Cataracts are caused by a clouding of the lens of the eye and are a leading cause of blindness around the world. Cataract surgery is a simple and beautiful operation in which the cloudy lens is taken out and replaced with a new, clear, artificial lens (IOL). The World Bank has said that it is one of the most cost effective medical or surgical procedures in the world.

Now a paper from Ling Zhao and Kang Zhang and their colleagues from UCSD and the Institute of Molecular Medicine at the Peking University have demonstrated a potential new treatment for cataracts: eyedrops!

This relatively short paper in Nature represents the culmination of an enormous amount of careful and very, very, clever science.

Zhao et al. found that an inherited form of cataract was caused by a genetic error that stopped the production of a naturally occurring steroid called lanosterol. In two families with a high burden of congenital cataract Zhao et al found mutations in the enzyme lanosterol synthase (vital in the production of lanosterol). This is, in itself, mildly interesting. What was truly novel was that Zhao and colleagues then tested to see whether lanosterol could help reduce cataracts that were not caused by mutations in lanosterol synthase. This was a very, very, clever move. Fascinatingly, in petri dish experiments with human lens cells, treatment with lanosterol reduced the clumping of lens protein that characterise cataracts. Zhao and colleagues then went on to show that treatment with lanosterol reduced cataract severity in a laboratory model that uses a dissected rabbit cataract. Most importantly they also went on to demonstrate that this treatment worked in vivo (that is in live animals). When lanosterol was given to dogs with age related cataracts by eye drop and injection the dogs' cataracts were significantly reduced. In some ways this is almost unbelievable, that protein aggregation could be undone by drops and injections. Its like a boiled egg reverting to an uncooked egg via the application of some drops onto its shell! This series of experiments is quite an incredible clinical and scientific tour de force.

Perhaps one day in the not too distant future we may be able to help our patients with cataracts through simple eye drops or injections.

The eye is a dazzlingly complex instrument whose intricacies gave even Darwin pause. In On the Origin of Species Darwin described the eye as "an organ of extreme perfection and complication... with all its inimitable contrivances for adjusting the focus to different distances, for admitting different amounts of light, and for the correction of spherical and chromatic aberration".

The eye works to focus light onto the retina which acts to capture this light and convert it into neural signals that can be interpreted by the brain as images. For light to be appropriately focused on the retina it must be sharply bent so as to come into focus on the retina itself. If the light isn't focused properly the images we see are blurred. The cornea (the front surface of the eye) and the lens of the eye (which sits behind the pupil) are the two most important parts of the eye that work to focus light. One analogy we use is that the cornea is like a windscreen, if the windscreen is dirty then you can't see through it. However this analogy is quite misleading because the cornea plays a much more active role than simply transmitting light. In fact the cornea does a lot of the heavy lifting in focusing light! The cornea contributes about 44 dioptres (a measure of light bending) to the total power of the eye and the lens contributes around 20 or so. Indeed some chauvinistic corneal specialists say that the much vaunted lens really just helps to tweak the light bending to ensure that light from different distances can be focused onto the retina. To see clearly both the lens and the cornea must beautifully transparent and appropriately bend the light coming into the eye so that it is focused onto the retina. Simple! However as the old proverb runs "there's many a slip betwixt the cup and the lip"... any damage or degenerative change to the cornea or lens will degrade the quality of the light focusing and thus our ability to see. Clouding of the lens is called cataract and is one of the leading causes of reversible blindness in the world. Currently cataract is treated by surgically removing the cloudy lens and inserting a plastic one in its place. (Although I have previously written about stunning new medical treatments that can help to reverse lens clouding without surgery).

Similarly if the cornea is sufficiently cloudy the only solution is to surgically remove the cornea and to transplant a donor cornea into its place. In fact there are now operations in which only certain part of the damaged cornea can be removed and donor parts replaced in their stead. Considering that the cornea is only around half a millimetre thick in the centre the idea that a human could, by hand, remove some of it and transplant a donor part back is mindboggling and yet these operations happen every day. Incredibly the first successful corneal transplant was in 1835 when an Irish ophthalmologist called Samuel Bigger who whilst being held captive by Bedouins in Egypt decided to transplant the cornea of one of his pet gazelles as it was blind from extensive corneal damage. “The cornea was taken from another animal of the same species brought in wounded but not quite dead; adhesion took place and 10 days after the operation, the animal gave unequivocal signs of vision, and the upper parts of the transplanted cornea remained perfectly transparent”. Those were the days! Unfortunately the early days of corneal transplantation were plagued by graft rejection and it was not until 1905 that the first successful human transplantation took place. Even today corneal graft rejection remains a problem with somewhere between 10% and 50% of corneal grafts being rejected in the long term. An ideal solution to this problem would be an auto-graft in which the host’s own tissue was used as donor tissue so that the immune system would not reject it. This has only been a dream until recently. In a recent issue of Nature Nishida and colleagues have reported a great breakthrough which has the potential to revolutionise corneal transplantation. Nishida and colleagues used human induced pluripotent stem cells (hiPSC) which are, roughly speaking, normal adult cells which have been genetically reprogrammed to go back to their embryonic state in which they can grow into any type of cell in the body. The medical potential for these cells is almost unlimited, but sadly also unrealised as yet. What Nishida and his colleagues did is to create an environment in which these special cells decided to try to grow into an embryonic eye. By sucking away the cells forming different bits of the eye the team was left with a small group of cells all developing into a new corneal epithelium (the surface layer or ‘skin’ of the cornea). They then went on to demonstrate that these cells could be grown into a sheet which could be transplanted onto the eye of rabbits which had lost their corneal epithelium (and their ability to regenerate it). This is an incredible scientific advance and one that promises to revolutionise our approach to corneal damage. However there are still many hurdles to overcome. Nishida and colleagues have, as yet, only managed to grow one specific layer of the cornea (the epithelium). Now it is true that this is one of the most important layers of the cornea, and it is the one most often damaged as it is the layer that faces the outside world. However the epithelium needs to be able to continually support itself and regrow all the areas that are damaged in the normal wear and tear of everyday life. These cells have not yet been demonstrated to be able to form a self perpetuating colony which would be able to do this (ie to fulfil the role of the limbal stem cell niche). Demonstrating that they can continue to replenish the corneal surface with epithelial cells in a long term fashion will be what Nishida and colleagues will want to do next and doing this will provide hope for all the people out there who are troubled by an inability to regenerate their own corneal epithelium (a problem caused by limbal stem cell deficiency).

The other great hurdle will be doing this, in real time, with cells from the patient in front of you. To fulfil its long term clinical promise we will need to be able to take cells from the adult patient who presents with corneal damage, transform them into hiPSCs and then create the corneal layer(s) we want in a dish using that person’s own hiPSCs and then transplant that corneal tissue back into the patient. Nishida and colleagues work is an incredible scientific tour de force but it is a long way from bench to bedside on something as complicated as this. However they are to be applauded for their pioneering work and we hope to see much more from their laboratory soon!