by At the heart of Doha Education City, a vast, sun-drenched campus of technology companies and universities, is a healthcare facility that Qatar hopes will become a beacon of personalized medicine in the Middle East.
Defined by the huge glass and ceramic wings that adorn the exterior of the building – a nod to the historic pearl trade in the nearby Arabian Sea – the Sidra Hospital has been built to create a regional hub for the treatment of children with rare diseases.
“Ninety percent of our patients are children, and they are very sick children,” says Dr. Khalid Fakhro, Head of Research and Chair of the Precision Medicine Program at Sidra.
“The thing about rare diseases is that it’s very difficult to diagnose, so families will go from clinic to clinic, and sometimes they have to go abroad. Health economics studies have shown that it takes five to seven years to diagnose a rare disease. It’s called a diagnostic odyssey.”
Inherited blood disorders such as sickle cell disease and other rare conditions, often caused by a single gene mutation, are particularly common in Arab nations due to a variety of factors, including high rates of first cousin marriages.
Although Qatar has taken various steps to try to combat the problem, including mandatory premarital genetic screening for all residents of the country since 2012, research has suggested that more than 50 percent of marriages in Qatar and the Arab world in general are still between blood. relatives
Research from the Center for Arab Genomic Studies has previously indicated that 2.8 million people are living with a rare disease in the Middle East, a significant public health burden.
But this has inspired one of the world’s most innovative precision medicine initiatives, one that is already at the forefront of quickly finding the cause of newly identified rare diseases and finding potential treatment solutions.
While scientists have traditionally turned to rodents to understand the biology behind a certain condition, Sidra’s pioneering program is based on a specific species of freshwater fish.
Genetic similarities
The striped fish is a species of fish that gets its name from the blue stripes found on each side of its body. Commonly found in the waters of southeast Asia, it fascinates geneticists because humans and zebrafish share 70 percent of our genes.
“No one would have imagined that a tiny fish from the Indian Ocean would be used in biomedical research,” says Dr Sahar Da’as, who heads Sidra Medicine’s Zebrafish Facility. “But of the genes we share, 84 percent are related to human disease genes.”
This is not as much as mice or indeed other mammals, but there are two crucial advantages of a grasshopper.
Researchers can easily keep thousands of fish in a small laboratory, developing very quickly. Within 24 hours of hatching as a single cell, they already have a beating head, tail and heart. By five days, they are fully formed and floating around.
“Five days in the life of fish is equivalent to nine months in humans, and that would be about 21 days for rats and mice,” says Da’as. “So within a week, we are able to give patients answers.”
When any child with mysterious, unexplained symptoms – which can range from seizures and muscle wasting 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 have a very unusual mutation, one that scientists have never encountered before, they begin the process of replicating the biology in a zebrafish embryo.
Down in the hospital basement, rows of tanks are surrounded by a series of complex machines, some capable of imaging internal organs or measuring brain signaling, while others examine patterns in their movement.
Depending on the mutation, the scientists will deactivate a specific gene or even inject a human gene into the fish, before waiting to see how it develops.
The team has even created a new breed of zebra fish, called Casper fish after the cartoon ghost, which are genetically engineered so that their skin is completely transparent. This allows them to observe precisely 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 is smaller than expected due to a mutation.
“Any biological changes that could affect the child’s ability to walk, we can detect through swimming. If fish have seizures, we can see because their tails will coil faster. We can do vision and hearing tests on them to see if their vision 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 fish using existing drug databases, to see if the symptoms can be improve various.
Da’as says she is treating a family of three brothers, who all have an inherited disease caused by a rare gene mutation that causes progressive nerve damage.
“The older siblings are 17 and 14 and 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 has low muscle tone due to the gene.
“We replicated it in fish and found that treatment with a high dose of vitamin B12 could have a protective effect. So it’s on that now and we’re hoping it will slow down the symptoms.”
Before long, Sidra researchers aim to be able to go from recognizing the symptoms of a rare disease to delivering a treatment within three months, a remarkably fast time frame.
In comparison, the European Commission reported that it usually takes five years for patients to receive a diagnosis. In the future, the hospital is looking to partner with pharmaceutical companies to run clinical trials in order to be able to develop new personalized medicines aimed specifically at patients with rare diseases.
“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 medicines for human use.”
But Sidra’s work is not only about understanding rare diseases, but the functions of fairly common genetic mutations, unique to Middle Eastern populations, identified over the past decade through the Qatar Genome Program.
Dr Said Ismail, the director of the program told the Telegraph that Qatar has now sequenced the genomes of more than 40,000 people, almost a tenth of the population.
Last year, a new paper described mutations in a gene called LMNA unique to the Qatari population. It showed that they cause a type 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 a 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, sticking to a low-fat diet and regular check-ups with a cardiologist.”
Ismail says Qatar is also working on identifying specific gene mutations associated with hereditary cancers such as breast and colorectal cancer.
“Many people know about the BRCA1 and BRCA2 genes being linked to breast cancer, but the mutations used to screen for the disease in Northern European populations are not found here,” he says. “Women 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 results will have public health benefits not just for Qataris but across the Middle East and North Africa.
“Genetic discoveries here will be relevant not only to the people who live here,” he says. “We are well represented within the Qatari population of a huge part of the world all the way from the Gulf to the Atlantic.
“So I think we’re in a very good position to show genetic information about 400 million people living in this part of the world.”
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