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

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Editor's Note

In this three-part Mighty feature, we explore what it really means to have an “orphan disease” — the name for conditions that affect less than 200,000 people in the U.S. There are 7,000 orphan diseases, collectively affecting 10 percent of the U.S. population. 

Part One followed John Hudson Dilgen, a teenager with epidermolysis bullosa (EB), an extraordinarily painful orphan disease. Part Two widened the lens to explore orphan diseases more broadly from the clinical and policy perspective. Part Three turns the camera around, to consider the similarities, today and tomorrow, between orphan and common diseases. It concludes: we are not so different.

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.


In 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.


Delegation 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.


Democratization 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.’”


Discourse 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.


In 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.


Two 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.


The 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.



Originally published: October 12, 2018
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