Evolutionary significance of color vision gene therapy

An aspect of the color blindness story that we didn't mention in our earlier post, but should have, is the evolutionary implication. Like humans, the monkeys in the experiment have three types of cone cells, L cells or cells that are sensitive to light of long wavelength, M, or medium wavelength sensitive cells and S, or short wavelength (blue) sensitive cells. Color blindness occurs in primates missing the L or M sensitive photopigment. In this experiment, the investigators introduced a photopigment gene that was expressed preferentially in M cone cells, into animals that were red-green color blind.

We quote here from the paper (Gene therapy for red-green colour blindness in adult primates, Mancuso et al., Nature, advance online publication 16 September 2009).

Classic experiments in which visual deprivation of one eye during development caused permanent vision loss led to the idea that inputs must be present during development for the formation of circuits to process them. From the clear change in behaviour associated with treatment, compared both between and within subjects, we conclude that adult monkeys gained new colour vision capacities because of gene therapy. These startling empirical results provide insight into the evolutionary question of what changes in the visual system are required for adding a new dimension of colour vision. Previously, it seemed possible that a transformation from dichromacy to trichromacy [from seeing 2 colors to seeing 3, which, in combination, allows us to see the full spectrum of color that we do] would require evolutionary/developmental changes, in addition to acquiring a third cone type. For example, L- and M-opsin-specific genetic regulatory elements might have been required to direct the opsins into distinct cone types⁹that would be recognized by L- and M-cone-specific retinal circuitry, and to account for cortical processing, multi-stage circuitry might have evolved specifically for the purpose of trichromacy. However, our results demonstrate that trichromatic colour vision behaviour requires nothing more than a third cone type. As an alternative to the idea that the new dimension of colour vision arose by acquisition of a new L versus M pathway, it is possible that it exploited the pre-existing blue-yellow circuitry. For example, if the addition of the third cone class split the formerly S versus M receptive fields into two types with differing spectral sensitivities, this would obviate the need for neural rewiring as part of the process of adopting new colour vision.

So, in these monkeys, M cone cells that were previously not sending signal to the brain began to do so after a functional photopigment gene was introduced and activated in the retina. Apparently no new brain circuitry was required for these monkeys to begin seeing color, because they began to do so at the same time that high levels of the expressed transgene were detectable. Thus, the investigators suggest this experiment is a reprise of the evolution of color vision, and that it didn't require new cortical function or circuitry but only the addition of a third cone type.

The latter conjecture is worth thinking about, but the basic color vision system is much older and many studies have been done about the gene arrangement, spectral sensitivity, and adaptive aspects of the system. It is not a simple evolution, much less a story of novel progress from simple to complex, not even in primates. But if it can help understand how eye-to-brain wiring and perception works, it will be a step forward.

Color blindness a disease?

Two color blind adult monkeys have been cured of their 'disease' with gene therapy, as described in an online Nature story. The story is picked up by the BBC and Science Daily, among others. One of the investigators is quoted in Science Daily as follows,

"We've added red sensitivity to cone cells in animals that are born with a condition that is exactly like human color blindness," said William W. Hauswirth, Ph.D., a professor of ophthalmic molecular genetics at the UF College of Medicine and a member of the UF Genetics Institute and the Powell Gene Therapy Center. "Although color blindness is only moderately life-altering, we've shown we can cure a cone disease in a primate, and that it can be done very safely. That's extremely encouraging for the development of therapies for human cone diseases that really are blinding."

The researchers introduced genes that produce a protein called long-wavelength opsin into the monkeys' retinal cells via an adenovirus delivery system. The virus gets into the cell and the opsin gene it has been engineered to contain is expressed as a protein, which the cell then processes properly enough that it works to respond to the right light frequency. Apparently the monkeys began to see color for the first time about 20 weeks after the injection of the genes. Here's a video showing how the monkeys' newfound ability to see color was tested.

Color blindness is a nuisance, though perhaps a non-trivial one when it comes to seeing traffic lights or other alerts, but many people live very successful lives without being able to see red or green. But, if gene therapy can cure other forms of blindness associated with cone cells, as Dr Hauswirth suggests, this is good news indeed.

However, the story in Science Daily goes on to say that

[t]he finding is ... likely to intrigue millions of people around the world who are colorblind, including about 3.5 million people in the United States, more than 13 million in India and more than 16 million in China. The problem mostly affects men, leaving about 8 percent of Caucasian men in the United States incapable of discerning red and green hues that are important for everyday things like recognizing traffic lights.

The reason that more men than women are color blind is that these color-sensing genes are on the X chromosome, and males only have one X, so that if they have a defective gene, all their cone cells will bear the defect. Women have two X's (that's what makes them female), and though each retinal cell only randomly picks one of the two to use, a woman carrying a mutant opsin gene will have half her retinal cells using the normal, functioning gene (it's rare for both to have a mutation, since the mutations are fairly uncommon).

But, color blindness is part of the natural spectrum of color-sensitivity variation. It isn't a 'disease' and in a tight-budgeted time for health care, suggesting that millions of people might be interested in a 'cure' might seem to be an almost cynical disregarding of priorities. Given that the numbers of people who are color blind is much greater than the numbers of people with true blindness, are the researchers emphasizing color blindness in an attempt to interest pharmaceutical companies in this new technology, or has this slant been introduced by the journalists? Hard to tell. This could be another Viagra, a blockbuster cure for something that hasn't needed pharmacologicals before now. If this is what happens, it would show (or confirm) how utterly socially irresponsible the pharmas are, and the governments who allow this to be done.

On the other hand, if the technique works and could be used to treat real genetic retinal disease, it will be a boon to society and an excellent example of the fact that, for things that truly are genetic and relatively simple, genetic engineering should work. Curing any genetic form of blindness would be a major advance.