After the third time he nearly died but before the fourth, David Fajgenbaum embraced a new motto: Think it, do it. “I got out of the hospital with this profound sense of, you need to make the most of every second,” he says. A former college football player with close-cropped dark hair and a firm handshake, Fajgenbaum, 31, is the picture of youthful vigor now. But that belies a frightening reality. Tomorrow the symptoms with which he’s all too familiar could return, sending him to the intensive care unit (ICU) with every organ failing.

Fajgenbaum was in his third year of medical school 6 years ago, on an obstetrics-gynecology (OB-GYN) rotation, when he was first hit by night sweats, fatigue, and weight loss. “I didn’t know what it was, but I knew something was terribly wrong,” he says. As his health deteriorated, he gritted his teeth and kept on delivering babies. After sitting through his OB-GYN exam, he stumbled a few blocks to the emergency room at the Hospital of the University of Pennsylvania (UPenn).

“They ran some bloodwork and they said, ‘Dave, your liver, your kidneys, and your bone marrow are not working, what’s going on?’” Fajgenbaum was hospitalized straight away. A retinal hemorrhage causing temporary blindness, along with fading organ function, landed him in the ICU. There he remained, without a diagnosis, for nearly 7 weeks. Eventually Fajgenbaum recovered, and his baffled doctors “kept saying, ‘Let’s just hope it doesn’t come back.’ We had no idea what it was.”

Fajgenbaum spent his first weeks out of the hospital combing through thousands of pages of medical records stretching back to childhood, hunting for something, anything, that doctors might have missed. As his medical saga unfolded, he learned that his potential killer was a rare and vicious immune disorder—Castleman disease, which strikes about 5000 people in the United States each year—and knowledge about it was in depressingly short supply.

Fajgenbaum abandoned plans to become an oncologist, skipped medical residency, and enrolled in business school instead—building a powerhouse network of hundreds of physicians, researchers, and drug company employees around the world to help him decipher Castleman. He co-authored papers with his doctor, wrote a case study about himself, proposed a new model of the disease, and currently coordinates a dozen Castleman studies from his small office at UPenn, where he is an assistant professor. His bare chest, pockmarked with blood moles that are a harbinger of a Castleman relapse, appeared on the cover of JAMA Dermatology in early 2013. It’s not exactly Mr. February, but Fajgenbaum is proud.

He acknowledges that he might die before completing his quest to understand and cure his affliction. “If this does come back and I don’t survive that episode, [I] would be sad … that I won’t be with my family and friends,” he says evenly. But “I’m literally doing everything humanly possible” to save myself and many others. And somewhat to his surprise, he’s crazy about his work. “I’m enjoying this battle,” he says. “I’m enjoying the chase after the unknown.”

A dire diagnosis

A Boston pathologist first described Castleman disease in 1954. Benjamin Castleman was mystified by a 40-year-old executive with fever and weakness who had an unusual mass in his chest. Doctors initially suspected cancer or another disorder, but the mass, when surgically removed, turned out to be something else al-​together—what would later become known as unicentric, or localized, Castleman disease.

The disease was considered a sort of “prelymphoma” with autoimmune features, in which cells in lymph nodes proliferate and attack various tissues. Over time, doctors pinpointed an immune-system messenger called interleukin-6 (IL-6) as key. They came to believe that Castleman flares when lymph nodes secrete excessive IL-6, setting off a massive inflammatory reaction, either locally or throughout the body.

Fajgenbaum was diagnosed with the disorder’s most dangerous subtype, idiopathic multicentric Castleman disease (MCD), during his second bout of flulike symptoms and organ failure, which hit while he was still recovering from the first at his family’s home in Raleigh. A lymph node biopsy revealed the typical Castleman mix of atrophy and enlargement in different parts of the node, along with blood vessel overgrowth. Physicians turned to their usual rescue for critically ill Castleman patients: aggressive chemotherapy, intended to wipe out the immune cells that were attacking healthy tissue.

