This genetic sleuth has uncovered a new category of disease marked by sporadic fevers and inflammation

The bizarre symptoms had tormented Sarkis Hagopian since he was a young child crawling around his Pittsburgh home. Every so often, one of his knees would balloon or an ankle would swell so much that he couldn’t put on his shoe. Fierce cramps would wrench his abdomen, leaving him unable to stand up straight. “I was pitched at a 45° angle,” recalls the now-60-year-old printing salesman.

Those mysterious bouts, which usually lasted 2 to 3 weeks, prevented him from playing youth sports. “I could not get through a season without a swollen knee or ankle,” he recalls. In third grade, he missed so much school that he was almost held back. Hagopian’s parents took him to several doctors, but none could figure out what was wrong. “They would say I must have banged my knee.” And after one severe episode during which he was hospitalized for weeks, doctors worried he had muscular dystrophy.

By the time he was 24, Hagopian had moved to Washington, D.C. He was determined to find someone there who could help. His joints were enlarging to grapefruit size in flare-ups that hampered his sales work. “When these symptoms show up, you are pretty much incapacitated,” he says.

The next doctor he saw was as mystified as the others, but had the good sense to refer him to the National Institutes of Health (NIH). Hagopian turned up for his first appointment there in 1985, he recalls, and in walked “this young guy full of energy with a big smile.”

The meeting was a watershed for both. Hagopian finally learned he suffered from a rare genetic illness, familial Mediterranean fever (FMF), and started to take the first treatment that salved his symptoms, the drugs colchicine and naproxen.

For the energetic, smiling guy, immunologist and physician Daniel Kastner, the encounter launched a more than 3-decade-long scientific quest into genetic diseases. Even before the human genome had been deciphered, Kastner teased out the DNA flaw behind FMF. He has gone on to define a new category of illnesses, known as autoinflammatory diseases, in which immune system malfunctions unleash inappropriate inflammation, resulting in a diversity of problems that includes arthritis, rashes, strokes, swollen eyes, and unexplained fevers.

Autoinflammatory diseases, which can vary from mild to lethal, affect more people than immunologists initially thought—FMF afflicts as many as one in 500 in certain populations. Researchers have uncovered more than 30 defective genes that trigger those conditions. Kastner and collaborators discovered or co-discovered 13 of them, reporting their most recent find in August.

By revealing what drives those diseases, Kastner’s work opened the door for life-changing and even lifesaving treatments for patients like Hagopian, other scientists say. “It’s the greatest example of bench to bedside you can think of,” says pediatric rheumatologist Ronald Laxer of the Hospital for Sick Children in Toronto.

Autoinflammatory diseases may also yield insight into the organization of the immune system by revealing “chokepoints,” or weak links that can fail and lead to illness, suggests Kastner, who rose through NIH’s ranks to become scientific director of the National Human Genome Research Institute (NHGRI) in 2010. In addition, the maladies could shed light on some common illnesses, such as Crohn disease, gout, and Alzheimer’s disease, that show autoinflammatory characteristics.

Having tracked a disease to its causative gene decades ago, Kastner now thinks the opposite approach could be fruitful: sequencing genomes from many people with unexplained health problems to pinpoint mutations and then determining whether those glitches are responsible for specific symptoms. “Taking these genotype-driven approaches,” he says, “maybe we can define diseases that we don’t even imagine right now.” That strategy has already enabled him and his colleagues to uncover an unusual new autoinflammatory disease, and he plans to search for others.

Kastner grew up in Lockport, a city near Buffalo, New York. Neither of his parents was involved in science—his factory worker father never graduated from high school—but Kastner says he has been enthralled by it “throughout my conscious life.” As an undergraduate at Princeton University, however, he couldn’t decide what to major in and eventually settled on philosophy. “You have freedom to think about a lot of things.”

Still, he ultimately decided to become a physician and enrolled at Baylor College of Medicine. But the mysteries of the immune system soon lured Kastner away from pursuing his M.D. “It was such an exciting time in immunology,” Kastner says. “There were lots of black boxes—that was really exciting for somebody with a philosophy background” who liked to ask questions. After completing a Ph.D., however, he returned to medical school and finished his M.D. “I wanted to pursue the dual existence of doing science and seeing patients.”

Kastner arrived at NIH in 1985 as a medical staff fellow, ready to begin his two-track career. Hagopian turned up shortly afterward and supplied a black box Kastner could try to pry open. Why FMF patients have periodic bursts of symptoms was a mystery, although some researchers thought the illness was an autoimmune disease, in which people’s own immune cells or antibodies attack their tissues.

FMF clearly ran in families, particularly ones with Mediterranean or Middle Eastern backgrounds. An ambitious plan germinated in Kastner’s mind. Francis Collins, the geneticist who now heads NIH, and other researchers were laboriously homing in on the gene that is defective in cystic fibrosis by using a technique called positional cloning. The approach involves identifying markers near the target gene by analyzing affected families. Kastner proposed a similar search to ferret out the mutated gene behind FMF.

