Three weeks ago the journal Science ran a fascinating story about a young doctor fighting to cure his own rare and deadly disease. I clicked on the link to the article and was immediately drawn into the saga of David Fajgenbaum. The journalist, Jennifer Couzin-Frankel, tells the riveting account of Fajgenbaum who, in his third year of medical school at the University of Pennsylvania, learned that his organs were failing, quickly. His health had been deteriorating for a few weeks prior, and he knew something was seriously wrong. Yet as a medical student in the midst of his obstetrics-gynecology rotation, he had little time to focus on his own mysterious symptoms.
The story goes on to describe in detail how Fajgenbaum, now 31 years old, and his dedicated team of physicians continue to try to solve the mystery of his potentially fatal illness. The first time his liver, kidneys and bone marrow were found to be malfunctioning he landed in the ICU for nearly seven weeks. There he suffered a retinal hemorrhage that caused temporary blindness. But that was only the beginning.
Once Fajgenbaum was stable enough to be discharged—still without a diagnosis—he applied his medical student knowledge and his natural tenacity to find answers. He decided to tackle his frightening illness on his own and figure out what had caused him to nearly die at age 25. More tests and more information soon led to a diagnosis: Castleman disease, a rare (about 5000 people in the U.S. are diagnosed each year) and potentially lethal disorder of the immune system.
First described in 1954 by pathologist Benjamin Castleman, the disease was believed to be a precursor to some form of lymphoma. Early research demonstrated that those with the disease exhibited lymph node cells that proliferated and attacked various tissues in an autoimmune process. More refined analysis led to the discovery that interleukin-6 (IL-6) plays a pivotal role in the disease process.
What makes Fajgenbaum’s experience with his disease so unique is the way in which he set out to find answers, and his determination to mobilize various resources to build a network of scientists, clinicians and business partners dedicated to understanding the illness. Diagnosed with the most dangerous subtype—idiopathic multicentric Castleman disease—he suffered multiple bouts within a few years. What kept him alive was aggressive chemotherapy aimed out wiping out the immune cells that were attacking his healthy tissue. At one point he was being treated with a chemotherapy cocktail comprised of seven different drugs; each episode represented a true “brush with death,” but eventually, a miraculous recovery.
During one remission stage Fajgenbaum had a revelation that despite numerous publications about Castleman disease in the medical literature, many critical questions about the disease mechanism remained unanswered. It hit him then that if he wanted to find more conclusive answers—information that could provide him the best possible chance to beat the disease—he would have to take it on himself. It really was as simple as that.
The power of a scientific community
What followed was his quest to build a community of scientists and enlist their help. He began by combing the PubMed database to identify every researcher in the world who had ever published information about the disease. He organized a meeting about Castleman disease at an upcoming conference of the American Society of Hematology and invited every one of those research scientists to attend. Those who did attend (27 total, plus five who called in to the conference) came to the shared conclusion that no consensus about the etiology, the pathway, or the best way to treat the disease existed.
The most important take-home message for Fajgenbaum was that in order to gain the consensus so badly needed to move forward, some business strategy was necessary. So, he applied to business school and earned an MBA. The training he gained while earning the degree enabled him to develop the Castleman Disease Collaborative Network (CDCN) to bring researchers together. In the midst of this effort he battled yet another relapse and “came perilously close to death for a fifth time.”
This particular episode motivated Fajgenbaum to question whether the IL-6 blocker he had been prescribed was the most effective way to fight his disease. The time had come to think outside the box and consider other alternatives, if they existed. With the help of the CDCN and his newly acquired business management skills, he succeeded in thoroughly cataloging all Castleman disease related projects. He then determined that the best approach to elucidating other mechanisms underlying the disease would require examining frozen lymph nodes sections obtained from Castleman disease patients worldwide, a step that had yet to be pursued. As of now, a patient registry is in development to better coordinate samples and findings, and plans to sequence the genomes of Castleman patients are underway as well.
In the meantime, Fajgenbaum does not waste a minute of a day. The current immunosuppressant he is taking is doing the job, for now. If you plan to continue following the story of David Fagjenbaum, it’s likely to include breakthroughs that will impact not only those with Castleman disease, but the general medical research community as well.
A different story; a similar quest
Fajgenbaum’s story may amaze and inspire you, as it did me. Perhaps even more incredible is that there are others like this. A few years ago The New Yorker published “A Prion Love Story” about 
a husband and wife on a mission to find a cure for fatal familial insomnia (FFI). Extremely rare—afflicting only one in a million people—FFI is an autosomal dominant genetic form of prion disease. The couple, Eric Minikel and Sonia Vallabh, were literally racing the clock as Vallabh had recently learned that she had inherited the FFI gene from her mother who had died of the disease at age 52.
The two met while planning their graduate education pathways, and both were on highly successful tracks to pursue their chosen professions—Minikel in the field of transportation planning, and Vallabh, in the field of law. Shortly after marrying, earning their respective degrees in Boston and beginning their careers, Vallabh learned she was destined to die at a young age from FFI. As the article summarizes what followed, both “quit their jobs and become researchers on FFI and related diseases” to figure out for themselves how to save Vallabh.
Their story has since been profiled in a variety of publications including the Boston Globe and The Atlantic, as well as a number of TV news shows. The path they pursued was all about self-education as they committed to learning everything they could about prions and FFI. Neither came from a traditional science background, but their quest for knowledge and capacity to grasp new concepts made a significant difference. They enrolled in molecular biology courses at Harvard University’s Extension School and created the Prion Alliance, a nonprofit organization devoted to prion disease treatment. Vallabh found work as a stem cell technician in a genetics labs to gain hands-on experience. Minikel landed a job in the same department at Massachusetts General Hospital as a code writer analyzing nucleic acid sequences.
In search of a deeper understanding of the science and desire to collaborate with those working on prion disease research, both applied to and were admitted to a PhD program in biological and biomedical sciences at Harvard Medical School in 2014. Their training and their commitment to finding an answer led to a dual invitation to join a lab at the Broad Institute that researches small molecule therapeutics. With a lab to support them they continue to make progress.
Promising progress
Contributions through the Prion Alliance and another online nonprofit they created, www.CureFFI.org, have helped the couple raise enough funds to support an experimental treatment called ANLE138b, a compound that inhibits prions. Their goal is to move the first stages of these experiments into human clinical trials. They continue to focus on the specific mutation embedded in Vallabh’s genome and located on chromosome 20, D178N (cis-129M), that causes the prion protein to misfold. They also have proven that everyone with this mutation gets FFI, usually beginning at about age 50.
Similar to Fajgenbaum’s strategy, Vallabh and Minikel have created a network of prion protein experts worldwide; they’ve organized scientific meetings to facilitate the sharing of data needed to speed up the often painstakingly slow process of drug development. Their work, in collaboration with others, has been presented at international conferences and published in peer reviewed journals. The clock is ticking but they are making impressive progress, and without a doubt, their commitment to understanding FFI will impact the lives of others with prion diseases.
Do you know of other inspiring stories like these? If you have any ideas for future blogs that you’d care to share with us, please let us know—we’d welcome the opportunity to write about them.
Nicole Sandler
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