Despite treatment, Fajgenbaum languished, and doctors told his Catholic family that he would not survive. A priest was called to offer last rites. It was November 2010, and Fajgenbaum was 25 years old.

Two days later, his body began to right itself. In an effort to safeguard his health, he decided to travel west to seek counsel from a world expert in Castleman disease, Frits van Rhee at the University of Arkansas for Medical Sciences in Little Rock. During that visit his symptoms returned. This time he was hit with seven chemotherapy drugs. Another brush with death was followed by slow recovery.

Despite spending 4.5 of the previous 6 months hospitalized, Fajgenbaum was feeling more upbeat. “I just trusted that the medical system was going to figure this out,” he says. The research papers he’d skimmed were reassuring. “People were speaking very dogmatically about how the disease works. I just assumed that if this is in the medical literature, this is the case.”

His optimism turned out to be misplaced. Fifteen months later, the familiar symptoms returned, and Fajgenbaum settled into a Little Rock hospital room for another extended stay and more chemotherapy. And now he began taking matters into his own hands, pressing Van Rhee for answers. Which immune cells were behind this? Which pathway? Why wasn’t treatment working? What was the contingency plan?

Van Rhee was unable to comment on this story before Science went to press. But Fajgenbaum recalls that his doctor’s answer was not comforting. “He said, ‘Dave, we’ve tried everything on you and you’re not responding to anything. What do you think we should do?’” At that point, “it hit me like a ton of bricks,” Fajgenbaum says. “I really realized how far away we were from the goal line.”

With his fiancée and two older sisters camped out next to him, Fajgenbaum made a promise: He would spend the rest of his life, however much remained, “trying to take this thing down.” The same seven-drug chemo cocktail saved him, and on 2 June 2012 he left the hospital. “I don’t think I’ve stopped sprinting since,” he says.

At first, Fajgenbaum had to figure out in which direction to run. Guidance came from another young man, Josh Sommer, now 28 years old, who was diagnosed as a freshman at Duke University with chordoma, a rare bone cancer that often appears in the skull and spine. Sommer later dropped out of college to form the Chordoma Foundation in Durham, North Carolina, which he’s headed ever since.

I got out of the hospital with this profound sense of, you need to make the most of every second. David Fajgenbaum, University of Pennsylvania

The two connected through a mutual friend in 2012 and met at a Raleigh coffee shop. Sommer had a message for Fajgenbaum: Every rare disease needs a quarterback, someone to marshal the team, harness the resources, and lay out a game plan. “People have to put their faith in this person,” Sommer says, to drive a sometimes rickety research train toward a clear destination. “I said, ‘Look … this disease needs you and you can make a huge impact,’” Sommer recalls. To garner respect among scientists, Fajgengaum would have to become literate in the disease—“a peer,” Sommer told him. The two talked for hours.

Meanwhile, Fajgenbaum’s initial hopefulness about his prognosis continued to fade. One trigger was his senior project for medical school, which began with a literature review of Castleman publications.

There was one mystery about his own case: Upon his most recent relapse, he was already taking a drug that blocks IL-6, which was then experimental and has since become the only approved treatment for MCD. But if IL-6 causes the disease to flare, and Fajgenbaum had none, how could Castleman come back? The papers deepened his confusion. Fajgenbaum came to believe that the accepted model—Castleman is caused by tumors secreting IL-6, which sends the immune system into overdrive—was unsupported by actual data.

One day, as he continued his senior project detective work, Fajgenbaum noticed something odd as he pored over images of lymph nodes from patients with autoimmune diseases, like lupus and rheumatoid arthritis. “They had almost identical lymph node features” to Castleman, he says. “It was so peculiar.” In Castleman, the lymph node abnormalities are considered drivers of the disease; in lupus, they are a reaction or side effect. Could it be, he wondered, that as in lupus, enlarged lymph nodes are an outcome of the disease, rather than its cause?

