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German Nucleic Acid Sample Prep Startup Rides COVID-19 Testing, Automation Waves

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NEW YORK – Early in the COVID-19 pandemic, a surge in demand for molecular diagnostic assays strained supply lines for several reagents, including nucleic acid extraction kits. Some European labs found relief from BioEcho, a small German startup offering an alternative to silica-based bind-wash-elute extractions.

Founded in 2016 by several former Qiagen employees, the Cologne-based company has developed what it calls reverse chromatography-based nucleic acid purification. Rather than have their separation matrix bind nucleic acids, they found a way for it to bind everything else, without the use of high-salt buffers that can cause downstream PCR to fail if not properly removed. Moreover, the method is fast, requiring only about 15 to 20 minutes to pipette a 96-well plate and a 1-minute centrifugation step.

When the pandemic hit Germany, BioEcho had only used its technology for DNA. In collaboration with a diagnostic laboratory customer, the firm developed the EchoLution RNA extraction protocol for use with COVID-19 samples. "It worked more or less immediately," said Frank Schäfer, cofounder and managing director at BioEcho. The company is merely weeks away from getting CE-IVD marking for its RNA kit, he said, and at the height of the pandemic last year, the method was extracting RNA for 15 percent of all COVID-19 tests done in Germany and Austria.

EchoLution technology is "the perfect solution for us," and shines in high-throughput testing, said Heiko Petersen, head of molecular pathogen diagnostics at Laboratory Dr. Fenner & Colleagues in Hamburg, Germany, adding that BioEcho's RNA extraction is cheaper and faster than most comparable methods. "We are working manually, and without these BioEcho products, we couldn't do 3,000 samples a day," he said. The lab is preparing to automate its process — a priority at BioEcho — which would provide even more throughput.

BioEcho's sudden success has helped grow the company from one that primarily served the ag-bio market to one that is now focused on molecular diagnostics. In addition to extraction kits, the company offers buffers and other reagents as well as durable lab products like scalpels. But the firm is already preparing for an environment without the pandemic pressures that drove business its way. Schäfer said the company now plans to develop its own molecular diagnostic assays built around its extraction technology.

"The sample prep area alone is quite huge already, but I think it is beneficial to us to provide a complete system," he said. "So not only extraction, but also detection." 

At the moment, BioEcho's extraction technology is only distributed in Europe, but that could change soon. "We have entered into a global OEM agreement with one of the largest sales organization worldwide; since their headquarters are in the US, we should gain traction in the US very soon, too," he said, but declined to name the OEM partner.

Schäfer, who led liquid biopsy development at Phoenix-based Caris Life Sciences for three years, added that BioEcho has hopes to establish a physical presence in the US, possibly by 2022.

"What can you do?"

When Schäfer and BioEcho's other managing director, Markus Müller — both life sciences tools veterans with long stints at Qiagen — began pitching investors on their company, they were met with skepticism.

"They asked, 'How can you found a company based on something as boring as nucleic acid extraction?'" Schäfer said. "'What can you do?'"

BioEcho's products use the principle of size-exclusion chromatography, employing a resin with pores that fits into a column in a deep-well plate. Smaller impurities are caught in the pores while BioEcho uses a combination of special lysis chemistry and matrix formulation to make sure that larger proteins are caught in the matrix, too, but Schäfer declined to be more specific.

Samples are lysed enzymatically, pipetted into the matrix, and centrifuged. Nucleic acids and water come out the other side.

The primary benefit, according to Schäfer, is that the extraction happens under the native aqueous conditions of the cell. "We don't use any problematic reagents," he said, which eliminates the wash steps found in other methods. That makes it about 20 times faster and reduces the number of steps to minimize handling failures, but it also means the company has access to numerous enzymes to employ in its chemistries.

For its early fundraising, BioEcho turned partly to crowdfunding. Using a European platform called Medifundo that focuses on healthcare and technology proposals, the firm raised approximately €300,000 ($363,000), about a fifth of its initial raise. Private investors, including DresInvest and FS Life Science Investment, made up the rest.

The firm is still private, and while it was seeking venture capital funding as late as September, the boost in business from COVID-19 testing allowed it to skip that. "We were going to make enough money without having to give out any shares," Schäfer said. Revenues for 2020 were "close to the two-digit millions," he said, a significant increase over 2019.

The company also nearly tripled in size, from 15 to 45 employees, with most in manufacturing.

While his lab is further investing in BioEcho's sample prep, Petersen said there are several caveats to using it.

First, the method requires very accurate pipetting, directly on the top of the column matrix, so that the solution does not go down the sides of the column. "If you're not pipetting accurately, we observe inefficiency in the PCR reaction," he said. "You just have to make sure you're strictly following the rules of pipetting and good lab practices." The necessity of proper sample loading is driving the lab's move to automation, he noted.

Also, the method does not concentrate samples. "Most technologies with magnetic beads have a concentration step," he said. "In BioEcho's solution, you have a fixed volume." This has implications for the limit of detection and the cycle threshold (Ct) values in PCR assays.

"We compared the quality of BioEcho with standard nucleic acid extraction prep. It is nearly the same, maybe it's one or two Ct later. For our application here, especially for coronavirus, it doesn't matter," Petersen said. "If you're going after the best sensitivity of nucleic acid extraction, then you would choose other technologies, which are more expensive."

Schäfer said BioEcho's kits are priced "in the premium range," not the cheapest on the market but not the most expensive, either. For the largest kit size, for eight 96-well plates, the method costs €3.13 per well, he said. But Petersen estimated the costs at about €2.50 per extraction, on the low end of other methods, which cost between €2 and €5 per sample.

While cost is always a concern, Schäfer said that speed and throughput is what will make BioEcho successful. "We can expedite the process by another factor of five," he predicted, adding that the company has invented an enzyme-free lysis chemistry that will make it possible to do "any nucleic acid purification in a matter of three minutes" from plant, animal, cell culture, and pathogen samples.

As the firm prepares to extract even more gains in speed and reliability by designing kits for automated systems, tunability will be important. The company has already invented a chemical, as opposed to an enzymatic, lysis protocol that will work well with automated equipment.

"When three minutes is too fast, you can prolong [lysis] by diluting it," he said. "If you can shorten your lysis time from hours to a couple minutes, then it really gets interesting," he added, with respect to automating sample prep. "We definitely have to be automatable. All the big throughput is more or less automated. This is going to be one of our key success factors in the future."

BioEcho is working with two different lab automation companies to bring its protocols onto their platforms, Schäfer said, but declined to disclose their names.

COVID-19 diagnostic testing won't be the driving factor in its business forever, but the pandemic could shape BioEcho for years to come. Customers are looking to use its products for RNA prep for next-generation sequencing-based virus surveillance, Schäfer said, and the firm has plans to develop extraction products for respiratory pathogen panel tests in the near future.

Multiplex PCR panels for infectious disease are the future, he said, and BioEcho might explore developing this type of test itself in the future.

 

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