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Dolomite Bio Aims to Develop Flexible, Streamlined Single-Cell Sequencing Applications


This article has been updated to clarify the price of 10x Genomics' Chromium instrument.

SAN FRANCISCO (GenomeWeb) – UK startup Dolomite Bio aims to streamline single-cell sequencing with its microfluidics-based instruments. The firm is part of the Blacktrace group of companies, which all have microfluidics expertise, and Blacktrace launched Dolomite Bio in 2016 to apply the technology to biology. Blacktrace has around 100 total employees and there is significant overlap among the brands under the Blacktrace umbrella.

Heike Fiegler, vice president of biology at Dolomite Bio, said that the company initially developed an instrument compatible with the Drop-seq protocol, a single-cell RNA sequencing protocol that uses droplets and microfluidics and was originally developedby researchers at Harvard University in 2015. 

A number of researchers have since used Drop-seq in single-cell sequencing studies, since it is high throughput and does not require expensive instrumentation, but the drawback is that unless researchers use microfluidics equipment and have expertise in working with microfluidics, it can be cumbersome. Dolomite Bio recognized that gap and its first product, the RNA-seq System, launched in 2016, specifically designed for use with the Drop-seq protocol. Last fall, it also launched a chip to support DroNc-seq, a modified version of Drop-seq developed by researchers at the Broad Institute for sequencing single nuclei. 

However, that system was modular and still required users to put together multiple parts. So last fall, the company launched Nadia, an automated stand-alone system that it says can process more than 6,000 cells per sample from up to 8 samples in 20 minutes. 

"The modular system provides flexibility, but it's not ideal for biologists who need a simple, reliable system," Fiegler said. Researchers "don't want to think about the procedure and putting instrument parts together."

Using Nadia, researchers load cells and barcoded beads onto the instrument. As they flow through the system, they are encapsulated in microdroplets suspended in carrier oil. Cells are lysed within the droplets and the oligos on the barcoded bead bind to the mRNAs. After hybridization, the bead-bound mRNAs are released from the droplets and reverse transcription and cDNA library amplification are then performed in bulk. 

In internal tests, Dolomite Bio has found that the Nadia system can capture around 10 percent of the input cells into individual droplets and around 1.8 percent of droplets are doublets, meaning they contain two cells. 

Currently, the Nadia system runs only the Drop-seq protocol, but the company is working on expanding its applications and will launch a chip for the DroNc-seq protocol next. 

"We're working toward menu expansion on the Nadia," Fiegler said. "That's the goal for the next one to two years."

For researchers looking for more flexibility, Dolomite Bio has an add-on to the Nadia, called the Innovate, which enables researchers to run different protocols or use different cell types. It lets users "open the system up so they can change protocols, depending on cell type or size, or buffer, and develop their own applications," Fiegler said. 

She noted that this flexibility is a particular advantage of the system over other systems in the market, such as 10x Genomics' Chromium. Although "10x is the clear market leader," Fiegler said, "we see ourselves differentiating in terms of flexibility," adding that "the single-cell space is a market with a lot of potential."

Naomi Habib, a researcher at the Broad Institute and a co-lead author of the DroNc-seq technique, said that she has tested the Nadia system just one time and got good results. She said that its main advantage "for non-microfluidics experts is that it's much easier to use compared to a home-made device," and that it has other advantages, such as being able to multiplex channels and use a lower amount of sample. In addition, she noted, it still maintains "flexibility to enable technology development, unlike commercial solutions that are more like a black box." 

Vincent Croset, a postdoctoral research scientist in Scott Waddell's laboratory at the University of Oxford's Center for Neural Circuits and Behavior, has tested Dolomite's initial modular system. A couple of years ago, his laboratory became interested in single-cell RNA sequencing, yet was not experienced in the area of genomics or transcriptomics. Initially, the group had been trying to sequence FACS-sorted cells, but after the Drop-seq protocol was published, it wanted to test that. In researching where to get the different components to build their own setup, Croset said, they came across Dolomite Bio's RNA-seq System and decided to test that. 

In April, the lab published a study in eLife Sciences evaluating single cells from Drosophila brain, which Croset said  would be a good model for single-cell sequencing studies because it only contains about 50,000 total neurons, not including the optic lobes, "so we can get the whole picture of the brain, which is something you can't do easily with other organisms."

In that study, they analyzed more than 10,000 cells. Croset said that the data from the system was good, but the main issue with the older version is that it requires a significant amount of hands-on time, as well as monitoring, to make sure the microfluidic chip does not clog. 

In the Nadia system, the Dolomite team sought to address the issue of clogging by incorporating automatic gentle stirring of both the cell and bead suspensions. 

Since that initial study, Croset said, the lab has continued to use the system and has also worked with 10x Genomics. Although the 10x Genomics system is more expensive, Croset said, it saves significantly on time and labor. He added that although the lab has not yet done a thorough analysis of the 10x data, "on first look, it seems that the quality of the data [between the two technologies] is extremely similar."

Croset said the lab plans to continue working on single-cell sequencing of the fly brain and is interested in looking at gene expression differences between flies who have been trained with memory tasks and those that have not. 

As for Dolomite Bio, whether it can make inroads into the competitive single-cell sequencing space remains to be seen. Fiegler declined to disclose the list price of the Nadia system, but said that it was competitive with other technologies on the market. By comparison, 10x Genomics' Chromium system has a list price of $125,000, which can be used for single-cell analysis as well as the firm's linked read applications for whole-genome and exome sequencing. 10x also markets a version of the instrument solely for single-cell purposes that it sells for $75,000. 

Aside from 10x Genomics, the firm will face competition from individual research groups that design their own technologies. For instance, the New York Genome Center last year described a droplet-based microfluidic device that it built to run Drop-seq. The researchers noted that the device was assembled from 3D-printed parts, at a cost of $540. 

Currently, Dolomite Bio's main focus is the research market, but Fiegler said that the single-cell market does "have the potential to move into the clinic, and when that happens, we'd be interested in expanding into that space as well."