Fajgenbaum needed the medical community’s help. He scoured the PubMed database to find every researcher who had published on Castleman, and wrote more than 400 personal emails, inviting them to a meeting he was organizing at that December’s American Society of Hematology conference in Atlanta. To his surprise, many seemed unaware of each other and their work.

One of those who said yes was Jean-FranÇois Rossi, a hematologist at Saint-Eloi Hospital in Montpellier, France. Castleman scientists “are from different origins,” Rossi explains, spanning hematology, multiple myeloma, lymphomas, and other specialties. Rossi was curious to learn more and eager to meet with other experts.

In Atlanta, 27 Castleman experts gathered in a conference room in the convention center, with another five dialing in over the phone. Fajgenbaum, an unknown medical student 6 months from graduation, ran the event. There were disagreements about disease terminology, about which cells were worth studying. “It became so clear there was no consensus,” says Fajgenbaum, who delicately calls the gathering “revealing.”

The challenges, Fajgenbaum came to believe, weren’t rooted in science so much as business. “There was no overarching strategy,” he says, no 5-year road map of the kind corporations embrace. He concluded that to tackle Castleman he needed to pursue an MBA, and successfully applied to one of the world’s best programs, at the nearby Wharton School at UPenn.

Well-suited résumé

“I remember when he came to interview,” says June Kinney, who teaches health care management at Wharton. “He looked very vigorous and healthy. ... How could he look so healthy and have this shadow hanging over him?”

Kinney was impressed not only by Fajgenbaum’s current plans but by a tragedy-fueled achievement in his past. When Fajgenbaum was 19, his mother had died of brain cancer. Devastated and isolated, he launched an organization for grieving college students called AMF—which then stood for Ailing Mothers and Fathers, and also his mother’s initials, Anne Marie Fajgenbaum. Since renamed Actively Moving Forward, AMF now has 55 chapters at colleges around the country. Fajgenbaum continued to head the sprawling organization through medical school. This year, he co-authored a book, We Get It: Voices of Grieving College Students and Young Adults, a collection of 33 personal narratives.

Launching and running the nonprofit “was the ultimate training ground” for overhauling the Castleman world, he says. Kinney agreed. “I don’t get very many people that come in and have that kind of accomplishment at that stage,” she says. “Obviously there’s a lot of innate talent there in terms of motivating and inspiring people to build an organization.”

At Wharton, Fajgenbaum shoehorned his class commitments around his sequel to AMF: the Castleman Disease Collaborative Network (CDCN). He also drew on class lessons on, for instance, negotiation strategies, the economics of drug development, decision-making, and management.

Networking the globe

Reaching across national borders, the Castleman Disease Collaborative Network is linking up doctors and researchers, including some who haven’t worked in the disease before.

During his first semester in business school, Fajgenbaum, his physician Van Rhee, and a medical school friend, Christopher Nabel, wrote a paper for Blood that proposed the new model for his form of Castleman disease. The trio suggested that the lymph node effects were secondary, and that the disease was driven by some sort of systemic inflammatory disease mechanism, like certain gene mutations, or autoantibodies, or possibly a virus. (One virus, called HHV-8, is known to be behind a subset of MCD cases, but Fajgenbaum’s form is idiopathic.)

Fajgenbaum was keenly aware that his own treatment matched the traditional model, in which IL-6–secreting tumors are the disease driver. He was still taking the IL-6 blocker that had failed him before, as well as some maintenance chemotherapy. As he readied the Blood paper for publication, the disease returned, and he came perilously close to death for a fifth time.

The experience prodded him to overhaul his own treatment. Based on studies of his own blood and his rethinking of the disease, he wondered whether a drug suppressing activated T cells might work. His doctors agreed, and he became, to his knowledge, the only Castleman patient taking a particular immunosuppressant approved for other conditions.

In a sense, each relapse had brought an epiphany—he needed Castleman experts, he needed to take on this disease himself. This time, “I was thinking to myself, I’ve spent every moment of every day, and it just wasn’t enough. … Maybe it’s that we need to make this bigger than Castleman disease, engage people outside” the field. He left the hospital 4 weeks later considering how to recruit more bright minds to the fight.

