Connie Cepko

In some ways, Connie Cepko’s job has gotten easier.

The Harvard Medical School genetics professor is working to uncover the mysteries of the eye, to understand how it develops and what can go wrong. Her work ranges from understanding the genetic roots of diseases like retinitis pigmentosa, which afflicts 100,000 Americans, to basic genetic research using the latest technology.

The work goes faster now than it once did because of major breakthroughs in genetics and information sharing made possible by the Internet. At the same time, there is an overwhelming amount of research needed to understand the complex interplay of genes involved in the development of the eye and the diseases that affect it.

Cepko’s interest in this sort of work started long ago, sparked by a seventh-grade science fair. She grew yeast on agar plates, a completely new experience for her. Her experiment won first place and the attention of the judge, John Palmer, who ran a nearby laboratory.

He invited her over to see the laboratory, and she found a new home. She grew up spending her Saturdays in his lab, which was dedicated to classifying tree fungi.

“It was a fabulous experience and I just loved it,” said Cepko, who in addition to her HMS position is a Howard Hughes Medical Institute investigator

There was no doubt about what she would study when she went to college at the University of Maryland. It had to be microbiology.

She specialized in marine bacteria. That interest led her to the Massachusetts Institute of Technology for her graduate and post-doctoral work.

Though she liked the field of virology, in which she worked for her thesis and postdoctoral projects, it felt crowded. It wasn’t the competition that bothered her, but the idea that so many people were spending their efforts on the same thing, she said. She looked for an area that was getting less attention and found the nervous system.

Cepko started by studying the eye. She chose it because at the time it was an easy entry point for a rookie without a strong background in neurobiology. It was physically accessible and there were a lot of basics known about it.

And yet, there was so much more to discover that she’s still at it today.

There are 160 different genes that lead to blindness and it’s not clear what triggers the death of the affected photoreceptors, upon which vision relies.

“Any little thing goes wrong and we go blind,” Cepko said.

Researchers in her laboratory are trying to link genes with specific diseases and to better understand how the cells of the eye develop and what can go wrong along the way. Eventually, understanding what can go wrong may lead to new ways to intervene.

When Cepko started, the only way to connect a gene to a problem was to painstakingly remove it from an organism. Researchers had to breed mice without the gene in question. But today, advances in RNA interference allow researchers to create bits of RNA that attach to a messenger RNA, efficiently blocking the function of a gene so researchers can see what happens without it.

By using the RNA interference process over and over again on different genes, researchers are collecting the pieces of a giant jigsaw puzzle whose image is a better understanding of the eye and the diseases that attack it. With the advances in science, more pieces are falling into place.

“Now, we have clues. We have many pieces of the puzzle,” she said. “Before, we had a 1,000 piece puzzle but only a few border pieces.”

The explosion of the Internet fosters the work because information and advances in other laboratories are more readily available. Researchers can quickly absorb the latest advances in other laboratories and apply them to their own research.

While her laboratory looks at the bigger picture of what makes a rod cell or a cone cell or another piece of the eye, it’s also tackling the specific problem of retinitis pigmentosa.

The disease affects 1 out of 3,000 people. It’s a genetic ailment that affects the rods of the eye, used to see in near darkness. Perhaps most vexing is that once the rod cells die, the cone cells, which are used for all of our daylight vision, also start to die even though they don’t have a genetic defect.

It’s not clear how the genes cause the rod cells to die or why the cone cells follow.

Researchers in her lab are trying to get a better understanding of what happens as the disease takes its toll. They are looking at what genes change in their expression during different stages of the disease. A postdoctoral fellow, Claudio Punzo, began their work in this area, and has recently published his findings in Nature Neuroscience. His work has provided a totally new view of the disease, and suggests that the cone cells might be starving, and then undergoing autophagy, a form of self-digestion.

Bo Chen, another postdoctoral fellow, working on what might keep the rods alive, has found that the addition of a gene encoding histone deacetylase 4 promoted rod cell survival far longer than in untreated animals. These clues are giving the group ideas on novel therapeutic targets to help prolong vision in individuals who are genetically predisposed to go blind.

There is serious work going on in her lab, but there is a collegial atmosphere, said Jeffrey Trimarchi, a post-doctoral fellow who has been working with Cepko for five years.

There are four Ph.D. candidates and nine post-doctoral students in the lab. Cepko chooses not only good scientists but also good people, Trimarchi said.

“It’s important to have people in the lab who get along,” he said. “You need to have people who will share what they’re doing and be willing to talk about their work.”

In some ways, she is hands off, letting researchers go in their own direction. At the same time, she works with them to put what they are doing into context.

Trimarchi said he had heard good things about Cepko’s lab when he was looking for a place to do his post-doctoral studies, but it was talking with her that convinced him.

“When I sat down with her, the ideas kept coming, one right after the other,” he said.

She keeps a white board in her office and uses it frequently for brainstorming.

While her primary focus is on basic research, Cepko keeps in mind potential real-world applications. She promotes that concept as co-director of the Leder Medical Sciences Program, which integrates the Ph.D. students with Harvard Medical School.

Participants take courses covering the basics of human biology and disease. They focus on organ systems and diseases ripe for investigation and novel therapeutic approaches. At the same time, they attend clinical conferences, participate in the Mentored Clinical Casebook program and attend workshops, lectures and other dinner series with people who work at the interface of basic science and clinical medicine, from all different venues.

“It offers them another perspective and lets them consider the possible applications of their laboratory work,” she said.