The malaria-causing parasite exacts a bloody toll from humanity, not least thanks to its ability to produce unique, dark crystals inside our blood cells. New research completely deciphers the structure of these crystals and paves the way for new drugs
Prof. Leslie Lizarowitz He first became aware of malaria when he was a small child in South Africa. His father, who plowed the continent in search of wood for the family business, returned home not only with stories of elephants and gorillas but also with ringing in the ears and skin rashes - side effects of quinine, an old malaria drug. A few decades later, Prof. Lizarowitz, a world-renowned expert in crystal research, discovered that malaria is relevant to his field of research: the parasite that causes the disease has surprising abilities in the field of building crystals that help it in its deadly mission. Prof. Lizarowitz began researching the crystals produced by the parasite, and later formed a collaboration with his colleague in the Faculty of Chemistry at the Weizmann Institute of Science, Prof. Michael Albaum, which specializes in advanced imaging technologies.
Although the incidence of malaria decreased dramatically in the first two decades of the 21st century, the disease still leads to the death of more than half a million people a year, most of them small children, and is a tremendous global health challenge. In a recently published study by Professors Lizarowitz and Albaum, revealed in unprecedented detail the structure of the crystals that the parasite builds. The research, which was carried out in collaboration with leading research groups around the world and was assisted by some of the most innovative imaging technologies available, may help trick the parasite that exacts a heavy blood price from humanity and lead to the development of new and improved drugs against the disease.
We and heme
As anyone who has learned about the drying of the marshes in the Land of Israel knows, the Anopheles mosquitoes, or rather mosquitoes, are the ones that transmit the malaria parasite - a single-celled creature from the Plasmodium family. After the bite of the infected mosquito and the entry of the parasite into the human body, it first migrates to the liver, where it spends about two weeks and waits for an hour of fitness. From there, the parasite breaks into the bloodstream and invades red blood cells, inside which it feeds on hemoglobin - the protein that carries oxygen in the blood. But the parasite's favorite dish carries a great danger: digesting the protein releases "heme" - a molecular aggregate that is indeed necessary for binding oxygen, but when it is not part of the complete protein it is toxic and can lead to the destruction of the parasite. To neutralize the danger, the parasite uses its impressive construction abilities: it transforms the dangerous heme molecules into unique crystals that no longer pose a danger to it. These dark crystals were discovered as early as the 19th century, but at first doctors thought they were produced as the body's response to malaria.
When Prof. Lizarovitz began to study malaria crystals, he was first fascinated by aspects related to their unique symmetry - a research topic on which he worked for many years with his colleague at Prof. Meir Lahav's institute. But in the context of the malaria crystals, these aspects become a matter of life and death: the symmetry of the crystals affects the rate of their development and therefore the parasite's ability to survive and thrive. Despite the great interest, the technologies that existed at that time did not allow to go to the depths of the many structural subtleties, and essential questions remained unanswered.
At the same time, in those years, Prof. Albaum studied the parasite from a completely different direction. Together with colleagues from the Hebrew University of Jerusalem, he focused on the structure of the parasite cell nucleus in its unique division process. While most of the cells we know reproduce by dividing into two, the malaria parasite first produces many copies of its various components inside the host blood cell, and only at the end divides at once into a large number of offspring that can infect new blood cells. When Prof. Lizarowitz presented his work on the malaria crystals at the department's seminar, the collaboration with Prof. Elbaum came about naturally.
As fate would have it, after some time the laboratory of Prof. Neta Regev-Rotsky, specializing in the biology of the malaria parasite, was opened at the institute. This made it possible for Prof. Albaum and Prof. Lizarovitz to move to the study of the natural crystals produced by the parasites inside the blood cells instead of synthetic crystals produced in the laboratory, as is customary in most research in the field.
To this end, the researchers used, among other things, an advanced imaging method developed by Prof. Albaum in collaboration with Dr. Sharon Wolf and Dr. Luther Houben from the Department of Chemical Research Infrastructures of the institute - cryogenic scanning transmission electron tomography or CSTET for short.
