Mysterious untreatable fevers once devastated whole families. This doctor discovered what caused them
Dr.
Daniel Kastner, right, in his lab in 2018 with Dr. Kalpana Manthiram, a
clinical fellow at the National Human Genome Research Institute and a
colleague of Kastner.
(CNN)It's an ancient disease that may have evolved to confer protection against the plague -- but until 20 years ago, it had scientists and doctors flummoxed.
They
couldn't explain why those afflicted, often in the same family, had
recurring fevers, abdominal pain, troublesome rashes and muscle aches.
Known as familial Mediterranean fever, the disease often went
undiagnosed for years, and it was sometimes fatal.
Unusual
in most parts of the world, it was more common in the countries that
border the Eastern Mediterranean -- including Turkey and Israel --
where one or two of every 1,000 people have it.
A similar, but unrelated, mystery fever was initially thought to affect families with Scottish and Irish heritage.
While these types of periodic fevers, now classed as autoinflammatory disorders, are regarded as rare, they cause misery for those who suffer from them.
"The
pain I felt back then, it moved around. One week the pain was in my
leg, and the next week my arm would hurt instead," said Victoria
Marklund, 47, a Swedish woman who suffered from TRAPS, or tumor necrosis
factor receptor-associated periodic syndrome, a disease first
identified in a family of Irish and Scottish descent living in the UK
city of Nottingham in 1982.
Her
father and grandfather died prematurely from kidney complications,
which were likely a consequence of the undiagnosed disorder.
Marklund
has now received an effective treatment and lives symptom-free --
largely thanks to the work of one US 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.
The Royal Swedish Academy of Sciences on Monday awarded Kastner the prestigious Crafoord Prize, considered a complement -- and for some winners, a precursor to -- a Nobel prize.
"What
Dr. Kastner has accomplished is absolutely groundbreaking. The concept
of autoinflammatory disorders didn't exist before he identified the
cause behind a number of them," said Olle Kämpe, a professor of clinical
endocrinology at Karolinska Institutet in Stockholm who is a member of
The Royal Swedish Academy of Sciences and chair of the Prize Committee. The academy also selects Nobel laureates.
Dr. Dan Kastner (center) is shown in his NIH lab in 1990 with his colleagues Dr. Ivona Aksentijevich and Dr. Luis Gruberg.
"His
discoveries have taught us a great deal about the immune system and its
functions, contributing to effective treatments that reduce the
symptoms of disease from which patients previously suffered enormously,"
Kämpe added.
Breakthrough
Kastner
first came across familial Mediterranean fever in a patient with
recurring arthritis and high fevers he treated as a rheumatology fellow
just months into his first job at the NIH in Bethesda, Maryland, in
1985. That chance diagnosis set him on a 12-year journey to find the
gene -- or genes -- responsible for the disease.
"It
was known that familial Mediterranean fever was a genetic disease. It
was known that 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 to chromosome 16. It
took another five years -- in 1997 -- for Kastner and his team to find
the mutated gene itself -- one misprint in a genetic code comprised of 3
billion letters.
After this breakthrough, he stayed at NIH, where he studied undiagnosed patients with similar symptoms. He identified 16 autoinflammatory
genetic disorders and found effective treatments for at least 12 of
them, establishing a whole new field of medicine.
Kastner
(third from right) is pictured with colleagues celebrating the
discovery of the familial Mediterranean fever gene in 1997.
Now
that the full human genome has been mapped, the process of detecting
the genetic root of such disorders is quicker, and greater 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 grader, he once created a
version of the twisted ladder shape using jelly beans and pipe cleaners
for a science fair.
Fast-forward
to Kastner's medical career, which started in the early heyday of
genetic research. He was inspired by the international race in the late
'80s to identify the cystic fibrosis gene -- an achievement that at the
time was called "one of the most important in human genetics."
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 submit his
manuscript detailing the gene mutation that caused familial
Mediterranean fever by hand to the journal Cell on a Friday afternoon.
These
were the days before papers could be submitted with the click of a
mouse. He hoped to publish his work first. Ultimately, the two teams
published their papers simultaneously in different journals -- both
fortunately arriving at the same finding.
"I love that type of thing," he said. "We still have races to the finish, and there's nothing like a good week of all-nighters."
Kastner
is shown in 2016 at the inaugural DADA2 conference in Bethesda,
Maryland, with a boy who has DADA2, an autoinflammatory disorder. The
award-winning scientist identified the genetic mutation that causes the
disease and also helped develop treatments.
Kastner had discovered
that the gene involved in familial Mediterranean fever produces a
protein called pyrin. Normally this helps to activate our innate immune
system -- our first line of defense to fight bacteria and viruses.
In
this case, however, pyrin made the innate immune system become
overactive, resulting in fever, pain and joint inflammation. He went on
to study patients with similar and more devastating symptoms --
identifying TRAPS and many more rare diseases.
The family of diseases identified by Kastner are distinct from autoimmune diseases like rheumatoid arthritis and lupus, in which a different branch of the immune system malfunctions.
More
recent research by Kastner and his colleagues has shed light on why
some of these genetic disorders might have evolved. It's possible that
the genetic mutation for familial Mediterranean fever may have offered
carriers some resistance against the bubonic plague, which ravaged parts of the Middle East and Europe in the Dark and Middle Ages.
Transforming lives
What
has motivated Kastner for five decades is how his work decoding the
genetics of inflammation can inform new treatments and ultimately
transform patients' lives.
"There's
nothing more gratifying in life and nothing more satisfying
scientifically," he said. He plans to step down from his role as
scientific director at the NIH in the next few months and then focus his
efforts on his clinic, where he has over 3,000 patients enrolled and
"find yet more disease genes, understand how they work, and develop new
treatments."
"Of course, one can never know how long that will last, but I love doing it, and will continue as long as I can."
In more recent work beginning in 2014, Kastner
identified and pioneered treatment for a severely debilitating genetic
disorder known as DADA2, short for deficiency of the enzyme ADA2
(adenosine deaminase 2), which can cause recurring fevers and strokes
starting in childhood. His research has radically improved the life of
the daughter of Dr. Chip Chambers.
"My
daughter, who is 23, was sick from age 2. She got very sick late in her
teen years. No one could figure it out. We didn't know what was wrong
with her," said Chambers, an assistant clinical professor of surgery at
Vanderbilt University Medical Center in Nashville, Tennessee, and
founder of the DADA2 Foundation.
"She's now at college and the improvement in her quality of life has been dramatic."
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Similarly, TRAPS survivor Marklund suffered for years before her diagnosis at the age of 38. Her
nephews, who both have TRAPS but have been given medicine from an early
age, don't feel the effects of the disease at all, she told The Royal
Swedish Academy Of Sciences.
"I
doubted many times that anyone would ever figure out what I was
suffering from. So now it feels fantastic, to be told what it was, to
understand the cause of the disease and that there is medicine that
helps."
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