FOOTNOTES
#1 Heredity
Because the gene therapy only targets the photoreceptors, and only affects cells in the retina (and possibly other areas of the eye), the genomes of the gametes (eggs and sperm) are unaffected. This means that the new copy of the gene is not inherited by the children of the individual who received the gene therapy, so there is no risk of “genome corruption” to anyone but the recipient themselves. Gene therapy of germ cells are possible, but the ethical implications of this have resulted in bans in many progressive countries.
#2 Gene Replacement Therapy
Gene therapy for CVD is not gene replacement therapy. In the discussed gene therapies, the old copy of the mutated gene stays in the genome, but when the new, “normal” copy of the gene is added to it, the old and new genes are coexpressed, i.e. your body produces the old AND new genes.
This works fine for almost all types of colorblindness, since they are recessive. The old non-functional version continuing to hang around doesn’t really matter.
However, blue-yellow CVD is usually caused by a dominant pattern of inheritance. Just adding a normal gene is not enough, you also have to remove the old gene or it will continue to be dominant. Gene replacement therapy requires a method of extracting that gene from the gene, such as CRISPR.
(note these terms are often used interchangeably)
#3 Youth
Unfortunately, for the dichromats reading this, even if this gene therapy technology was available for red-green colorblindness in 5 years, its likely you will never get a significant benefit out of it because you have never used that third red-green opponent channel, and your brain may be too old to adapt significantly.
However, the brains of anomalous trichromats do use their red-green opponent channel, so inserting a gene that increases the distance between the L- and M-opsins would probably be pretty successful in achieving close to normal color vision regardless of age.
#4 Polymorphic
The genetics of opsins in squirrel monkeys (and all new world monkeys) works differently than humans (and apes + old world monkeys). In humans, we have two genes (at least one of each L- and M-opsin) on each X-chromosome. So males and females will both be trichromatic (normally).
In polymorphic squirrel monkeys like Dalton and Sam, there is only one gene on each X-chromosome, so the males only get one M-opsin and are always dichromatic. However, females with two X-chromosomes have 2 copies of the gene, and there is a lot of diversity in the alleles, so heterozygous females will have trichromacy. Homozygous females will also be dichromatic.
The existence of trichromatic females means that squirrel monkeys as a species have the neural capacity to be trichromatic. Since its doubtful that there is neurological sexual dimorphism, males probably have all of the prerequisites for trichromatic color vision despite being naturally dichromatic.
TRANSCRIPT
In 2009, we cured colorblindness… in monkeys. Human trials seemed just one step away, when everything came to a grinding halt. 13 years after these two red-green colorblind squirrel monkeys were gifted “normal color vision”, there are STILL no public plans to repeat this in humans or even animals……. What? WHY ARE WE STILL WAITING?
Today on Chromaphobe, we will take a look at the current outlook for a cure for red-green colorblindness, centered on the only viable option on the table: gene therapy. I’m actually going to make this video in 2 parts. In the first part – this video – I’ll go over the fundamentals and history of gene therapy for colorblindness. In part 2, I’ll take a look at some brand new results that just came out last week, which MAY be the first human cured of their colorblindness… KINDA.
DEMAND
Colorblindness may not be the most debilitating condition, but there is still strong demand for a cure. Nine months ago, I made a video looking at 12 fake pseudoscience cures for colorblindness from homeopathy to hypnosis. The pervasiveness of these fake treatments shows there is a demand for a cure, but a real lack of a supply. Daniel Flück – owner of the ColBlindor website – performed a poll of 280 colorblind individuals in 2010, showing that the cost an average colorblind person would be willing to pay for a cure was at least $3300. Apply that to the 300 million or so colorblind people in the world, and you’ve got yourself a trillion dollars waiting to be spent on a cure… That’s high demand.
