Research can benefit from serendipity now and then

Fort Lauderdale, FL-A successful research career often includes a little serendipity as well as dedicated pursuit of a hypothesis, suggested Andrew J. Fischer, PhD, who received the Cogan Award from the Association for Research in Vision and Ophthalmology for his contributions to the fields of myopia and vision-guided ocular growth, retinal stem cells, and retinal regeneration.

He discussed his research during the Cogan Award lecture, citing several instances in which he made a discovery after curiosity led him to follow up when the unanticipated happened.

"Sometimes serendipity can be a powerful scientific tool," said Dr. Fischer, associate professor, Department of Neuroscience, The Ohio State University, Columbus. "It's important not [always to] stare directly at the expected hypothesis-driven outcomes.

Retina-guided ocular growth

As a PhD student, one of Dr. Fischer's areas of study was which cells in the retina detect and discriminate between plus and minus defocus. He began looking more closely at the transcription factor early growth response protein 1. In the presence of growth-slowing visual stimuli, these cells quickly upregulate, but when a stimulus is applied that accelerates ocular growth, the percentage of cells that express this factor goes down.

This work led to subsequent investigations of the role of amacrine cells, numerous transcription factors, and DNA repair of damaged cells. He found that just a few days after damage induced by N-methyl-D-aspartate (NMDA), numerous cells had re-entered the cell cycle, gone through one cycle of division, and persisted in the retina for several days, becoming progenitor-like cells.

One of the implications of this line of research was that it was not logical to inflict harsh, cytotoxic damage on a retina that was slowly degenerating, as is usually the case with human retinal diseases; instead, the objective was to stimulate neurogenesis from Müller glia without causing this type of damage.

In another series of experiments with retinal explants, Dr. Fischer and colleagues discovered that the combination of fibroblast growth factor (FGF) and insulin-originally found in the culture medium-initiated a wave of cell proliferation beginning at the periphery of the retina. These new cells turned out to be Müller glia; a small percentage of them eventually form new neurons or Müller glia, while the vast majority appear to remain as undifferentiated progenitor-like cells. Importantly, this process does not cause damage, unlike NMDA.

"This is perhaps a way to stimulate the cells to become neurogenic without destroying numerous neurons," he said. "With NMDA treatment, you need sufficient levels of death to stimulate these Müller glia to re-enter the cell cycle and become progenitor-like, and most remain as undifferentiated progenitor-like cells. Insulin-FGF works similarly, but without the damage."

Since these early studies, Dr. Fischer's lab has learned more about the importance of FGF to stimulate Müller glia to dedifferentiate, found that map kinase signaling is important, and shown that without baseline levels of notch-signaling, the FGF-mediated dedifferentiation is shut down.

Stem cells at the peripheral edge of the retina normally don't produce all the different cell types in the retina, Dr. Fischer said. Although they can be stimulated to produce ganglion cells, it has not yet been possible to stimulate these cells under normal conditions to create photoreceptor cells. In intact eyes, nonpigmented epithelial cells in the ciliary body can sometimes be stimulated to produce a neuron.

Dr. Fischer also discussed his lab's study of the extensive buildup of glucagon-positive neurons at the retinal periphery.

"This small population of cells plays a rather important role in the eye in regulating both retinal growth and equatorial eye growth," he said.

In another example, Dr. Fischer again highlighted the importance of following up on or returning to what might seem like inconsequential information. His lab recently found a novel type of nerve cell in the avian retina, and Dr. Fischer realized he had seen similar cells about 10 years ago but, being unable to identify them, had moved on to other projects.

Picking up this thread of information, he found that although these cells were negative for a number of well-known glial markers, they did not seem to be astrocytes. Once these novel cells have been stimulated with IGF-1, Dr. Fischer's team has observed that the retina becomes more susceptible to excitotoxic damage and incurs numerous focal detachments and folds associated with cell death.

Another researcher studying these cells used retroviral lineage tracing to determine that they originated in the optic nerve and labeled them astrocytes based on their morphology. She and Dr. Fischer have discussed their separate findings, and in his view, the verdict is still out on the identity and function of these cells in normal, healthy retinas.

FYI

Andrew J. Fischer, PhDPhone: 614/292-3524
E-mail: fischer.412@osu.edu

Dr. Fischer did not indicate a financial interest.