Epidermolysis Bullosa

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    Going to College With Epidermolysis Bullosa and Experiencing Fear

    Before I was even born, my body was already covered by wounds that could be easily mistaken for third-degree burns. Before I was even able to enunciate my name, I had to go through surgeries and daily bandage changes that were (and still are) tremendously painful. After minutes of being born, I was diagnosed with a life-threatening skin condition called epidermolysis bullosa (EB). This skin condition, while classified as rare, has still taken the life of so many, some who are very close friends of mine. The doctors thought I wouldn’t make it past some days, like most EB patients –yet here I am, nearly 20 years later, completing my four years of university. This is a feat that most EB patients are unfortunately unable to accomplish, due to the physical limitation and immense pain we go through every day. Having EB is not easy; it feels like a daily obstacle that I must conquer. EB is something I cannot hide, nor do I have the option of deciding whether I want to share it with others, because it’s so visible to the eye and anyone who looks at me will notice the difference in my physical appearance. Not only is the pain difficult, and not only are the continuous wounds overwhelming, but the stares, the questions and people’s assumptions are what make this journey even more challenging. We all know that college is a journey. College is the place for the individual to grow as a person, to find their purpose and to gain skills. Typically, the college student worries more over getting the classes they need than what others may think about them, or whether or not they’ll be accepted. The second scenario was my case. My past experiences of walking through a school campus or entering a classroom had all been so traumatizing that I feared of college being the same. I feared of people asking, “What happened to you?” rather than being interested in my major. Not only has acceptance been a fear of mine, but prior to starting college and during my freshman year of college, I wondered if it’d really be worth it. I wondered if companies would really hire a wheelchair user with visible scars and bandages, despite having the skills required for the position. I wondered if I’d be able to handle the daily bandage changes, bad pain days, and doctor’s appointments alongside all the homework and tests assigned. In a few months, I’ll be starting my third year of university, and thankfully, through the past two years of experience, most of my fears and questions have been addressed. People have been more than accepting. I realized people in college are adults who oftentimes have kids, jobs or other responsibilities, and don’t have time to wonder why I wear bandages. I have also realized that the only acceptance I truly need is self-acceptance, not from anyone else. I have yet to master the “double life” that I lead. Being a chronic illness patient and a college student is not easy. Sometimes I’m writing essays while my mom is doing my foot bandages. Or sometimes, I’m studying through my phone as I wait for my iron infusion to finish. I have been able to balance everything, but it has not been simple. My family and I feel very proud of myself for fighting and deciding on continuing with my education regardless of my challenges. I feel very proud that even though EB brings pain when completing the daily tasks others may take for granted, I’ve still kept my determination and fought through to accomplish my dreams. I am the first one from my family and one of the few from the EB community to attend college, let alone a four-year college. Every day is a challenge. It’s been hard having to go through surgeries, treatments and endless bandage changes knowing that this is my life and I’m unable to do anything to make the suffering easier. From the bottom of my heart, I hope that my determination and eagerness to complete my education, no matter the obstacle, inspires and motivates other college students to do the same, with or without an illness. Follow this journey on the author’s Instagram.

    Community Voices

    Hi Everyone I thought I’d share the link to an interview I did for a series of women with different types of skin conditions. I provided my input on what it’s like having a skin disorder in the beauty industry an environment that lacks on diversity. 🦋💓 https : //www.skinstories.us/stories/2019/6/28/meet-ariana-covarrubias ? fbclid=IwAR1httpVZi3zFJatatYFTQYRBZbl01nEbRMR6PQp6lo7qIvQlHcH9Ao5wmA #ChronicIllness #Disability
    #Advocacy #EpidermolysisBullosa

    Community Voices

    Living with Epidermolysis Bullosa Simplex

    People don't respect this condition and the pain the skin blisters cause me on a daily basis. It restricts my life espceically when I can not use my assistive devices prescribed by my doctor.
    #CheckInWithMe

