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Healing The Wounds that Never Heal
Last summer, Alfred Lane, the chair of the Department of Dermatology at Stanford University Medical Center, walked into a class in Moral Issues offered by the director of ethics programs at the Markkula Center for Applied Ethics. As a member of a team of scientists developing gene therapy for a deadly illness, Lane was looking for guidance with a moral dilemma: How should his team decide who would get the potentially life-saving treatment? This article represents his struggle toward an answer to that question.
By Alfred Lane, M.D.
All of us have at one time or another developed a blister from a burn or from shoes that didn't quite fit. Infants with the genetic disease Epidermolysis Bullosa (EB) develop blisters just from the trauma of being born. The simple process of changing a diaper can cause skin damage. Over time, their bodies may be covered by blisters and sores.
When I was recruited to do research at the Stanford University Medical Center in 1990, finding a cure for EB was a focus of the Dermatology Department, but I avoided involvement in this project. As a pediatrician in private practice, I had found I became too attached to my patients, especially sick babies and their families. As a pediatric dermatologist who was a member of a medical school faculty, I dreaded treating EB children because we could offer them no hope.
Because of defects in the DNA (human genetic material) of EB sufferers, they lack any one of many different specific proteins that "glue" the outer layer of skin onto the inner layer. Depending on which "glue" is missing, patients may have infrequent blisters or constantly open wounds. They may suffer from frequent skin infections or inadequate nutrition because of mouth sores.
Many infants with one of the severe types of EB feel constant pain and die in infancy. Survivors into adolescence or adulthood may eventually die from cancers that develop as a result of wounds that never heal.
From Hopelessness to Hope
Fortunately, the picture for EB sufferers is beginning to brighten. Gene therapy-science fiction just 10 years ago-has shown promise. With support from the National Institutes of Health (NIH) and private donations raised through the Epidermolysis Bullosa Medical Research Foundation (EBMRF), the Dermatology Department at Stanford has made progress in understanding the disease. In cell culture systems, researchers have been able to isolate the defective skin cells and transfer the correct DNA into them. The corrected cells can then produce the "glue" that allows damaged skin to heal.
In 1995, the chair of the department became the dean of the Medical School, and I stepped into the chairmanship. Part of my new role is to keep the EB team focused and successful. Right now, we have only to establish that the correction of defective cells continues for more than several months, and the Food and Drug Administration will allow us to begin human trials. Once we obtain FDA approval, we will be ready to convert the defective cells into healthy skin tissue. We will have the facilities for transplanting the corrected cells-in short, we're medically prepared to begin treating children. But as we come closer to this goal, I am more and more concerned about the moral issues.
A Rare Disease, A Common Problem
Of course, the very fact that we are doing research on gene therapy means that we have already considered certain ethical questions about fairness in the allocation of medical resources. Each year, NIH provides approximately $200,000,000 of support for gene therapy. This is occurring at a time when more than 20 percent of our children have minimal access to basic health care, such as immunizations or well-baby care.
In that context, how can we justify research on a comparatively rare disease like EB? The most severe forms affect about one in 20,000 children. About 50,000 to 100,000 people have some form of the disease.
Despite the relatively small number of sufferers, an investment in EB research should have broader applications. EB is interesting because the biology of the disease is important to the structure of the skin. It involves the basement membrane, tissue that joins the inner and outer layers. Wound healing and many common skin injuries involve this junction. As we study it, we understand more about basic problems: how the skin protects itself from the environment, how it keeps the inside in and the outside out.
So, we can justify allocating scarce research funds to this rare disease because understanding it may help in a broad range of medical problems. But we also have to look at how to distribute those EB funds equitably.
Imagine we have $100,000 to spend. We could invest that money in further research, helping two or three scientists, who may be able to raise millions of dollars in grants. Of course, their work may produce no progress. Currently, more than 175 clinical trials are being attempted or have already failed to develop effective gene therapy for any disease.
We could invest the same $100,000 in treatment. Once we begin a gene therapy treatment, the total cost per individual may be as high as $100,000 for the first year. Because gene therapy is an experimental procedure, we do not expect to obtain financial support through the patients' health insurance, so we might well need to spend our entire $100,000 on helping one infant. How would we choose that infant?
Patient Selection: A Difficult Choice
Physicians and ethicists have addressed patient selection in the past in relationship to organ transplantation. We know currently that with the cost of organ transplants and the scarcity of organs, everyone who needs a transplant will not receive one. Gene therapy for EB will face the same dilemma.
In the beginning, we will be guided largely by medical considerations. One selection criterion will be imminent death, which has always moved patients to a higher priority for a given therapy or transplant. In the severest form of EB, if we don't treat immediately, the infant will soon develop fatal skin damage. We will want to do the cell transplantation as quickly as possible so the patient will still be relatively healthy when we begin.
The severe form of EB we will first be able to treat is uncommon, so we do not expect too many patients for our initial trials. Still, I fear this scenario: We have the therapy; a family calls, and we have to say, "We can't do anything for you because we don't have the resources."
The situation is complicated by the fact that, at least in the beginning, Stanford would be the only location to offer the treatment. In all probability, the first patients would not be local. Aside from their medical requirements, these infants would need to be flown to California with their families, who would have to be accommodated at hotels for the several months of treatment. Should we spend some of our scarce resources on these auxiliary needs?
This problem will be compounded when we are able to treat additional EB patients with more common and chronic types of EB. One approach will be to develop simple, cost-effective techniques of gene therapy that can be transferred to other medical centers within the United States and throughout the world. Transporting small pieces of skin and gene therapy grafts to local treatment centers rather than transporting patients long distances will be more cost-effective.
But however we reduce costs, we will still confront income barriers to treatment. We could simply confine the therapy to patients whose families can afford to pay for it, but generally, we do not want finances to limit therapy. Of course, if some of our patients' families have their own money, that would free up resources to treat others. The problem is that many EB families are not wealthy.
Some are raising money through such groups as the EBMRF, established by a woman whose two children died of the disease. Families are selling Beanie Babies and doing other projects to contribute research dollars. If we can only treat two or three patients in our initial study, should we give priority to these families? Some have argued that it is fair to give special consideration to patients who might provide highly valuable services, including those whose families would donate money to provide additional resources that would then aid others. Another patient selection option is to look at the resources any individual might use and select those who require relatively little over those who need more. In the case of EB, we may eventually face the prospect of excluding extremely rare defects, which require more effort, money, and resources.
The availability of a supportive environment for the patient is another widely used criterion in medicine and deemed necessary during and following treatment. But here we have to exercise caution. This standard can be a cover for an ability-to-pay criterion, as the poor may lack the means to obtain certain kinds of supportive care. Securing financial help for these patients will be extremely important.
If other criteria prove unworkable, we may resort to random selection, which means serving patients on a first-come-first-served basis or using a lottery system.
Though EB is a rare disease, our effort to come up with patient selection criteria is being or will be replicated in labs across the country as gene therapy is developed for others of the more than 4,000 diseases of genetic origin-cystic fibrosis, Huntington's disease, and Tay-Sachs, among them. Just as our medical research may pave the way to understanding other illnesses, so our approach to patient selection may have an impact on the way other researchers look at the ethical issues they face.
Alfred Lane, M.D., Chair of the Dermatology Department at Stanford, is a master's student in SCU's Pastoral Ministries Program.
Kilner, J.F. Who lives? Who dies? New Haven: Yale University Press, 1990.
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