They were unable to explain why the affected people, usually in the same family, had recurrent fevers, abdominal pain, skin rashes and muscle pain. Known as familial Mediterranean fever, the disease was often undiagnosed for years, and was sometimes fatal.
A similar, but unrelated, mysterious fever was initially thought to affect families with Scottish and Irish heritage.
“The pain I felt back then changed. One week the pain was in my leg, and the next week my arm would hurt,” said Victoria Marklund, 47, a Swede who suffered from TRAPS, or periodic necrosis factor syndrome associated with recipient, a disease first identified in a family of Irish and Scottish descent who lived in the city of Nottingham, UK, in 1982.
Her father and grandfather died prematurely of kidney complications, which were probably a consequence of the undiagnosed disorder.
Marklund has now received effective treatment and lives without symptoms – largely thanks to the work of a U.S. physician and health researcher, Dr. Dan Kastner, a distinguished investigator at the National Institutes of Health who serves as scientific director of the National Human Genome Research Institute.
“What Dr. Kastner accomplished is absolutely innovative. The concept of autoinflammatory disorders did not exist before he identified the cause behind several of them,” said Olle Kämpe, professor of clinical endocrinology at the Karolinska Institutet in Stockholm who is a member of Real Swedish Academy of Sciences and Chair of the Award Committee. The academy also selects Nobel winners.
“Their findings have taught us a lot about the immune system and its functions, contributing to effective treatments that reduce the symptoms of diseases that patients previously suffered enormously,” added Kämpe.
Advance
Kastner came across familial Mediterranean fever in a patient with recurrent arthritis and high fevers that he treated as a rheumatology fellow, just months after his first job at NIH in Bethesda, Maryland, in 1985. This casual diagnosis put him on a 12 years to find the gene – or genes – responsible for the disease.
“Familial Mediterranean fever was known to be a genetic disease. It was known to be inherited recessively, but no one knew what the gene was, not even the chromosome,” he said.
He traveled to Israel, where he collected blood samples from 50 families with familial Mediterranean fever.
It took Kastner seven years to locate the mutation on chromosome 16. It took another five years – in 1997 – for Kastner and his team to find the mutated gene itself – a misprint in a genetic code made up of 3 billion letters.
After that discovery, he stayed at NIH, where he studied undiagnosed patients with similar symptoms. It identified 16 autoinflammatory genetic diseases and found effective treatments for at least 12 of them, establishing a new field of medicine.
Now that the complete human genome has been mapped, the process of detecting the genetic root of such disorders is faster, and more patients with these rare and unexplained diseases are being helped as a result of Kastner’s work.
Every night
There are few images in science more iconic than the double helix structure of DNA, discovered in 1953 by James Watson and Francis Crick, two years after Kastner’s birth. When he was in seventh grade, he once created a version of the twisted ladder shape using jelly beans and pipe cleaners for a science fair.
His work to identify the gene that caused familial Mediterranean fever had its own element of competition. In the summer of 1997, to beat a rival team led by French researchers, Kastner took a last-minute flight from Bethesda, Maryland, where the NIH is based, to Boston to send his manuscript detailing the genetic mutation that caused the familial Mediterranean fever by hand for the Cell newspaper on a Friday afternoon
Those were the days before articles could be sent with the click of a mouse. He hoped to publish his work first. Ultimately, the two teams published their articles simultaneously in different journals – both fortunately reaching the same discovery.
“I love that kind of thing,” he said. “We still have races to the end and nothing like a good week of whole nights.”
Kastner had found that the gene involved in familial Mediterranean fever produces a protein called pyrine. This usually helps to activate our innate immune system – our first line of defense to fight bacteria and viruses.
In this case, however, the pyrine made the innate immune system hyperactive, resulting in fever, pain and inflammation in the joints. He went on to study patients with similar and more devastating symptoms – identifying TRAPS and many other rare diseases.
Transforming lives
What motivated Kastner for five decades is how his work decoding the genetics of inflammation can inform new treatments and ultimately transform patients’ lives.
“There is nothing more fulfilling in life and nothing more satisfying scientifically,” he said. He plans to leave his position as scientific director at NIH in the coming months and then focus his efforts on his clinic, where he has more than 3,000 patients enrolled and “find even more disease genes, understand how they work and develop new treatments. “
“Of course, you never know how long it will last, but I love doing it and I will continue as long as I can.”
In more recent work started in 2014, Kastner identified and pioneered the treatment of a severely debilitating genetic disorder known as DADA2, short for deficiency of the enzyme ADA2 (adenosine deaminase 2), which can cause recurrent fevers and strokes since childhood. His research radically improved the life of Dr. Chip Chambers’ daughter.
“She is now in college and the improvement in her quality of life has been dramatic.”
Likewise, TRAPS survivor Marklund suffered for years before her diagnosis at 38. Her nephews, both with TRAPS, but who received medication at an early age, do not feel the effects of the disease, she told the Royal Swedish Academy Of Sciences.
“Many times I doubted that anyone would ever find out what I was suffering from. So now it is fantastic to hear what it was, to understand the cause of the disease and to know that there are remedies that help.”