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Stem Cell Surge

Cellular Dynamics, a pioneer in induced pluripotent stem cells, is creating a new services sector

by Rick Mullin
March 14, 2011 | A version of this story appeared in Volume 89, Issue 11

Credit: Cellular Dynamics
CDI’s automated production of iPSCs supports drug companies’ discovery efforts.
Credit: Cellular Dynamics
CDI’s automated production of iPSCs supports drug companies’ discovery efforts.

Stem cell research has undergone near-revolutionary change in recent years. A major roadblock on use of the cells was lifted in 2007 with the identification of induced pluripotent stem cells (iPSCs), which are derived from adult cells as opposed to human embryos. And in the resultant ramp-up in research activity, the use of stem cells as drug discovery tools has emerged alongside their use in developing therapies.

Drug discovery is now a primary focus, given that stem-cell-derived tissues are ready to be harnessed for drug toxicity and other tests on human cells at preclinical stages of development. Regenerative therapies based on stem cells, on the other hand, remain farther out on the horizon. Most major drug companies are involved in both areas of research.

Amid the burgeoning activity, a company launched in 2004 by James A. Thomson, a pioneer in both iPSCs and human embryonic stem cells at the University of Wisconsin, Madison, is positioning itself as a major player in supplying terminal cardiomyocytes—fully formed human heart cells that are derived from iPSCs. The company, Cellular Dynamics International, launched industrial-scale production of its iCell cardiomyocytes in December 2009 after years of work on characterizing cells with customers including Roche, Pfizer, and GlaxoSmithKline.

The cells, which exhibit the electrophysiological and biochemical properties of normal human heart cells, provide researchers with a more accurate model for discovery than nonhuman cells, such as Chinese hamster ovary cells, according to CDI. More important, says Chris Parker, CDI’s chief commercial officer, the company can now produce billions of terminal cardiomyocyte cells daily. CDI, he claims, is at the forefront of an emerging pharmaceutical services sector.

To manufacture iPSCs, CDI takes human samples, such as skin, blood, or hair, and adds plasmids containing reprogramming genes that induce stem cell transformation. The plasmids regulate gene activity but do not integrate with the genome itself. After about four weeks, isolated iPSCs multiply under cell culture conditions. Cell differentiation is then directed into specific cell lineages, including cardiomyocytes, hematopoietic (or blood-generating) cells, and neurons.

CDI, which has received approximately $70 million in funding from Tactics II Stem Cell Ventures, a Northbrook, Ill., venture capital fund, plans to expand production of cardiomyocytes this year. It also plans to launch iPSC-derived hepatocytes (human blood cells) as well as neurons and endothelial cells as products this year.

“This is the first time these cells have been available to a broad market,” Parker claims. CDI supplies drug companies and biotech firms as well as academic labs. “In a lot of ways it’s analogous to the microarrays industry,” Parker says. “In the early days, the drug companies made their own. When a company like Affymetrix came along that could actually manufacture them, drug researchers could stop making them.”

With the availability of high-quality third-party stem cells, pharmaceutical firms are beginning to explore their potential in drug discovery. They are doing so in concert with suppliers such as CDI and Cellartis, a Swedish company that specializes in hepatocytes.

GSK is working with CDI on stem-cell-derived cardiomyocytes in drug discovery, according to Jason Gardner, head of the drug company’s newly launched stem cell discovery performance unit. In particular, GSK is exploring the use of cardiomyocytes for toxicity screening and for identifying targets for cardiac drug discovery, Gardner says.

Although quantity of supply is important, the focus of the collaboration is on cell quality and purity. “If you have the right cells in the dish, it doesn’t matter if you’re working with 10 cells or 10 million,” Gardner says.

Collaborating with Massachusetts General Hospital and Harvard University, Roche is investigating the utility of iPSCs and iPSC-derived tissues in predicting therapeutic outcomes. With CDI, it is working on stem-cell-derived cardiomyocytes that can be used to test for toxicology and other criteria in vetting new therapies. The objective at Roche, as at GSK, is to better manage attrition by testing drugs in vitro on cell models that behave like human cells.

Roche began collaborating with CDI in 2008, says Kyle Kolaja, Roche’s U.S. director of predictive toxicology screening and investigative safety. “We were looking at existing models for predicting cardiac injury, such as rodent-based cultures,” he recalls. The investigation led to iPSC-derived cardiomyocytes. “IPSCs were just beginning to be discussed, and there were no commercial providers,” Kolaja says. “But it looked like a useful model to dramatically improve what we had already. So we started working with CDI.”

In 2009, the companies announced a two-year partnership under which CDI supplies Roche with purified cardiomyocytes for cell characterization, toxicology, and electrophysiological response experiments. The goal is to detect drug-induced changes in cardiomyocyte activity across a spectrum of therapeutic compounds.

“The fact that CDI can make iPSC-derived cardiomyocytes in mass quantities is amazing,” Kolaja says. “But the challenge is getting enough purity in the cells to make them useful. CDI has genetically modified their product to make it purified for the cell type of interest, allowing us to get 99% pure cardiac cells.”

Pfizer has worked with CDI on differentiating stem-cell-derived cardiomyocytes, according to Sandra J. Engle, senior principal scientist from Pfizer’s Genetically Modified Models Center of Emphasis, a group that works on implementing stem-cell-based models into drug discovery across Pfizer. Although the company plans to dissolve its regenerative therapies research group, Engle says it is actively exploring the use of stem cells in drug discovery.

“In the case of cardiomyocytes, we saw that CDI had developed the technology much further than we had,” Engle says. Pfizer began the collaboration in 2009, receiving cells from CDI in exchange for doing initial assays to see whether the cells would be useful. “We share information and hopefully learn together what the cells can and cannot do.”

CDI is not the only supply option, Engle notes. Pfizer does business with Cellartis, for example, on stem-cell-derived hepatocytes. She says Pfizer is not locked into contracts with any supplier and will access cells from whatever firm best meets its technical and purity specifications.

Gardner, Kolaja, and Engle agree that iPSCs are likely to emerge as a significant commodity in the drug industry, and they credit CDI with establishing itself early. “At early stages of development, producing these cells requires a lot of expertise,” Kolaja says. “We could do it ourselves, but it would be very difficult to do what CDI has done.”

Engle also sees a stem cell supply industry emerging once preliminary investigation into their potential in drug discovery settles down. “There is a lot of exploratory science going on with iPSCs, which have only been available for three years,” she says. “At some point, the field will start to mature. People will say this isn’t so much about science but about tools that allow you to do science. And that is the phase where CDI is poised to make a killing.”


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