TRANSPLANT
So what kind of options do we have for curing colorblindness? The vast majority of cases of colorblindness are purely genetic. They are caused by an inherited, mutated gene. To cure it, you need to replace the bad genes with normal genes. The shotgun approach would be a retinal, or just a full-eye transplant. Take an eye from someone with normal color vision and just pop it in your eye socket. In the 2002 movie Minority Report, they made Tom Cruise’s full eye transplant look trivially easy… but for a scifi film where there are literally mutants predicting the future… this afternoon eye transplant was perhaps the most far fetched part of it. In the real world, eye transplants are largely considered a pipe dream because of the complexity and fragility of the optic nerve. They’re simply not gonna happen anytime soon, so let’s instead look at the… I dunno… sniper rifle approach?
GENE THERAPY INTRO
This method involves leaving your eye where it belongs, but just gently injecting a functional gene in the cells where it’s needed, like a casual suggestion to your retina. Like… “Hey… how about you try this gene out, see if you like it, no big deal, we’ll leave it up to you… we trust you… retina”. If done right, the cell will start using that new gene, thereby curing your colorblindness. This is Gene Therapy. Gene therapy isn’t only for the eyes though, it can be used to treat any genetic disorder. The first successful human application of Gene Therapy was way back in 1990, but it took another 25 years until the first niche application of gene therapy was finally approved by the FDA… because medicine be hard. To date, there are less than a dozen FDA-approved therapies, but human trials are ongoing in everything from cancer to Alzheimer’s.
GENE THERAPY BASICS
The core principle of gene therapy revolves around a viral vector: the tool to get the new genes into the target cells. For example, they start with a virus like HIV, replace the angry DNA with friendly DNA, poke a bunch of holes into your eyeball and inject the virus… behind your retina. Sounds terrible, which is why we give it a friendly name like gene therapy. Of course, the whole deal with viruses is that they replicate by sneaking their DNA into your cells, which your cells then happily produce for them, leading to more viruses. The viruses are perfectly evolved for this task, but we can re-engineer them to instead inject pretty much any DNA that we want.
That new DNA then ideally gets incorporated permanently into the cells’ genomes, and in most cases, functionally replaces the old gene. After gene therapy, the color vision should not be that different to normal color vision. By the way, those numbers are footnotes for tidbits that I had to cut for time, but you can still read it on my website, link in the description.
PERCEPTION
So why is Gene Therapy to cure colorblindness so hard? Well the first answer is that everything is hard once you get the brain involved. Colorblindness is often compared to hemophilia, because genetically they work in very much the same way. It’s not surprising then that there are multiple gene therapies for different types of Hemophilia, which will imminently receive FDA approval. These beat colorblindness gene therapy to market not only because injections into your liver are way less invasive than into your eyeball, and not only because hemophilia… it sucks… but also because once the genes are in the liver, it’s almost as if… they were never missing? As soon as the new gene gets expressed to make the new proteins, specifically clotting factors, your body is ready to clot next time you – say – stick your fingers somewhere they don’t belong… it’s simply… Sayonara Hemophilia…
Gene therapy for vision though is different, because not everything else necessary for vision is just waiting in standby for that one missing functional gene – that missing link in the chain – to be made available.
That’s because a critical part of the visual transduction pathway is obviously, your brain, and this leads to the “Plasticity Problem”, which is a term I just made up, but it sounds cool, right.
NEUROPLASTICITY
Neuroplasticity is the brain’s way of reorganizing itself to optimize its interpretation of the inputs it receives. Let’s consider your visual cortex, which is NOT a deterministic, hardwired circuit that will behave the same way to the same inputs over and over again. Rather, it will continuously reconfigure its circuitry depending on the signals it gets from your retinas. If someone is born totally blind, the visual cortex doesn’t just hang around hoping to be useful one day, it ADAPTS to perform non-visual tasks, often auditory and language tasks.
But say you find a switch that can eliminate the problem that caused the blindness in the first place, something like, I dunno… gene therapy… would it literally be like a light switch turning on? Definitely not.