    Community Voices
    Eli Cahan

    Part Three: Darwin’s Orphan - A Childhood With Epidermolysis Bullosa

    Part Three: Us Orphan diseases present a dually individual and systematic challenge of how to diagnose, investigate, develop, advocate, finance, and treat for patients within subpopulations of illness. Facing the horizon, the difficulties proposed by orphan disease today resemble similar questions to be presented by a movement towards personalized medicine tomorrow. A differential method of management in hypertensive patients following genomic sub-stratification is a not-too-distant analogy in a not-too-distant future. Just as orphan disease patients personify “natural experiments” for the effects of bodily functions gone awry, the orphan disease ecosystem is a model environment for the future of healthcare. Per Mary Woolley: “[Patient communities are] leading us towards the dawn of precision medicine… and rare diseases will take us there more rapidly than anything else.” John’s disease foreshadows our disease. *** I n 2010, Erik Tambuyzer envisioned, in a treatise to this effect, that: Much can be learned from rare diseases to predict what future direction [personalized] healthcare will take, including…the use of expensive treatments for smaller patient populations…the role of industry…and the collaboration with patient groups. This field is a “societal laboratory.” The core of Dr. Tambuyzer’s clairvoyance is an imminent decentralization of the healthcare system. The illusion of one-size-fits-all treatment of the majority will be dispelled in favor of tailored therapies for its copious, diverse minorities. Gilles Frydman, an early icon in the now-called participatory medicine movement, went one step further: “You cannot compel minorities to [behave identically] to the majority. The very basis of democracy is to defend and empower minorities.” In this vein, Roni Zeiger, former CMO of Google, conceptualizes patients as microexperts “well suited to address and solve some of their own daily issues.” Crowdsourcing, as it were. He believes patients are “the single greatest wasted resource in healthcare.” To this end, Mr. Frydman and Dr. Zeiger founded Smart Patients, a networking platform for patient communities. The landscape of disease, however desolate, provides a fertile environment for common ground. Theirs is a kibbutz model of medicine: a unified mobilization for successful cultivation of the catastrophic common ground. A village, of a new breed. *** D elegation of responsibility to tame clinical heterogeneity will demand a sea change in the practice of medicine. Lee Sanders, chair of general pediatrics at Stanford, described the necessary transformation so: “The physician needs to disallow of hubris… our role will become more peripheral than we might think.” Similarly, Paul Wise, director of the Stanford Center for Policy, Outcomes and Prevention, has reprimanded the “untethering of medical research from our central goals,” submissive to the “tyranny of the P value,” confusing “rigor for relevance” (71). “Comprehensiveness,” he states, “is no substitute for coherence.” (72) Larry Chu, founder of the MedicineX initiative, has also scrutinized these patterns. He believes “we got here from a series of very well-meaning mistakes that have taken the humanity out of medicine.” To Dr. Chu, the necessary reorientation “an understanding that in clinical care, we only see the tip of the iceberg, what tips over the surface when the patient comes into our view.” It is a frameshift that “the vast majority is self-care, at home, with family, with community.” In Silver’s words: “Families spend 95 percent of their lives thinking about their particular illness. Doctors, maybe, 5 percent of their working days. Maybe.” Thus, the stated goals of MedicineX (like participatory medicine more broadly) are to “flatten the hierarchy and acknowledge the expertise that [one] has by living, full time, with a (chronic) condition.” The invocation trumpets through MedicineX’s tagline: “Nothing about us without us.” (73, 74) A third coconut oil, a third Aquaphor, a third Medihoney, mixed and slathered: the recipe is not invalid simply because the chef did not train in Paris. *** D emocratization of the table in the cafeteria must start with our scientific institutions. The National Center for Advancing Translational Sciences (NCATS) provides precisely this platform. Christopher Austin, the director of NCATS, is as charming as he is motivated. His commitment to the mission began with a long night in training decades ago: “I was taking care of a patient with Amyotrophic lateral sclerosis (ALS), and spent the whole evening sitting there as he lost the ability to breathe in front of me. I was there to turn off the monitors when he died.” He continued: “As I sat there, a sense of helplessness and rage overcame me. It was simply unacceptable. And this was at the best acute care facility in the world, at Man’s Greatest Hospital, with the global experts in ALS! This was Mecca!” He concluded, “If I was at a rural community, then I could have had an excuse. But I had no out. It told me, despite everyone’s best efforts, this system needs a fundamentally different approach.” Subsequent stops were influential: during a stint at Merck, he discovered “an integrative ecosystem that was entirely new to me.” Taking the red pill at the precipice of the Matrix, he was enlightened to a dogma that, whereby “translation literally means ‘to carry across,’ what you do [at the bench] needs to be important to someone else, someone outside your tribe.” Dr. Austin’s goal, in sum, is for collaboration and commonality, extending to persons and principles alike. It seeks an elevation of pluralism and a diminution of reductionism in scientific enterprise, vanquishing exclusion criteria in favor of inclusion potential. Reclaiming relevance as a virtue of basic science, inclusion of different perspectives catalyzes progress for Dr. Boat’s whats and hows. *** A similarly inclusionary doctrine has been preached by Dr. Wise. He elaborates that the “intermingling of disciplinary languages” can lead to “a hybridized, pidgin language… fostering a cohesive research community.” The outcome is a “market setting” where ideas may be negotiated, bartered, and exchanged (75). Pluralism is embraced over reductionism. In Dr. Haffner’s alien territory dominated by unpronounceable diseases, common language enables commerce, and currency confers the means for survival. Matt De Silva, founder of Notable Labs, is an exemplar to this end. Notable uses high throughput screening to identify drug cocktails effective versus tumor cells of individual patients. It epitomizes personalized oncologic medicine. De Silva founded the company after his father died from Stage IV glioblastoma multiforme (GBM). GBMs, which allow on average 10 months of life after diagnosis, have a way of amplifying the ticks on a seconds hand. De Silva describes the “restrictive power of protocol” as a “sacred dogma,” or alternatively, a “massive ball and chain.” He wondered out loud why “evidence lower than Phase III should be deemed ‘not good enough’ for the clinical canon when patients have no better option.” Bench to bedside ought involve he who inhabits the bed. Calling from a slick, automated lab in San Francisco, De Silva is another fighter entering the fore and the forum. Time will tell if he and his ilk are welcomed. As murmured by Dr. Austin: “We may know more about disease than G-d knows, but as the saying goes, ‘What brought us here can’t get us there.’” *** D iscourse as to how such a system might look structurally tends to descend into discord. On a very basic level, the healthcare delivery system must more effectively adapt to an era in which chronic, dissimilar, personalized diseases are the rule. Much attention has been drawn to the systematic burden wrought by the 5 percent subset of “chronic users,” deemed “hot spotters.” (76) The pediatric landscape is similar, in that so-called children with special healthcare needs (CSHCNs) comprise 10 percent of the population but constitute 70 percent of the spend (77, 78). Economic costs tally in the hundreds of thousands annually per child, considering lost productivity of the entire family (79). One sophisticated prototype is the Japanese system for nambyo (translating roughly to “difficult condition”), which provides complete coverage of supporting services (beyond clinical care alone) in qualifying disorders (80). Alleviation of suffering and augmentation of functionality — these ideals are especially germane to pediatrics, since, per Dr. Wise, “The child is the father of the patient.”