Connie Cepko: A life in science mapping the retina — and working to save it

Key Takeaways:

• For decades, HHMI Investigator Connie Cepko meticulously mapped the lineages of retinal cells, strengthening our understanding of how vision develops.  
• Cepko’s later research strove to address the many genetic causes of vision loss. Her lab identified eight candidate neuroprotective genes that counter stresses driving photoreceptor death, offering a potential path to preserving vision in patients with inherited and age-related conditions.
• As she retires, Cepko is advancing these gene therapies for inherited retinal disease toward clinical trials — and hopes to launch a science mentorship program for middle school girls.

Before her 50-year career as a developmental biologist, HHMI Investigator Connie Cepko was a twelve-year-old girl in Laurel, Maryland, more interested in sports than science. But during a mandatory seventh-grade science fair, she found herself unexpectedly captivated by her project — growing yeast.

A science fair judge, John Palmer, noticed Cepko’s enthusiasm and invited her to visit his Forest Disease Lab at the US Department of the Interior. Decades later, Cepko still remembers the white clapboard building tucked in the woods, with a glass case of tree fungi at the entrance. For several years, she spent Saturdays learning microbiology at Palmer’s side.

“I’ve had many wonderful mentors,” she says, “but he taught me how to think about science — how to ask questions and how to experiment.”

From Dead End to Discovery

On the cusp of earning her undergraduate degree in microbiology and biochemistry from the University of Maryland, several mentors urged Cepko to pursue medical school. In 1976 — before the biotech boom — the job market for PhD scientists was bleak. Though she was drawn to understanding cancer, she knew she didn’t want to be a physician. Instead, she joined the Massachusetts Institute of Technology lab of future Nobel laureate Phillip Sharp, determined to study how adenovirus causes tumors.

But there was a problem: the tools to do so didn’t exist. The ability to clone, sequence, and express genes was still years away. “It was a miserable year and a half,” Cepko recalls. “I couldn’t get any traction, and I felt like a failure.”

She tried several approaches to target the tumor-causing virus — including monoclonal antibodies, a technique to latch onto and disable a specific target protein that had just been developed, but each attempt failed. As a last-ditch effort, she tried a simpler target: the virus’s outer shell, its capsid. When her antibody approach finally succeeded there, she followed the breakthrough, leaving the cancer project to investigate how the virus assembles itself. It was an early lesson in letting the work, not her plans, chart her course.

Focusing on Retinal Development

Following her postdoc, Cepko became the third hire at Harvard Medical School’s newly formed Department of Genetics. Though she had spent her training developing viral tools to deliver genes into cells — a technique with early promise for treating genetic disease — she saw the field quickly filling up. “I wanted my contribution to be unique, and to mean something,” she says.

The nervous system offered a new frontier: complex and understudied. Though she had once turned away from medicine, Cepko now attended Harvard Medical School classes to learn neurobiology. She realized that the viral tools from her gene therapy work could also mark cells and follow their descendants — a technique called lineage tracing, which reveals a cell’s family tree. And as an accessible, complex, and late-developing part of the central nervous system, the retina was an ideal system to deploy this method.

The pivot was not seamless. When she switched from virology to neurodevelopment, well-meaning colleagues advised her against writing NIH grants on her new projects, where she had no track record or preliminary data. But she ignored them and was funded. Now, she advises her mentees: “If you have a novel idea you believe in, go for it.”

Fate and Function

Cepko became fascinated by cell fate when she and her first graduate student, Dave Turner, discovered that retinal progenitor cells — the dividing cells that generate the retina — can produce many different cell types.

“We would see the daughter cells from a single cell division, and they could be two completely different cells, and wonder — how does that happen?” she says. “What tells each daughter cell what to become?”

A working retina requires both cellular heterogeneity and precise organization. Using retroviral lineage tracing, Cepko’s lab mapped how these cells are generated and arranged. Their current model suggests that roughly 500 founding cells can generate an entire retina.

“Much of cell fate seems to be hardwired,” Cepko says, “but the details are shaped by cell-cell interactions — and sometimes by chance.” Understanding how the retina builds itself is also a step toward understanding how it breaks down.

Tackling Many Diseases with One Strategy

Cepko’s lab gained another focus when she received an unexpected call from a stranger, who asked: “What are you doing about blindness?”

Cepko explained that as a basic scientist studying retinal development, she wasn’t working on disease. But the caller’s grandson had been born blind, with no available treatment, and he pressed her: what would she do if it were her own child?

She couldn’t shake the question and began to consider how her expertise — particularly in gene therapy — might be applied to retinal disease.

A central challenge in treating blindness is its genetic variation. When Cepko began working on inherited retinal disease, about 100 disease genes were known; today, she says, there are more than 300. Rather than pursue therapy targeting one gene — a costly approach that would help relatively few patients — her lab pursued a gene-agnostic strategy, focusing on what these conditions share rather than their individual mutations.

In many inherited retinal diseases, mutated genes affect rod photoreceptors, which process low-light and peripheral vision. Cones — responsible for color and high-acuity, daylight vision — degenerate later. “Cones are much more important for quality of life. That’s why we’re focused on saving them,” Cepko explains.

Her lab hypothesized that dying rod photoreceptors create a harmful environment for cone photoreceptors. They identified three common factors across inherited retinal diseases: oxidative damage, inflammation, and metabolic dysfunction.

Over 25 years, her team identified eight candidate genes that counter these shared stresses in mice. The hope is that delivering these protective genes could extend vision across many forms of inherited blindness.

Training the Next Generation

Even with her many breakthroughs, Cepko is clear about what she is proudest of: “My trainees.” She has mentored more than 100 graduate students and postdocs and is quick to credit them for the lab’s achievements.

Cepko’s influence extends well beyond her lab. She helped launch and lead Harvard Medical School’s Biological and Biomedical Sciences (BBS) Graduate Program — a role she held for more than a decade. She later co-founded the Leder Medical Sciences Program, now the Leder Human Biology and Translational Medicine, which she continues to co-direct today.

Paying it Forward

Although Cepko is retiring from Harvard and HHMI in July 2026, she plans to keep pushing the therapies she’s helped develop for blindness toward the clinical stage.

She also hopes to launch a one-on-one mentorship program pairing 12- and 13-year-old girls with female graduate students and postdocs. The goal is simple: two weeks in a lab over the summer, learning how science works and what a scientific career can look like. She is especially committed to reaching girls at the age when many turn away from STEM.

It’s no coincidence that she was 12 when a mentor first invited her into a lab — and changed the course of her life.