How to Rewire an Optic Nerve
Vision Screening Made Fun
A Victory in Utah
AMD: Once, Twice, Three Times a Genetic Defect
When Work Is a Pain
How to Rewire an Optic Nerve
Finding a way to repair damaged optic nerves moved a tiny step toward the realm of possibility this spring with the discovery that astrocytes block regenerating axons from reaching the brain.
In the Journal of Cell Science,1 researchers from Schepens Eye Research Institute and Harvard Medical School report they had succeeded in repairing severed optic nerves in mice.
In effect, their experiments returned the eyes to an important embryonic stage: the time when retinal ganglion cells grow long axons, connecting the retina to the visual cortex and forming the optic nerve.
In mice, this stage of visual development ends about two days before birth; in humans, it occurs in the third trimester of pregnancy, said the project’s leader, Dong Feng Chen, MD, PhD, assistant scientist at the Schepens Eye Research Institute and assistant professor of ophthalmology, Harvard University. After that, more axons just won’t grow from the optic nerve, Dr. Chen said.
Caption: Robust optic nerve regeneration in
mice expressing Bcl-2. Two photomicrographs
show the morphology of regenerating nerve
fibers at one to two days after optic nerve
crush.(top) A photomicrograph montage of
adjacent longitudinal optic nerve sections
with the regenerating fibers labeled by red
dye.(bottom) A higher-power confocal
epifluorescence photomicrograph of the optic
nerve taken at the site posterior to the injury
Regenerating nerve fibers are stained red.
Arrowheads indicate the injury site.
“We were trying to find out why the optic nerve can’t regenerate axons,” she said. “We wanted to know if retinal ganglion cells lack the intrinsic capacity to grow, or how they lose it during embryonic development.”
First, one of her coauthors, Schepens research associate Kin-Sang Cho, PhD, created gene “knockout” mice engineered to overexpress an apoptosis-blocking molecule called Bcl-2. These mice showed regrowth in their injured optic nerves, but the axons failed to elongate properly.
Complete axon growth occurred only when the researchers also blocked formation of a “glial scar” in the brain—which, they found, consists of aggregations of astrocytes that become mobilized after neurons suffer stress or trauma.
The axons stopped their rapid growth when they encountered such scars in the extracellular matrix. But when glial scars weren’t allowed to form, the axons extended fully into the visual cortex within a few days, the group reports.
“We noticed during the regeneration that the axons selectively grow to vision-related areas. Occasionally, the new nerve fibers go to wrong places, but the brain seems to eliminate those after a while,” Dr. Chen said.
The clinical implications of such research are obvious—but also far in the future, Dr. Chen said. In addition to the issue of how to deliver Bcl-2 or an astrocyte-inhibitor (such as a glutamate analog) to the proper brain site, scientists will have to assure that doing so would not cause brain damage elsewhere, she said.
“The danger is probably not cancer because we don’t induce indefinite proliferation of the axons,” Dr. Chen said. “The astrocytes are suppressed only for a short time, and then they return. But, because astrocytes are important for maintaining the extracellular matrix and function of the neurons, if we remove them excessively it might damage some neuronal function or cause pain.”
The group’s next studies will try to determine whether the newly grown axons produce a functioning visual system.
“This is the closest science has come to regenerating so many nerve fibers over a long distance to reach their targets and repair a nerve previously considered irreparably damaged,” Dr. Chen said.
1 J Cell Sci 2005;118:863–872.
Vision Screening Made Fun
Waiting for debates to be settled over how best to detect amblyopia doesn’t interest James W. O’Neil, MD, a pediatric ophthalmologist in Phoenix. He’d just like to see youngsters identified quickly and efficiently.
So, Dr. O’Neil and others at The Amblyopia Foundation of America developed a video game vision screener that is easy to administer, fun for kids and amenable to computerized evaluation and tracking of results.
In the game, the child performs the same sorts of tasks that occur with manual tests of visual acuity and stereopsis. The computer stores results, and a printout tells parents if their child needs to visit an ophthalmologist.
“We’re not trying to replace the vision screening programs run by school nurses, Lions Club or others,” Dr. O’Neil said. “We’re trying to allow them to do their job more efficiently.”
A 1,000-child pilot study of the game’s effectiveness is in the final stages, and the next step is an independent clinical trial comparing it with currently used vision screening tests.
When it does become available, Dr. O’Neil said his group’s primary goal is to make it possible for all children in America to be screened.
“We’re not selling this software to schools,” he said. “Our goal is to give it away.”
On the Frontlines: A Victory in Utah
On Feb. 10, U.S. District Court Judge Bruce Jenkins granted summary judgment in favor of defendant ophthalmologists and managed care company Intermountain Health Care Inc. in a closely watched case that pitted Utah optometrists against ophthalmologists. The optometrists claimed that IHC and individual ophthalmologists conspired to exclude optometrists as a class from IHC’s eye care provider panels. The optometrists asserted that IHC violated federal antitrust laws because it excluded optometrists from its panels for the purpose of increasing IHC’s dominant position in the market for hospital and surgical facilities in the region.
