Deepak Kaji, MD, PhD

Each year, medical schools confer MD-PhD degrees to those willing to devote years to doctoral research alongside their clinical training. However, the residencies that follow are typically structured so that many aspiring physician-scientists end up becoming one rather than both.

“Residencies rarely make sufficient room for physicians to also train as scientists, and we’re losing a lot of physician-scientists because of it,” says Deepak Kaji, MD, PhD, an Assistant Professor of Psychiatry at the Icahn School of Medicine at Mount Sinai.

Because the PhD is sandwiched between years of medical school, MD-PhDs arrive at their residency program after two years away from the bench. Afterward, physicians must either look for postdoctoral positions to reorient themselves to a lab or bid farewell to that part of their training.

Dr. Kaji found a rare opportunity in the National Institutes of Health-funded R25 Physician-Scientist Training Program within the Psychiatry Residency at The Mount Sinai Hospital.

“Choosing Mount Sinai allowed me to begin building my research career on day one instead of starting a decade later,” he says.

Recruiting the Right People

As an undergraduate, Dr. Kaji studied how to direct pluripotent stem cells toward becoming heart tissue, an entry point into what he describes as the field’s central marvel.

“Every human being begins as a ball of cells with essentially infinite potential,” he explains. “Somehow, nature guides those cells toward becoming hair, teeth, pancreas, liver, or the heart.”

His affinity for stem cell research arrived as scientists were learning to reproduce that process in a dish. Gordon Keller, PhD, then at Mount Sinai, was coaxing stem cells into heart tissue, while others were making pancreas and brain tissue. For Dr. Kaji, watching those lineages being built for the first time was both exciting and an invitation.

“The idea of making something new felt like a crowning achievement,” he says.

When Dr. Kaji first showed interest in the MD-PhD program at Mount Sinai, program leadership emphasized the physician-scientist track residencies as a selling point. “They told me that being a scientist and a physician would dovetail, that each would make me better at the other,” he says.

It was encouraging that they were describing their residency program to someone who had not yet started medical school. This approach suggested they were thinking about the entire arc of a career, not just the next four years.

Applying Stem Cell Biology to Psychiatry Research

In the MD-PhD program, Dr. Kaji applied his stem cell biology background to musculoskeletal biology. His doctoral work focused on generating a protocol to create tendons and fibrocartilage from stem cells.

Returning to the clinical portion of medical school, he found himself drawn to psychiatry and investigating the mysteries of the brain and behavior. The question was then how to deploy his scientific training.

“Once I knew what I wanted to do, I started thinking about ways to apply my techniques to generate organoids as models of specific brain regions,” says Dr. Kaji. An organoid is a cluster of cells grown in a lab to mimic some of the structure and functions of a real organ.

“Choosing Mount Sinai allowed me to begin building my research career on day one instead of starting a decade later.” — Deepak Kaji, MD, PhD

Dr. Kaji began investigating schizophrenia based on his conviction that the disease starts far earlier than its diagnosis suggests.

“In twin studies, the twin who eventually develops the disorder is typically late to walk, speak, and potty train,” explains Dr. Kaji. “That gradual developmental divergence signals a slow degradation of the cognitive repertoire that happens for decades before the disease outwardly manifests.”

This is precisely the developmental window an organoid occupies by recapitulating the earliest phases of brain development. His proposal to use organoids as a model system to study schizophrenia earned him the 2024–2025 Lipschultz Research Scholar Award from the Friedman Brain Institute.

Neuropsychiatric disease is difficult to study—it is hard to explain why something in the brain breaks when no one fully understands how the brain works. Although an organoid does not answer every question, it offers insights that other models cannot.

“If you want to know how the disease disrupts high-order circuitry, this isn’t your system,” Dr. Kaji says. “If you want to know what happens as those circuits are being assembled, as cells differentiate and the brain organizes in the first trimester, it’s a great one.”

Creating New Tools for Hard Questions

One revelation from his work is the role of cell-autonomous effects, meaning that a cell’s identity may drive its vulnerability to disease. Dr. Kaji explains that radial glial cells, an early brain progenitor, appear heavily disrupted in organoids generated using stem cells from patients with schizophrenia.

“We’re seeing powerful disruptions in this one cell type at a developmental stage before any type of circuitry has formed,” he says. This suggests that vulnerability is a consequence of the molecular programming responsible for a cell’s final identity.

“Organoids allow me to build the cells, watch them come into existence, and ask how those programs confer vulnerability or resilience,” explains Dr. Kaji.

But that question can only be asked about cell types that science knows how to build. Protocols do not yet exist for every lineage, the developmental route a stem cell takes to become one specific cell type. Because building a brain region means learning how to make the cell types that define it, that gap leaves some regions off-limits to organoid research.

The hippocampus region of the brain is Dr. Kaji’s current focus. “I can’t think of a single neuropsychiatric or neurodegenerative disease without hippocampal involvement,” he says. “I’m working on creating hippocampal organoids because a better tool improves every disease model that follows.”

The benefit would also extend beyond individual diseases. Dr. Kaji notes that in Alzheimer’s disease, some regions are affected early, some late, and some almost never.

“This suggests that cells in each region show an intrinsic vulnerability or resistance to the disease,” he explains. “If we could identify what makes cells resilient, the next question is whether that resilience could be extended to vulnerable cells.”

A Long-Term Investment in Physician-Scientists

After entering the MD-PhD program, Dr. Kaji watched those ahead of him in the physician-scientist track and saw a pattern. They found mentors suited to their interests, began building research programs during residency, and left with faculty positions and career development awards that help confer scientific independence.

“It’s not uncommon for people to receive a K Award in their 40s,” he says, describing the National Institutes of Health Career Development Award grants designed to help early-career researchers become independent scientists. “I was watching people here get them in their mid-30s because the residency program followed through on its promise to make time for research.”

That track record has produced a faculty population that is substantially homegrown. Approximately 50 percent of those who complete the Psychiatry Physician-Scientist Residency Program stay at Mount Sinai, which Dr. Kaji sees as a sign of mutual respect.

His own transition from resident to faculty member was smoother than most, the product of a decade of relationships built as a student and resident. He just received his K08 career development award and now runs a lab two floors above where he completed his doctoral work, in a building where his former instructors are now his colleagues.

“They never stop investing in us,” he says. “For those who stay, there is a real commitment to helping us finish what we set out to build.”