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With 'Line of Sight' to Clinical Apps, GIS, Fluidigm Open Asia's First Single-Cell Genomics Center

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SINGAPORE — A new center located in this Asian city-state should expand regional single-cell biology research efforts and aid in the development of new diagnostics and therapies, according to its founders.

The Genome Institute of Singapore and Fluidigm last week hosted a ceremony to open the Single-Cell Omics Center at GIS' facilities within the country's Biopolis research and innovation park.

The new center is a 25-square-meter laboratory that contains Fluidigm's C1 Single-Cell Auto Prep System for isolating single cells, as well as two of the firm's BioMark HD Systems for single-cell gene expression applications.

Both GIS and Fluidigm said that it is the first center of its kind in Asia, and its opening follows the establishment of a similar center last year at the Broad Institute in Cambridge, Mass. According to Fluidigm CEO Gajus Worthington, the firm plans to open other centers in the US and Europe by year end, and may open additional centers in Asia in the future.

Worthington told BioArray News at the event that the company sees these centers as "scientific lighthouses" that can demonstrate to other researchers "what can be done" using the company's tools. He said that Fluidigm already has a number of clients in the region who use its BioMark HD for single-cell gene expression, including customers in Japan, China, Korea, and Australia, who could benefit from their proximity to the new center.

In addition, Worthington said that that Fluidigm's collaborators at GIS are working on research projects that could develop into clinical applications, adding to the firm's "confidence" that the single-cell genomics market will continue to grow.

The center's initial efforts are focused on performing single-cell analysis on lung and colon cancers in solid and circulating tumor cell forms, GIS and Fluidigm said in a statement. Another project involves the development of methods to compare cells treated with a drug against cells that have not been exposed to the drug in order to measure how differently the cells react. Such measurements can then be used to create more effective treatments.

Paul Robson, the principal investigator at GIS who will lead the new center, said that there is "great interest in the clinical community" in Singapore and elsewhere in harnessing single-cell genomics for diagnostic and therapeutic development, "particularly within the oncology field."

Robson, whose area of focus is cell development, told BioArray News that the center is now working with researchers who are developing CTC isolation technologies, as well as with clinicians who wish to apply single-cell analysis to CTCs.

Robson believes that the C1 should accelerate those efforts. Introduced last June, the automated system isolates, lyses, and pre-amplifies nucleic acid from single cells. Using the tool, customers can capture and prepare 96 individual cells for analysis per run. Fluidigm customers can currently profile expression in 96 wells across 96 mRNA targets on the company's BioMark HD instrument. And last December, the company introduced C1 mRNA Seq Kits and integrated fluidic circuits to enable the processing of up to 96 single-cell cDNA libraries for quantitation of mRNA expression on Illumina sequencers.

Robson said that the C1 will allow GIS researchers to generate 192 individual cell libraries per day, replacing manual processes that supported the production of at most 20 individual libraries per day, and, in turn, enabling larger, higher-throughput studies.

The center is already designing a method to convert cells from solid tumors into cells floating in a liquid solution. The C1 will subsequently be used to isolate and prepare each cell for sequencing. The researchers also aim to compare the profiles of solid tumor cells with CTCs. If the two types of cancer cells are found to be similar, the researchers believe that clinicians could monitor cancer cases by drawing blood samples, rather than relying on invasive surgery to obtain a biopsy.

"I think there is a lot of interest in clinical applications here," said Robson. "At first pass, we are just trying to understand the biology, but the biology is in a clinical setting."

Single-Cell Evangelists

Fluidigm's decision to establish the center with GIS is in part linked to a long-standing relationship with researchers in the island nation.

Founded in South San Francisco, Calif., in 1999, Fluidigm decided to manufacture its integrated fluidic circuit biochips and instruments in Singapore in 2005, and later added R&D and regional sales and marketing operations from the same location (BAN 4/6/2010).

As the firm noted in a statement, the C1 and the BioMark HD systems installed at SCOC were all manufactured in Singapore. And because of this local presence, Worthington said that he visits Singapore about once every quarter.

Though Fluidigm has intensified its effort to position itself as a leader in the single-cell genomics market in the past year by launching the C1 and helping to open the centers at the Broad and GIS, Worthington said that Fluidigm actually began "evangelizing single-cell work" six years ago by offering single-cell gene expression applications on the BioMark platform.

