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Bio-Rad, Illumina Launch Codeveloped Single-Cell Sequencing System


This story has been updated to include information about an additional competing single-cell sequencing technology.

NEW YORK (GenomeWeb) – True to a timeline announced last year, Illumina and Bio-Rad have launched a single-cell sequencing system for research use. The system was codeveloped by the firms, which will also jointly market and sell the product.

Financial terms of the arrangement, originally announced last January, have not been disclosed.

Called the Illumina Bio-Rad Single-Cell Sequencing Solution, the workflow includes elements from each company.

Bio-Rad contributed its Droplet Digital PCR technology to a single-cell isolator called ddSEQ. "We started with the same basic engineering designs as our QX200, which we've been making and selling for about five years," Carolyn Reifsnyder, senior marketing manager at Bio-Rad Laboratories, said in an interview.

The firm modified a few hardware parts and the routine — specifically, the way the instrument runs in terms of pressure and time is different for this application — and the microfluidic cartridges are also a different design. But the engineering and much of the hardware and components are the same, leveraging the firm's existing expertise, Reifsnyder said.

Notably, the time from a single-cell suspension to single cells and barcoded beads in droplets is five minutes.

This is "very fast," Kevin Taylor, Illumina's senior manager of complex disease who coordinated the Bio-Rad collaboration, said in an interview. "We like that time of five minutes because it limits the amount of time that cells can be unhappy," he said, noting that some of the other methods available can take 30 to 60 minutes. With those methods, "If you're working with sensitive primary cells, they can undergo cell death in the time it takes to isolate and barcode," he said. Reifsnyder also noted that the speed to isolation should also better preserve the transcriptional profile of cells.

From the ddSEQ cell isolation step, the cells are lysed in the droplets, mRNA binds to the barcoded beads, and first strand synthesis is initiated.

The Illumina contribution comes into play first with a kit called the SureCell WTA 3' Library Prep Kit, Taylor said.

"One of the reasons why we entered into this relationship with Bio-Rad is, we really like their Droplet Digital technology, and it set up a scenario where they could work on refining the technology for single-cell [sequencing] and we could work on building the library prep kit — it was really two teams coming together to accelerate development," he said.

The kit, which is based on Illumina's library prep expertise with its Nextera XT technology, will be co-branded. "It will have everything a customer needs to isolate and barcode single cells, and perform the library prep," Taylor said. Specifically, it will have the cartridge that goes on the ddSEQ as well as the reagents.

Illumina also contributed analytics to the system. This includes an RNAseq app in the firm's cloud-based BaseSpace informatics suite that allows a customer to do primary and secondary analytics, providing basic metrics such as number of cells sequenced and genes per cell.

The app will also enable common tertiary analytics, such as principle component analysis, in BaseSpace.

Illumina further partnered with FlowJo, a flow-cytometry analysis software developer, to create a software called SeqGeq for use with the system. "You'll be able to go from BaseSpace into SeqGeq and perform additional tertiary analysis," Taylor said, adding that this component will also provide visualization functionalities.

Overall, the system is scalable, such that there will be one kit format to process hundreds to low thousands of cells and one kit format for larger projects that need to analyze up to tens of thousands of cells.

Taylor added that the firms are also planning to build out a menu of assays but have declined to disclose them at this time. However, they could be in line with RNA and DNA assays people typically use to profile single cells.

The ddSEQ platform has a list price of $60,000, and the kit price amounts to about $1 per cell, Taylor said. The workflow can be done in seven hours, not including the cell prep, but the protocol spreads that over a few days so that it is more amenable to customer work routines. "We stretched out the protocol so that it is a very gentle day and a half [and] you're going onto the sequencer on the second day," Reifsnyder said, adding that this allows customers to "still fit business meetings and lunch breaks in."

Regarding the coselling agreement, the firms have divvied up the market into realms that reflect their respective expertise and natural fits. Illumina will be contacting primarily next-generation sequencing customers, while Bio-Rad will focus on cell biologists. "We think with the two teams we can provide excellent support for both of those customer segments," Taylor said.

Sales teams from both companies can quote the solution, although the kits will come from Illumina and the instruments will come from Bio-Rad. However, customers should expect a "seamless" interaction, Reifsnyder said. "Customers get a single purchasing and technical support experience," she said, noting that the firms will also have "double the sales force out there bringing awareness to the market."

Competition for single-cell sequencing platforms comes primarily from Fluidigm at this point, but Taylor and Reifsnyder said the Illumina/Bio-Rad system has a faster run time and provides a more complete solution. It may also be more cost effective, as they estimated the initial capital investment is about one-third less, while the per-cell cost for the Fluidigm approach is $3.50 to $18. Finally, they noted that the codeveloped system is more agnostic to mammalian cell size and type, and that the droplet approach heads off any problems with clogging of fluidics.

Last year 10X Genomics also launched a droplet-based technology with an application for single-cell analysis. That system, called the Chromium Single Cell Solution, interrogates hundreds to millions of cells, is compatible with Illumina HiSeq, NextSeq and MiSeq sequencers, and the instrument has been priced at $50,000. The firm prevailed in arbitration with Bio-Rad in 2015 over intellectual property regarding the technology, and most recently it announced this week that it will partner with Perkin Elmer to offer automated NGS solutions.

Illumina and Bio-Rad have provided the Single-Cell Sequencing Solution to a number of early access users so far. Maroof Adil, at University of California, Berkeley, for example, has been using the platform since September to study the heterogeneity of stem cells cultured in 3D biomaterial platforms. "This knowledge may help in the large-scale manufacture of stem cells for many biomedical needs," Adil said in an email.

A postdoc in the lab of David Schaffer, Adil said the lab did not try any other single-cell sequencing approaches previously, but that Bio-Rad approached Schaffer through a colleague to try out the new technology coincidentally around the same time that the lab was realizing it would benefit from looking at its stem cell cultures with single-cell resolution.

Adil noted that the processing is rapid, and the seven-hour workflow spread over two days is correct. "The protocol is simple and easy to follow for anyone with molecular biology experience, and especially easy for anyone who has done Illumina-based sequencing using any other platforms," he said, although he noted that the system is being used by others in the Berkeley facility and he hadn't yet had a chance to use it multiple times.

At the moment, the lab is considering purchasing through a shared resource facility that would provide access to other labs at UC Berkeley. Adil said he had not personally compared prices against competitors, but "cheaper instruments with the same or better functionality are always attractive."