(81) The pediatric orphan with chronic needs is the sentinel case for the adult. There is also concern for the viability of a system aimed at delivering tailored treatment to the massed minority multitudes. Mindy Morin, CMO of AthenaHealth, believes the key to “unbreaking healthcare” is “by putting the chart back in the patient’s hands.” The analogy is to flying: a passport for health, containing individualized information on the journey informing a route towards the destination. This is preferable to a status quo requiring a different passport for every airport (or worse, every airline). Eric Topol, in his prophetic “The Patient Will See You Now,” foresees care indivisible from the individual patient (82). Or, as he prefers, the “unpatient” (83). This patient is “unplugged” from the system (health data are acquired ubiquitously and peripherally); simultaneously, the system is better plugged into her (84). It is “n of 1” healthcare, from “pre-womb to tomb.” (85, 86) It is a Copernican upheaval: individualized un-patient-hood is preferable to the anarchy of redundancy and incompletion in a Balkanized system. In the long-term, the efficiencies and efficacies derived from such alignment of incentives are obvious. In the short-term though, it is expensive, challenging and time-consuming. Election cycles are every two years, after all. *** I n a world where genotyping becomes the norm, distinctions muddy between “risk factor,” “preexisting condition,” and “disease prodrome.” An era looms in which physical idiosyncrasy is medicalized and imperfection pathologized easier than ever before. The implication — that any common disease, sufficiently “salami sliced,” contains orphan subpopulations — begs: what can and should we expect from healthcare? Healthcare, at its most rudimentary, makes interventions in the lives of individuals— intervention being a less-than-benign word, etymologically — and intervention being a less-than-benign action, clinically. As intoned by Peter Adamson, chair of the national Children’s Oncology Group: “Nearly all interventions have side effects.” How and whether to intervene is precisely the question at hand (87). If this ultimatum is left to profit-maximizing market forces, resource constraints — in terms of care quality, care quantity (availability), and care dollars — seem unavoidable. (88) Given the marginal costs in medicine are measured in days of life, such constraints are ever more sinister. Michael Pollan, culinary and agricultural science luminary, coyly recommended as the ideal diet: “Eat food. Not too much. Mostly plants.” In healthcare, avoidance of systematic overconsumption may follow a similar tenor: Give care. Not too much. Mostly prevent. A disease like epidermolysis bullosa peels back the skin of a sclerotic system. Flaws become apparent when so exposed to the sunlight, and ignorance is hardly bliss against imminent contagion. Anticipation and prevention — the application of sunscreen, as it were — may be the best medicine for us all. *** T wo years ago, John was accepted to his first clinical trial; or rather, he was eligible for inclusion; or rather, he was not excluded. The trial, known unceremoniously as “A Study of FCX-007 for Recessive Dystrophic Epidermolysis Bullosa,” takes place at Stanford. FCX-007 is a skin graft, using patient-derived stem cells to regenerate skin tissue, later placed surgically on sites of interest. It is a dermatologic quilt. I met John and Faye on a dewy spring morning. Chicks chirping, sun shining, bugs buzzing: Mother Nature captured the spirit of renewal. Their journey was documented through a punctuation-and-emoji-ridden series of Facebook updates: of note, TSA took the liberty of patting down John at the airport — a mercilessly efficient way of “taking liberty” for a person whose skin is resilient as nori seaweed. I am standing in the waiting room when they arrive on the Cardinal Red carpet. The principal investigators, Peter Marinkovich and Jean Tang, meet us: Dr. M is tall and lanky, with tufted graying hair, and a clunky sense of humor, and Dr. T is short and squat, with a tight trim, and a tender effect. They make an odd duo. Superheroes come in all shapes and sizes. Cordialities were exchanged, and our entourage follows the VIP du jour to the back (“he’s here,” whispers one nurse to another). A laminated but less coiffed sign on the door reads: “Reserved for study patient.” John is helped from his wheelchair to the elevated, cushioned throne of physical examination, settles, and requests the time. 9:20. He requests his Dilaudid. Faye declines. (He took his first dose three hours ago.) The goal of this clinical appointment is to initiate the grafting process: which entails baseline biopsies and acquisition of stem-cell-rich tissue. The first order of business is to “map” the skin, to strategize the battlefield. Dr. M and Dr. T convene with John: “That one’s new, this one is old, this one here is virgin,” they confer, as bandage after bandage is unwrapped. At one point, Dr. M remarks with glee that he sees hairs above the left knee (hair follicles are flush with stem cells). Meanwhile, the potent, almost gangrenous scent of John’s raw wounds perfuses the room, a sort of cologne des les misérables. The ambiance is heightened by the music on John’s playlist: “Happy” by Pharrell drips of irony. “Jailhouse Rock” comes on next, perhaps more apt to his circumstances. The time for biopsies arrives, and John requests quiet. He asks Faye to hold his hand. As Dr. M conducts the “punches,” John reels in agony. He chastises Faye for not squeezing hard enough (“It’s all I’m asking you to do!”). “Mamma Mia” blasts out. Eventually, it is time to place new bandages. The time is now 11:30. John’s pain is oppressive. “Please just do it right the first time,” he pleads Faye, who leads the ritual dressing. John’s legs shudder and torso tremors. Dr. M keeps trying to help; he can’t help it; intervention is the reflex of medicine. Each time, John, although bent headfirst over the table, says, “No, not you.” He, with the tragedy of experience, can distinguish the helping hand. The wrapping is completed, the prince dons his new suit of armor, and cheer again permeates the room. John, distracted, picks at a scab near his sternum. “Go easy, Hudsey,” Faye begs. *** T he last line in Dr. Lee’s JAMA paper “Zero Pain…” confesses: The data will never be perfect. The measures will never be perfect. The guidelines will never be perfect. And neither will clinicians and their performance. But by acknowledging these imperfections…physicians can more effectively reduce the suffering of patients. (31) When I left John that day, he was being wheeled to his pre-operative anesthesia appointment. Watching John maneuvered across the parking lot, I pondered his suffering, his imperfections, and ours. I remembered one last quote he impressed upon me: “If you tell one person, they can tell others, and that can make a really big difference.” John told me. I’m telling you. The weekend before John’s graft placement surgery, he contracted an allergic reaction and fever. The procedure was canceled. The cultured graft cells from the biopsies are only viable for a month, and the process must be restarted. The date of any operation, when this article went to press, was still pending. Read Part One and Part Two of this series here.

