It is an implacable inherited disease of a million microscopic cuts, changing red blood cells into miniscule daggers that attack organ after organ-spleen, brain, lungs, heart, kidneys, liver, eyes, bones and joints-until almost nothing in the body has escaped its damage. It often delivers its most savage blows in infancy, leaving those who carry its genes partially paralyzed, or robbed of half their native intelligence. It has an additional special weapon, signature episodes of pain that leaves its victims in breathless agony.
It is sickle cell disease, a textbook case of a medical condition caused by a single error in a single gene. The gene in this case is the one that controls the production of hemoglobin, the substance that gives blood both its red color and its ability to deliver oxygen throughout the body. Hemoglobin is composed of an iron-containing pigment called heme and a protein, globin.
Though the biochemical cause of sickle cell disease has been known for a half century, its clinical management has long remained static. The clinical picture has changed markedly for the better since the 1970s, owing in no small measure to the concerted efforts of a group of physicians at the Keck School of Medicine. Their collaboration over the course of three decades has produced key insights into improving treatment. If there is to be a cure, it may very well come from allied groups of different specialists like this.
A Genetic Mutation
In 1949, biochemist Linus Pauling of the California Institute of Technology led the team that proved that a single genetic mutation changed the composition of the hemoglobin molecule-produced in red blood cell factories in the bone marrow-from the life-giving elixir called hemoglobin-A (HbA) to an evil-twin substance called hemoglobin-S (HbS).
About 8 percent of African-Americans carry the sickle cell trait, which is a single copy of the gene that produces HbS instead of HbA. One copy of the gene produces no symptoms. It takes two copies of the gene-one from each parent-to produce the disease, a double dose of bad luck that occurs in about 1 in 400 African-American babies.
Newborns have a special form of hemoglobin all their own, fetal hemoglobin, HbF, which masks the condition for the first months of life. But once the bone marrow begins to produce cells with HbS, the damage begins.
Red Blood Cell Alteration
Few are more familiar with this damage than hematologist Cage Johnson, M.D., professor of medicine at the Keck School of Medicine and director of the USC Comprehensive Sickle Cell Center (CSCC). Established in 1972, the CSCC is one of 10 clinical and research centers funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health to serve as national centers of basic, clinical and applied research into sickle cell disease.
In order to move through the body, Johnson explains, red blood cells-the plump disk-shaped packages into which the body’s hemoglobin is packed-must be able to slip through capillaries smaller in diameter than the cells themselves. In order for the red blood cells containing normal HbA to make the squeeze, they easily flex, fold and refold themselves to move through the small openings.
In contrast, cells containing HbS harden when they give away the oxygen they carry. HbS molecules inside the cells crystallize into a rigid, spike form. These spikes of crystallized HbS push out the walls of the red blood cells, distorting their shape from disks into the characteristic sickle shape that gives the condition its name.
Such deformed HbS cells cannot squeeze and fold to move through the capillaries. Instead, they clump and block, or they stick to the walls of blood vessels that they can enter and block them, causing strokes (in the brain) or “ischemic” (caused by lack of blood) tissue damage elsewhere in the body.
“The rigid, irregularly shaped cell is believed to be responsible for the problems caused by sickle cell disease,” reports Johnson in a 1988 review paper. “It is so fragile that it is easily destroyed as it passes through the blood vessels, curtailing its life to 15 to 30 days instead of the normal 120. The bone marrow must increase its production (of red blood cells) drastically in order to keep up with the rate of destruction.
“But even at maximum output, the marrow is unable to manufacture enough cells to maintain normal levels. A severe anemia-a shortage of working blood cells-results.”
These occurrences multiply over the years, says Johnson, leading to problems throughout the body-a process he has observed over and over in the hundreds of patients he has followed for decades.
Risky health habits acquire added dimensions for sickle cell disease patients. Smoking cigarettes severely stresses lungs damaged by sickle cell disease, compounding the difficult task of getting oxygen into the lungs. And drinking alcohol dehydrates the body, which puts additional strain on sickle cell-damaged kidneys.
According to Johnson, the disease causes people to “just get beaten down, which leads to depression. They become dependent on treatment. They’re always in the clinic and the office; they need to feel something is being done.” He says that for teenagers, viewing their illness as a death sentence may lead to depression and become a self-fulfilling prophecy.
Not a bright picture-but the quality of life for patients has been steadily improving. Particularly helpful is the drug, hydroxyurea, which somehow tricks the bone marrow into producing hemoglobin in the fetal form (HbF). Such hemoglobin not only functions normally in the bloodstream but also blocks the crystallization of HbS in the red blood cells, for reasons that are still being investigated.
However, since hydroxyurea is toxic, patients with liver or kidney problems cannot take it. Also, the consequences of long-term usage for others are not yet known. Yet, “its effect on sickle cell disease sufferers is dramatic,” says Johnson, reducing sickle cell attacks and allowing patients to live far more normal lives.
Another intervention method for sickle cell patients is to transfuse whole, normal blood, often in conjunction with drugs that stimulate production of red blood cells. However, the number of transfusions a patient can receive is limited by the amount of iron (found in hemoglobin) the body can recycle. Too many transfusions can cause iron poisoning.