At the time, the Human Genome Project to sequence our DNA had not started, and the whereabouts and identities of almost all human genes were unknown. Positional cloning was still unproved, and when Kastner proposed the project, his supervisor exploded. “He called me an idiot and other choice names.” Kastner eventually won him over, but doubters remained. “Most people looked upon me as a Don Quixote figure.”

Even before the project got off the ground, Kastner and colleagues hit a stumbling block—locating the large families with lots of FMF cases that could provide DNA. Hagopian is of Armenian ancestry, and Kastner first tried to recruit Armenian Americans from the Washington, D.C., area, enlisting a local priest to help. The church members who responded to his request rattled off plenty of health complaints, Kastner says, but none had FMF. Kastner eventually teamed with an Israeli doctor, Mordechai Pras of the Chaim Sheba Medical Center at Tel HaShomer, who had tracked down hundreds of patients with the disease. In 1989, Kastner flew back from Israel with 347 cell lines from patients and unaffected family members, which furnished a trove of DNA.

The researchers needed two other ingredients to complete the first step of their project: a set of DNA probes that would latch onto specific nucleotide sequences in the genome and a supply of fresh human placentas. The scientists planned to add the probes individually to DNA from the Israeli subjects and correlate the binding patterns with the pattern of FMF inheritance in the families.

The placentas, meanwhile, were meant to address a shortcoming of the probes: They were embedded in larger pieces of DNA that tended to stick to irrelevant “decoy” sequences scattered around the genome. Other researchers had found that DNA from placental tissue would glom onto those decoys and allow the probes to home in on their intended chromosome locations.

The probes were hard to come by; few researchers in the world could supply a comprehensive set that recognized sequences across the chromosomes. As for the placentas, Kastner picked up a supply every month from a local hospital. Kastner’s older son was born during the study, but his wife forbade him from using that placenta, he recalls with amusement.

After 2 years and a wrong turn during which the scientists became convinced that the mutant gene resided on chromosome 17, they traced it to chromosome 16’s short arm in 1991.

That was the easy part, Kastner says. The next stage—tracking down the gene itself—took another 6 years and required an international collaboration with researchers at the Los Alamos National Laboratory, the University of Adelaide, and other institutions then sequencing chromosome 16 for the Human Genome Project. “We were a microcosm of the genome project,” Kastner says. “We had to go through all of the steps” they went through, such as generating high-resolution gene maps.

By June 1997, the researchers had winnowed the candidates to 10 genes near one tip of chromosome 16. Once they cleared several final hurdles, including a crucial mix-up over whether one of the Israeli subjects had the disease, the scientists nabbed the causative gene. Called MEFV, it encoded a novel protein of unknown function that they named pyrin, from the ancient Greek word for fire or heat. In a near-tie, a team of French researchers identified the same gene at almost the same time.

With the FMF project complete, Kastner and colleagues began to search for additional mutated genes that trigger similar illnesses. As sequencing projects deciphered more and more of the human genome, the task grew easier. The researchers also had a bit of luck as they pored over DNA from seven families with unexplained fevers and other symptoms. Evidence suggested the gene fell within a region on chromosome 12, and the first gene the team checked turned out to be the right one. The gene, which they identified on Thanksgiving Day 1998, codes for one of the receptors for tumor necrosis factor alpha (TNF-alpha), a potent inflammation-stimulating molecule, and they named the disease that results from the faulty receptor TRAPS.

The discovery of a second disease-causing gene suggested ailments marked by fevers and inflammation might not be oddballs. Patients with FMF and TRAPS did not carry the self-targeting antibodies characteristic of autoimmune diseases such as lupus and rheumatoid arthritis. So Kastner and his team made an intellectual leap, arguing that TRAPS and FMF belonged to a new category of illnesses, which they dubbed autoinflammatory diseases. The name, he says, was a riposte to the “naysayers” who contended that the conditions had to be autoimmune diseases.

Kastner and other scientists have since identified many other autoinflammatory diseases, which go by an alphabet soup of acronyms, including DIRA and DITRA, CAPS and CAMPS, DADA2, HA20, PLAID, CANDLE, and SAVI. The diseases attack many parts of the body, but they share a general mechanism. The faulty genes behind them perturb the intricate control circuits that keep inflammation in check. That natural surge of white blood cells and the pathogen-fighting substances they release is vital to combating invaders, but the response can tilt from beneficial to damaging if is too intense, lasts too long, or happens in uninfected parts of the body.

In at least nine of the diseases, the inflammasome—an inflammation-managing, pinwheel-shaped protein cluster inside certain cells—occasionally goes into overdrive. A defect in pyrin, which normally responds to pathogens by forming an inflammasome, is often the culprit. In FMF, for example, mutations in MEFV cause cells to produce faulty pyrin that provokes inflammation without any apparent pathogenic trigger. CAPS results from defective copies of the protein NLRP3, part of which resembles pyrin and helps form inflammasomes.

