‘Making science fiction come true’

A world without disease seems impossible, but is it? An upcoming book by Lloyd Minor, MD, dean of Stanford University School of Medicine, makes the case that this futuristic vision is within our grasp.

In Discovering Precision Health: Predict, Prevent, and Cure to Advance Health and Well-Being, Minor explains: “We are in the midst of a revolution in science and technology related to the mechanisms of disease and, of equal importance, to the determinants of health and well-being. The impact of these advances and their broad dissemination are going to have a profound effect on our ability not just to treat diseases but to prevent them from developing in the first place. And in those instances when diseases cannot be prevented, they will be diagnosed much earlier and therefore treated much more effectively.”

The book lays out the barriers to achieving this vision, proposes solutions and gives examples of progress already being made. Among those examples are many originating at Stanford, including this one offering hope for a permanent fix for an agonizing skin disease.

The book, co-written by Matthew Rees, will be published by John Wiley & Sons Inc. Proceeds will go to Stanford University.

Excerpt: Treating a painful and debilitating skin condition

A rare skin disease called epidermolysis bullosa (EB) is among the most painful and debilitating conditions ever diagnosed. “The word ‘pain’ itself doesn’t even describe how bad EB is,” said one courageous young man, Paul Martinez, living with the condition, in a 2015 film about EB patients called The Butterfly Effect. “Your body is constantly on fire — it burns from the wounds from raw flesh, and it keeps repeating over and over and over. The cycle is never ending.”

Approximately 1 in 200,000 babies is born with EB. There are different subtypes of the condition, but a common one is caused by the absence of a gene that results in the skin being unable to make something called anchoring fibrils. They are primarily composed of collagen and function like a staple — keeping the top layer of the skin (the epidermis) attached to the next layer (the dermis). As a result, for people with EB, virtually any force applied to the skin leads to blistering and that part of the epidermis falling away. These wounds never heal, resulting in mutations that trigger metastatic skin cancer and take the lives of many of these patients.

In the absence of any treatments for EB, most of those with the disease have not lived past their mid-20s. But in recent years, Stanford dermatology professors have been making steady progress in developing a treatment that can deliver life-changing wound healing treatments for EB patients and potentially help remedy other, more common conditions.

One of those Stanford professors is Jean Tang. She and some colleagues in the dermatology department have been working on a therapy called EB101, whereby they take somatic keratinocyte cells off a patient’s skin, use a retrovirus to reinsert the gene, and then graft those cells onto the patient. A Phase 1 clinical trial showed that these grafts are safe and lead to durable wound healing for up to four years and counting. A Phase 3 clinical trial was set to begin in mid-2019, and positive results would mark an important step toward one of the ultimate goals: securing FDA approval for a drug to treat EB.

Anthony Oro, the Eugene and Gloria Bauer Professor of Dermatology, is working on the next generation of therapy to treat EB. His focus is developing a product that would cover the wounds of EB patients and permanently heal those wounds — and do so at an early age so that they don’t get skin cancer from the chronic wounding.

His research aims to develop a scalable manufacturing platform to make large amounts of corrected tissue stem cells. In 2014, Oro was one of the authors of a study with Marius Wernig, an associate professor of pathology at Stanford. The study showed that it was possible to create induced pluripotent cells from the skin cells of EB patients and then replace the disease-causing gene with a healthy version of the gene. (“Making science fiction come true,” says Tang.) Oro described this development as enabling “an entirely new paradigm for this disease.”

“Normally, treatment has been confined to surgical approaches to repair damaged skin, or medical approaches to prevent and repair damage. But by replacing the faulty gene with a correct version in stem cells, and then converting those corrected stem cells to keratinocytes, we have the possibility of achieving a permanent fix — replacing damaged areas with healthy, perfectly matched skin grafts.”

This process involves the use of autologous CRISPR-corrected induced pluripotent stem (iPS) cells. These cells are made by collecting cell samples from someplace easy to access, such as skin or blood. The cells are then treated in a dish with a combination of genes that enable them to go back in time — a process known as cell reprogramming — so that they resemble the cells from which all tissues are formed. John Gurdon and Shinya Yamanaka were awarded the Nobel Prize in Physiology or Medicine in 2012 for this pioneering work in regenerative medicine.

“The CRISPR technology was very efficient,” says Oro, “and it allowed us to develop a very robust, one clonal step manufacturing protocol to make the autologous CRISPR corrected iPS cells.” (Previously these cells were being derived through multiple clonal steps, which brought more risks, as they were in culture longer and subject to more mutations.) The effect was to reduce cost and increase safety and to mark a shift from “this could be done” to “now it’s being done less expensively and with more safety.”

This process has also made it possible to grow the cells in much larger quantities. The next step is inducing activity of the cells to make the skin, which results in a thin sheet of skin cells derived from the iPS cells. Like EB101, these sheets are akin to a Band Aid that’s roughly the size of a smartphone. Each one is laid onto a patient’s wound, and it then grafts onto the patient’s skin. The benefits are realized almost immediately, says Oro, as the grafting heals the wounds. “Kids can walk around and not have to worry about what will happen if they accidentally bump into something.”

Today, the grafts are small and only cover a small fraction of a patient’s skin. The ultimate goal is to have the graft cover all of a patient’s skin — and perhaps even for the product to come in a liquid form that can be sprayed onto the patient’s skin.

As with so many other medical and technological discoveries developed for the treatment of a rare disease, the same technology can then be generalized to more common diseases. The iPS technology has a range of potential applications beyond EB. Oro points out that the therapy can be very effective for wounds that are slow to heal or don’t heal at all — such as those caused by injury, burns, or diabetes.

The technology of making tissue from iPS cells that have undergone genetic manipulation is also being used to make stem cells for other tissues. There is already research underway on the thymus, the bladder, and even the heart. Tang points out that much of the progress that’s been achieved is the result of many years of basic research (particularly in the area of recombinant DNA) as well as powerful tools (like electron microscopy) and tests that reveal valuable information (like indirect immunofluorescence). “It’s very gratifying when all of these elements come together to give a patient hope that their suffering can be reduced — if not eliminated.”

The many potential applications for the skin grafts are encouraging, and we remain hopeful that there will be continued progress in developing a remedy for EB that can end the suffering of those with the disease. Paul Martinez, whom I mentioned at the start of this section, has participated in EB clinical trials, and he’s said that the results have been promising.

“Even if I can’t get any benefit from it … I just want the disease to stop for the future. … I’ve been blessed to live longer than most people with this disease. But it’s kind of bittersweet. Thirty-five years is a long time to live with the pain that I go through. And I don’t want any children to go through that. If I’m in a position where I can help the future of EB, then I’m going to do it.”