7.22 One, two, or three eyes

(Yang Jian, the 3-eyed god-general)

In Homer's Odyssey, Book 9, Mr Odysseus ran into Mr Polyphemus, a cyclops. The one-eyed giant ate a few of Odysseus's crew before losing his eye to Mr O's trickery. In Chinese mythology, The Investiture of the Gods (封神演義), Chapter 97, Yang Jian (楊戩) was born with three eyes; the third, sitting vertically on the forehead, can see beyond space and time.

While it is possible for a vertebrate embryo to develop only one eye, the three-eyed variety probably does not exist because this will require a fundamental re-structure of the cerebrum into three 1/3 brains. If we want to venture a guess, General Yang's third eye was most likely either a birthmark or a nevus that looked like an eye.

Cyclopes result from a problem with the prosencephalon which normally divides into right and left brains. Failing so, only one eye forms in the place where the nose is supposed to be. Cyclopes are mostly stillborns, so it was highly unusual for Polyphemus to even grow up, but then his Dad probably intervened (as far as life-support).

Actually, a close inspection reveals a complicated origin for each tissue in the eye. For those who for some reason must know, here is a quick summary:

Neuroectoderm: the retina, epithelium of the ciliary body/iris, and optic nerve
Surface ectoderm: the lens and corneal epithelium
The surrounding mesenchyme (neural crest origin): the sclera, the remainder of the cornea, the choroid, ciliary body/iris, and blood vessels

In the vertebrates, the development of the eye is through several invagination processes with precise timing. Any insults from microbes or toxins can of course cause mutations and congenital eye diseases. (See previous posts under Pediatrics.)

Here is something new and interesting: The development of the lens maybe controlled by the Six3 gene which in turn regulates Pax6, the master gene for eye development. The presence of gene product of Six3 does precede that of Pax6. In fact, problem with Six3 leads to holoprosencephaly. And the worse case? Yes, Mr Polyphemus the Cyclops and a kitten named Cy (see image below).

(Cy the kitten, the only living cyclops ever, even if for only one day - from cbsnews.com)

So Six3, in effect, initiates the whole cascade of gene activation in the development of the eye. We wonder why Poseidon did not see this coming.

7.21 Never say never?

(Warner Bros, 1983)

After years of education by sci-fi movies and TV shows, some members of the general public actually believe eye transplant is a reality. Well, it is not, not yet anyway. And is it just a pipe dream or shall we quote Mr James Bond, "Never say never again" in view of the tremendous progress in recent medical research?

If it is possible to transplant anything at all, the candidates must have been blinded by an incurable eye disease yet still with some residual, functional neural (visual) activity. And the procedures must of course subject to the IRB approval.

Now, let's review what the major obstacles may be, one scenario at a time - an FAQ of sorts:

1. Transplant the whole eyeball?

Sure, assuming we can keep the donor eyeballs alive, or more important, for the tissues, especially the cornea, lens, and the retina, to remain functional after transplant. The eyeballs must be kept at 0-4°C; although the best way is probably to connect the arteries, branching from the ophthalmic artery, to a miniature circulator using oxygenated artificial blood enriched with 5.5mM glucose, so that the ocular group of arteries can continue to supply and sustain tissue metabolism.

Now we come to the second problem: how to reconnect the optic nerve.

Picture an undersea fiberoptic cable that got severed during a major earthquake. Do you then retrieve the cable, and reconnect the many thousands of fibers one by one? No, you'd replace the entire section. The optic nerve has 1 million nerve fibers. And at present, there is no way of joining two damaged nerve fibers to make it one functional unit. Also, unlike the undersea cables, the optic nerve is not an isolated section with connectors at both ends, so you cannot replace the optic nerve itself.

Assuming you can somehow coax the nerve fibers to repair their cell membranes and join end to end, it probably won't be the whole 1 million fibers. Then it depends on how many are revived which will then determine the visual field size and the attainable visual acuity.

After all the above, the visual cortex will need to exercise all its plasticity to interpret the images, since it now receives signals from most definitely mis-wired optic nerve fibers. Whether this is possible is still anybody's guess.

Last but not least, the extraocular muscles must be re-attached so that the eye can move according to the direction of gaze. This is cosmetically important as well.

So, transplanting the whole eyeball seems a bit impractical, at least for now.

2. Transplant the retina?

OK. The full-thickness retina or just the photoreceptor layer? The whole retina or just the macula?

First, the retinal viability and the reconnection of "wires" (this time with the optic nerve) are both still the major obstacles. The image below is a whole mount retina specially stained for the retinal ganglion cell fibers (downloaded from webvision.med.utah.edu). You can see numerous fibers all converging toward the optic disc (the black "hole" in the center) and each one must be re-connected with its corresponding fiber in the optic nerve. Technically, with open-sky vitrectomy, perhaps the whole thickness retina/macula can be replaced in toto, but not the photoreceptor layer itself (remember it faces posteriorly the pigment epithelium) - it is simply a humanly impossible task.

Still a bit unrealistic, this retinal transplant deal. But then as in eye transplant, it may just be a matter of figuring out how to fuse nerve fibers through some clever means. And other innovations may then follow.

3. What about electronics?

Ah, now we enter the realm of practicality. A project led by Dr Eberhart Zrenner of Tübingen and Regensburg universities in Germany has implanted retinal chips in patients with retinitis pigmentosa (see image below - from The Economist, 7 June, 2007).

This chip is composed of 1,540 photodiodes which, when stimulated by light, send electric pulses to retinal ganglion cells and the excitation is transmitted all the way to the visual cortex. So now we have roughly 40 x 40 pixels that cover most of the visual field. The patients can differentiate black and white as well as some shapes. For some, this is already a huge difference.