Despite the breakthroughs achieved, the crystals did not easily yield to researchers. After exhausting the advanced tools available to the institute's scientists, the crystals were sent to Britain in search of the missing pieces of the puzzle. Using a new approach to crystallography, based on electrons instead of X-rays, scientists at the University of Oxford and the Diamond Light Source, the UK's national synchrotron, produced amazing images of the crystals, and the deciphering was still not completely complete, and they proposed to add another partner to the research - this time from the University Vienna.
"This is how the research became a kind of relay race - each laboratory offered to add prominent experts in another field," recalls Prof. Albaum. "Finally, an international 'star team' was formed that combined forces to achieve a highly sophisticated analysis of the crystals." The scientific article is ultimately signed by 17 authors from Israel, Great Britain, Austria, the Czech Republic and the United States.
The cross-continental collaboration produced an ultimate three-dimensional structure of the crystal at the level of the single atom, and more importantly - many insights that may advance the study of malaria and its cure. Among other things, an aesthetic mystery that occupied the institute's scientists was solved: the crystals resembled a butcher's knife, where the side of the "blade" was always sharp and smooth, but the side of the "handle" was different from crystal to crystal and was usually rough. "We wondered how nature created something so ugly - some of the crystals look as if someone had given them a bite," recalls Prof. Lizarowitz.
The new study gave an explanation for the strange shape: when heme crystallizes, its molecules join in pairs, and these form the basic units of the crystal. Because the front and back sides of the heme molecule are chemically distinct, the molecules can pair up in four different ways. In other words, there are four basic units of heme crystals; Two of them are symmetrical, while the other two are chiral, i.e. they are a mirror image of each other, and therefore, similar to our palms, they cannot be placed on top of each other and create a perfect overlap. As the crystal grows and develops, the result on the surface can be a surface that is messy at the atomic level and has a rough appearance. But this is not just an aesthetic issue: this precise understanding of the surface of the crystal is essential for the development of drugs that can bind to the crystal and prevent its development.
In fact, most of the existing anti-malarial drugs work, as far as is known, by disrupting the mechanism of the formation and development of the crystals, but many of them have lost their effectiveness, due to the resistance developed by the parasite. Therefore, the new findings may advance the development of new drugs, as they allow for a good and accurate calculation of the expected interactions between the crystals and potential drugs. The study also revealed subtle but fundamental differences between synthetic heme crystals produced in the laboratory and the natural crystals produced by the parasite inside the body's blood cells. This discovery emphasizes how important it is to develop future drugs based on the biological crystal structure that the parasite itself produces.
The exciting findings were recently presented by Prof. Albaum at a scientific conference held at the institute to mark Prof. Lizarowitz's 90th birthday and held under the title "Leslie at 90: A Scientific Odyssey".
Also participating in the study were Dr. Paul Benjamin Klar from the University of Bremen, Germany; Dr. David Geoffrey Waterman from the Rutherford Appleton Laboratory, Great Britain; Dr. Tim Green from the University of Vienna; Dr. Bakshi Molik from the Department of Chemical and Biological Physics of the Institute; Dr. Yun Song, Dr. James Boris Gilchrist and Dr. C. David Owen from the Diamond Light Source in the UK and Prof. Feijun Zhang from the Diamond Light Source and the University of Oxford; Dr. Wen Wen and Prof. Noah Marom from Carnegie Mellon University, United States; Dr. Idan Biran from the Department of Molecular Chemistry and Materials Science of the Institute; Prof. Ron Dzikowski from the Hebrew University of Jerusalem and Dr. Lux Platinos from the Institute of Physics of the Czech Academy of Sciences.
In their previous research on the malaria crystal, Prof. Elbaum and Prof. Lizarovitz collaborated with many other researchers who made essential contributions to the research, including Dr. Sergey Kapishnikov, currently at University College Dublin and SiriusXT in Dublin, Ireland, and Prof. Jens Els-Nielsen from the University of Copenhagen.
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