The visual cortex would not be able to suddenly cope with the brand new visual signals that it’s never seen before. It needs a considerable amount of time to readjust to the new inputs. The inputs into your brain are actually neatly organized into three “opponent channels”. One that carries the black and white image, and the other two that add the color. Someone with monochromacy has a brain accustomed to interpreting that one black and white channel but has never had to interpret signals from the other two channels: those that carry the color signals. Flip the switch that brings those 2 color channels online and the brain will need a considerable amount of time to be able to interpret them into a meaningful colorful image.
BABIES
You may have heard that babies are born colorblind. It was really popular a few years ago to see “science-based” black and white baby toys and books that really lean hard into this notion, that somehow they’ll be more visible to infants. While these toys are kinda bullshit, it’s not UNTRUE that babies are colorblind. It’s actually a fascinating topic that I have plotted out for a future video, but in short it takes babies SIX MONTHS for the visual cortex to organize enough to take advantage of all that visual info. This includes interpretation of color, which undergoes major improvements around the 3-4 month mark. Think of it this way… when a baby is born, they are essentially cured of blindness… cuz not like he was using his eyes in the womb. The 6 months it takes them to adapt to sight is actually super fast, because babies have super neuroplasticity.
But the older you get, the less plastic your brain becomes. If you flip that switch to cure a 75 year old that has been blind their whole life, it’s likely that their brain will NEVER be able to understand the new visual signals because their visual cortex has been largely set in stone completing other tasks. Actually, expose their newly rehabilitated eyes to a visual feast like fireworks, and those neural signals may do nothing in the brain but give grandpa a migraine. This is why gene therapy for colorblindness is best performed young, while the brain is still as plastic as possible. We simply don’t know HOW plastic a brain has to be in order to adapt to the new color signals, and this was the main unknown we had to answer when we started testing on gene therapy on animals.
SQUIRREL MONKEYS
In 2009, a team out of the Neitz Lab at the University of Washington was able to cure colorblindness in a pair of squirrel monkeys: Sam and Dalton.
Dalton: Named after me? What an honor… But who the hell is Sam?
No idea man…
Like most mammals, male squirrel monkeys are dichromats and therefore considered colorblind, at least relative to your typical human. They have the equivalent of S-opsins and M-opsins, so this study delivered a human L-opsin in the form of 27 TRILLION viral vectors injected subretinally. After the injections, the monkeys’ color vision was tested daily using a pretty standard test for colorblindness. You may recognize it as the Ishihara test, but instead of showing digits, the monkeys would just have to touch the re-coloured region, which traveled randomly around the screen, for which it would get rewarded with some sugar.
After daily testing for over 4 months, the monkeys showed no significant improvement, which was surely disheartening for the researchers. They used Electroretinography to essentially see that there WERE trichromatic signals coming out of the retina, but they didn’t seem to be getting picked up by the brain. How long would they have to wait for the neuroplasticity to kick in? Or would it ever? Well, after 20 weeks, the test results did this… there was a sudden and drastic improvement to the monkeys’ red-green color vision, showing plainly that they had indeed developed trichromatic vision. This is interestingly about the same amount of time that it takes human babies to start seeing in color. Even 2 years after the procedure, the monkeys had retained their improved color vision, showing us that the cure was permanent. Huge Success. Dozens of pop-science articles were written about this achievement.
The extrapolation to humans felt imminent, but 13 years later, what do we have to show for it? There has been ZERO movement on starting clinical trials to cure my colorblindness. Meanwhile the only progress in animal tests seems quite REgressive, with just a pair of studies out of China that succeeded in making monochromatic rats dichromatic again… cool.
…So… what the hell are we waiting for?
RISK
Well… the problem with extrapolating this to humans, is that subretinal injections are a risky. That’s because the subretinal injections are quite invasive, traditionally involving a number of incisions around and through your eye to get the needle to where it has to go, which of course carries risks of complications and in the worst case, losing an eyeball. They’re also largely unproven, underdeveloped procedures, which you can tell by the fact that they don’t even have a wikipedia article. I for one would definitely not risk even a 1% chance of going blind even if curing my CVD was a certainty. The benefit is simply not great enough to overcome such a significant risk, and it’s this skewed risk-reward balance that seems to be the sticking point preventing these trials from continuing.
