A new synthetic enzyme, crafted from DNA rather than protein, ‘flips’ lipid molecules within the cell membrane, triggering a signal pathway that could be harnessed to induce cell death in cancer cells.

This work highlights the enormous potential of synthetic DNA nanostructures for personalised drugs and therapeutics for a variety of health conditions.

Alexander Ohmann

Researchers at the University of Cambridge and the University of Illinois at Urbana-Champaign say their lipid-scrambling DNA enzyme is the first to outperform naturally occurring enzymes – and does so by three orders of magnitude. Their findings are published in the journal Nature Communications.

“Cell membranes are lined with a different set of molecules on the inside and outside, and cells devote a lot of resources to maintaining this,” said study leader Aleksei Aksimentiev, a professor of physics at Illinois. “But at some points in a cell’s life, the asymmetry has to be dismantled. Then the markers that were inside become outside, which sends signals for certain processes, such as cell death. There are enzymes in nature that do that called scramblases. However, in some other diseases where scramblases are deficient, this doesn’t happen correctly. Our synthetic scramblase could be an avenue for therapeutics.”

Aksimentiev’s group came upon DNA’s scramblase activity when looking at DNA structures that form pores and channels in cell membranes. They used the Blue Waters supercomputer at the National Center for Supercomputing Applications at Illinois to model the systems at the atomic level. They saw that when certain DNA structures insert into the membrane – in this case, a bundle of eight strands of DNA with cholesterol at the ends of two of the strands – lipids in the membrane around the DNA begin to shuffle between the inner and outer membrane layers.

To verify the scramblase activity predicted by the computer models, Aksimentiev’s group at Illinois partnered with Professor Ulrich Keyser’s group at Cambridge. The Cambridge group synthesised the DNA enzyme and tested it in model membrane bubbles, called vesicles, and then in human breast cancer cells.

“The results show very conclusively that our DNA nanostructure facilitates rapid lipid scrambling,” said co-first author Alexander Ohmann, a PhD student in Keyser’s group in Cambridge’s Cavendish Laboratory. “Most interestingly, the high flipping rate indicated by the molecular dynamics simulations seems to be of the same order of magnitude in experiments: up to a thousand-fold faster than what has previously been shown for natural scramblases.”

On its own, the DNA scramblase produces cell death indiscriminately, said Aksimentiev. The next step is to couple it with targeting systems that specifically seek out certain cell types, a number of which have already been developed for other DNA agents.

“We are also working to make these scramblase structures activated by light or some other stimulus, so they can be activated only on demand and can be turned off,” said Aksimentiev.

“Although we have still a long way to go, this work highlights the enormous potential of synthetic DNA nanostructures with possible applications for personalised drugs and therapeutics for a variety of health conditions in the future,” said Ohmann, who has also written a blog post on their new paper.

The US National Science Foundation and the National Institutes of Health supported this work.  

Alexander Ohmann et al. ‘A synthetic enzyme built from DNA flips 107 lipids per second in biological membranes.’ Nature Communications (2018). DOI: 10.1038/s41467-018-04821-5

​Adapted from a University of Illinois at Urbana-Champaign press release.

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