Crystallizing our comprehension of malaria

An exciting new study led by Prof. Michael Elbaum and Prof. Emeritus Leslie Leiserowitz, conducted in collaboration with prominent research teams worldwide, may help outwit the malaria parasite. The scientists revealed, in unprecedented detail, the structure of crystals that the parasite builds to survive. As most antimalarial drugs interfere with the formation and growth of these crystals, the discovery might lead to improved antimalarial medications.

Malaria is a mosquito-borne infectious disease caused by a parasitic microorganism—Plasmodium falciparum—which feasts on hemoglobin, the oxygen-carrying protein in the blood. Digesting the hemoglobin releases heme, an iron-containing molecular complex needed for binding oxygen. Freed from the surrounding protein, heme is so reactive that it can kill the parasite. That’s when P. falciparum pulls a survival stunt: it renders the heme harmless by packaging it into dark-colored crystals known as malaria pigment, or hemozoin.

Prof. Leiserowitz, from the Department of Molecular Chemistry and Materials Science, has built an extensive career studying the crystallization process. Prof. Elbaum, from the Department of Chemical and Biological Physics, develops cryo-tomography methods to study nanoscale materials and biomolecular machines. The two scientists began a collaboration years ago to investigate hemozoin production. More recently, they joined forces with the labs of Prof. Neta Regev-Rudzki in the Department of Biomolecular Sciences, and Prof. Ron Dzikowski at the Hebrew University Medical School, who could provide them with infected red blood cells in which the hemozoin crystals form naturally.

These natural crystals did not divulge their secrets easily. Even after an in-depth, three-dimensional analysis at the Weizmann Institute, key pieces of the structural puzzle remained elusive. Determined to uncover the full picture, Profs. Elbaum and Leiserowitz sent their pigment samples to colleagues at the University of Oxford and the Diamond Light Source (the UK’s national synchrotron), where a newly developed electron crystallography technique provided information about the arrangement of the atoms in unprecedented detail. This collaborative effort soon expanded to include 17 researchers from Israel, the UK, Austria, the Czech Republic, and the US.

The result of this international collaboration—a definitive, atom-by-atom 3D structure of the malaria pigment—supplied valuable insights. Previous Weizmann studies had revealed crystals of a peculiar trapezoid shape that resembled a kitchen cleaver: The “blade” end was always smooth and sharp, like a chisel, while the “handle” end was variable and often jagged.

The detailed structure resolved the kitchen cleaver quandary. In principle, there are four distinct heme building blocks of hemozoin crystals. Two are symmetrical, while the other two are chiral (mirror images). However, only one of each is actually found in the crystal. When these two grow together in a single crystal, the result is that certain surfaces will be perfectly ordered on one side, but atomically disordered on the opposite. Scientists had previously assumed that growth is fast at the jagged end, but the new insights indicate that the handle shape forms because a part of the surface actually grows more slowly. Such a clear understanding of the crystal surfaces is essential to designing or evaluating drugs that can bind to the crystal and inhibit its growth.

Finally, the study revealed subtle but essential differences between natural and synthetic malaria crystals, underscoring the importance of designing future drugs based on structural information about real-life crystals made by the parasite.

Pictured from left: Prof. Michael Elbaum, Dr. Lothar Houben, and Prof. Leslie Leiserowitz.

Prof. Michael Elbaum is Head of the Fritz Haber Center for Physical Chemistry and the incumbent of the Sam and Ayala Zacks Professorial Chair.

Prof. Neta Regev-Rudzki is Head of the Kleinman Cancer Cell Sorting Facility and Head of the Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics. Her research is supported by the Brenden-Mann Women’s Innovation Impact Fund and the Karen Siem Fellowship for Women in Science.