Scientists find 'ultracool' tiny needle that could someday deliver gene editing therapies

Gene editing has been limited to a few sites in the body because of restrictive delivery mechanisms. Scientists have now discovered a tiny needle that a bacterium uses to kill insect cells that could someday widen the world of gene editing therapeutics. 

Researchers from the Broad Institute of MIT and Harvard and the McGovern Institute for Brain Research at MIT have found a way to use a natural bacterial system to create a new protein delivery system that could have applications for gene editing therapies such as those based on CRISPR-Cas9 as well as cancer treatments. The scientists—led by famed CRISPR pioneer Feng Zhang, Ph.D.—detailed their work in the journal Nature on Wednesday afternoon, describing a system that could be used to deliver a variety of proteins.

Zhang’s team used a tiny syringelike injection structure derived from a bacterium that naturally binds to insect cells and delivers a payload into them, according to a release from the Broad Institute. The syringe was engineered using an artificial intelligence tool called AlphaFold to deliver useful proteins to both human cells and live mice.

“It’s astonishing,” said microbiologist Feng Jiang from Beijing’s Chinese Academy of Medical Sciences Institute of Pathogen Biology, in a press release issued by Nature. His research was cited in the study. “It is a huge breakthrough.”

In nature, these bacteria use the tiny syringe-like machine, called extracellular contractile injection systems (eCISs), to inject proteins into host cells. Previously, researchers had shown that eCISs can target insect and mouse cells. But the Nature study's first author Joseph Kreitz thought the tool could be modified for human cells as well. That was done via the AI tool, and the syringe was “tricked” into becoming a delivery mechanism for whatever protein the scientists chose.

This new mechanism could broaden the use case for gene editing, Zhang said in the Nature press release. Clinical trials have so far been limited to therapies that target the liver, eye or blood cells. “The reason we don’t see brain or kidney diseases getting tackled is because we don’t have good delivery systems,” Zhang said.  

The team led by Kreitz, a graduate student from Zhang’s lab, developed eCISs to target cancer cells that expressed the epidermal growth factor receptor (EGFR), which is associated with dozens of cancers including glioblastoma, small cell lung cancer, pancreatic adenocarcinoma and many more. The eCISs killed 100% of the cells without affecting cells that did not have the EGFR.

In another test, eCISs were used to deliver proteins to the brain in live mice without provoking a detectable immune response. This showed that eCISs could someday be used to safely deliver gene therapies in humans.

“Delivery of therapeutic molecules is a major bottleneck for medicine, and we will need a deep bench of options to get these powerful new therapies into the right cells in the body,” Zhang said in the Broad press release. “By learning from how nature transports proteins, we were able to develop a new platform that can help address this gap.”

In terms of next steps, Kreitz said in the release that scientists should tinker with other parts of the eCIS system beyond just the tail that was engineered in this research to see if cargos such as DNA or RNA could be delivered.

One researcher, Asaf Levy, likened the microscopic syringe breakthrough to Zhang and other scientists’ work to develop CRISPR-Cas9. This new research could be just the beginning of big things to come—just as the world saw with CRISPR, which is now being used in many therapeutics working through the clinic.

Levy, a computational microbiologist at the Hebrew University of Jerusalem, said the ability to engineer the payload and the specificity is “ultracool.”

The research was funded in part by the National Institutes of Health and others.