Epidermolysis Bullosa sufferers are known variously as "butterfly children," "cotton wool babies," and, in South America, "crystal skin children." It's an affliction worthy of the mythologization—"the most completely debilitating and awful" disease in all of dermatology, in the words of Stanford researcher Jean Tang. EB is rare, affecting one in 50,000 children, but it's uncurable and essentially untreatable. The disease is managed mostly via pain medication and bandages. Severe cases are almost invariably lethal.
A team of doctors at Stanford has been at work unravelling the disease for nearly 30 years, the culmination of which is just now being realized in the form of the world's first clinical trial of a stem-cell-based method intended to replace a patient's defective skin cell genes with healthy ones. The group's work is described in the very worth-reading summer issue of Stanford Medicine, the medical school's triannual in-house magazine.
Dermatologist Paul Khavari recalls his first on-call weekend at Stanford in 1997 and the admission of an infant named Garrett Spaulding. "His whole body, his skin was blistered and falling off everywhere someone had touched him," Khavari tells SM. "His parents were devastated, of course, at a time that was supposed to be one of the most joyful of their lives."
That's the particular cruelty of EB. It punishes the slightest touches, the barest minimums of human contact: "trivial trauma," as it's known in the literature. There are different variations of the disease, but the general pathology involves the protein connections that anchor the skin's outermost layer, the epidermis, to the next-deepest layer, the dermis. These connections keep the two layers from moving independently and rubbing against each other. In EB patients, these anchors are deficient or absent, allowing the layers to easily separate, forming sores and blisters. The resulting damage is often likened to third-degree burns, according to an International EB Forum fact-sheet.
While some versions of EB are mild, requiring a minimum of medical attention, "approximately half of the patients with junctional EB do not survive past their third year of life, due to malnutrition and anaemia caused by serious blistering in the pharynx and the oesophagus," according to the Forum. Junctional EB is the most dire form of the disorder, affecting what's known as the basement membrane, the final boundary between the body's connective tissues and not just skin, but the linings of the respiratory and gastrointestinal tracts as well.
Garrett Spaulding is now 18. As with many patients sharing his form of EB, he lives his life covered from head to toe in gauze bandages. It's a necessary protection: underneath is a maze of perpetually occurring deep, open wounds. Blisters grow and merge continuously, eventually rupturing and leaving vast sores. It's not uncommon for all of this blistering and rupturing to result in the fusion of the patient's fingers and toes. For Spaulding, the bandaging and unbandaging process can consume five hours a day. As a child, he would tell his mother, "I want to die."
The stem cell experiment is promising. The basic idea is to replace the stem cells that go on to become keratinocytes, which make up the shingle-like layer of tissue separating you from the outside world. These cells also produce type-7 collagen, the protein that forms the aforementioned anchor points between skin layers absent in EB patients. Healthy stem cells should produce healthy keratinocytes, which in turn should produce the needed collagen. The patient's own stem cells are first removed and then genetically modified such that they're capable of encoding the required proteins. Sheets of skin cells are then grown in a lab from the modified stem cells, which are then grafted onto the patient. It's not an easy fix.
From the Stanford piece:
In layman's terms, the process goes something like this: Collect two, 8-millimeter-square skin biopsies from patients; isolate the keratinocytes, which will contain epidermal stem cells as well; infect the cells with the genetically engineered virus carrying the corrected type-7 collagen gene; grow the cells over a period of about three weeks into eight thin sheets (each roughly the size of a playing card); conduct a series of tests on the cells to ensure their purity and safety; and then carefully, oh so carefully (!), hand-carry the newly minted skin in a small, air-tight box to the operating room where the patient waits under general anesthesia.
The result, it's hoped, will be healthy or at least healthier skin. The current trial is only the first stage, however, which is intended to demonstrate the stem cell method's safety only. The graft has been done on four different patients, with a fifth in progress. If this stage is successful (read: safe), the group hopes to actually test the therapy's efficacy.
Paul Martinez, 32, is one of the four:
"Even though my grafts are only the size of a playing card, the results have been life-changing," says Martinez. "If you can minimize skin breakage, you minimize pain in that area, you minimize the chance of skin cancer in that area. It may not seem like a big deal, but this has really improved my quality of life."
There is more promising EB research taking place elsewhere. At the University of Minnesota, doctors are focusing on bone marrow transplants. One transplant, performed on a six year old named Keric Boyd, has already proved successful, while the associated clinical trial will eventually feature 30 patients. The bone marrow approach is something of a catch-22, however: a marrow transplant results in severe immunosuppression, while the constant sores and wounds of an EB patient require robust immune responses. Four patients so far (out of an already very small group) have died during the course of the transplantation.