    Eli Cahan

    Part Two: Darwin’s Orphan - A Childhood With Epidermolysis Bullosa

    Part Two: Them For better or worse, this story is not just about John. This story is not just about Faye, nor the tribulations of the subclinical world. This story is not just about Dr. Tolar, nor the challenges of preclinical science. This story is not just about EB. It is a social story, of systems and values. It is the orphan story. Of the many people with orphan diseases, more than two-thirds are children (23). Up to 90 percent of conditions are considered “serious or life-threatening” and one in three children die by their 5th birthday (24, 25). On average, orphan diseases take seven years to diagnose, and one in 10 are misdiagnosed during this time (26, 27). For the fortunate patients who receive an accurate diagnosis, in 2013, only one in 20 had pharmacologic treatments. Few of those are curative (28, 29). This begs the question: what is the role of medicine when it can’t cure? And, what are those who so longingly desire to propel it forward to do in the meantime? *** O n October 4 , 2010, an Institute of Medicine (IOM) investigation committee chaired by Thomas Boat publicized these figures to the medical community. Dr. Boat had a personal stake: his granddaughter Katie had been diagnosed with a brain tumor called neuroblastoma (most childhood cancers are orphan diseases on a prevalence basis). Katie went through chemo. Her tumor killed her within two years of diagnosis. Katie died before her 4th birthday. The experience prompted two revelations for Dr. Boat: firstly, “medicine rarely cures, even today.” Secondly, “care has context.” To this end, he noted that “improvement of welfare is a really important outcome… on par, or even above, prolonging life.” A JAMA paper by Thomas Lee titled “Zero Pain is Not the Goal” asks a similar question. He wrote, “What should healthcare be trying to accomplish?” Pain is part of life and part of medicine. Suffering is… inherent to medicine; the word “ patient” comes from the Latin for “one who suffers.” Patients want efficient relief from their symptoms, of course, but… patients place greater emphasis on the how (whether they are receiving care that is compassionate, coordinated and focused) than the what (whether their pain is completely controlled). Zero pain is not always the goal. The reduction of suffering often is, and that is something more complex than analgesia alone. Dr. Lee’s ethos is that patients crave good interactions over perfect lab values. For patients like John, aiming for perfect medicine can be the enemy of good care (31). Dr. Boat’s conclusion was similar: “We know what to do, but not how to do.” (1, 30) *** W hile the orphan disease story exploded with the IOM report, the narrative commences in the early 1980s. On a quiet Wednesday evening during the ides of March, an episode of “ Quincy ,” a popular medical mystery series, aired on TV. The episode, titled, “Seldom Silent, Never Heard,” featured the titular coroner investigating the homicide of boy who had uncontrolled Tourette’s syndrome (32). The backdrop of the episode was a 1980 appeal of a Tourette’s patient to the House Subcommittee on Health and Environment for development of therapies for rare diseases. The star of “ Quincy ,” Jack Klugman, caught wind of the hearing — his brother had a rare cancer — and took to convey the message through his medium (33). The screening impelled a sequence of events that led to a testimony by Klugman to Congress in 1981, the introduction of a bill by Representative Henry Waxman in 1982, and its passage in 1983 (34). Deemed the Orphan Drug Act (ODA), it drew its name from a statement by Waxman that patients with rare diseases, in lieu of therapeutic options, “are very much like children without parents.” (35) The ODA was primarily concerned with the provision of incentives to pharmaceutical companies to facilitate investment in drug development for orphan diseases (36). Marlene Haffner, the first director of the FDA’s newly minted Office of Orphan Products Development (OOPD), is petite in stature, with closely cropped graying hair and a slow, deliberate drawl. She fell into this line of work “rather randomly.” As Dr. Haffner recalled, her early career was shaped by time working for the Navajo in New Mexico: “There I was on the reservation, seeing a group of underserved, dealing with… methemoglobinemia, tularemia, plague…[illnesses] that almost didn’t exist anymore in Western society.” The parallels between diseases forgotten on differential diagnoses and those erased from them are manifold. By the time Dr. Haffner was running the OOPD, she had learned a key lesson in “how”: that “ivory tower medicine is ineffective” in certain habitats. Her doctrine is steeped in practical considerations of culture, of terroir . These talents translate profoundly for “parents with a new diagnosis that often they can’t even pronounce.” *** F rom the outset, Representative Waxman, and a mother from Connecticut named Abbey Meyers, understood the importance of the language barrier faced by families airdropped into hostile illness terrain. Ms. Meyers, an activist whose son had Tourette’s, was a driving force behind the ODA legislation. Her own dispatch occurred watching her as-of-yet undiagnosed son David flail uncontrollably while attempting to read a comic strip. To avoid tears, she reached for a Parade magazine. The cover story was on a child with Tourette’s. She called to her husband with a simple refrain: “Come here, I found out what’s wrong.” He responded in disbelief: “Whoever heard of a diagnosis made by a Sunday magazine?” With a new Monday on the horizon, the Meyers’ only question was, “Where do [we] start?”(37) They started by founding the National Organization for Rare Disorders (NORD). This “coalition” was an effort to ally families with rare diseases under one banner, for purposes of support, education, fundraising, advocacy, and lobbying (38). It was a motley nation, consisting of parents from dispersed pathological city-states, a federation united in the face of overwhelming odds. The founding history is intensely American. Appropriately, NORD was inaugurated at a backyard barbeque. Meyers wrote, “Hope is like a road in the country; there never was a road, but when many people walk on it the road comes into existence.” (37) In the time since NORD trod the path less traveled, it has paved the highway for those in its wake: today, NORD serves 260 patient organizations and contains information on more than 1,200 diseases (39). That singular, slippery question — W here do we start? — is a common one encountered by families like the Dilgens. NORD serves 7 million users, and on Orphanet, the European analog, half of the visitors are first-time users (40). With regards to “diagnosis through the Sunday magazine,” 93 percent of these users are either seeking specific disease information or a support group, and the majority of patients find Orphanet through Googling (41) . Most patients with orphan diseases see at least three doctors before the correct diagnosis is made (42). The so-called diagnostic odyssey , an incessant brand of limbo, persists. Furthermore, in an age of alternative facts, information veracity is critical: while 87 percent of patients ascribe at least some importance to internet-sourced information, only one in 25 sources is certified by verification agencies (43, 44). The shelters built by communities like NORD simultaneously provide a refuge amidst the burdens of reality and a refuge from the dangers of fallacy. But these tribes are important beyond rote information. Acceptance into a tribe engenders a sense of identity. Andrew Solomon characterized the relationship of illness and identity to astonishing effect in his landmark work, “ Far From the Tree “: We often use illness to disparage a way of being, and identity to validate that same way of being. This is a false dichotomy…Many conditions are both illness and identity, but we can see one only when we obscure the other. Identity politics refutes the idea of illness, while medicine shortchanges identity. Both are diminished by this narrowness. (45) A diagnosis medicalizes a set of symptoms; appearance devolves into illness; irregularity degenerates into pathology. Such medicalization is accompanied by a prognosis, almost always poor, and certainly never “ normal .” Yet illness, to the extent it fosters community and vanquishes isolation, can be enlivening. Per Solomon: “Acceptance allows children to become most fully themselves… fully recognized citizens of the tiny nation that is family.”