Ringo the Superdog: how rare genetic variations can lead to new treatments
Nibbler Vs. Krypto by JD Hancock via Flickr CC BY 2.0 (cropped)
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Ringo the Superdog: how rare genetic variations can lead to new treatments
Ringo the golden retriever was never expected to have a long life. Born in 2003 in a Brazilian dog breeding facility, he had been specially bred to carry the genetic fault responsible for Duchenne muscular dystrophy - a devastating fatal muscle wasting disease affecting around one in 3,500 boys, leaving them wheelchair bound by their teens and usually not making it past their thirties.
The disease is caused by a fault in a gene called dystrophin, which is found on the X sex chromosome in humans and dogs. This means that female dogs, who have two X chromosomes, with one faulty version of the gene will be OK, as the healthy version on the other chromosome can act as a backup. But male dogs have one X chromosome and one Y chromosome, so they have no backup and will have the disease if they inherit just one faulty version of the gene on their single X chromosome.
Ringo had been specially bred so that he would carry a faulty version of the dystrophin gene similar to the version found in the human disease, so that researchers could understand more about how it develops and find new treatments. But while his brothers in the litter all started to show the signs of the doggy version of Duchenne’s, Ringo was just fine.
Lead researcher Mayana Zatz was baffled. Genetic analysis showed that Ringo did indeed have the muscular dystrophy mutation, just the same as his brothers. So what was going on?
But while Zatz and her team were getting busy in the lab trying to figure out why Ringo wasn’t developing doggy muscular dystrophy, he was getting busy too. He took every opportunity to sneak out and engage in what’s best called an ‘informal breeding programme’, managing to sire an impressive 49 puppies with four different females.
Curiously, while most of Ringo’s pups did also inherit the Duchenne genetic variant and developed the disease, one of them - Suflair - inherited the gene fault but never showed any signs of muscular dystrophy.
Now they had two related dogs, that was enough for the researchers to start trying to home in on whether anything else in the animals’ DNA was protecting them.
By comparing Ringo and Suflair’s genomes with those from other golden retrievers, they were able to home in on a specific alteration in a gene called Jagged 1, which was present in the two resistant dogs but none of the other affected dogs in the colony.
Intriguingly, lab tests revealed that this variation led to unusually high levels of Jagged 1 being produced in the muscles of Ringo and Suflair, presumably having some kind of protective effect. And when the team put this version of Jagged 1 into zebrafish that were also missing dystrophin, the fish were protected against developing muscle tears or other signs of muscular dystrophy.
Sadly, Ringo passed away in 2014 at the age of 11 - not a bad innings for a purebred retriever - and I’ve been unable to find out whether Suflair is still with us, although I suspect not. But their legacy lives on in the work that’s now ongoing to try and figure out exactly how their version of Jagged 1 is acting to protect muscles against the impact of faulty dystrophin.
The answers could pave the way for new treatments for children with Duchenne muscular dystrophy and potentially other conditions too, such as the muscle wasting that happens in old age. So, thank you Ringo and Suflair - you have been Very Good Boys!
Sharlayne’s superpower
The story of Ringo the Superdog is just one example of how variations lurking within the genome might be able to compensate for the harmful effects of disease-causing mutations. By figuring out which molecules and pathways are involved, researchers can then start to unlock possible new treatments such as drugs or even gene therapies that can mimic their effects and mitigate disease.
Another neat example of how unusual genetic variations can lead to new ideas for treatments comes from superheroes like Sharlayne Tracey - an African American woman in her 40s, who was being studied by researchers at the University of Texas Southwestern Medical Center in Dallas.
In almost all respects, Sharlayne is completely normal...except one. While many Americans struggle to get their so-called ‘bad’ cholesterol level below 100 milligrams per decilitre, Sharlayne smashes it with a score of just 14.
Sharlayne’s superpower is thanks to the fact that she carries two rare versions of a gene called PCSK9, one inherited from her mum and one from her dad, which pretty much completely knocks out its function entirely.
PCSK9 normally encodes for a protein made in the liver, which keeps a check on the number of receptors for fatty cholesterol molecules on the surface of liver cells - the main way that harmful cholesterol is removed from the blood where it can contribute to clogged arteries or heart disease.
Without PCSK9, there are many more receptors on the cells, so the liver can mop up much more of the bad cholesterol before it can cause trouble. While both her mother and father had relatively low cholesterol levels, due to carrying one non-functional version of the gene, Sharlayne’s were lower still because she had both.
Researchers raced at breakneck speed to develop and test drugs mimicking the effects of having a non-functioning version of PCSK9, and the first PCSK9 inhibitors were approved for use in the UK in 2016 as an alternative to cholesterol-reducing statins, which aren’t right for everyone.
These drugs could be a potentially life-saving option for hundreds of thousands of people in the UK who are at risk of heart disease due to high cholesterol, and millions worldwide. Now that truly is helping to save the world - beat that, Batman!
Holding out for a hero
The final way that genetic superheroes can help science is in the search for external factors - like things in the environment or people’s diets, lifestyles or even microbiomes - that could help to mitigate the impact of harmful variations in their genes. And that’s incredibly exciting because those things are (at least in theory) easier to change than developing brand new drugs or doing tricky genome engineering.
As Cisca Wijmenga told me, “In the end there are still people running around with these mutations but still have no disease. I think if we were able to find out that this is environmental that's even better because if you can find out what those factors are, you have much better ways to treat people with those ‘bad’ genes. Because genetics is much harder to change than your environment.”
The search for genetic and environmental explanations for the superpowers of genetic superheroes is not going to be simple. This kind of research needs a LOT of detailed data about DNA and health from a LOT of people, and that kind of stuff isn’t easy to come by.
The US-based Resilience project is taking a novel approach to solving the problem, recruiting a million people who think they could be heroes (or are just interested in taking part in research) through an app launched in April 2020.
They’re looking for people with a strong family history of conditions like Alzheimer’s, sickle cell disease, heart disease or high cholesterol, but are unaffected themselves, as well as people who seem to be resistant to developing infectious diseases even though they’ve been infected, including COVID-19 and tick-borne Lyme Disease. It’s just the start, but hopefully as the idea of searching for genetic superheroes and learning their secrets grows, we’ll see other similar projects take off all over the world.
Geneticist Daniel Macarthur noted in a commentary accompanying the 2016 superhero paper, “Finding genetic superheroes will require other kinds of heroism—a willingness of participants to donate their genomic and clinical data, and a commitment by researchers and regulators to overcome the daunting obstacles to data sharing on a global scale.”
The real heroes we need aren’t fictional fighters in fancy suits - they’re the people who are willing to engage in genetic research on a deeper level to help improve health for us all. And that could be any one of us. As the great David Bowie once said, ‘We could be heroes, just for one day’.