For patients without a semi-functional eye, the alternative is to implant electrodes directly into the visual cortex. The electrodes are connected to a spectacle-mounted digital camera which functions as the eye. As with retinal chips, the resolution is quite low (around 15 x 16 pixels) and the patients can only "see" white dots on black background.

These artificial sensors no doubt will further improve so that the resolution may become high enough with little power requirement and that each implanted chip can last a lifetime. There are also attempts to teach other senses such as auditory and taste to receive and interpret electronic visual signals - with varying degrees of success.

The electronics are not a bad first step towards bionic vision - a popular notion ever since the debut of the "Six Million Dollar Man" series (ABC TV) in 1978.

4. Stem cells?

Yes, this can be very promising especially for replenishing photoreceptor cells lost to retinal degeneration. Previous attempts of directly injecting retinal cells from young rabbits into the adult rabbit eyes have produced intriguing results: There was incorporation of the photoreceptors in the the retina that formed "rosettes". Photoreceptors were present at the luminal side of the rosettes surrounded by layers corresponding to inner layers of the normal retina. So the transplanted retinal "bits" appear to have a natural tendency to self re-organize. Stem cells grown into retinal cells, when implanted, will most likely behave the same way.

The potential problems in stem cell transplants are surgical injury, tumor formation, and vector-mediated infection. These can be avoided as the transplant process evolves. The biggest hurdle in stem cell research seems political, at least at the present time.

5. No more gene therapy?

Not at all. In fact, this research is proceeding in great earnest. As previously posted, gene therapy has already been tested in Leber's congenital amaurosis (LCA) to correct a defective RPE65 gene. This project was carried out last year at University College London Institute of Ophthalmology and Moorfields Eye Hospital, led by Prof Robin Ali with Drs James Bainbridge and Tony Moore. If successful, it will no doubt lead and change the way of genetic eye disease treatment.

Hmm, James Bond maybe right after all.

7.20 Mr Sulu, take us home

(Star Trek IV, The Voyage Home, 1986)

You all remember the Star Trek movie, "The Wrath of Khan (1982)", in which Captain James Tiberius Kirk receives a pair of reading glasses as a birthday present from Dr Leonard (Bones) H McCoy. Kirk proceeds to lament rather unconvincingly the onslaught of old age. Presumably, by the 23rd Century, presbyopia has already been eradicated. Unfortunately, Capt Kirk is allergic to Retinax V - the medicine for treating Presbyopia, or "老花眼old blurry eyes" in Chinese and "老眼old eyes" in Japanese. The keyword: "old".

Funny the script did not follow the more creative vein as that for Captain Jean-Luc Picard who chooses to be bald (Ha!!) There is perhaps a lack of imagination on the screen writers' part. Because even now, there are invasive ways of manipulating presbyopia. Not that this is necessary, a pair of inexpensive OTC readers, bifocals including bifocal contacts, or monovision correction of various kinds (from LASIK to contact lenses, to spectacles) all can quickly resolve the issue.

Presbyopia is an age-related loss of crystalline lens deformability for focusing at near. This was described by Thomas Young (1773-1829) in 1793. To explain the process, he had invoked the elasticity theory. The Young's Modulus (stress = E x strain) is dependent on the material. In the case of accommodation, the lens capsule appears the candidate (see image below). Young's argument was that the capsule elasticity had diminished during aging. Indeed, recent measurements confirmed that the Modulus was about 6 × 10⁷ dyn/cm² in children which decreased to 3 × 10⁷ dyn/cm² at age 60, and to 1·5 × 10⁷ dyn/cm² in extreme old age. Similar to tired old rubber bands which cannot resume the original lengths when the tension is released.

(Lens capsule is the outer most layer which envelops the whole lens
- it is the faint band to the left (anterior to) the single-cell-layer epithelium in the above image)

That is not the whole story, though. There are three parts involved in the accommodation process (see below, 1-3):

(1: The zonules; 2: the crystalline lens; and 3: ciliary muscle)

The ciliary muscle must first contract to allow a decrease in the tension of the zonules, so the capsule can re-shape the lens. Does the ciliary muscle change with aging as well? Not the contractility. It appears the diameter of the ciliary muscle ring does decrease owing to a configurational change. The overall result is the zonules no longer have enough space to relax. And the weakened capsule also can no longer deform the lens as much as before. Did the lens diameter increase with aging also? Some say no; although the only way to make sure is to do a large-scale high-resolution MRI of the eye, because the lens is hiding behind the iris, inaccessible through optical means. The zonules? It is assumed, but never quantified, that the zonular fiber elasticity also changes with time.

Loose ends galore, indeed.

So, how can presbyopia be manipulated surgically? At least in theory, the ciliary muscle ring can be re-positioned to create more space for the zonules. This procedure has already been attempted; although the outcome is still unclear. Alternatively, Conductive Keratoplasty (CK), using radiofrequency to heat and shrink collagen fibers in the cornea, can be done. This to steepen the curvature of the appropriate area of the cornea, so that more plus power is produced for near tasks. CK takes about 3 min and is done to only one eye - a monovision correction as well. It seems to work for some, for a limited duration anyway (about 4-7 years). Interested parties are urged to consult their own eye doctors.

It's been 26 years since "The Wrath of Khan" and we still don't know the composition and the mechanism of effect of Retinax. Well, the sci-fi writers have already pointed the way, perhaps pharmacological researchers can now take us home - to a presbyopia-free world.