(45) *** S till, disease communities may offer more than knowledge and empathy. Their worth is not restricted to the past and present. They can be productive . They can impact the future. Pat Furlong — a former nurse, mother of two boys with Duchenne’s Muscular Dystrophy (DMD), and founding CEO of Project Parent Muscular Dystrophy (PPMD) — has embraced this mantra. She is a Valkyrie, a tireless admiral against the unrelenting tides of disease and an inexhaustible general against the inhospitable landscape of bureaucracy. This is despite the death of both of her children 8,400 days ago. To Furlong, a diagnosis is but lexicon, a “verbal confirmation of what you already knew.” Thus, “you need to separate the diagnosis [and prognosis] from the little boy who’s still the little boy… not talk about what will happen later.” Instead, Furlong prefers to discuss what might happen later. “There’s always something to do,” she avows. Her crowning achievement: 21 years after her children died, the FDA approved the first drug indicated for DMD (46). Organizations like Research!America, the largest and oldest “nonprofit advocacy alliance,” provide the megaphone for lobbying in Washington. It was founded by, among others, Mary Lasker — the marketing savant turned activist who almost single-handedly convinced Nixon to declare the “War on Cancer.” Mary Woolley, current CEO and Lasker incarnate for orphan disease, believes within the “flawed system in D.C.” (which is neither “neat nor linear”) all of the “biggest steps forward have come from the patient community.” They have not, she emphasizes, come unilaterally from “the findings of science.” The key to policy change is about “meeting at the heart before getting to the mind.” Facts are informative but not necessarily influential. Per Woolley, lawmaker decisions are “more often emotional than evidentiary.” Thus, Research!America is a Rosetta Stone between scientific semantic and lawmaker lingo. For Woolley, since it is “underrealized that all of science’s activities take place within a public context,” the optimal path forward entails “standing shoulder to shoulder with patient families.” This narrative reverberates through the hallowed historical halls: the March of Dimes, the War on Cancer, and the AIDS Movement followed an analogous route. Furlong echoes the sentiment. Reflecting on the past, she recounted, “Thirty years ago, there was no village — only two boys in Middleton, Ohio, with DMD.” Observing the present, she remarked PPMD, a “grassroots” movement, had provided a “compass,” a vector, with which to “raise our voices and accelerate research.” Envisioning the future, she hopes “we can keep our sons on their feet.” In DMD, a child’s ability to stand is more than metaphor. It is a proxy for mortality. *** “Godforsaken Collagen VII,” Alex Silver retorts when you dare mention the protein-that-shall-not-be-named. Silver, founder of the EB Research Partnership (EBRP), is a financier by day and a crusader by night. He emanates the zeal, devotion, and grit to match. He holds a gripping gaze and opines with fervor, frequently forced to brush his salt-and-pepper hair out of his eyes. Silver’s son, Jackson Gabriel Silver, has EB. The story of Jackson’s diagnosis is eerily similar to John’s (a bare heel at birth), and Silver’s retelling mirrors Furlong in tone: “Confirmation that this was EB, confirmation that it was a severe subtype, and besides that [Silver bangs the table], we don’t know.” Like John, these early wounds have never fully healed for Jackson. Their heels, like Achilles, remain a constant symbol of their mere mortality. Unlike Achilles, it takes less effort to remind them of the misfortune. Yet, Silver’s relationship with Collagen VII betrays his outlook: he thinks of it as an elusive holy grail, rather than a villain. He was not, and is not, satisfied with the therapeutic opportunities of the present, nor the prognostic damn-near-certainties of the future. Impetuous and inspired, Silver believes “the most important thing I could do was give my son a chance at a good life. I was going to get there, or I was going to die trying.” As such, he set out to do more than “commiserate, holler and march.” He was not, and is not, satisfied with the model of the village that nourishes its own, hoping for change, wielding its voice only when so invited. As he put it, “running a charity from a ‘goodness of your heart’ perspective is not a robust strategy.” EBRP is a nomadic clan at war, and Silver is its dogmatic chieftain. EBRP operates through a venture philanthropy model, a model that leverages his numerical talents and his numbing tenacity: raise money, invest it in preclinical research, optimize developmental prospects, and sell at a return. This is effectively a private-public partnership, with philanthropic entity as de-risking middleman. In other words, Silver seeks to redefine charity: “nonprofit is a tax-advantaged revenue structure, not a business model.” He scoffed: “There’s a funny stigma, that nonprofits exist not to make a profit. That’s insane. They exist to make as much of a profit as possible, and to plow that back into their missions.” He fumed: “The nonprofit business model sucks. Yet people say it shouldn’t be done our way. Tell me why? Because it hasn’t? I think it’s the most inane answer. It needs to change.” Make no mistake: disruption requires being disruptive. This motivated misbehavior may be even more indispensable in the nonprofit realm, given the calamities addressed. As Silver put it, since most EB patients live to no more than 30, “If we can accelerate development by three years, that’s 10 percent of life.” *** H esitation to adopt the venture philanthropy model emerges from the refrain against “having skin in the game.” Critics argue lopsided allocation of capital towards discrete causes is a violation of bioethical purity (disease disparities will mirror wealth disparities) and a contamination of experimental sterility (introduction of inextricable biases). Tachi Yamada, former Health Principal at the Gates Foundation, disputes this stance. Dr. Yamada, divining with oracular insight, subdivides the notion of innovation into two distinctive principles: “that which is evolutionary, and that which is revolutionary.” Innovation by evolutionary means adhering to convention, eschewing “peerlessness in favor of peer review.” It is risk-averse, seeking projects with a high probability of success. It is non-radical and linear, the plodding procedure of the “fat and content.” Revolution, on the other hand, is instantaneous and parabolic, the raucous outburst of the displeased and deprived. It revokes convention in favor of invention. It is averse to the static, festering stench of process. History invariably bears out the necessity of such conceptual violence. The word “c oup,” — translated alternatively as “blow,” “jab,” “lash,” “slug,” “sock,” or “wallop” — hardly describes a gradual, civil progression. More likely than not, those spearheading the revolution have themselves felt victim to such systematic violence: coup d’soi precedes coup d’etat. This sequence is dramatized by a pugilistic, emaciated Matthew McConaughey in “ Dallas Buyers Club” (47) . The Hollywood ending — true, in this case — was the FDA approval of azidothymidine (AZT) for treatment of HIV. AZT was the first drug developed under the auspices of the ODA. Upheaval is rarely instigated by the “comfortable.” Desperation is a nearly nuclear substrate to this end. Dr. Yamada is neither surprised nor disturbed that, increasingly, “money comes from the true sufferers of the disease,” nor that they “put a disproportionate share in the diseases that most affect their future.” As he wrote in 2008, the highway towards the future is through “bold ideas — even wacky ones — [needing] just a little help getting tested.”(48). Dr. Yamada’s bets are on “little science” to seize the day (49). Validating this approach, between 2000-2006, trials funded by nonprofit sources were 75 percent more likely to be published than those funded by industry alone (50). Having skin in the game is the most potent catalyst precipitating revolutionary change. For patients with EB, the idiom is more than a metaphor. *** M ost orphan diseases, however, lack a Silver or a McConaughey. As a result, they default their prospects of therapeutic salvation to pharmaceutical companies. There has long been a tenuous relationship between patients and pharma, which has come prominently to the fore through so deemed “price-gouging.” Recent examples are many: “pharma bro” Martin Shkreli’s price jacking of Daraprim 55 fold is a particularly nefarious case study (51). Patients’ distrust and disenfranchisement come with little wonder: the pursuit of profit can seem an exercise in profiteering. But the issue is more complex than price tags. It better understood as disconnect on three dimensions: efficacy, effectiveness, and equity. Efficacy denotes the ability of a drug to achieve statistical significance in preclinical experimental models. The frustration is that development of novel, useful molecules does not occur fast enough. A 1999 study indicated that only 1.3 percent of pharmaceutical revenues are devoted towards drug discovery, whereas 25 percent are committed to marketing; a pill “producing to pushing” ratio of one to nineteen (52-54). From 2006-2015, nine in 10 potential therapies failed clinical testing (55). Between 2007-2010, two-thirds of drugs progressing to phase-2 trials lacked any clinical efficacy whatsoever (56). Next is the question of effectiveness. Effectiveness describes the ability of a drug to exhibit clinical significance — a trickier matter, not in least part, due to its subjectivity. Historically, some 85 percent of drugs do not exhibit “therapeutic gains” over existing treatments (57). In an analysis of a group of common medications, only 65 percent demonstrated any effectiveness (versus placebo) — 36 percent on