Surprising University of Maryland-Led Discovery Points to New Treatments for Blood Disorders and to New Lines of Medical and Biological Research

A multi-institutional team of researchers led by University of Maryland Professor Iqbal Hamza has for the first time found that mammals unexpectedly share a trait with the Malaria parasite—the production of a crystallized, non-toxic form of heme known as hemozoin. This finding holds promise for new treatments for blood disorders and for other new lines of medical and biological research.

Found in almost all living things, heme is an iron-containing molecule essential for many life enabling biological processes. It is most widely known for its role as the essential component of hemoglobin. the protein that makes it possible for red blood cells to carry live-giving oxygen. Ironically free heme is also highly toxic to living organisms.

Throughout his seventeen-year UMD career, Hamza, a professor of animal and avian sciences, has made multiple pioneering heme discoveries, including identifying long-sought proteins that in mammals and many other organisms act as secure containers allowing toxic heme molecules to be safely transported and recycled within an organism.

In the latest research, Hamza and colleagues unexpectedly found that the production of non-toxic hemozoin—a biological adaptation of lower-level microorganisms for protecting against heme toxicity—-is also present in mice and likely in other mammals. Previously hemozoin had only been found in microorganisms that “feed” on red blood cells, like the malaria-causing parasite, plasmodium.

The new finding, in turn, opens up important, entirely new lines of research, including research into if and how hemozoin occurs in humans; and research to find out if the production of hemozoin in mammals can be translated into new treatments, not only for malaria and other parasitic infections, but also for hemolytic diseases like sickle cell disease.

Mutating Heme-Transporter Proteins in Mice

Each second humans, mice and other mammals recycle vast numbers of heme-iron molcules from worn-out red blood cells. The recycled heme is then used to make new red cells.

Hamza explained that for this study, he and his team of scientists genetically altered mice to mutate the main heme transporter, thus blocking safe recycling of toxic heme. ThIs should have been lethal to the mice, but surprisingly, the researchers found that the mice, instead of dying, formed hemozoin. “This had never been seen in mammals before,” he said. Hamza said that if hemozoin production occurs in mice, he is “willing to bet” it also occurs in humans.

Hemozoin has, in rare cases, been found in humans, but it has been assumed to be “foreign” hemozoin made by malaria parasites during a bout of malaria. “We didn’t know that mammals could make their own hemozoin until now,” Hamza said.

“I bet that there must be some humans with hemozoin in their liver, spleen, and marrow, and it is only a matter of time before we find them. Our data predicts that these people will be protected from heme toxicity. We have to actively go and look for these patients… because they will have less severe ailments than what we would typically expect,” Hamza said.

Finding these patients is important for the future study of this mutation and for finding potential therapeutic functions of this mechanism, such as perhaps providing relief for patients that suffer from sickle cell disease or malaria.

“Blocking the heme transporter gene transiently [in mammals] should be able to overcome acute heme toxicity in diseases such as sickle cell and malaria where the cells become significantly injured, causing pain. This would create some hemozoin in the body, but the animals should survive giving them extra time to reprogram themselves to deal with heme toxicity, ” he said.

Hamza noted that in addition to this possible application, there are a slew of other exciting research possibilities that are opened up by the discovery of hemozoin in mammals.

The mechanisms underlying how hemozoin is made and how heme tolerance occurs are unknown, and being able to answer these questions in a human cell are important to the future of this work according to Hamza. He said he has already gotten a lot of interest in this work, with collaborators coming out of diverse fields including immunology, parasitology, neuroscience and microbiology. There are even urologists who think this pathway may be important in urinary tract infections and want to collaborate, Hamza said.

“The discovery is very exciting, and I’ve gotten several calls already about all the different directions we can take this,” says Hamza. “It’s great to see the support in the scientific community, and we are already planning to search for this in humans to continue the path towards treatment of parasitic diseases, hemolytic diseases, like sickle cell, and many others.”

The paper entitled, “Hemozoin produced by mammals confer heme tolerance,” is available at eLife, DOI: 10.7554/eLife.49503.

Additional collaborators: X-ray fluorescence microscopy was performed in collaboration with Martina Ralle, assistant professor in the Department of Molecular and Medical Genetics, Oregon Health and Science University. Macrophage analyses were performed in collaboration with Dr. Malay Haldar, assistant professor of pathology in the Department of Pathology and Laboratory Medicine, University of Pennsylvania. X-ray powder diffraction analyses were performed in collaboration with Dr. Eiji Nishibori from University of Tsukuba, Japan and Hiroshi Sugimoto, structural biologist from RIKEN SPring-8 Center, Japan.

Past UMD releases about Professor Hamza’s heme research include:

(2017) UMD-Led Research in Bloodless Worms Reveals How Organs Communicate their Status of Life-Giving Heme

(2013) UMD Scientists Discover Protein that Enables Safe Recycling of Iron from Old Red Blood Cells