Judge Jenkins demolished the optometrists’ antitrust claims of an illegal group boycott, contracts in restraint of trade, illegal tying arrangements and a conspiracy and/or an attempt to monopolize the hospital and surgical-facilities market. The court found that the optometrists lacked legal standing to bring their private antitrust action, as they did not compete in IHC’s managed care health plan market or the market for hospital and surgical facilities. The optometrists could not sustain their claim that they were injured through defendants’ alleged anticompetitive conduct.
At the heart of this case is a question of great importance to ophthalmologists: May a limited health care plan appoint a limited number of service providers of a particular kind to its provider panels? The court in Abraham, vs. Intermountain Health Care Inc. found nothing in the antitrust laws to prohibit a vendor of health care plans from composing its provider panels as it sees fit. The opinion does point out, however, that the “open” vs. “limited” model of provider panels ultimately lies within the power of the state legislature to regulate. But judicially, after spending as much as $3 million in legal fees, the optometrists in the Abraham case now find the antitrust door shut on them, unless they can successfully appeal.
—Katherine Salazar-Poss, JD,
Academy’s In-House Legal Counsel
AMD: Once, Twice, Three Times a Genetic Defect
Genetic changes that stick a single molecule of histidine into the wrong place on a string of 1,200 amino acids could be responsible for half of all cases of AMD.
That would seem like overstatement, if three groups hadn’t all converged through different methods onto the same conclusion this spring—and if it hadn’t been reached with staggering levels of statistical significance. (The weakest P-value in the studies was 0.0080; the strongest was 4.95 x 10-10 [i.e., 0.000000000495].)
Writing a trio of papers in Science, the groups estimated that 43 percent to 50 percent of the risk for AMD is conferred by the altered gene and the faulty immune-system protein it produces.1–3
The researchers reported on work in which they:
- Examined chromosome 1q32 of 400 people with AMD from high-risk families, looking for single nucleotide polymorphisms (SNPs) within the macular degeneration-associated gene known as ARMD1, then compared what they found with unaffected controls.
- Compared SNPs between groups of AMD patients with different types of disease.
- Typed the entire genome of 146 people, 96 of them with AMD, to see which of 105,980 relevant SNPs examined were common to the macular degeneration patients.
All three approaches led the scientists to two SNPs, either of which when present multiplies the risk of AMD from three- to sevenfold, depending on whether the person carries one or two copies of the SNP, the researchers report. The SNPs result in a gene that produces a protein in which a single molecule of the amino acid tyrosine is replaced by histidine. The substitution occurs within a string of 20 repetitive units, with 60 amino acids per unit, which make up an immune system molecule called complement factor H (CFH).
The involvement of this protein suggests a new molecular explanation for the association between inflammation and AMD, the authors say. Normally, CFH serves as an inhibitor of complement activation, the process that mobilizes an immune response and leads to cell lysis. CFH also contains binding sites for the vascular-system protein heparin and for C-reactive protein, the inflammatory marker associated with both AMD and cardiovascular disease.
“In principle, altered binding of CFH to CRP or heparin on outer retinal surfaces caused by the [histidine replacing tyrosine] substitution could affect the level of inflammation in the outer retina, thereby contributing to AMD,” says one paper, whose lead author is Albert O. Edwards, MD, ophthalmologist at the Presbyterian Hospital of Dallas.1
This also could explain why smoking and advanced age correlate with higher AMD risk, notes another paper, whose lead author is Robert J. Klein, PhD, researcher in the Laboratory of Statistical Genetics at Rockefeller University in New York City.3 Both those risk factors influence plasma levels of the CFH protein, the paper notes.
“The findings of these studies are very exciting, as they reveal a significant link in the multifactorial etiology of AMD,” said Christine R. Gonzales, MD, retinal specialist and assistant professor of ophthalmology at the University of California, Los Angeles. “Understanding the underlying mechanisms of disease is important in the development of new therapeutic approaches. These findings fuel the argument for the importance of inflammation in the pathogenesis of AMD.”
1 Science 2005 Mar 10; [Epub ahead of print].
2 Haines, J. L. et al. Science 2005 Mar 10; [Epub ahead of print].
3 Science 2005 Mar 10; [Epub ahead of print].
|In the Office: When Work Is a Pain|
Take care of your patients, take care of yourself. A survey concludes that 15 percent of ophthalmologists must limit work because of musculoskeletal pain.
Based on a mailed survey of 2,529 ophthalmologists in the northeastern United States, the study found that 51.8 percent of the 697 respondents experienced work-related musculoskeletal symptoms in the previous month.
That figure might be higher than the real prevalence, if unaffected doctors just didn’t respond to the survey, noted the study’s senior author, Jeffrey L. Marx, MD, retinal specialist at the Lahey Clinic, in Burlington, Mass. But the reaction he’s received since the study’s1 publication has reaffirmed Dr. Marx’s belief that musculoskeletal disorders remain a workplace issue for ophthalmologists.
“I’ve never gotten more phone calls from doctors about any other topic,” Dr. Marx said. “I’ve gotten calls from doctors around the country, either who have had musculoskeletal problems themselves or who are residency program directors. I think there’s an incredible [groundswell of] understanding in the ophthalmologic community that these conditions do exist, and that we can teach residents in the future how to avoid them.”
1 Dhimitri, K. C. et al. Am J Ophthalmol 2005;139(1): 179–181.