the basis of surrogate markers, rather than symptom relief or more common clinical outcomes (58). Perhaps the crux of the effectiveness issue resides in exclusion criteria , which tightly control trial patient populations. The spectral uniqueness of individuals is suppressed beneath the monochromatic shading of study cohorts. Per Solomon, “In nature, variation is the only invariable.” (45) Finally, equity relates to the ability of patients to access a given drug. The most common boundary to access is price. This is the most strained axis between patients and pharmas. Whereas the ODA was originally aimed at providing incentives to coax pharma interest, evidence now shows that orphan drugs are equivalent in economic value to non-orphan drugs (around 400 million apiece) (59). The average cost paid per patient for orphan drugs was $140,443 in 2016, or 28,300 tubes of Aquaphor from Walmart. In theory, orphan drugs should only consume 0.75 percent of therapeutic spend on account of disease burden . In reality, they consume multiples higher — and individual drugs, like Revatio, drain a skewed fraction of the spend (60-62). Worth noting: Revatio is a reformulation of sildenafil, the active molecule in medications for erectile dysfunction. Per Silver: “Now that everyone can get Viagra, diseases like EB should be top of the pipeline.” *** N evertheless, one would be naïve to disregard the profound value pharmaceutical companies add to society. Ian Maitland wrote in 2002: Whatever the public’s misgivings, it shows no signs of being willing to forgo the benefits of the market…The result is that drug makers are whipsawed between conflicting public expectations. On the one hand, they are expected to maintain the flow of new life-saving and life-enhancing medicines. On the other, they are exhorted to price their products “responsibly.” We rely on the profit motive to mobilize vast resources to fight disease, but we are shocked when new drugs earn ‘windfall’ profits. We enjoy the fruits of capitalism, but we expect firms to behave a little less capitalistically. (63) Numerical support of pharma’s contributions are legion: $15 billion in drug expenditures yields $427 billion in increased productivity, and a $1 increase in drug spending saves three and a half times that on hospital costs annually (63). They have played a significant role in the seven-year increase in life expectancy since 1960 (at a cost of only $20,000 per year gained) (64). Yet, vilification of the industry is easier than valuation and comes more naturally than valorization. Maitland says pharma has become a “pariah industry…the villains of contemporary populist folklore. The merchants of life, as it were, have become almost as reviled as the ‘merchants of death’ formerly were…victim[s] of [their] own success.” (63) On its best days, orphan pharma might appear as described by Jayne Gershkowitz, chief patient advocate at Amicus: “A patient-centric business model, with integrity and patient focus, grounded in the notion that if we develop novel medicines that have a profound impact, then profits will follow.” Mantra: do well while doing good. On its worst, orphan pharma might seem as embodied by Steven Bull, director of portfolio strategy at Recordati: an agent manipulating “a system in which most people never see the price,” and where the “majority of insurers cover the drug” regardless of price; a salesman that determines price “by tipping our toe in the water and seeing what the market will bear;” and a dealer that will “continue to exploit so long as government refuses to have difficult conversations.” Dr. Bull, who prefers conversations on his cell rather than his landline because he “likes to walk and talk,” personifies the underbelly of the oft-portrayed monster. *** J ohn LaMattina, former Pfizer executive, believes the plot is thicker: “The bottom line… is that the payers are the hurdle.” Within free markets, prices reflect value. Insurance companies must be the stewards of both our value and our values. The financial and moral buck must stop with them. Indeed, payers are the last line of negotiation in the U.S. market. Yet payer decision-making is notoriously subjective. In a typifying article titled “I had a tough day today, Hillary”, the writer recounts a day of reimbursement decisions and decision-making. Internal biases and arbitrary considerations pervade the piece. Responders had a field day, inflamed with shock and sadness and awe that so many lives be left to the whims of a single party (65). In the U.S., this party is most frequently a profit-maximizing actor. Other systems, such as the National Institute for Health and Care Excellence (NICE) in the U.K., are more quantitative. NICE determines reimbursement based on the incremental cost-effectiveness ratio (ICER) of a given intervention per quality-adjusted life year (QALY) gained by the intervention (66). Ideally, this comprehensively considers and properly weights the variables at play, from the input of the populace at large. Rationality, however “cold” it may seem (the major criticism of NICE), may be vital for a sustainable public health system. Payers play judge and jury when it comes to healthcare coverage. One hopes the jury incorporates the input of peers and that the judge rules according to rational, objective criteria. *** T he three-part concoction of helplessness, confusion, and frustration for orphan disease patients in accessing potentially curative therapies — whether due to lack of development (at the level of research enterprise), lack of access (at the level of pricing), or lack of coverage (at the level of insurance) — has led to an implosion of faith in the healthcare system and an explosion of efforts to bypass it. This has crystallized into the variously named “right to try,” “compassionate use,” and “expanded access” movements sweeping the country. Right to try legislation, implicitly blaming the FDA for bottlenecking the approval process, allows patients with diseases refractory to available therapies to appeal for access to non-approved pipeline drugs. Those in support, including Vice President Mike Pence, claim it “gives patients a fighting chance” by “circumventing the bureaucratic processes at the FDA.”(67, 68) Aaron Kesselheim, Harvard internist, lawyer, and scholar, fundamentally disagrees. For starters, he cites that the FDA approves 99 percent of applications in end-stage circumstances. He went on, “Right to try movements are misguided — efforts driven by libertarian activists seeking to upend the pharmaceutical regulatory structure… and exploiting very sad cases to do that.” He says right to try bills are “generally useless” and “may be unconstitutional.” Art Caplan, a prominent and vocal NYU bioethicist, was less tactful: “There’s nothing for patients at such early stages of research. If something did work, it would have to get published in a religious journal because it would be a miracle.” Another incarnation of these animal spirits manifests through the 21 st Century Cures Act. Part of the Act prioritizes surrogate biomarkers — biologic proxies — in the approval process. The EB example would be intracellular Collagen VII levels, a digit on a spreadsheet that may not correspond very well to John’s ability to tolerate mist from a showerhead. The elevated importance of biomarkers acquired through patient registries and case series comes at the relative demotion of more traditional methodologies such as randomized controlled trials. The aim is to accelerate the process by enhanced evidentiary flexibility. The argument hails data, for its potential, over methodology, for its consistency. Dr. Kesselheim’s response is perfectly captured in the title of his JAMA editorial, “New ‘21 st Century Cures’ Legislation: Speed and Ease versus Science.” He notes that “the establishment decades ago of FDA standards… transformed the US pharmaceutical industry from purveyors of uncertain remedies into one of the most successful in the world.” (69) He believes abandonment of rigor for rapidity is myopic. One of Dr. Kesselheim’s colleagues, Florence Bourgeois, worries for potential toxicity associated with a rush of unproven “remedies:” in a 2015 study evaluating agents for orphan cancers, only one-fifth showed evidence of clinical outcomes, whereas 97 percent had evidence of serious adverse events (70). The differentiation between snake oil and olive oil becomes difficult when the only endpoint assessed is whether they float in water. Per Caplan: “Disease can be coercive to patients. Hope is a potent elixir. In this case, it’s witch’s brew.” *** D o we place our faith in speed or science, speculation or certainty, empiricism or pragmatism? One side sees government as a wise pair of spectacles over the shoulder. The other perceives a bumbling fool who cannot get out of his own way. Distilled to their essence, these are constitutional (legislatively and morally) questions: of liberty versus libertarianism; of intervention versus interference; of protectionism versus paternalism. Resolution will require discourse and compromise, both of which take time. Unfortunately, time is the orphan patient’s scarcest resource. Editor’s note: This post has been revised to clarify details. Read Part One and Part Three of this series.

