NEW YORK – For some, Bio-Rad Laboratories' announcement last month that it will acquire digital PCR firm Stilla Technologies for $275 million was a bit of a head scratcher.
Whle experts waiting for broader appreciation of digital PCR expressed some anxieties about whether Stilla's systems would continue to be commercially available, at the same time, those who were somewhat wary of the deal also said it may in fact help to further catalyze increased clinical uptake of dPCR technology.
"I must admit, this news came a bit as a surprise," said Wim Trypsteen, director of the DIGPCR Core, the digital PCR core facility at Ghent University in Belgium. While he was aware of Stilla's interest in being acquired, he did not expect Bio-Rad to be the company to make the move.
Trypsteen and his colleague Jim Huggett — a researcher at the University of Surrey in the UK and director of biological metrology at the National Measurement Laboratory at LGC — are stewards of standards labs and core facilities, as well as authors of digital PCR publication guidelines. As such, they have evaluated almost every dPCR system commercially available.
Calling Stilla "fascinating and dynamic," Huggett noted that the jewel in the crown of the Paris-based firm is, arguably, its clever software designed to help parse the firm's color combination approach to multiplexing.
Analyzing highly mulitplexed digital PCR results, in particular, requires robust software, but Huggett said could Stilla's software accumen may also be beneficial to Bio-Rad and its QX systems. Now that Stilla will become part of Hercules, California-based Bio-Rad, Huggett said he hoped that Bio-Rad might work to improve Stilla's technology as it makes it more widely available.
However, both Huggett and Trypsteen expressed some trepidation about the continued availability of Stilla's systems and noted that after Bio-Rad acquired RainDance roughly a decade ago, that firm's technology was seemingly shelved and is no longer commercially available.
Trypsteen also said that the dPCR community has been watching to see what might become of the innovative droplet-based Dropworks technology Bio-Rad acquired in 2021. Bio-Rad had previously sued Dropworks over alleged infringement of its droplet IP, and had said in October that it would postpone development of a system using the Dropworks technology.
Regarding Stilla and its commercialized Nio system, Steve Kulisch, Bio-Rad's VP of product management for the digital biology group said Bio-Rad made the buy, in part, because serving the genomics needs of customers in academic research, biopharma, and applied markets requires multiple systems with different features.
Bio-Rad's all-in-one QX Continuum system includes the Dropworks technology, Kulisch affirmed, and is currently in development with an anticipated release this year. In contrast to Stilla, Dropworks did not have a commercialized product when Bio-Rad acquired it, he said.
Similar to Bio-Rad's oil-emulsion Droplet Digital approach, also called ddPCR, Stilla's technology uses droplets that are arrayed in a two-dimensional 'crystal,' or chip. Bio-Rad sued Stilla in 2019 over the use of droplets, and two firms settled in 2021. Trypsteen noted that by acquiring Stilla, Bio-Rad will also now have more droplet-based intellectual property, which he said could prolong its IP position. Stilla's all-in-one Nio also aligns with the needs of users for faster, easier testing, he said.
Among the panoply of molecular approaches, dPCR allows for fairly effortless absolute quantification compared to qPCR's standard curve approach, while also being faster and cheaper than sequencing. Recent research has even shown that dPCR can be tweaked to rival the 20-minute turn-around times of isothermal chemistries, potentially making it suitable for use at the point of care, and it is also being adapted for infectious disease testing.
But digital PCR has seemingly been on the cusp of a breakthrough for decades, after hitting its stride in 2012 with advances in nanofabrication and microfluidics, then graduating into the in vitro diagnostics space in the US in 2019 with Bio-Rad's QXDx BCR-ABL %IS Kit as the first US Food and Drug Administration regulated digital PCR assay.
Brandon Couillard, an investment analyst at Wells Fargo, said that though he was also somewhat surprised by the acquisition, the Nio system has "pretty unique fluidics and a great workflow," and added that "The ability to continuously load is obviously ideal for a diagnostic lab."
With a dPCR business that generates revenues of about $300 million per year, Bio-Rad, Couillard said, brings commercial resources to this equation. Bio-Rad has strong global channels into clinical and research labs capable of accelerating adoption of Stilla's technology, while Bio-Rad will also be capable of servicing platforms in a way that may have challenged Stilla's smaller team.
Stilla also fills a hole in Bio-Rad's portfolio, Couillard said, in that it is on the somewhat lower end in terms of cost but is an all-in-one system that appeals to the the higher-end clinical market. How this fits with Bio-Rad's all-in-one QX Continuum, however, isn't as clear, he said.
