Tiny pumping stations play outsize role in cellular health and disease

October 12, 2020

In order to carry out their astonishingly varied tasks, living cells make use of a range of micromachines. One of the most crucial of these — known vacuolar ATPase or V-ATPase — is responsible for ferrying protons into cellular compartments or organelles. Without it, cells could not survive.

Once set in motion, this natural motor — ensconced in the cell organelle’s fatty outer membrane — spins like a helicopter blade at 100 times per second, sweeping in protons from outside the cell’s organelle.  Abhishek Singharoy is a researcher in the Biodesign Center for Applied Structural Discovery and ASU’s School of Molecular Sciences. Download Full Image

Scientists have long known of the indispensable role of V-ATPase. But understanding the workings of this intricate minifactory have been challenging to tease out, until now.

In new research appearing in the journal Science AdvancesAbhishek Singharoy and his colleagues combine high-resolution cryo-EM images made at the Department of Energy’s SLAC National Accelerator Laboratory with supercomputer simulations, in order to peer into the intricacies of this proton pump for the first time.

Singharoy is a researcher in Arizona State University's Biodesign Center for Applied Structural Discovery and ASU’s School of Molecular Sciences. His work helped fellow researchers visualize the complexities of V-ATPase through supercomputer simulations conducted at the Oak Ridge National Laboratory.

“Molecular motors exemplify some of the most intricate chemo-mechanical devices, and our team in SMS and CASD has developed highly sophisticated computational tools to address the energy source and sinks of the motor’s ratcheting motion," he said. "In 2017, we started working on the soluble part of the V-type motor, namely V1 ATPase. Now that we have a good control on the transmembrane Vo motor, it’s a great step forward towards simulating the entire motor in collaboration with Soung-Hun Roh, Stephan Wilkens and Wah Chiu.”

The current findings will have implications for intelligent drug design as well as furthering our understanding of how cells combat viruses and other pathogens.

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Richard Harth

Science writer, Biodesign Institute at ASU


Newly discovered leprosy genomes help fill historic gaps

October 12, 2020

History books often link disease and colonization, in which explorers unknowingly bring with them illnesses that spread to native people. New findings on the origin of leprosy in the Pacific Islands, however, contradict this suggestion. 

Arizona State University graduate students Kelly Blevins and Adele Crane are the primary co-authors of a study identifying nine new genomes of Mycobacterium leprae, one of the two pathogens that cause leprosy. Previously, only two other genomes of M. leprae had been recovered in the Pacific Islands.  Map of the Pacific Islands M. Leprae Genomes Figure 1. “Map of the Pacific showing source locations of novel and previously sequenced M. leprae strains from branch 0 and branch 5. Novel strains from this study all fall within these branches and are shown as diamonds,” the researchers wrote. “Comparative data are shown as circles.” Strains of M. leprae have geographical associations. The newly discovered genomes belonged to strain 0, which is predominantly found in East Asia, and branch 5, which is largely the Pacific Islands. Reprinted with permission from the Philosophical Transactions B journal. Download Full Image

These nine novel strains fall into the most ancient lineages in the family tree of M. leprae, branches 5 and 0. The last time that these branches shared a common ancestor was almost 4,000 years ago.

These findings suggest that leprosy was not introduced to the Pacific Islands during colonialism in the 1800s, as previously thought. Colonialism may have brought subsequent strains of leprosy to the Pacific Islands, but those strains would belong to different branches of the evolutionary tree. 

“Specifically, our results suggest that leprosy was probably present in the Pacific prior to European contact and likely spread via trade/voyaging networks,” said Anne Stone, ASU Regents Professor and senior co-author of the research. 

Leprosy is a chronic infectious disease that can be fatal. While it is still around today, it can be treated with antibiotics.

The tissue samples for this study came from the Hawaiian Pathologists’ Laboratory. Blevins and Crane received the samples at ASU’s Lab of Molecular Anthropology, selected and adapted a method for extracting DNA, analyzed data and wrote the manuscript.  

The research team also conducted bioinformatics work, comparing their data with publicly available M. leprae genomic data records. (See Figure 1 from the research paper.) 

This additional data also helped Blevins and Crane analyze relationships between strains and create phylogenetic trees. Crane called them the “family trees” of the pathogen, showing the evolutionary history of the various strains.

ASU graduate students lead the study

Blevins and Crane are both doctoral students at ASU — Blevins in anthropology at the School of Human Evolution and Social Change, and Crane in evolutionary biology at the School of Life Sciences. They designed the study and executed the laboratory work and data analysis. 

Blevins and Crane come from different areas of primary research and past academic work, but now they both want to know where diseases come from.

Blevins’ work and research during her undergraduate and graduate studies focused on osteology (studying bones) and paleopathology (studying ancient disease). This background provided a good foundation for a transition into genomics research.

“You can only tell so much from bones,” Blevins said. “They’re like a signpost saying ‘something was causing disease here,’ so getting into genomics helps better piece together what was going on.”

Crane comes from a background in molecular biology. She originally wanted to become a veterinarian and study wildlife diseases, but her research journey has led her to study how new interactions with the environment are affecting humans. She hopes to work in government research or surveillance of modern diseases. 

Original concept and implications for future research

This research concept came from Keolu Fox, a native Hawaiian and University of California, San Diego assistant professor. He is working to expand the genome database to include more underrepresented populations.

Crane said future research will include more data, including more samples and different types of samples.

“These nine genomes have formed our understanding of leprosy in the Pacific right now,” Crane said. “We have a much better picture of where it is and what’s going on.” 

But, she is interested in gathering data from a wider geographic area. Crane is continuing to research leprosy with the Hawaiian Pathologists’ Laboratory as part of her dissertation, for which she is researching bacterial populations within a host. 

The paper “Evolutionary history of Mycobacterium leprae in the Pacific Islands” was published in a special themed issue of the Philosophical Transactions B journal, “Insights into health and disease from ancient biomolecules.”

Taylor Woods

Communications program coordinator, School of Human Evolution and Social Change