Extreme cases of sickle cell disease can be treated by a bone marrow transplant-but it is often difficult or impossible to find a donor match even among family members. On the horizon are genetic counseling techniques that may eventually give at-risk parents-couples in which both carry the sickle cell trait, and therefore have a 25 percent chance of having a child with sickle cell disease-ways to improve the odds of having a healthy baby.
Research Makes Connection
Keck School researchers have made fundamental improvements in managing the disease, with one researcher playing a key role in many of them.
A standard treatment for sickle cell disease in young children, a proven lifesaver, comes directly out of a clinical discovery made three decades ago by research that included Darleen R. Powars, M.D., a professor of pediatrics at the Keck School. Then a young physician beginning her career, Powars was among the first to closely examine the causes of death in a broad cross section of young sickle cell patients and find a striking occurrence of sudden-death syndrome.
“An infant would be brought in with a high fever-a common pediatric problem-be examined and treated routinely, and then be dead in a few hours from overwhelming infection,” she recalls. At the time, sickle cell disease was typically not diagnosed at birth, but six or eight months later when the newborn’s fetal hemoglobin was replaced with HbS blood.
Analysis yielded an obvious explanation: The first organ attacked and disabled by sickled cells is the spleen. Without a spleen, patients are susceptible to bacterial infection. The physicians had no idea that the infants they were treating needed the same intensive care as patients who had their spleens removed. Powars’ study of a large patient sample was a revelation: “When we looked at the data, the correlation jumped out at us,” Powars says.
As a direct result of Powars’ study, the mortality picture of the disease in the United States has changed. All children with sickle cell anemia now receive oral penicillin, which has increased survival rates so that 90 percent live to their twenties. A recent report to Congress by the National Heart, Lung, and Blood Institute singled out the penicillin therapy as “the first real breakthrough in saving lives,” saying it “dramatically changed the management of infants and children with sickle cell disease.”
Powars’ more recent work centers on another crucial component of the disease: childhood strokes. At least nine percent of children with sickle cell disease have a major stroke, usually between ages 3 and 10. Powars’ research definitively established that children who had one stroke were likely to have more, in the absence of transfusion therapy.
Powars is finding that damage to the brain is common-a mosaic of tiny injuries from sickle cells that add up to severe neural deficits in many children. Working with the Keck School neuro-imaging team, she is using sophisticated brain imaging systems to correlate deficits in function with precise lesion locations in the brain. The hope is this will enable clinicians to more precisely diagnose damage without invasive testing.
In another set of studies, Powars elucidated a number of strains of the disease, tracing them back to different areas in Africa. She found some strains to be benign, some much more likely to be fatal. These distinctions, detectable with DNA testing, now guide treatment.
Solutions through Collaboration
While Powars was explaining the role of sickle cell disease in both overwhelming infections and brain deficits, another Keck School physician, cardiologist L. Julian Haywood, M.D., was illuminating its effects on the heart. He saw a characteristic pattern of heart enlargement and mitral valve problems in sickle cell patients at the Comprehensive Sickle Cell Center and found indirect evidence of subtle damage in heart tissue caused by the blockage of small blood vessels. He has begun a study that will look for better external indicators of heart damage, measuring subtle heart arrhythmias to try to detect the damage early, improving outcomes.
Other Keck School researchers are working in direct collaboration with Johnson. Keck School molecular biochemist Vijay Kalra, Ph.D., has a particular research interest in stopping sickle cells from adhering to blood vessel walls, which blocks blood flow.
This adhesion is caused by a lock-and-key fit between a compound found on the surface of the sickled cell, and another found in the blood vessel. The trick, according to Kalra, is to find an effective way to prevent the blood vessel from producing the “lock” substance. This would prevent some of the destructive stroke-causing, tissue-damaging blocking of the blood vessels. Another solution suggested by recent in vitro research by the scientist is that high levels of anti-oxidants like vitamin E may help protect the blood vessels by counteracting damaging “free radicals” produced by the sickle cell and blood vessel wall interaction.
In another collaboration, Kalra teams with USC chemist Surya Prakash, Ph.D., the Olah Nobel Laureate Chair of Chemistry. The pair are developing a chemical compound to change the properties of the sickled cell, increasing its flexibility and reducing its adhesion.
Another Keck School investigator, physiologist Herbert J. Meiselman, Sc.D., is studying the mechanical properties of sickle red blood cells and their ability to deform and enter small blood vessels. He has been applying physical techniques to understand the flow behavior of sickle blood.
During the past two years, Meiselman and his colleagues, assistant professor Timothy Fisher, M.D., and research associate Jonathan Armstrong, Ph.D., have developed a potentially important new approach to therapy in this disease-permanently attaching a thin polymer coating to the surface of red cells. This coating abolishes the tendency of sickle cells to clump together and thus improves the flow properties of blood; it also markedly reduces adhesion of sickle red cells to blood vessel walls. While this coating approach would not be a cure-even normal red cells only exist in the circulation for about four months-such treatment promises to offer a reduced risk of stroke and temporary relief from pain without the need for frequent blood transfusions. On a broader scale, this polymer coating technique may turn normal blood into “universal donor” blood-blood that can be given to any recipient for a transfusion.
Despite the advances, Cage Johnson, Darleen Powars, and their colleagues are not complacent. But after decades of fighting sickle cell disease, they think the tide may have begun to turn in favor of the patient.
For more information about the USC Comprehensive Sickle Cell Center, or to learn about The Doctors of USC, call 1-800-USC-CARE (1-800-872-2273).