In terms of the competitive landscape within dPCR, Couillard said that Bio-Rad has heretofore been vying more for high-end users while Qiagen has been competing for low-end or routine qPCR and dPCR customers. Both firms have also launched dedicated diagnostics instruments, namely the QXDx and QiAcuity-Dx. Now, Bio-Rad may be even more of a competitive challenge for Qiagen, Couillard said. In the meantime, Roche has also entered the digital PCR arena, and while it is still early days for that firm's technology, it has its eyes focused on the clinical market as well.
As for the Bio-Rad/Stilla combination, Kulisch said that Stilla's digital PCR portfolio enhances Bio-Rad's ability to expand into new Droplet Digital PCR products, while its presence in the research and diagnostic arenas complements Bio-Rad's strategy to develop droplet-based solutions for these segments. However, he said that it is too early for the firm to comment on any specific products for the system in the pipeline.
"We view Stilla’s Nio System as a potential next-generation platform that could accelerate and broaden our ability to provide enabling tools to advance science and improve the quality and efficient delivery of healthcare in the genomics research and applied markets, for the benefit of our customers and patients," Kulisch said.
Bio-Rad's QX and Stilla's Nio instruments, together, will offer a comprehensive digital PCR product portfolio, he said, "Serving customers from gene expression analysis in academic research to high-throughput biopharma assay or oncology testing."
Furthermore, "The combined portfolio will have a range of plex level, sample volume, throughput, and workflow flexibility," he said, including scalable multi-instrument workflows and fully integrated instruments.
Moving into the clinical space
Bio-Rad's acquisition comes as digital PCR continues to slowly penetrate the clinical space.
The importance of having CE-IVD or IVDR-certified systems is a major trend in the dPCR space, Trypsteen said, related to the overall push to introduce digital PCR into clinical diagnostics. Over the past decades dPCR was first implemented in research settings within academia, he said, followed by industrial R&D, but now it is starting to make its way into the clinical setting.
While Couillard estimated that Bio-Rad's dPCR business is still approximately 80 percent in the research domain, he noted that companies like Geneoscopy, Biodesix, and Oncocyte are increasingly standardizing their testing services on digital systems.
"I think they are excited that dPCR is a great alternative to NGS," Couillard said.
Along with the QX Continuum, Bio-Rad is currently working on registration of its QX600 system for the IVD market, but Kulisch declined to comment on a timeline for commercial release at this point, or on any menu items in development internally or with partners.
He noted that the company currently offers more than 450,000 research-use ddPCR assays on its QX systems, and remains "committed to providing similar value to any future digital PCR customers as we integrate new technologies."
In addition, he said Bio-Rad is focused on delivering high-value research assays to enable a variety of biopharma and oncology applications on the QX ddPCR systems.
Overall, however, the company has opted to partner with third parties through its certified kit provider program, Kulisch said, to bring cleared tests, such as Gencurix's Droplex CE-IVD oncology assays, to market.
Additionally, Bio-Rad is investing in strategic partners like Oncocyte and Geneoscopy, "to bring future high-value diagnostic tests to market on our Droplet Digital PCR platforms," Kulisch said.
From Huggett's perspective, dPCR's binary output is like a native speaker of software's language compared to qPCR's fluorescence intensity curves, so software tweaks making digital approaches more amenable for point-of-care testing should be even simpler, in principle.
Whether the futuristic scenario of rapid bedside dPCR can be built upon dPCR's past is unclear, and the two decades it took to commercialize the first digital PCR instrument may also serve as a cautionary tale.
Trypsteen said that for the digital PCR market to expand, platform providers now need to address a diversity of customer throughput needs, which may require changing their hardware for liquid handler compatibility or increasing sample numbers per run.
Another challenge is that different end users require different degrees of flexibility in terms of dynamic range and input volume, which might be tackled by adapting the number of partitions, partition size, and cycled volume, he said. To his mind, platform providers also need to better support assay design and offer off-the-shelf assays, particularly for situations with up to 30 targets in one reaction.
For Trypsteen, whose work developing HIV assays brought him into the dPCR space, helping expand the field in the clinical domain is a major goal. To reach these customers, most of the bigger players have doubled down on webinars, but Trypstten has also advocated for dPCR providers to think about building the community, noting that Qiagen has been particularly focused on this approach.
As for the Bio-Rad/Stilla deal, Trypsteen said it remains somewhat challenging to imagine the two digital technologies side-by-side in the same company and, going forward, he remains "very curious to see what Bio-Rad will do."