Dartmouth Medical School professor of pharmacology and toxicology Christopher Lowrey and colleagues have proposed a new model that links hemoglobin induction with cell stress signaling. The findings were published last month in Experimental Hematology.

Lowrey and his team sought to find alternative methods to combat sickle cell disease (SCD) and beta-thalassemia in humans. Prior to their study, research using drug therapy involved pharmacologic agents such as DNA methyltransferase (DNMT) inhibitor, butyrate derivatives, and hydroxyurea (HU) to induce the production of fetal hemoglobin (HbF), which can take the place of normal hemoglobin and reduce the symptoms of disease. These methods, though they seemed potentially successful, never became clinically active because the results failed to balance safety, ease of use, and efficacy.

In 2001, researchers Ikuta and colleagues at the Howard Hughes Medical Laboratory found that cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) — two proteins that play key roles in cell signal transduction pathways —affect beta-globin induction positively and negatively, respectively. This implies that HbF production can be regulated by more than just the primary actions of HbF inducing agents. Two years ago, the DHMC team looked into this particular research project. Their ultimate goal was to create an HbF inducing drug that would not caused significant side effects, would not demand DNA incorporation to be effective, and could be administered orally.

Lowrey and his team propose a new model that offers one of the first unifying theories of HbF induction since the hypothesized erythropoietic stress model from the 1980s. The model makes four predictions: most HbF inducing agents will initiate cell stress signaling, members of these cell stress signaling pathways are needed for the beta-globin gene and production of HbF, and beta-globin promoter hypomethylation and histone hyperacetylation would also result from beta-globin inducing agents. Their model places the p38 MAPK signaling pathway in the center because it has been associated with the actions of many HbF inducing agents.

Lowrey’s involvement with hematology began with a research project he participated in as an undergraduate student at Bowdoin College. As he proceeded to get his masters from the University of Pennsylvania and medical degree from Boston University Medical School, Lowrey’s interests shifted from gene therapy, based on the little progress being made in the field due to lack of sufficient technology, to drug therapy.

Though there have been positive results in the functionality of this model, Lowrey cautioned that “it is just a hypothesis.”

It is “off to a great start,” he said, but it “still [has] a long way to go.”

He said of the project: “[It] wouldn’t have gotten this far without the help of undergraduate and graduate students at Dartmouth College. They have played a huge role in the process.”