    Eli Cahan

    A Childhood With Epidermolysis Bullosa, an Orphan Disease

    Part One: Him J ohn Hudson Dilgen hates baths, but he does take them. Lots of them. Every other day, in fact. Yet, while most throw a toe to the surface imagining the possibility of chill or burn, he does so knowing the inevitability of pain. That’s because his baths contain bleach, and many surfaces of his body lack skin. Given the small ulcers on his arms, the intermediate ulcers on his legs and that huge ulcer on his back, none of which have healed over the course of years, nor have any plans to do so in the near future, bleach is the primary means of preventing the inexorable sequence of infection, sepsis and death. So, every other day, John submerges resentfully into the bathwater. The cause of John’s ulcers is a so-called “orphan disease” named epidermolysis bullosa (EB). Known colloquially as “butterfly boys,” children with this condition have skin that shears under the slightest pressure, not unlike a butterfly shedding its cocoon before taking flight. Elegant, if not devastating, transformation is an appealing metaphor until realizing John’s trajectory is degenerative rather than ascendant. This experience is not John’s alone. It is not exclusive to EB. Orphan diseases in the U.S. are defined as those affecting fewer than 200,000 individuals. There are up to 7,000 orphan diseases, and, collectively, they affect up to 10 percent of the U.S. population, or some 35 million Americans (1). This is six times the U.S. occurrence of Alzheimer’s disease, more than double the number of American cancer patients and involving 5 million more Americans than does Type-2 diabetes (2-5). Globally, 350 million individuals have an orphan disease, roughly the size of the entire U.S. population (1). This is more than 10 times the number of people in the world with HIV and involves some 130 million more per year than malaria does (6-8). The literature refers to orphan diseases interchangeably as rare diseases. That, statistically, seems inaccurate. John is both unique and very much not so. His scars are a microcosm of the pain sustained by patients facing analogous circumstances elsewhere, cornered by insurmountable hurdles at the scientific and systemic levels alike. A thorough probing of his ulcers, their ulcers, our ulcers, may be both diagnostic and therapeutic at once. *** I met John on the third hour of the second day of my first week in medical school at New York University, when he was wheeled into Alumni Hall auditorium. We were learning about cell biology — specifically, the links that anchor skin to underlying tissue — and he was our “case model.” Put differently, he was a personification of pathology. Put differently, he was a patient. These are all synonyms, really. John was my first patient. In the time that followed, he thoroughly rebuked my flawed expectations: maturity, hope and determination superseded misery, hopelessness and desperation. I wanted to help him. But it wasn’t until three months later that I called his mother, Faye. Soon thereafter I found myself on a journey to the tail of Staten Island, seeking out an orphan disease in the orphaned borough. *** Out the window of the subway car, rickety houses line the streets. A stray dog lopes across the road, vines veil boarded-up factories, and dented, rusty trucks bundle together in lots. The mottled, organic imperfections of the human condition express themselves through the architecture here. Indeed, Staten Island is in pain, physically and existentially: a storm of opioid addiction is sweeping across the island, killing hundreds and hospitalizing thousands over the past several years (9). It seems an appropriate place to seek the medically outcast. Tottenville, John’s community, has ranked in the top five of New York City neighborhoods with the highest rate of opioid deaths for two years running (10). I get off at the last stop (“The End,” a sign reads) and walk down quiet side streets to the Dilgens’ colonial-style bungalow. Faye beckons me in. John reclines on a heavily padded, dilapidated armchair in front of the TV. “The Price is Right” is on. A throw blanket with NHL team logos hangs off his back. John, 14 years old and two months a middle school graduate, was recently named amongst the 50 Most Influential residents of Staten Island. I am a guest in the royal court. He reigns, the bandages running down his arms and legs poorly concealed. Only his hands and head remain uncovered. It is a strange kind of regalia, for an unusual kind of prince, presiding over a unique kind of fame. As with most princes, this throne was his birthright, this kingdom his mandate. EB is genetic. He is pale and slim. His chestnut brown eyes effuse wisdom beyond their years. His father, John Sr., sits on the couch next to us. His golden retriever, Dash, and his spotted kitten, Romeo, lie at his feet. The court’s jester, Bob Barker (it’s a rerun), is underwhelming across from him. John seems used to the rabble. *** O ne way of conceptualizing John’s condition is through his appearance. John sketched his self-portrait: My body is covered in bandages, and everywhere there is a bandage, there’s a wound. My feet have wounds, my shins, my thighs. My arms have wounds. My back, that would be the worst; my whole back is like a sheet of wounds. Alternatively, consider his EB by the structure of his day. He starts his morning by taking innumerable medications. The current tally is somewhere between 15 to 18, John Sr. clarifies. Each year, he receives a couple more: some for his anemia, some for his depression, some for his analgesia and some for his analgesia-induced headaches (on the headaches: “It’s funny, the only thing that even helped were the mints.”). Dad also clarifies, grinning, that only one kind of mint, Icebreaker Duos, works. The Dilgens have a bulk purchasing deal at the local candy store. The agenda of a day depends on when the bath is because John is usually exhausted thereafter. When the bath is, in turn, “depends on when [the nurses] come. Sometimes I’ll have a bath at 9:30 in the morning, which pretty much ruins the afternoon.” After the bath, he rests “for a couple hours, so I can do things later,” like eat dinner downstairs. Otherwise, consider John’s condition through his experience of pain. His pain is constant, though alternatively dull and sharp, throbbing and stabbing. It is unpredictable. Sometimes the small wounds, or the large ones, will hurt; sometimes the new or the old; sometimes those that excoriate the fastest, or the slowest. Previously, he had used a cup to pour water during his baths because the faucet pressure was too high. He elaborated, “Recently, we got a new shower head that sprays mist, but even the mist, it’s not like mist mist .” He takes his current painkiller, Dilaudid, as often as he can. Pharmacologically speaking, every four hours. He settled on Dilaudid after trying 10 other analgesics because he could feel it. It takes 45 minutes to kick in, providing about two hours of relief (Icebreaker Duos are administered). Relief diminishes his pain from a nine to a seven out of 10. His experience of pain is inverted from that of normal: analgesia being the exception, rather than the norm. He nodded in affirmation of the calamity. Faye and John Sr. shook their heads. Dash and Romeo yawned. Barker chortled. Finally, attempt to fathom John’s EB through his relationship with school. Or, his lack thereof. John missed both six th and seven th grades because he could not sit through a day of class. More than a couple of hours in a school chair efficiently and unceremoniously tore the skin off his buttocks. He recounted: “I tried to start six th grade. But sitting in class, my body was aching. I couldn’t focus. I tried. I just couldn’t. ” In lieu of school, there are few things to occupy the vast number of hours. One gains a newfound appreciation for the virtue of school when these basic structures are subverted. Even knowing John has a 60-percent chance to walk, alive, at graduation. As such, he spends ample time with Romeo, “a nice distraction,” and Dash, “a great companion.” Distraction provides welcome variety from the placidity of elapsing time. The one command the Dilgens taught Dash, outside the trainer’s jurisdiction, was “get Mom.” *** F aye Purpura Dilgen is endlessly energetic and unapologetically enthusiastic, with the paired patience of a psychiatrist and impatience of an innovator. This serves her well in her working life as a physical therapist and in her family life as a caregiver. The title of caregiver , for a mother of a child with an orphan disease, is universal: giving care, in the absence of a cure, involves every step from acquisition to administration. The vocabulary of the caregiver, ranging from allograft to zymogen , is equally vast. Thirty-eight percent of parents of children with orphan diseases must reduce their workload to provide care, and one-third cease working entirely (11). Faye grew up in a religious Catholic family: one brother is a priest, and one aunt is a nun. Sitting with her feels like sitting with Mother Mary. On the question of her relationship with God, as the mother of a child with an incurable disease, she declines “that it changed anything.” Rather, her interaction with religion is more pragmatic. She prays, “Firstly for a cure. In the meantime, for comfort and if something happens, that it happens quickly and painlessly.” She recounts the story of receiving John’s diagnosis. In the seconds following birth, those huddled around the newborn noticed a region of skin absent at his left heel. In the minutes thereafter, the nurses placed EKG leads on his back, which subsequently tore the skin off there, too. In the hours that followed, the clinicians grew suspicious and workup for EB began. In the coming days, biopsies were taken and luminescent stains came back positive. A week after diagnosis, she received her first, “Congratulations on the baby boy,” from an EB specialized case-worker. In the same way, she describes her effort to alter John’s prognosis. The caregiver’s role to this end is subclinical : responsible for the regimented, mundane, non-academic activities of day-to-day maintenance outside of the specialized healthcare setting. That is, ensuring John’s survival with each passing 24-hour interval. The hope is for optimization of health along the existing trajectory, until therapies emerge capable of rerouting. It is a war waged against natural history of disease, using the firepower available through standard of care . The campaign started immediately following diagnosis: Faye was attempting to use a dressing as instructed on the label, but John’s pain was excruciating. She appealed to one of the few EB support groups at the time. Someone asked, “What are you buttering it with?” She answered that she doesn’t butter, it doesn’t say to butter, and, oh yeah, what is buttering? They wrote back again: “Use 1/3 coconut oil, 1/3 Aquaphor, 1/3 Medihoney, mix it, slather it, fold it in half, and put the primary layer underneath.” The notion that “it takes a village to raise a child” is especially true for children with orphan diseases. The recipes shared by mothers in the village extend beyond the kitchen. Simultaneously, Faye does her darnedest to make John comfortable and make him happy. Even dinner, the stalwart of the calendar, is a complicated chore, since EB affects the lining of John’s GI tract, and John’s analgesics give him stomach aches. In Faye’s words, he faces “an eternal conflict between being hungry and not wanting to eat.” Mac n’ cheese is a staple, and in situations where John develops an esophageal stricture (due to scarring), it serves a diagnostic role: if he can’t swallow it, he flies as an emergent case to the University of Cincinnati for dilatation. In celebratory circumstances, John’s favorite food is crab legs, which his mother dutifully deconstructs bedside following a successful surgery. Nonetheless, immaculate though she may be, Faye’s ability to alter the trajectory of John’s life is limited. John as a toddler T he ability to alter the sequence of events at the bedside is, scientifically, derived from the bench. To combat, much less conquer, disease, a tactician must first understand its nature. The nature of epidermolysis bullosa summons from the dysfunction of a protein called Collagen VII, a microscopic bridge yoking cells together. At the skin ( epidermis ), it anchors the surface layer to the basement membrane ( dermis ), providing resilience amidst trauma. Without Collagen VII, the epidermis yields ( lysis ), the dermis is exposed, and blisters arise ( bullae ) (12-15). One of the champions of the bench is Jakub Tolar. Originally from the Czech Republic, Dr. Tolar now works at the University of Minnesota. Formally trained as a hematologist and a pioneer of gene therapy, Dr. Tolar began his work on EB after a mother who “broke in cradling her son” confronted him at a conference. She knew his work and insisted he “has to figure out how to make this work,” pushing her son into his spaghetti-limp arms. Dr. Tolar dons an unbranded pair of narrow black glasses that frame his perspective on the role of a physician, a role fundamentally requiring “humility, in the face of things you’ve been called upon to combat.” His combat objective is immodest and uncompromising: to “open a future that has not existed before.” Appropriately, his research, which re-engineers the genetic code of epidermal cells to produce Collagen VII, could do just that for patients with EB. John could benefit greatly from a future, not least because he has a 40-percent chance of dying before the age of 20. He will most likely die from metastatic skin cancer (13). A scientist is naught but for the ripples he creates, and Dr. Tolar is aiming for a tsunami. Ripples, though, are unpredictable. ”Great science,” Dr. Tolar laments, “is oblique.” Serendipity and discovery are products of circumstance rather than planning. Thus, rather than camping out behind a bush waiting for the declaration of gravity, a scientist must play Newton, placing themselves in a position sufficiently vulnerable as to let the apple fall. Scientific breakthroughs necessitate a resignation to the chaos; the apple of knowledge is consumed by way of observation rather than insistence. Dr. Tolar acknowledges the depraved irony. Nature is incomprehensible in its complexity, yet experimental elimination of confounding variables is, by design, an exercise in fabrication. Alas, the academic research industry of grants and tenure depends on narrow hypotheses, artificial environments and precise objectives. It has little tolerance for failure. This dynamic has contributed to the well documented “publication bias” against negative results (16). Results in the negative are often disregarded as failed hypotheses rather than successful observations — and subsequently, not accepted for publication. Illustrative: in trials for antidepressants, 94 percent of those published were positive, whereas 50 percent of those assessed by the FDA were positive (17). The so-called “reproducibility crisis” similarly derives from twisted incentives favoring productivity over transparency (18). The result is that, as John Ioannidis wrote in 2005, “most published research findings are false,” and 85 percent of effort therein is wasted (19, 20). In 2016 he concluded that “most clinical research is not useful”(21). Up to three-quarters of patients with a given disease do not respond to drugs indicated for them (22). “We can’t ask [EB] patients to have patience,” exhorts Dr. Tolar, “they are not privileged with time.” Yet, he studies a disregarded disease in a derelict pocket of the Northwest subject to a system ill-suited for facilitating breakthrough science. Tip-toe incrementalism is incentivized over innovation. Urgency is lacking. John’s clock ticks. At least there are Icebreaker Duos? *** Read Part Two and Part Three of this series.

