Dr Daniel Kastner: pioneer in the discovery of autoinflammatory genetic disorders

“The pain I was feeling at the time, it was moving. One week the pain was in my leg, and the next week my arm was aching instead,” said Victoria Marklund, 47, a Swede who suffered from TRAPS or tumor necrosis factor. Periodic receptor syndrome, a disease first identified in a family of Irish and Scottish descent living in the British city of Nottingham in 1982.

Her father and grandfather died prematurely from kidney complications, which were likely a consequence of the undiagnosed disease.

Marklund has now received effective treatment and is living symptom-free – largely thanks to the work of American physician and health researcher, Dr. Dan Kastner, a prominent researcher at the National Institutes of Health. who is scientific director of the National Institute for Research on the Human Genome.

“What Dr Kastner has accomplished is absolutely revolutionary. The concept of autoinflammatory disorders did not exist until he identified the cause behind a number of them,” said Olle Kämpe, professor of clinical endocrinology at Karolinska Institutet in Stockholm, which is a member. of the Royal Swedish Academy of Sciences and chair of the Prize Committee. The academy also selects the Nobel Prize winners.

“His findings have taught us a lot about the immune system and its functions, contributing to effective treatments that reduce symptoms of the disease that patients previously suffered greatly,” added Kämpe.

Breakthrough

Kastner first encountered familial Mediterranean fever in a patient with recurrent arthritis and high fevers whom he treated as a rheumatology fellow just months after his first job at NIH in Bethesda, Maryland, in 1985. This random diagnosis led him on a 12-year journey to find the gene or genes responsible for the disease.

“We knew that familial Mediterranean fever was a genetic disease. We knew it was recessively inherited, but no one knew what the gene was, or even the chromosome,” he said.

He traveled to Israel, where he took 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 printing error in a genetic code made up of 3 billion letters.

After this breakthrough, he remained at NIH, where he studied undiagnosed patients with similar symptoms. It identified 16 auto-inflammatory genetic diseases and has found effective treatments for at least 12 of them, establishing a whole new field of medicine.

Now that the entire human genome has been mapped, the process of detecting the genetic root of these disorders is faster, and more patients with these rare and unexplained diseases are being helped thanks to Kastner’s work.

All night long

There are few scientific images more iconic than the double helix structure of DNA, discovered in 1953 by James Watson and Francis Crick, two years after Kastner was born. As a seventh grader, he created a version of the twisted ladder shape using jelly beans and pipe cleaners for a science fair.

His work to identify the gene responsible for familial Mediterranean fever had its own competitive element. 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 submit his manuscript detailing the genetic mutation that caused the familial Mediterranean fever by delivery to Cell magazine on a Friday afternoon.

These were the days before articles could be submitted with the click of a mouse. He hoped to publish his work first. In the end, the two teams published their articles simultaneously in different journals – both luckily achieving the same result.

“I love this stuff,” he says. “We still have some races to finish, and there is no such thing as a good week of sleepless nights.”

Kastner had discovered that the gene involved in familial Mediterranean fever produces a protein called pyrin. Normally, this helps activate our innate immune system – our first line of defense in fighting bacteria and viruses.

In this case, however, the pyrin made the innate immune system overactive, leading to fever, pain and inflammation of 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 the lives of patients.

“There is nothing more rewarding in life and nothing more scientifically satisfying,” he said. He plans to step down from his role as Scientific Director at NIH in the next few months, then focus his efforts on his clinic, where he has more than 3,000 patients enrolled and “finding even more disease genes, understanding how they work, and how they work.” develop. new treatments. “

“Of course you can never know how long this will last, but I love to do it and will continue for 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 ADA2 (adenosine deaminase 2) enzyme deficiency, which can cause recurrent fevers and strokes as early as childhood. Her research has 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 the age of 38. Her nephews, both of whom have TRAPS but received medication from a young age, are not feeling the effects of the disease at all, she told the Royal Swedish Academy of Sciences.

“I have repeatedly doubted that anyone could ever understand what I was suffering from. So now it’s fantastic to know what it was, to understand the cause of the disease and that there are drugs that help. “