Why genetically modified fish are being bred to fight rare childhood diseases

Doha, Qatar – In the heart of Doha’s Education City, a vast, sun-bleached campus of tech companies and universities, lies a healthcare facility that Qatar hopes will become a beacon of personalised medicine within the Middle East.

Defined by the giant glass and ceramic wings which adorn the outside of the building – a nod to the historic pearl trade in the nearby Arabian Sea – Sidra Hospital has been built to create a regional hub for treating children with rare diseases.

“90 per cent of our patients are kids, and they’re very, very sick kids,” says Dr Khalid Fakhro, Chief of Research and Chair of the Precision Medicine Program at Sidra.

“The thing about rare disease is that it’s very hard to diagnose, so families will go from one clinic to the next, and sometimes they have to go overseas. Health economics studies have shown that it takes five to seven years to diagnose a rare disease. It’s called the diagnostic odyssey.”

Inherited blood disorders such as sickle cell disease and other rare conditions, often caused by a single gene mutation, are particularly prevalent in Arab nations due to a variety of factors, including high rates of marriages between first cousins.

While Qatar has taken various steps to try and address the problem, including compulsory premarital genetic screening compulsory for all residents in the country since 2012, research has suggested that more than 50 per cent of marriages in Qatar and the wider Arab world are still between blood relatives.

Research from the Centre for Arab Genomic Studies has previously indicated that there are 2.8 million people living with rare disease in the Middle East, a significant public health burden.

But this has also spurred one of the world’s most innovative precision medicine initiatives, one which is already leading the way when it comes to swiftly pinpointing the cause of newly-identified rare diseases and uncovering possible treatment solutions.

While scientists have traditionally turned to rodents when it comes to understanding the biology behind a particular condition, Sidra’s pioneering program is all based around one particular species of freshwater fish.

Genetic similarities

The zebrafish is a minnow species which gains its name from the blue stripes found on either side of its body. Commonly found in the waters of southeast Asia, it appeals to geneticists because humans and zebrafish share 70 per cent of our genes.

“No one would imagine that a tiny fish from the Indian Ocean would be used in biomedical research,” says Dr Sahar Da’as, who leads the Sidra Medicine Zebrafish Facility. “But of the genes we have in common, 84 per cent are related to human disease genes.”

This isn’t as much as mice or indeed other mammals, but zebrafish do offer two crucial advantages.

Researchers can easily maintain several thousand fish in a small lab, while they develop remarkably quickly. Within 24 hours of being hatched as a single cell, they already have a head, tail, and a beating heart. By five days, they are fully formed and swimming around.

“Five days in the fish’s life is equivalent to nine months in humans, while that would be around 21 days for rats and mice,” says Da’as. “So within one week, we are able to give answers to patients.”

When any child with mysterious, unexplained symptoms – which can range from seizures to muscle wastage to a malformed skull – presents to doctors at Sidra, their genome is immediately sequenced and screened for known gene mutations.

If the patient is found to carry a particularly unusual mutation, one that scientists have never encountered before, they begin the process of attempting to replicate the biology in a zebrafish embryo.

Down in the basement of the hospital, rows of tanks are surrounded by an array of complex machines, some capable of imaging internal organs or measuring brain signalling, and others examining patterns in their movement.

Depending on the mutation, the scientists will either inactivate a particular gene or even inject the human gene into the fish, before waiting to see how it develops.

The team have even created a new breed of zebrafish, dubbed Casper fish after the cartoon ghost, which are genetically engineered so that their skin is completely transparent. This allows them to precisely observe the formation of the internal organs.

“We can see the formation of the liver, pancreas, motor neurons, muscle development,” explains Da’as. “From our imaging, we can tell if the brain size is smaller than expected due to a mutation.

“Any biological changes that might affect the ability of a child to walk, we can detect through their swimming. If fish are experiencing seizures, we can see that because their tails will coil faster. We can do visual and auditory tests on them to see whether their sight or hearing is normal.”

Once they know what the gene is doing, the next step is to screen for potential treatments and then test them in the fish using existing databases of drugs, to see whether the various symptoms can be ameliorated.

Da’as says she is currently treating a family of three brothers, all of whom have an inherited disease caused by a rare gene mutation which causes progressive nerve damage.

“The eldest siblings are 17 and 14 and they’re wheelchair bound, so it’s too late to really modify the neurodegeneration,” she says. “But the youngest is seven, and he’s still walking but he has a low muscle tone due to the gene.

“We replicated it in the fish and found that high dose vitamin B12 treatment could have a protective effect. So he’s now on that and we’re hoping it will delay the symptoms.”

Before long, Sidra researchers are aiming to be able to go from identifying signs of a rare disease to delivering a treatment within just three months, a timeframe which is astonishingly fast.

In comparison, the European Commission reported that it typically takes patients five years merely to get a diagnosis. In future, the hospital is also looking to partner with pharma companies to run clinical trials with the aim of being able to develop novel, personalised medicines specifically aimed at rare disease patients.

“We finally got the necessary accreditation from the ministry earlier this year,” says Fakhro. “So now we have a facility downstairs, which is completely ready to produce clinical grade products and medications for human use.”

But Sidra’s work is not only about understanding rare disease, but the functions of relatively common genetic mutations, unique to Middle Eastern populations, which have been identified over the last decade through the Qatar Genome Programme.

Dr Said Ismail, the programme’s director told the Telegraph that Qatar has now sequenced the genomes of more than 40,000 individuals, almost a tenth of the population.

Last year, a new paper described mutations in a gene called LMNA which are unique to the Qatari population. It showed that they cause a form of heart muscle disease called dilated cardiomyopathy where the heart chambers enlarge and lose their ability to contract, making them at a much greater risk of suffering cardiac arrest during high intensity exercise.

“We used the zebrafish model to understand what was happening in the heart as a result of the mutations,” says Da’as. “It means we can screen patients and refer them to early interventions such as avoiding high intensity exercise, keeping to a low-fat diet and having regular check-ups with a cardiologist.”

Ismail says that Qatar is also working on identifying specific gene mutations relating to inheritable cancers such as breast cancer and colorectal cancer.

“Many people know of the BRCA1 and BRCA2 genes which are linked to breast cancer, but the mutations which are used to screen for the disease in Northern European populations are not found here,” he says. “Ladies with these familial forms of breast cancer in the Middle East have other mutations, still within those genes, but different. So we have to design our own screening programs.”

He predicts that many of the findings will not only hold public health benefits for Qataris but across the Middle East and North Africa.

“Genetic discoveries made here will resonate not only for people living here,” he says. “We have a good representation within the Qatari population of a huge part of the world all the way from the Gulf to the Atlantic.

“So I think we are in a very good position to represent genetic information relating to 400 million individuals living in this part of the world.”



Email: [email protected]
Phone: +974 400 373 65