This leaves us with two possibilities going forward:
- We find a less invasive way to get the viral vectors to the cone cells.
- We make subretinal injections less risky.
AVALANCHE
Let’s look at the first option. In 2015, the same Neitz Lab entered into a partnership with Avalanche Biotech that promised to decrease the risk of the gene therapy by replacing the subretinal injections with less invasive intravitreal injections… simple shots that you could in theory get from your family doctor. The tradeoff though is they don’t deliver the viral vector to where your cone cells are, so have been a lot less effective in related clinical trials. The biotech company named these technologies AVA-322 for protans and AVA-323 for deutans and projected starting clinical trials by the end of 2016.
To commemorate their new partnership with the Neitz Lab, Avalanche even released a new website www.colorvisionawareness.com so us colorblind folk could track the progress of – and soon register for – those clinical trials. Don’t bother registering now though, because that site no longer exists… Resorting – as I do – to archive.org. I found that the website lasted for only about a year and half before being replaced by – and I kid you not – one man’s blog reviewing Tokyo Prostitutes… I have so many questions! Are they relevant to the story? Not at all, but I guess I’ll find out later.
NEITZ
Come mid-2016, not only was the website gone, but there was no mention anywhere on the internet of the partnership or the clinical trials. Now… I am accustomed to performing 99% of my research on the internet, but I put on my big boy pants and got in contact with Dr. Jay Neitz at the Neitz Lab to get the rest of the story… through email… of course. Apparently, soon after the partnership went public, Avalanche’s flagship gene therapy for macular degeneration suffered some disappointing clinical results. Since this was supposed to be foundational to the red-green gene therapy, the poor results – along with ensuing turmoil in the company’s executive – eventually led to the cancellation of their partnership. And like any good divorce, there is never an easy way to divide who owns what, and in this case, the IP issues turned a bit ugly, and really put a damper on any research going forward.
However, Dr. Neitz also assured me that there is still some slow… slow progress going on behind closed doors. Last year they even treated yet another monkey and now have some fresh preliminary results… but still, it feels like we are no closer to a cure than we were almost 13 years ago.
ACHM
Where there HAS been significant progress is on the 2nd pathway: that is, refining the subretinal injections and proving their safety through repeated application in gene therapy for… Achromatopsia.
While the red-green colorblind have ONE of their three cone cells affected, those with achromatopsia have ALL of their cone cells affected. Unlike red-green colorblindness, their opsin genes are typically normal, but one of the genes for necessary proteins downstream in the phototransduction pathway is mutated and the cone cells are unable to trigger the optic nerve.
As a result, achromats ARE colorblind, but colorblindness is actually the LEAST of their concerns, compared to the co-occuring symptoms of dayblindness (photophobia), which makes it literally painful to see during the day and poor visual acuity that cannot be corrected with glasses. The disability of achromatopsia is an order of magnitude worse than red-green colorblindness, so even a partial cure is a much bigger benefit to the individual. That risk-reward balance therefore tips in favor of “yes, please slice my eyeballs open!”
While subretinal injections are risky now, many of the challenges can be overcome – at least hypothetically – with continuous development, which naturally improves the more achromats that opt to go under the needle. But I’m getting greedy. Achromatopsia gene therapy is not just a stepping stone. It’s probably way more important than any cure that I’ve got coming, so let’s take a closer look at them.
ACHM TRIALS
Starting in 2007, around the same time as the squirrel monkeys, studies for gene therapy to cure achromatopsia have gained a much steadier momentum. After animal trials in Mice, Dogs and Sheep, human clinical trials for gene therapy in achromats started in 2020 and the first positive results just came out a few weeks ago… as in, we may have the first instance of colorblindness being cured in humans. I definitely want to get a lot deeper into those results which are super interesting, so I’ll be covering that in part 2 of this video, which will follow in just a couple weeks. If it’s ready by the time you’re watching this, there should be a card in this corner and also a thumbnail link in the end card.
This is Chromaphobe.
Leave a Reply