how well it is working. “We’re spending time investing in quality control,” he says. “It is important that when we send out this test it works the way we say it works.”