People with FMF, CAPS, and most other autoinflammatory diseases inherited the faulty genes that cause their illness from one or both parents. But a gene-first approach has now led Kastner and collaborators to an exception. The idea for the research, Kastner says, came from an “impatient young person,” NIH genetics fellow David Beck, who proposed sequencing more than 800 genes involved in a process that enables cells to dispose of unneeded proteins. After analyzing those genes in more than 2500 patients who had come to NIH with undiagnosed conditions, the researchers discovered three middle-aged men who suffered from problems such as lung inflammation, skin lesions, and irritated cartilage in the nose and ears. All three carried glitches in a gene called UBA1. By searching other groups of undiagnosed patients, the team uncovered 22 more people with mutations in the gene.

The novelty of VEXAS syndrome, as Kastner and colleagues called it in their 2020 report, was that patients had acquired their disease-causing mutations during their lives, in much the same way that sporadic cancer results from new mutations. Because the gene is on the X chromosome, men only have one working copy, so they have a much greater chance of developing VEXAS. Researchers have since reported cases of VEXAS syndrome in older women who had lost one of their two X chromosomes from some of their cells. Other, as-yet-undiscovered autoinflammatory diseases may also stem from acquired mutations.

“Most concepts in immunology have a life span of 5 to 10 years,” says immunologist Jean-Laurent Casanova of Rockefeller University. “The concept of autoinflammatory diseases is good and will stand the test of time.” Pediatric immunologist Hal Hoffman of the University of California, San Diego, adds that the concept helped explain recognized immune disorders that nobody knew how to categorize. What Kastner has done, he says, is “give all those diseases a home and give us a way to think about treating and managing them.”

The idea promises to deepen understanding of other conditions as well. Some researchers argue, for example, that autoimmune and autoinflammatory diseases fall along a single continuum of immune system disorders.

Helen Lachmann, a physician who studies autoinflammatory diseases at University College London, says Kastner’s impact reflects his ability to pick the right challenges. “He’s very good at spotting not just the big problems, but the solvable problems. It’s a rare gift.” And once he has identified a problem, he knows how to marshal research talent to solve it, she adds. Two scientific talents he helped nurture, his former postdoc Ivona Aksentijevich and former rheumatology fellow Raphaela Goldbach-Mansky, have collaborated with him on most of the gene discoveries and independently probe autoinflammatory diseases as NIH researchers.

Kastner’s legacy also includes the first targeted treatments for several types of autoinflammatory diseases. Until his discoveries, the standard therapies were drugs such as colchicine, an anti-inflammatory that doctors have deployed against conditions as diverse as cancer, cirrhosis, and heart arrhythmias. But uncovering the genes that go awry in FMF and related diseases pointed to specific causes for symptoms, such as surges in inflammation-promoting molecules like interleukin 1 and TNF-alpha.

Pharmaceutical companies have developed several drugs, such as anakinra and canakinumab, to block those proinflammatory molecules. Those medications have become standard therapies for autoinflammatory diseases.

The best illustration of the treatments’ power may be NOMID, a severe variant of CAPS, Kastner says. Rashes and fevers begin when patients with the illness are infants. But as the patients age, they develop meningitis that by their teen years can lead to deafness and brain damage. Kastner, Goldbach-Mansky, and colleagues gave anakinra to NOMID patients in a 2006 clinical trial. “Within a few hours the fevers go away, the skin rash goes away,” he says. Brain scans showed that neuroinflammation subsided in the patients who had meningitis.

However, Kastner notes, children with NOMID must start treatment early in life—and continue on the drug as they age—to gain any benefit. The treatment can halt, but not reverse, brain damage. Now, a few clinical trials are assessing other potential therapies for autoinflammatory diseases.

Kastner has spent his entire working life at NIH. He recently turned 70 and has no plans to retire, though he is stepping down as NHGRI’s scientific director. One reason he is leaving, he says, is to give the institute a chance to increase diversity in its leadership. His replacement, announced 13 September, is genetic epidemiologist Charles Rotimi, born in Nigeria.

Kastner plans to continue the physician-scientist’s double life. “I think having the combined existence was really important for me,” he says. “I will continue to see new patients and hopefully will continue to discover new diseases.”

One long-term patient he still sees is Hagopian. The colchicine and naproxen Hagopian started taking in 1985 tamped down his symptoms for 30 years. However, Hagopian says the drugs were deceptive. “When you get relief from a treatment, you feel like you’ve been cured.” Six years ago, he had to be rushed to the hospital because he had developed an intestinal obstruction caused by adhesions, belts of connective tissue in the abdomen that result from inflammation.

Kastner suggested Hagopian start injections of anakinra. The drug banished nagging problems, such as back pain he had attributed to aging, Hagopian says. “I never knew what it felt like to be normal until I was 55 years old.”