    Eli Cahan

    Eli Cahan Epidermolysis Bullosa References

    References for “Darwin’s Orphan: A Childhood With Epidermolysis Bullosa,” by Eli Cahan Interviews: (40, 89-119) Boat ea. Rare Diseases and Orphan Products: Accelerating Research and Development: Institute of Medicine; 2010 [Available from: http://www.nationalacademies.org/hmd/Reports/2010/Rare-Diseases-and-Orphan-Products-Accelerating-Research-and-Development.aspx . Howlader N NA, Krapcho M, Miller D, Bishop K, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA SEER Cancer Statistics Review, 1975-2013  [4/8/17]. Based on November 2015 SEER data submission, posted to the SEER web site, April 6.]. Available from: https://seer.cancer.gov/csr/1975_2013/ . Inzucchi SE. Clinical practice. Diagnosis of diabetes. N Engl J Med. 2012;367(6):542-50. Mitchell SL. Advanced Dementia. N Engl J Med. 2015;373(13):1276-7. Ohman EM. CLINICAL PRACTICE. Chronic Stable Angina. N Engl J Med. 2016;374(12):1167-76. Hankey GJ. Stroke. 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    What Epidermolysis Bullosa Looks Like

    This is what an invisible disease looks like. It looks like nothing at all. There are thousands of them and they run the gamut from rare to common, physical to mental, life-threatening to debilitating. But they all have one thing in common – they leave no noticeable mark. To the outside world, we all look healthy. Mine, and my children’s, is called epidermolysis bullosa, a rare genetic disease whose hallmark is debilitating blistering of the skin in response to heat, friction, injury or rubbing. I was encouraged to write something about it for Epidermolysis Bullosa Awareness Week. Truthfully, I didn’t know what to share. I don’t have a picture of our blisters. I don’t have pictures of the guttural sobs that come from the pain. I don’t have a picture of my husband carrying my 9-year-old to the bathroom because he can’t walk. I don’t have a picture of the hot shame that washes over my face when someone questions why I parked in a handicapped space. I don’t have a picture of the loneliness that comes from the things we miss out on because of a disease no one has ever heard of. But even if I did, I wouldn’t share them. Not because they’re ugly or agonizing. But because they wouldn’t be the whole picture. Yes, this is a terrible disease. And yes, it’s hard. But it’s also beautiful. Because of it, I had to learn how to be independent at an early age. I had to learn to be comfortable with being different, with being myself. I had to learn to shrug off the things that people think about me. And although it was painful, it made me stronger. It made me confident. It made me empathetic. It made me grateful for the friends who have always been there for me, not when it was convenient, but when it was hard. It made me understand that what a person looks like from the outside is only a fraction of their story. Or maybe I do have a picture after all. Maybe it’s this picture — my son’s “senior buddy” giving him a piggyback ride so he could participate in his school’s Halloween parade. Maybe it’s this picture — a letter from a University of Virginia basketball coach who is inspired by their perseverance and their kindness. The letter says, “Jack, Thank you for being my friend. I admire so many things about you. You are strong, courageous, tough and kind. These characteristics will carry you through life. I love your never quit attitude. You can do and accomplish anything. Enjoy the rest of the summer. Your friend, Ron” Maybe it’s this picture — a wonderful coach who has given my children the opportunity I never thought they would have — to play their beloved sport like all the other kids — simply because he looks at them and sees what they can do, not what they can’t. Maybe it’s this picture — two smiling boys who look just like everyone else but fight through unimaginable pain every day. Two boys who understand that tears are a sign of bravery and that not every battle is waged with a sword. Two boys who don’t view every door as closed. Instead, they see the light coming through the keyhole. And all of that doesn’t make the hurt go away. But it does give it a soft place to land. Yes it’s a terrible disease, like so many others. And yes, it’s hard. Not just physically but emotionally. But it made me who I am. What it has taken from me pales into comparison to what it has given me. And I hope it will do the same for my boys. And maybe that’s not such a bad deal after all. For more information about epidermolysis bullosa, go to www.debra.org. We want to hear your story. Become a Mighty contributor here .