An important tidbit to know about researching rare diseases: Find that one gene that isn’t working as nature intended, and it can lead to the reasons why other, not-so-rare diseases develop.
One prime example is the statin, that ubiquitous, everybody-knows-what-it’s-
This discovery came before the genome was mapped, before remarkable devices could pinpoint what gene went awry in a sick individual, and before people with that same awry gene could put their names into a registry designed just for them, so researchers could more easily find them.
“This is often the case,” said Dan Kastner, MD, PhD, this year’s recipient of the 2021 Crafoord Prize for his discovery of rare, autoinflammatory diseases. “Figure out some rare disease that puts you on an important pathway of human biology, and then find other ways that pathway can be harnessed or modulated in more common conditions.”
This persistent but patient, well regarded researcher, who also is the scientific director of the National Human Genome Research Institute, can speak to this research strategy. In his nearly four decades at the NIH, he and his team found many of the underpinnings of these autoinflammatory diseases: rare (1 in 200,000 cases or fewer) diseases whose origins are in the innate immune system — the system we are all born with. (The coronavirus vaccines are targeting the adaptive immune system.)
Starting in the late 1980s, his group spent about 12 years to find one gene, the source of familial Mediterranean fever. People with this condition have on-and-off stomach pain, joint inflammation, rashes, aching muscles and recurring fevers.
These researchers had no genome map, no remarkable devices. But once the gene that activates IL-1 was identified, a treatment came quickly – because it was already on the shelf.
Other discoveries soon followed, including a mutation in the receptor of tumor necrosis factor, another inflammation-associated molecule. The disease associated with this mutation is called TRAPS. A disease that starts in childhood, it has symptoms that are similar with familial Mediterranean fever; both diseases can kill.
Since 1999, more than 50 diseases, whose origins trace to a problematic gene, fit under the umbrella term of autoinflammatory disease. (As an aside, the same people who determine the Nobel Prizes also decide the winner of the Crafoord awards.)
People with autoinflammatory diseases can inherit the disorder from their parents, or the mutation can happen because, for just one example, the person’s DNA was damaged, so a molecule designed to send one message to a cell ends up sending a wrong, and usually debilitating, message.
For the Kastner group, IL-1, or interleukin-1, has been under the microscope, as it were, for years. IL-1 is a cytokine, which can be very good for producing the inflammation needed to control infection, and very bad when it’s out of control. (Think Covid cytokine storm.) TNF has also been a target, and in time, the Kastner group has added another cytokine called IL-6 to the list. IL-6 inhibitor medications like tocilizumab help people with rheumatoid arthritis. These diseases all attack joints and tissue. (Tocilizumab is now being used in certain Covid-19 patients.)
“A lot of the diseases we have worked on, involve, in one way or another, a mutation to regulate … or somehow have an impact on IL-1, TNF and IL-6.”
In nature, no molecule acts on its own. So it’s not just controlling IL-1 or IL-6; it’s finding whatever molecule or molecules that are responsible for telling this particular cytokine to go haywire.
Dr. Kastner lights up when he discusses “the most dramatic” of his lab’s findings, and what ensued.
Neonatal onset multisystem inflammatory disease, or NOMID, once had a horrible prognosis, said Dr. Kastner. The mutation is in a gene called NLRP3, which regulates the all-important cytokine IL-1.
“From birth, these children have fevers, hives like a skin rash, aseptic meningitis [inflammation of the fluid and membranes in the brain and spinal cord whose source is neither bacterial or viral] — they just have spontaneous inflammation. They can have inflammation of the eyes and inner ears,” said Dr. Kastner, whose Zoom backdrop is a sweet-looking bear hanging on a tree that grew in Alaska.
All this inflammation can cause blindness, deafness and intellectual disability. “Many children died by adulthood or were institutionalized. The prognosis was horrible.”
After finding the mutation, they located 18 people with NOMID to test an existing drug called anakinra, an IL-1 inhibitor. “We hypothesized that an IL-1 inhibitor might help.The staff clinician and I wrote a clinical protocol to test anakinra in these children.” This work occurred in the early 2000s.
“It was like a miracle,” he said. “Within a couple of days the fevers went away, the hive-like skin rashes went away. .. We monitored the inflammation by [magnetic resonance imaging.] Within 3 months the inflammation in the brain went away.”
This discovery had a little help from some mysterious forces. At the same time that the Kastner lab was working on NOMID, another lab had found the errant gene, NLRP3, for another autoinflammatory disease called Muckle-Wells — a milder form of NOMID, Dr. Kastner said. At the same time, a patient with this disease was referred to Dr. Kastner. At the same time, two interns were working with two patients with similar symptoms.
And — at the same time — a visiting fellow from Argentina just happened to have two DNA samples of NOMID, “on the off chance that somebody might be studying [NOMID].” The mutations were found in each person.
Remarkably, these diseases also have an environmental component: people with familial Mediterranean fever will often have flares under stress. And, depending upon where the person with FMF lives, may or may not develop what is called amyloidosis. Amyloid is essentially the byproduct of inflammation that accumulates in various organs. In the case of FMF, it’s the kidneys. Without proper treatment, these patients will die. However, patients who have moved from their country near the Mediterranean — Italy, Turkey, and so on — to a more industrialized country, they may not develop this condition, Dr. Kastner said.
“There is environmental interaction even for a single gene” disease, said Dr. Kastner.
In a few months, Dr. Kastner plans to retire from his position as senior director, and re-enter the lab and clinic full time. The clinic at the NIH has 3,000 patients, one-third of whom have a diagnosis. He also will be spending more time in the lab.
For the last decade, the Kastner team has been studying Behçet’s disease. People with this disease have constant inflammation of blood vessels, painful ulcers in the mouth and genitalia, arthritis, and inflammation in the eyes, which can lead to blindness. It is prominent among people who live in the Middle East — Turkey, Israel and so on — into China. Dr. Kastner said a joint genome-mapping study between his lab and colleagues in Turkey located an important anti-inflammatory cytokine called IL-10. Those with Behçet’s had a different form of this cytokine that tampered with its anti-inflammatory effects.
He likes working with patients, which he says is “very gratifying.” And he likes finding those genetic mistakes.
“The fallibility of DNA replication in expanding populations .. is just a continuous source of more genetic diseases that are there to be solved. There is no end in sight. There will be plenty to work on.”