Schepens Eye Research Institute, the largest free-standing eye research institute in the United States, is renowned for major breakthroughs in treatment of retinal disease, optic nerve regeneration, new cures for macular degeneration, diabetic retinopathy, glaucoma, other types of retinal and optic nerve degenerations and damage, dry eye, and eye tissue transplants. In this REALab article, JEOL focuses on only one area of research, after visiting with Dr. Ilene Gipson who kindly allowed us to visit her lab and learn about her work as Ocular Surface Scholar and Senior Scientist.
Center for Corneal & External Eye Disease Research
Dr. Ilene Gipson
“Mucus is beautiful,” a sign posted in a lab at Schepens Eye Research Institute proclaims. Composed of mucins, a class of glycoproteins, mucus lubricates the surface of the eye and helps remove debris. It also protects the ocular surface, including the cornea (the clear part of the eye) and conjunctiva (the white part of the eye) from infection.
“We often think of mucus as a result of a bad cold,” Dr. Ilene Gipson concedes, but “mucus is so much more, it’s how a surface in the body maintains its wetness and it has a protective nature against pathogen invasion.”
Dr. Gipson is an Ocular Surface Scholar & Senior Scientist and, as one of Schepens’ more than 20 principal investigators, she also serves as Professor of Ophthalmology at Harvard Medical School. She and her staff associate, Ann Tisdale, have made mucus the focus of their investigation into dry eye disease in recent years. They have worked together for three decades, and are as enthusiastic about their research today as if they had only just begun.
Mucins as Cancer Markers
They can tell you that mucus has everything to do with not only the health of the eye, but also with the wet epithelial coat on the surface of the respiratory, gastrointestinal, and reproductive tracts in the human body. Mucins are released from surface epithelial cells and if surface epithelial cells become cancerous, they serve as markers for the specific types of cancers.
“Looking at the surface of the cornea as a model system for mucosal biology we learn about eye disease but we also learn about other diseases,” says Gipson, explaining that mucins have been assigned names in order of their discovery. MUC 1, the first mucin discovered, is also breast tumor cell marker, MUC 7 relates to bladder cancer , and MUC 4 to pancreatic cancer. MUC 16, a major membrane mucin found in the human cornea, is also found in the reproductive tract of women and is an ovarian tumor cell marker. Dr. Gipson recently published her favorite paper on MUC 16 in relation to its shedding from the uterine surface during which time implantation can occur.
Epithelial Surfaces a Barrier to Infection
Mucins also provide clues to infection. “Eighty percent of infections occur across the wet-surfaced epithelia of the eye, respiratory tract, gastrointestinal tract and urogenital tract. To learn more about how this happens, Dr Gipson and her colleague Ann, an electron microscopist, study epithelial surfaces and image them with the SEM. Epithelial surfaces have a glycocalyx composed of membrane anchored mucins which extend from the epithelial surface that resembles a “lawn of grass.” Some pathogens have learned how to “mow the grass” to cause infection.
Using SEM to Study Mucins on the Surface of the Eye
“The ability to use field emission scanning electron microscopy to study surface structure and composition of the wet-surfaced mucosal epithelium opened up a whole new way for us to map the surfaces of cells. It is allowing us to look at the structural arrangement of molecules to try to understand the structure / function issues related to surface protection. It allows specific labeling of molecules on the surface of the epithelia with gold tagged antibodies to those molecules, in order to see the distribution patterns of proteins/glycoproteins on the epithelia relative to surface membrane structure.” A related project opens up a whole new area in mucosal infection. “We found in particular that a bacterium that causes bacterial conjunctivitis is secreting a product that acts as a lawnmower for the ‘grass,’ the membrane tethered mucins on the surface. We are in the process of characterizing that component; perhaps it is secreted by other infective agents.”
On the Sugar Biology Frontier
Mucins present unique challenges to investigation. “Surface mucins are the biggest molecules known to mankind and the largest glycoprotein in the body. Mucins are heavily glycosylated, meaning that they have large numbers of sugar chains attached to their protein backbone,” Gipson says. “Glycan (Sugar) biology is the new ’frontier.’ Little is known regarding how the sequence of sugars in a chain is accomplished and what alterations there are in glycan in the disease process. We know through our work in dry eye disease that there’s an alteration in the glycan component of mucins.”
Ongoing Multiple Research Programs at Schepens
Dry eye disease affects older people - mostly post-menopausal women - as well as contact lens wearers. Schepens has a long history of research in the field and has developed therapies for it. One of these therapies, TheraTears, is now marketed by an associate of the Institute.
Schepens Eye Research Institute’s many major discoveries have given new hope to people challenged by profound eye diseases as well as blindness. The institute was founded in 1950 by the famed retinal surgeon Charles L. Schepens, M.D. The first published electron micrographs of the cornea were taken at Schepens. The institute’s ever-expanding research program has addressed some of the most advanced investigations into the eye and has trained more than 600 postdoctoral fellows in various disciplines of eye research; trained more than 500 eye surgeons who now practice around the world; and published more than 4,600 scientific papers and books about health and eye disease.