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Depixus Seeks to Commercialize 'Magnetic Tweezers' for Drug Discovery, Liquid Biopsy Research


NEW YORK – Depixus, a startup with operations on both sides of the English Channel, is working on commercializing technology that it says can assay the same nucleic acid molecule multiple times, potentially evaluating a different aspect each time.

Based on the concept of so-called "magnetic tweezers," Depixus' Magna instrument affixes a magnetic bead to one end of a single-stranded nucleic acid and a solid support to the other. Using a magnetic field to raise and lower the bead, the strand becomes available for repeated analyses that can target epigenetic base modifications; molecular structures, such as RNA secondary structures; and interactions with other molecules, including proteins, small molecules, or other nucleic acids.

"Our aim is to go beyond what is easily achievable with NGS," said Depixus CEO and Cofounder Gordon Hamilton. "We want to open a new space and add to datasets coming off sequencing instruments."

With a peer-reviewed publication describing its technology published last year and a December €30.6 million ($34.5 million) Series A financing round in the bank, the company is looking to build showcase collaborations.

"These capabilities unlock previously unattainable insights into the 'dynamic genome' — the layers of information beyond the four-base coding sequences of DNA and RNA that are key to gene expression, regulation, and control," Hamilton said.

To succeed, the firm will have to convince researchers that it can provide better data than what can be achieved with NGS alone. Doing so won't be easy: At least one other company offering a novel technology to interrogate biomolecule binding dynamics, Roswell Biotechnologies, has reported difficulty raising its Series B financing round and recently had to lay off employees.

Though it was founded in 2012, Depixus didn't really get going until 2015. "We took a little while to get the core intellectual property out of the French academic system," Hamilton said.

The firm's cofounders include Vincent Croquette and Jean-François Allemand of France's École Normale Supérieure, biophysicists who developed Depixus' magnetic tweezer technology. "At the heart of their lab is an instrument system to track beads with high precision," Hamilton said. Magnetic tweezers are themselves a derivative of optical tweezers, a discovery that led former Bell Labs researcher Arthur Ashkin to become a 2018 Nobel laureate in physics. The magnetic version is easier to scale than optical or acoustic tweezers, Hamilton said.

In 2015, Depixus obtained its first equity financing and has since raised at least €41 million, including £600,000 ($790,000) from Innovate UK and a €2.1 million ($2.3 million) H2020 SME Instrument Phase 2 grant from the European Commission. The company has approximately 50 employees between its locations in Paris and Cambridge, UK.

One of the platform's benefits is that it can repeatedly analyze native DNA without amplification. Its method ligates adapters to either DNA or RNA, converting them into hairpin structures. Using a magnetic force of approximately 15 piconewtons, the strands mechanically unzip and rezip when the force is relaxed.

"When ligands that bind to nucleic acids are introduced into the system, their bound presence on the molecule can disrupt hairpin unzipping or rezipping, and the position of these transient blockages can be precisely mapped to the sequence of the hairpins," according to the firm's Communications Biology paper, published last year. "This makes it possible to determine both the on-rates of different binding ligands (based on the probability of observing the bound state), and their off-rates (from the average time of the transient hairpin blockage)."

The blocking molecule might be for a specific sequence motif, or it could be an antibody for a specific base modification.

Using optical technology, the firm is "able to track [bead position] with incredibly high precision," Hamilton said. "We're getting down to sub-nanometer precision, which is important because that's close to resolving within one base pair."

Each flow cell can currently analyze thousands of molecules, but as the firm begins to get its tech into the hands of customers, it wants to up that number to hundreds of thousands of molecules per flow cell. The longest molecule the company has analyzed is approximately 10 kb, Hamilton said, though 1 kb to 4 kb is a more typical length. "We're also interested in really short molecules," he said, in the tens to hundreds of bases. "In many ways, especially in the RNA space, short molecules really matter, too."

Putting it all together, a customer might be able to determine aspects of a molecule's sequence, then its length, then interrogate it for modified bases.

In its proof-of-concept study, the firm analyzed DNA from Escherichia coli and the human FMR1 gene's 5' untranslated region in cells derived from a fragile X syndrome carrier.

"From these kilobase-length enriched molecules we could characterize the differential levels of adenine and cytosine base modifications on E. coli, and the repeat expansion length and methylation status of FMR1," the authors wrote. They also analyzed RNA isoforms in a mouse model, for which there was "close correlation" with results using RNA isoform sequencing on Pacific Biosciences' platform, they said.

Hamilton declined to provide any insight on costs, saying the firm is still working to scale the technology. The company is also working to deliver a direct electronic readout. It plans to grow its headcount by approximately 50 percent this year.

Depixus is not yet generating revenue and sees its next phase as building collaborations with researchers, especially in drug discovery, particularly RNA therapeutics, and liquid biopsy, "where differential methylation seems to be implicated in disease processes," Hamilton said.

"We're on the lookout for and actively pursuing early collaborations with key opinion leaders," he said, but declined to disclose who they might be.

"The phrase 'platform technology' is bandied about a lot, but for Magna, that is a term that is really very appropriate," Hamilton said. "It is a new way of looking at the biological world, of exploring the way that biological molecules interact with each other."

With new data types provided by the technology, "we're just beginning to scratch the surface of what's possible," he said.