Wednesday, July 23, 2025

Stealth genetic switch in mosquitoes halts malaria spread

Novel system uses CRISPR to replace one molecule and block parasites that cause malaria infection

University of California - San Diego

Transmission blocked — image:
Mosquitoes that readily transmit malarial parasites carry the FREP1 amino acid known as L224 (red dots inside mosquitoes and marked with “L”). The newly developed system uses an allelic gene drive system (scissors) to convert mosquitoes into a population that now carries the malaria-suppressing Q224 allele. (highlighted in green and marked with “Q”).
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Credit: Audrey Yeun, Bier Lab, UC San Diego

Mosquitoes kill more people each year than any other animal. In 2023, the blood-sucking insects infected a reported 263 million people with malaria, leading to nearly 600,000 deaths, 80% of which were children.

Recent efforts to block the transmission of malaria have been stalled because mosquitoes have adapted resistance to insecticides and the parasites within mosquitoes that cause malaria have become resistant to drugs. These setbacks have been amplified by the COVID-19 pandemic, which impeded ongoing anti-malarial efforts.

Now, researchers at the University of California San Diego, Johns Hopkins University, UC Berkeley and the University of São Paulo have developed a new method that genetically blocks mosquitoes from transmitting malaria.

Biologists Zhiqian Li and Ethan Bier from UC San Diego, and Yuemei Dong and George Dimopoulos from Johns Hopkins University, created a CRISPR-based gene-editing system that changes a single molecule within mosquitoes, a minuscule but effective change that stops the malaria-parasite transmission process. Genetically altered mosquitoes are still able to bite those with malaria and acquire parasites from their blood, but the parasites can no longer be spread to other people. The new system is designed to genetically spread the malaria resistance trait until entire populations of the insects no longer transfer the disease-causing parasites.

“Replacing a single amino acid in mosquitoes with another naturally occurring variant that prevents them from being infected with malarial parasites — and spreading that beneficial trait throughout a mosquito population — is a game-changer,” said Bier, a professor in the UC San Diego Department of Cell and Developmental Biology (School of Biological Sciences). “It’s hard to believe that this one tiny change has such a dramatic effect.”

The newly developed system uses CRISPR-Cas9 “scissors” and a guide RNA to make a genetic cut at a precise location within the mosquito’s genome. It then replaces the unwanted amino acid that transmits malaria with the beneficial version that does not.

The system targets a gene that produces a protein known as “FREP1” that helps mosquitoes develop and feed on blood when they bite. The new system switches an amino acid in FREP1 known as L224 with a genetic alternate, or allele, called Q224. Disease-causing parasites use L224 to swim to the insect’s salivary glands, where they are positioned to infect a person or animal.

Dimopoulos, a professor in the Department of Molecular Microbiology and Immunology and the Johns Hopkins Malaria Research Institute (Bloomberg School of Public Health), and his lab tested strains of Anopheles stephensi mosquitoes, the main vector of malaria transmission in Asia. They found that the L224-to-Q224 switch could effectively block two different types of malarial parasites from reaching the salivary glands, thereby preventing infection.

“The beauty of this approach lies in leveraging a naturally occurring mosquito gene allele,” said Dimopoulos. “With a single, precise tweak, we’ve turned it into a powerful shield that blocks multiple malaria parasite species and likely across diverse mosquito species and populations, paving the way for adaptable, real-world strategies to control this disease.”

In a range of follow-on tests, the researchers found that although the genetic switch disrupted the parasite’s infection capabilities, the mosquitoes’ normal growth and reproduction remained unchanged. Mosquitoes carrying the newly inserted variant Q224 exhibited similar fitness to those with the original L224 amino acid, a key achievement since the FREP1 protein plays an important role in the biology of the mosquito, which is separate from its role in being exploited by malarial parasites.

Similar to a gene-drive, the researchers created a technique for mosquito offspring to genetically inherit the Q224 allele and spread it throughout their populations, halting the transmission of malaria parasites. This new “allelic-drive” follows a comparable system recently engineered in the Bier Lab that genetically reverses insecticide resistance in crop pests.

“In that prior study, we created a self-eliminating drive that converts a population of fruit flies from being resistant to insecticides back to its native insecticide-susceptible state. Then that genetic cassette just disappears, leaving only a re-wilded insect population,” said Bier. “A similar phantom drive system could convert mosquito populations to carrying the parasite-resistant FREP1Q variant.”

