They could not explain why the afflicted, often in the same family, had recurrent fever, abdominal pain, troublesome rash and muscle aches. The disease, known as familial Mediterranean fever, was often undiagnosed for years, and it was sometimes fatal.
It was initially thought that a similar, but unrelated, mystery fever affects families with Scottish and Irish heritage.
“The pain I was feeling at the time was moving around. One week the pain was in my leg, and the next week my arm would rather be sore,” said Victoria Marklund, 47, a Swedish woman suffering from TRAPS or tumor necrosis. factor suffered, said. receptor-associated periodic syndrome, a disease first identified in a family of Irish and Scottish descent living in 1982 in the British city of Nottingham.
Her father and grandfather died prematurely of kidney complications, which were probably the result of the undiagnosed disease.
Marklund has now received effective treatment and is living symptom-free – mainly thanks to the work of one American doctor and health researcher, Dr. Dan Kastner, a leading researcher at the National Institutes of Health. who serves as Scientific Director of the National Human Genome Research Institute.
“What Dr. Kastner has achieved is absolutely groundbreaking. The concept of auto-inflammatory disorders does not exist until he has identified the cause of a number of them,” said Olle Kämpe, a professor of clinical endocrinology at Karolinska Institute in Stockholm, said. of the Royal Swedish Academy of Sciences and chairman of the prize committee. The academy also selects Nobel Prize winners.
“His discoveries have taught us a lot about the immune system and its functions, which contribute to effective treatments that reduce the symptoms of diseases that patients have suffered a lot from in the past,” Kämpe added.
Breakthrough
Kastner first encountered familial Mediterranean fever in a patient with recurrent arthritis and a high fever that he treated in a rheumatology partner, just a few months into his first job at the NIH in Bethesda, Maryland, in 1985. That chance service put him on a 12-year journey. to find the gene – or genes – that are responsible for the disease.
“Family Mediterranean fever was known to be a genetic disease. It was known to be inherited recessively, but no one knew what the gene was, or even the chromosome,” he said.
He travels to Israel, where he takes blood samples from 50 families with familial Mediterranean fever.
It took Kastner seven years to detect the mutation on chromosome 16. It took another five years – in 1997 – for Kastner and his team to find the mutated gene themselves – one wrong imprint in a 3 billion letter genetic code.
After this breakthrough, he remained in NIH, where he studied undiagnosed patients with similar symptoms. He identified 16 auto-inflammatory genetic disorders and effective treatments found for at least 12 of them, which created a whole new field of medicine.
Now that the complete human genome has been mapped, the process of tracing the genetic root of such disorders is accelerating and larger numbers of patients with these rare, unexplained diseases are being helped as a result of Kastner’s work.
All-nighters
There are few images in science more iconic than the DNA double helix structure, discovered in 1953 by James Watson and Francis Crick, two years after Kastner was born. As a seventh learner, he once made a version of the twisted leather mold with jelly beans and pipe cleaners for a scientific fair.
His work to identify the gene that caused familial Mediterranean fever has its own element of competition. To beat a competitive team led by French researchers in the summer of 1997, Kastner flew one last minute from Bethesda, Maryland, where the NIH is based, to Boston to submit his manuscript outlining the gene mutation that familial Mediterranean fever caused by handing over to the trade magazine Cell on a Friday afternoon.
These were the days before papers could be submitted with the click of a mouse. He was hoping to publish his work first. Eventually, the two teams published their papers simultaneously in different journals – both happily coming to the same conclusion.
“I like that kind of thing,” he said. “We still have races to the end, and there is nothing like a good week of all-nighters.”
Kastner had discovered that the gene involved in familial Mediterranean fever produces a protein called pyrine. Normally, it helps activate our innate immune system – our first line of defense to fight bacteria and viruses.
In this case, however, pirine caused the innate immune system to become overactive, resulting in fever, pain, and arthritis. He will study patients with similar and more devastating symptoms – identify TRAPS and many more rare diseases.
The transformation of lives
What has motivated Kastner for five decades is how his work, which decodes the genetics of inflammation, can inform new treatments and ultimately change the lives of patients.
“There is nothing more gratifying in life and nothing more scientifically satisfying,” he said. He plans to retire from his role as scientific director at the NIH in the next few months and then establish his efforts at his clinic, where he has more than 3,000 patients enrolled and ‘can find even more pathogens. How it works and develops new treatments. “
“Of course one can never know how long it will take, but I like to do it and will continue as long as I can.”
In recent work that began in 2014, Kastner identified the treatment and did pioneering work for a severely debilitating genetic disorder known as DADA2, short due to the deficiency of the enzyme ADA2 (adenosine deaminase 2), which can cause recurrent fever and strokes that begin in childhood. His research covered the life of the daughter of Dr. Chip Chambers drastically improved.
“She is now in college and the improvement in her quality of life has been dramatic.”
Similarly, TRAPS survivor Marklund suffered for years before her diagnosis at age 38. Her cousins, who both have TRAPS but received medication from an early age, do not feel the effects of the disease at all, she told The Royal Swedish Academy of Sciences.
“I have many times doubted that anyone would ever notice what I was suffering from. So it feels fantastic to tell what it was, to understand the cause of the disease and that there is medicine that helps.”