As reported by the New Haven Register, January 9, 2005.

Little Progress Made in Treatment of Sickle Cell

About 10,000 years ago, the only oxygen-carrying protein in blood mutated.

By Abram Katz

The protein was like normal hemoglobin — except for one different amino acid.

Red blood cells carrying this irregular hemoglobin became elongated, curved and weak.

This undesirable protein would have been ejected from the gene pool, but it had a significant advantage to the people living in Africa at the time.

The mosquito-borne Plasmodium protozoan that causes malaria could not easily live in the long, bent red cells.

So the protein helped protect its bearers from malaria, which still kills about 1 million people a year.

About 30 to 40 percent of modern Africans still carry this trait, which has come to be known as sickle cell.

About 10 percent of African Americans are born with the gene. Sickle cell also appears in smaller percentages in certain parts of Asia and Europe.

Sickle cell is of no benefit in North America now.

The mutation causes only pain, sickness and premature death, mostly among blacks, said Dr. Howard Pearson, director of the Pediatric Sickle Cell Program at Yale-New Haven Hospital.

A man and woman who both carry the trait have a 25 percent chance of having a child with sickle cell disease.

Despite years of research, little headway has been made in treating the disease, which gradually destroys cells, overwhelms the spleen, causes liver damage, and makes sickle cell patients prone to infection.

The genetic nature of sickle cell disease makes it a frustrating foe, Pearson said.

Thirty years ago, the life expectancy of someone with sickle cell disease was 14, he said.

Now it’s 47. Advances in fighting infections are largely responsible for the increase, Pearson said.

Marrow transplants seem like the best strategy now, Pearson said.

Normal marrow would produce normal hemoglobin.

The life-sustaining molecule consists of two alpha chains and two beta chains. Each pair contains an iron atom.

Each chain consists of about 560 amino acids. The sickle cell mutation occurs on the beta chains, when a valine amino acid takes the place of a glutamic acid.

When faced with low oxygen — during an asthma attack, an athletic event or an infection — sickle cell hemoglobins form long chains, or polymers.

These polymers distort the cells and give them the characteristic "sickle" shape.

The normal bi-concave doughnut-shaped disk becomes a long rod with bends at both ends.

Sickle cells last 10 to 15 days, compared to the 120-day life cycle of a normal red cell.

This makes patients anemic, Pearson said.

What’s far worse is that the misshapen cells get stuck in small arteries.

Without oxygen, tissues served by the vessel die.

The body responds with inflammation, which lowers oxygen levels and prompts more cells to "sickle."

Normally the spleen, which is part of the lymph system, filters out old or damaged red cells. The organ also clears bacteria.

People with sickle cell disease often overwhelm their spleens.

Efficiency drops, and frequently the spleen must be removed, increasing the risk of infection.

About 20 percent of babies with sickle cell disease used to die of pneumococcal infection until pediatricians were able to administer pneumococcal vaccine, Pearson said.

"There are two ways to treat a disorder — the cause or the effect," said Dr. Thiruchandurai V. Rajan, chairman of pathology at the University of Connecticut Health Center.

"In a number of disorders, the symptoms can be lethal," he said.

Sickle cell disease falls into that category.

Rajan said there is no known way to de-polymerize the hemoglobin in sickle cells.

Fortunately, the immune system does not react to the misshapen cells. The result could be fatal.

"Many strategies have been suggested," Rajan said.

Infants have fetal-globin that can substitute for beta-globin. Some people do not switch to "adult" hemoglobin.

If fetal globin production could be sufficiently stimulated in sickle cell patients, the fetal form might be able to out compete the sickle cell hemoglobin, Rajan said.

A sickle cell patient able to make 50 percent fetal-globin red cells could probably lead a normal life, he said.

One way to turn on the quiescent fetal-globin gene is by using a chemical called hydroxyurea, Rajan said.

However, this is risky because hydroxyurea cannot be precisely controlled and could cause unwanted tissue growth or cancer, he said.

"Ultimately, we’ll treat sickle cell disease with gene therapy," he said.

This would probably entail killing all of the patient’s bone marrow and implanting healthy marrow, he said.

But about 0.25 percent of the U.S. population has sickle cell disease, and bone marrow transplants cost about $200,000 each, Rajan said.

A national program would need to be organized to identify donors. It would be very expensive, Rajan said.

But it could be done.

"I honestly think sickle cell is not a priority. We’ve known the molecular structure of hemoglobin for 50 years," he said.

"The problem is that these kids are not the most affluent or politically savvy," he said.

"Who’s talking for little black kids with sickle cell anemia? Everyone knows that bone marrow transplants would do it," Rajan said.

The other option is to wait for the sickle cell gene to slowly disappear. The gene has no evolutionary value here, he said.

Since Africans were enslaved in North America, the prevalence of the gene in the population has dropped from 30 to 40 percent to 10 percent.

"It will take hundreds of years for the gene to decline," Rajan said.