While the researchers demonstrated the effectiveness of the L224-to-Q224 switch, they don’t yet fully grasp why this change works so efficiently. Ongoing research into how the Q224 amino acid blocks the parasite’s infection transit route is underway.

“This breakthrough is the result of seamless teamwork and innovation across institutions,” said Dimopoulos. “Together, we’ve harnessed nature’s own genetic tools to turn mosquitoes into allies against malaria.”

Genetically modified mosquito larvae express fluorescent markers of the FREP1 gene — RFP (pink), GFP (blue) or both (yellow) — to indicate whether they spread or block infection from malarial parasites.

Credit

Zhiqian Li, Bier Lab, UC San Diego

Journal

Nature

DOI

10.1038/s41586-025-09283-6

Method of Research

Experimental study

Subject of Research

Animals

Article Title

'Driving a protective allele of the mosquito FREP1 gene to combat malaria

Article Publication Date

23-Jul-2025

COI Statement

Professor Ethan Bier has equity interest in two companies he co-founded: Agragene Inc. and Synbal Inc., which may potentially benefit from the research results.

OUTLAW DEEP SEA MINING

World-first deep-sea DNA study reveals global connectivity of marine life

A world-first study led by Museums Victoria Research Institute has revealed that beneath the cold, dark, pressurised world of the deep sea, marine life is far more globally connected than previously imagined.

Museum Victoria

Published today in Nature, this landmark study maps the global distribution and evolutionary relationships of brittle stars (Ophiuroidea), the ancient, spiny animals found from shallow coastal waters to the deepest abyssal plains, and from the equator to the poles.

By analysing the DNA of thousands of specimens collected on hundreds of research voyages and preserved in natural history museums around the world, scientists have uncovered how these deep-sea invertebrates have quietly migrated across entire oceans over millions of years, linking ecosystems from Iceland to Tasmania.

This unprecedented dataset offers powerful new insights into how marine life has evolved and dispersed across the oceans over the past 100 million years.

‘You might think of the deep sea as remote and isolated, but for many animals on the seafloor, it’s actually a connected superhighway,’ said Dr Tim O’Hara, Senior Curator of Marine Invertebrates at Museums Victoria Research Institute and lead author of the study.

‘Over long timescales, deep-sea species have expanded their ranges by thousands of kilometres. This connectivity is a global phenomenon that’s gone unnoticed, until now.’

This is the most comprehensive study of its kind, using DNA from 2,699 brittle star specimens housed in 48 natural history museums across the globe. These animals which have lived on Earth for over 480 million years are found on all ocean floors, including at depths of more than 3,500 metres.

Unlike marine life in shallow waters, which is restricted by temperature boundaries, deep-sea environments are more stable and allow species to disperse over vast distances. Many brittle stars produce yolk-rich larvae that can drift on deep ocean currents for extended periods, giving them the ability to colonise far-flung regions.

‘These animals don’t have fins or wings, but they’ve still managed to span entire oceans,’ said Dr O’Hara. ‘The secret lies in their biology – their larvae can survive for a long time in cold water, hitching a ride on slow-moving deep-sea currents.’

The research shows that deep-sea communities, particularly at temperate latitudes, are more closely related across regions than their shallow-water counterparts. For example, marine animals found off southern Australia share close evolutionary links with those in the North Atlantic, on the other side of the planet.

Yet, the deep sea is not uniform. While species can spread widely, factors such as extinction events, environmental change, and geography have created a patchwork of biodiversity across the seafloor.

‘It’s a paradox. The deep sea is highly connected, but also incredibly fragile,’ said Dr O’Hara. ‘Understanding how life is distributed and moves through this vast environment is essential if we want to protect it, especially as threats from deep-sea mining and climate change increase.’

This research not only transforms our understanding of deep-sea evolution but also highlights the enduring scientific value of museum collections. The DNA analysed in this study came from specimens collected during 332 research voyages, many undertaken decades ago, and preserved in institutions including Museums Victoria’s Research Institute.

‘This is science on a global scale,’ said Lynley Crosswell, CEO and Director of Museums Victoria. ‘It demonstrates how museums, through international collaboration and the preservation of biodiversity specimens, can unlock new knowledge about our planet’s past and help shape its future.’

This world-leading project was made possible through partnerships with more than 40 institutions globally, spanning natural history museums, universities and marine research organisations including support via grants of sea time on RV Investigator from Australia’s CSIRO Marine National Facility.

Dr Tim O’Hara, Museums Victoria Research Institute.

Photographer: Eugene Hyland. Source: Museums Victoria