Recruiting the best

“I’m a cog in their machine,” says W. Ian Lipkin, a renowned microbe hunter who runs a 50-person lab at Columbia University. Lipkin was familiar with the viral form of Castleman disease. But he had no idea there were Castleman patients, like Fajgenbaum, without any obvious sign of that virus.

Lipkin fits neatly into Fajgenbaum’s grand design: Identify the most pressing Castleman projects, then recruit the best person for each job. Fajgenbaum connected hundreds of researchers through an online portal, crowdsourced for a list of possible Castleman studies, then prioritized them—a strategy inspired by a Wharton exercise in which all 800 first-year business students had to collectively come up with five approaches to combat climate change.

The final tally included about 20 studies. One involved sifting through tissue samples from patients and looking for viruses, bacteria, or other nonhuman DNA or RNA that might trigger the disease. “Once we knew we wanted to do pathogen discovery, the first thing was an inventory” of every expert in the world, Fajgenbaum says. He and Nabel tapped immunologists, rheumatologists, and deans—“people who have a really good pulse.” Lipkin’s name rose to the top.

Lipkin’s lab hums along with more than $4 million a year in federal funding. So the $57,000 CDCN could offer him was unlikely to be much of an incentive. But the young doctors had a connection. Chris Nabel’s father is Gary Nabel, an old friend of Lipkin’s and former head of the Vaccine Research Center at the National Institutes of Health.

“Gary called me in June of 2014 and asked whether or not I could help his son and some of his friends,” Lipkin says. “After I spoke with these kids, I got involved because they’re earnest and committed.”

Lipkin asked for 25 frozen lymph nodes from 25 different patients, which seemed an easy request because everyone with Castleman gets a lymph node removed. Then Fajgenbaum and Nabel discovered that in more than 95% of cases, the lymph nodes are embedded in paraffin and kept at room temperature—not stashed in a freezer as Lipkin needed for analysis.

The global network of researchers, which then numbered about 350, came through. Two physicians in Japan and another in Norway had some samples to offer. Eventually CDCN pulled together 34 samples for Lipkin. There followed material transfer agreements and more paperwork. It took 14 months from the time the lymph node hunt began until all the samples arrived at Columbia, for a study slated to last 3 months that should be complete any day now.

“I think David is doing this in a very modern way,” says Alexander Fosså, a medical oncologist at Oslo University Hospital and the Norwegian who, to Fajgenbaum’s delight, had frozen samples. For Fosså, as for many other physicians, Castleman is “like a small niche” that he’s pursued since residency, when he struggled to treat his first patient. “When I do this as a hobby, I need to have some positive experience,” Fosså explains. “That’s what [Fajgenbaum] guarantees me—he’s fun talking to, he’s fun emailing with; that makes me smile.”

Fosså holds that IL-6 is key to the disease, as evidenced by a clinical trial he was involved in, which led to the approval of an antibody drug, siltuximab, for Castleman in 2014. But he agrees it’s not the underlying cause. Studies to identify other mechanisms are moving forward, including genome sequencing of about 10 Castleman patients and their parents, and comparing levels of proteins during flares and remissions.

In February, CDCN, UPenn, and a drug company inked an agreement to set up a patient registry; the cost and the company’s identity are still under wraps. The goal is to better understand the trajectory of Castleman, examine which treatments patients are taking, and identify those that might work.

High on that list is Fajgenbaum’s own experimental treatment. Fajgenbaum has been on his immunosuppressant for 2.5 years now and remains healthy. The patient in him wants to “scream from the mountaintop,” telling everyone to try this treatment. The doctor in him is cautious and declines to even name it, for fear his good health is due to chance, not biology. If he remains relapse-free at 3 years—for another 6 months or so—then he plans to submit a case study describing his experience.

“I need to be absolutely prudent,” Fajgenbaum says. He’s not just another Castleman patient.