While he admitted that the firm "didn't get much encouragement" from the market at that time, GIS' Robson was one early and local convert.

"Paul Robson was one of the first people in the world who said that it could make a difference in the science he was doing," Worthington said.
Robson's group published one paper in the journal Developmental Cell in 2010 that showcased data generated using Fluidigm's BioMark platform. In the paper, Robson and co-authors reported that cell types could be distinguished at varying stage of development according to their quantitative expression profiles, and that expression of certain markers could provide insight into developmental mechanisms. Since it first appeared, the paper has been cited in 128 other publications.

"Paul published the first real landmark study that showed that the cell-to-cell heterogeneity was driving the biology," said Worthington. "He was one of the first and most aggressive scientists to go after single-cell genomics, and has been one of the most successful too," he said. "Two years ago, when we decided that the world was going to need single-cell genomics centers, this was one of the first places we came to."

"My lab has been focused for the last five years on doing single cell biology, starting from a fertilized egg and understanding how other cells are formed," Robson said. "This new center makes it that much easier."

In general, the center will prepare cells on the C1 and analyze them using the BioMark or RNA seq. Often both approaches will be used, with BioMark assays "bookending" the sequencing, Worthington said. For instance, the researchers may prepare cells using the C1, sequence a number of them to identify genes of interest, and then move the project to the BioMark to screen hundreds of cells. Or the researchers may also choose to control the quality of their cells using a panel on the BioMark prior to sequencing.

"Before you sequence the 96 transcriptomes, run them on a BioMark chip, see if they all look reasonable," suggested Worthington. "It costs a few dollars per cell to see if all the libraries check out," he said.

Worthington also said that Fluidigm and GIS will make use of the center to develop new methods for single-cell analysis. "We may try to do things here that we may not do anywhere else, different types of chips, new protocols, try things that may or may not work, but if they do, could potentially find a new avenue for the science that is going on here," he said.

Robson noted that a third of GIS' PIs are computational or mathematical biologists who will be called on to generate new algorithms to analyze data at the single-cell level, adding to the center's resources.

"We want to be thought of as a center of single-cell biology," said Robson. "We want to become a center of excellence, where people will reach out to us to collaborate or just for our expertise."

Two Pillars

Fluidigm has seen single-cell genomics become one of its major focuses in the past year, as well as a significant revenue driver. Worthington noted on the company's fourth-quarter earnings call that it has placed three dozen of its C1 systems since launching the instrument last year, and that about 40 percent of Fluidigm's $15.5 million in Q4 revenues were driven by single-cell genomics customers (BAN 2/19/2013).

At the new center's opening, he described single-cell genomics as one of "two pillars of the company," the other being what Worthington referred to as "production genomics," the use of its biochips in high-throughput, industrial settings including agricultural biotechnology and biobanking.

"In the long run, we believe single-cell genomics is going to be very commonplace," said Worthington. "Individual cells of the same tissue type can be very different from one another, and those differences are not stochastic, they can and indeed do drive the biology," he said. "We are certain that this field is going to be pretty pervasive," he added. "It's going to take time and it's going to be driven by the science."

Worthington also noted that the possibilities for clinical applications to emerge from single-cell genomics have encouraged the company's interest in the market.

"One of the things that gave us confidence early on that this was going to be big was how quickly we had a line of sight to applications that could be moved to the clinic or be used in therapeutic development right away," said Worthington.

"We have several customers who are able to look at cancer stem cells, separate them on a C1, and then look at pathways that are uniquely druggable for the cancer stem cells that are related to the regenerative properties they have, that make them chemo resilient," he said. "If you figure that out, you could have a companion therapeutic, give a patient a drug that would bring down the shields of the cancer stem cells and target them uniquely and then do radiation or chemotherapy."

Another potential area for clinical application is in HIV diagnostics and therapies, Worthington added.

"We figured this would be research for quite some time, but the potential diagnostic and therapeutic applications emerged surprisingly quickly," said Worthington. He noted that it would be "hard to predict" when single-cell applications could become available clinically, because of questions related to regulatory oversight, reimbursement schemes, and "other questions that may dominate the time to having something clinically useful much more so than having the actual science."

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