By David N. Leff
"In this world," observed Benjamin Franklin, "nothing can be said to be certain, except death and taxes." He should have added cataracts.
"If we live long enough," said Michael Brownstein, "virtually every one of us is going to get a cataract." To which clinical and research ophthalmologist Lois Smith added: "In adults, cataracts are a huge problem. Their extraction and replacement probably occasion the commonest form of surgery in the elderly."
But cataracts in the eyes of the very young are a different, and rarer, story.
Brownstein is senior author, and Smith a co-author, of a paper in the current Proceedings of the National Academy of Sciences (PNAS), dated February 2, 1999. It is titled, "Progressive juvenile-onset punctate cataracts caused by mutation of the gamma-D-crystallin gene. Brownstein is at the National Institute of Mental Health (NIMH), in Bethesda, Md.; Smith is at the Harvard-affiliated Children's Hospital, in Boston.
Juvenile punctate cataract (JPC) babies are born with clear eyes and normal vision. But insidiously in the early months and years of life, small, opaque dots begin to appear in their ocular lenses.
"If you look very hard for them," Brownstein said, "you might be able to see those dots in the first few months of life. But, more typically, people in the family recognize them later, looking at their child's eyes around age two or three, and seeing all those little dots. At that point, the incipient cataract wouldn't give a kid very much trouble.
"The problem," he said, "is that each one of those dots refracts light. In other words, instead of coming straight in, the light is shot in all directions, causing fuzzy, glared vision. And that's troublesome. As the dots increase in number and coalesce, the youngster can't see through them any more. At that point it's not just glare any more. It's actual obstruction of vision. So, typically, kids around 10, 11, 12 would need their defective lenses removed and replaced with clear, synthetic ones."
Opthalmologist Smith saw her first and only cases of JPC when she directed an illuminating microscope at the eyes of a four-year-old child, and witnessed the mass of telltale, sight-limiting dots. "It looked obvious," she said.
That small patient was one of ten JPC members in a three-generation family of 30. Recognizing the disorder as genetically inherited, she and Brownstein decided to track down the mutated gene among the proteins forming the ocular lenses of those affected family members.
"This unique kindred would give us a clue," she observed, "for finding more cases of this very rare disease in the general population, and an insight into cataract formation generally."
Brownstein said, "I think geneticists are opportunists, and this family came to light." He mobilized a gene-hunting posse of 14 co-authors from the National Institutes of Health, plus Harvard University.
"There are probably a very large number of genetic alterations that can wind up causing cataracts," he told BioWorld Today. "JPC is particularly uncommon.
"Initially," he said, "we did linkage analysis - a genome-wide scan of our kindred with dinucleotide repeat markers. Then, after we found evidence for linkage, we realized that in the middle of that linked locus, on the long arm of chromosome 2, was the gamma-crystallin complex of proteins that form the lens of the eye. And those seemed like excellent candidates for the mutant gene itself."
What they found was a missense mutation that resulted in the substitution of an arginine amino acid for a cysteine. All ten of the JPC family members had this alteration, but none of 400 control chromosomes did.
Brownstein explained that there are "important structural proteins in the lens. What was interesting about this particular mutation was that we predicted it will not affect folding, but instead affect the interaction between gamma-crystallin and other molecules in the lens.
"Another thing that's really interesting about lens cells," he said, "is that they're like red blood cells, in the sense that as they mature they extrude all of their organelles, including their nuclei. These would refract light, and prevent the lens from functioning as it needs to. Consequently, the cells that form the nucleus of the lens, the oldest part of the lens, have been with us since we were fetuses.
"Like an onion, almost," Brownstein explained, "those cells, which are very elongated, form layers and layers of tissue that builds up as lens. Their transparency and clarity comes partly from their protein constituents, and partly their absence of organelles. And the proteins in those cells, since they can't be regenerated, have to last for a lifetime. So, if we live long enough, virtually every one of us is going to get a cataract. And what's kind of neat about it is that the system works so well, that our lenses last so long."
John Shoemaker, assistant vice president of the Prevent Blindness America association, in Schaumberg, Ill., told BioWorld Today that one in every seven Americans over 40 years old - 12.9 million persons - has cataracts.
Brownstein said, "We're not alerted to this as a public health problem as much as we might be. I think nearly everybody understands that sunblock is a really important thing, because if we are careful not to get too much sun, and block ultraviolet light from our skin, then maybe we won't wind up with basal-cell, squamous-cell or melanoma cancers. People don't point out in the same way that wearing [ultraviolet]-protective glasses may be very important, if you want your eyes' lenses to survive."
Seeking Several Ounces Of Prevention
One of Brownstein's goals now is "to create a transgenic mouse model, and look for factors that would contribute either to a more rapid or a slower development of cataracts in the rodent. If we could learn, by studying an animal model, how to slow down or speed up this process, we might be able to imagine how to do that in a useful way in people."
He cited some "fantasy versions" as examples:
"Say you could show that some antioxidant therapy, vitamin E or vitamin C could slow down the progression of this trait in animals, perhaps you could argue that it would be useful for all of us to take those antioxidant vitamins preventively," he said. "And there may be some other drugs that could delay the inevitable development of cataracts in adults. If you could slow it down by ten years - since it's a trait that usually gets to be a problem in folks who are pretty well along in years - you could probably stave off the necessity for cataract surgery in a very significant number of people.
"In terms of biotech," Brownstein concluded, "that seems to me a pretty good target."