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.

“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.

“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.”