Vexas would have been discovered a long time ago if it were a garden variety genetic disease, caused by an inherited genetic mutation. For instance, the single gene responsible for familial Mediterranean fever, also an inflammatory disease, was identified in 1997 by screening the DNA of families that carried the disease. But Vexas can’t run in families. Like cancer, Vexas is caused by what scientists call a “somatic mutation,” a gene mutation that develops in someone’s body after they are born.
Because somatic mutations appear later in life, they affect only a fraction of a person’s cells, which makes them difficult to find. Conventional genetic analyses will miss them entirely: If a particular mutation only shows up in some of a person’s DNA, it may get labeled as a mistake. To find somatic mutations, scientists must look very, very carefully.
But looking that closely at the entire genome is untenable: There would be far too much data to sift through. So when David Beck, an assistant professor of medicine at New York University, decided to go looking for disease-causing somatic mutations, he knew he needed to focus. He ended up targeting a cellular process known as ubiquitylation, in which proteins are marked with another protein called ubiquitin, often to be destroyed or shuttled elsewhere in the cell. It’s a fundamental cellular process with wide-ranging consequences, and previous research has shown that ubiquitylation issues can cause inflammatory disease.
Still, ubiquitylation is complex: Beck identified 841 different genes that are involved. But that focus was narrow enough. After searching through a database of over 2,500 people with undiagnosed diseases, both inflammatory and otherwise, he found three men who shared a somatic mutation at the same spot in the same gene: UBA1, which helps initiate the ubiquitylation process. These men all had problems with their blood—too few platelets, unusually large red blood cells—and immune system issues like cartilage and lung inflammation.
But because Vexas shares these symptoms with a number of other disorders, no one would have suspected these men all had the same disease without Beck’s genetic sleuthing—there are just too many people out there with unexplained inflammatory conditions for researchers to identify such subtle symptom patterns. They were just three men among the masses of people chafing under ill-fitting diagnoses.
For years, David Adams was one of those people, too. An affable man in his seventies, he’s spent almost an entire decade in and out of the hospital with pneumonia, severe inflammation, and pain so bad “it almost feels like your body is trying to push out through your pores.” He might never have discovered what was happening to him had it not been for his tenacious primary care physician, Risa Huber, who sent him to rheumatologists, hematologists, and, eventually, the NIH, where he was diagnosed with Vexas.
Treatment-wise, that diagnosis hasn’t meant much to Adams so far. As of now, the only cure for Vexas is a bone marrow transplant, a procedure that carries substantial risks. Adams was supposed to get a transplant last year, but doctors discovered that his right coronary artery was almost entirely blocked. He received a stent, and he hopes to get a transplant sometime soon, but for now he remains dependent on the steroids he has had to use since he got sick.