If any malady proves the fragile grace of the human genome, it is sickle cell disease.
If experimental treatments receive regulatory approval, it would be a watershed breakthrough for tens of thousands of Americans.
It occurs because of a single "misspelled" letter of DNA, causing red blood cells to run low on oxygen and transforming the hemoglobin in each cell into a stiff rod. Normally round cells become rigid crescents that hamper the flow of blood throughout the body, like leaves clumping in a drain.
Strokes in toddlers are merely the beginning of the circulatory calamities this disease may inflict. Most sickled cells cannot carry oxygen through the body, causing anemia as well as excruciating chronic pain. Older patients are at risk of kidney failure, heart disease and all the other collateral damage caused by poor circulation. Few live beyond middle age.
The only way to cure it has been through a bone marrow transplant from a donor, which requires not only a closely matching volunteer, but bouts of chemotherapy to allow new stem cells to take root, as well as rounds of immunosuppressive drugs that may last for years.
Recent advances in genomic medicine may soon alter the disease's outlook, although many obstacles remain.
In one treatment under development, patient's skin cells are converted into stem cells, allowing them to be inserted into the bone marrow without the need for a donor. Another treatment known as gene therapy involves replacing the aberrant gene in the patient's body with new genetic material.
Although both remain in clinical trials -- and also require at least chemotherapy -- they have shown promise. Matthew Hsieh, a hematologist and staff scientist with the National Heart Lung and Blood Institute in Maryland, has performed about 10 gene therapy procedures over the past three years as part of a clinical trial. Ongoing tweaks in the procedure have led to the blood in more recent patients showing sickle cell trait -- not a perfect outcome, but one that leaves patients with far fewer symptoms than if they have the full-blown disease.
If one or both treatments receive regulatory approval, it would be a watershed breakthrough for the tens of thousands of Americans who suffer from the disease.
Yet it is entirely possible many patients may decline the cure.
A Painful History
The vast majority of sickle cell sufferers in the U.S. -- well beyond 90 percent -- are African-American, a population with a historically uneasy relationship toward healthcare.
"There is a lot of data on distrust between African-Americans and American medical institutions," says J. Corey Williams, a psychiatrist with the Children's Hospital of Philadelphia who has written extensively on racial disparities in healthcare. "It comes from a long legacy of feeling victimized by medicine."
"What you hear from many patients is 'I am not going to be your guinea pig, and I am not going to be experimented on.'"
As a result, Williams is among several clinicians interviewed for this story who believe a cure for sickle cell disease would be embraced reluctantly.
"What you hear from many patients is 'I am not going to be your guinea pig, and I am not going to be experimented on.' And so the history of African-Americans and research will manifest as we develop gene therapies for [these] patients," says Christopher L. Edwards, a clinical psychologist and researcher with the Maya Angelou Center for Health Equity at the Wake Forest University School of Medicine.
Fear among African-Americans of becoming guinea pigs is well-founded. The first c-sections and fistula repairs occurring in North America were performed on enslaved women -- all without consent and virtually none with anesthesia.
Modern 20th century medicine led to the Tuskegee syphilis experiments conducted by the U.S. Public Health Service. Researchers withheld treatment from some 400 African-American men from the 1930s well into the 1970s to observe how they reacted to the disease -- even though curative antibiotics had been around for decades. Only news reports ended the experiment.
The long-standing distrust of American healthcare in the African-American community is also baked into the care provided to sickle cell patients. Despite affecting one in 365 African-Americans, there is no disease registry to assist clinical trials, according to Mary Hulihan, a blood disorders epidemiologist with the Centers for Disease Control and Prevention. Edwards says many sufferers are suspicious of being monitored.
Meanwhile, only two drugs are available to alleviate the worst symptoms. The first one, hydroxyurea, received FDA approval only in 1998 -- nearly 90 years after the disease was first diagnosed. Moreover, Edwards says that some sufferers shy away from using hydroxyurea because it is also used to treat cancer. It's part of what he calls the "myth and folklore" in the African-American community about sickle cell disease.
Economics plays a role as well in the often-fragmented care such patients receive. According to CDC data, many patients rely extensively on public insurance programs such as Medicaid, whose coverage varies from state to state.
A Tough Transition
Edwards notes that sickle cell sufferers usually receive good care when they're children because of support provided by family members. But that often breaks down in adulthood. According to CDC data, an adult sickle cell patient visits a hospital emergency room three times as often as a child patient.
The consensus is that the path to a medical cure for sickle cell will first need to be smoothed over with a talk cure.
Modupe Idowu, a hematologist with the University of Texas Health system, estimates that there are perhaps a dozen comprehensive care centers for the estimated 100,000 sickle cell patients in the U.S., including the one she operates in Houston. That means a significant proportion of those afflicted are on their own to procure care.
And since many patients are on Medicaid, "a lot of hematologists that train to take care of blood disorders, many are not interested in treating [sickle cell disease] because the reimbursement for providers is not great," Idowu says.
Hsieh acknowledges that many of his patients can be suspicious about the care they are receiving. Frustration with fragmented care is usually the biggest driver, he adds.
Meanwhile, the skepticism that patients have about the treatments they seek is often reciprocated by their caregivers.
"The patients have experiences with medication and know what works at a very young age (for their pain)," Edwards says. Such expertise demonstrated by an African-American patient often leads to them being labeled as narcotics seekers.
The Correct Path
This all begs the question of how to deploy a cure. Idowu, who regularly holds town hall-style meetings with Houston-area patients, often must allay anxieties. For example, the gene therapy approach uses a harmless virus to transport new genetic material into cells. That virus happens to be a benign version of HIV, and convincing patients they won't be infected with HIV is a fraught issue.
The consensus is that the path to a medical cure for sickle cell will first need to be smoothed over with a talk cure.
Idowu tries to hammer home the fact that patients are afforded vastly more protections than in the past. "There are a lot of committees and investigational review boards that keep track of clinical trials; things just don't happen anymore as they did in the past," she says. She also believes it helps if more providers of color communicate to patients.
Hsieh is very straightforward with his patients. He informs them about the HIV vector but assures them no one has ever tested positive for the virus as a result of its use.
Edwards notes that since many patients suffer psychosocial trauma as a result of their chronic pain, there already is some counseling infrastructure in place to help them cope. He believes such resources will have to be stretched further as a cure looms closer.
In the absence of formal mental health services, straight talk may be the best way to overcome wariness.
"If patients have misgivings, we try our best to address them, and let them know at the end of the day it is their decision to make," Hsieh says. "And even the patients who have gone through the gene therapy and it didn't work well -- they're still glad they took the chance."
Shota Kuwahara, a DAWN employee with muscular dystrophy. Ory Labs, Inc. 