Mission Possible

Jason D. Gibson pursues a faster path to iPS cell line creation with Callisto

Spotlight

Jay Gibson’s story is misleadingly straightforward. His interest in biology began in childhood, where rather than playing the video games that consumed his peers’ attention, “I was always that kid looking under rocks and chasing after bugs and animals.” He studied molecular and cell biology at the University of Connecticut, where he received his PhD in genetics and now teaches and works as an assistant research professor in the Nelson Lab, pursuing decidedly more complicated endeavors. 

“The backbone of my research has largely been focused on defining genetic pathways and transitional signatures that govern cell lineage commitment,” Gibson explains. The goal is to develop directed stem cell differentiation strategies for advancing cell-based therapeutics. It’s the real-life version of familiar sci-fi stories in which scientists use a person’s own cells to regenerate tissue that has been damaged by injury or disease. And it’s a challenge Gibson and his colleagues are approaching from multiple angles, with his attention focused on the reprogramming of somatic cells into induced pluripotent stem (iPS) cells.

The research field of human embryonic and induced pluripotent stem cells is both well-established, having existed for over a decade, and very new, as a still largely unknown aspect of human biology.

“There’s a huge gap of knowledge that we have yet to come in contact with as far as developmental biology is concerned,” Gibson says. “That is: the true genetic regulatory elements that guide the specification of a cell type and the commitment of a cell lineage.

“How does one cell become another cell type?”

Our current knowledge of cell types is based on a relatively small number of characteristic markers, which Gibson says leaves biologists in need of better phenotype classification and greater understanding of the genetic regulatory elements that determine cell fate. This limited understanding is frustrated by the difficulty in establishing successful protocols for induced pluripotency. The best to date using exogenous introduction of reprogramming factors without genetic modulation of barriers and enhancers yield a success rate of less than five percent, meaning only a small fraction of the cells a researcher cultures are actually usable. It’s a problem the field must solve before regenerative medicine can become a reality.

In the summer of 2015, Fluidigm announced its new cellular modeling system, Callisto™,  which leverages the company’s signature microfluidic technology to allow cell culture—a process typically described with heavy sighs as highly laborious and delicate—to take place on-chip in precisely controlled environments with walkaway automation and remote monitoring. Funded in part by the California Institute of Regenerative Medicine (CIRM), Callisto enables long-term, multistage cell fate studies up to three weeks in duration, letting scientists simultaneously test different combinations of cellular programming factors to identify the most effective ones and reproduce results with precision.

“I immediately felt that Callisto was going to be an extremely useful tool,” Gibson says, explaining that the automated dosing and closed-system modeling preclude inevitable human error, thereby increasing confidence and quickening the time to data. The improved control afforded by Callisto also lets him experiment with assays or variations that he might not yet explore if the process were not so determined.

As confident as Gibson was with the new system, he couldn’t have anticipated the first results. “In direct comparison with our macro-well cultures, it appears that many of the reprogramming factors that are hallmarks of this process that we examine and look for actually appear to turn on a little bit earlier and appear to be at a higher expression level in our on-chip cultures,” he reports.

Better-than-expected results are not the norm in cellular reprogramming. Variability is a problem at every step, from environmental factors and human reliability to data efficiency. But Gibson has replicated the trials with the same factors, and so far the results appear consistent with the initial data in a way he hasn’t seen before. “So this may eventually lead to confirmation of achieving a higher efficiency on-chip,” he continues. “And that’s very exciting.”

Higher efficiency can mean more cells to work with and a clearer path to creating iPS cell lines, an important step toward developing stem cell therapies. Speaking on day 48 after the initial Callisto trial, Gibson reports the cell colonies harvested from the system and now growing on-plate are reflective of induced pluripotent stem cell states. He speaks conditionally—these cell colonies take time to grow into a cell line—but if the cells continue to develop as indicated, Callisto  could prove to provide a faster, more consistent and easier method for developing iPS cell lines.

Gibson explains that the biggest challenge facing stem cell scientists is reproducibility. It’s common for different labs using the same protocol and materials to get dissimilar results. If the Callisto system delivers consistent data regardless of the location or operator, it could change the stem cell game by allowing anyone with the right training to reliably produce iPS cell lines.

“Having this equipment as an intermediary to eliminate that lab-to-lab variation is going to be a remarkable thing to unify the scientific field,” Gibson says. 

New technology is often met with skepticism because of cost or unfamiliarity, but good data can abate most hesitation. “When researchers can view the equipment as being a unifying resource, where the results that are reported to be obtained can be obtained by anyone, it’s going to be a revolutionary aspect of what Fluidigm has been able to provide.”

Conversation with Gibson is calm and deliberate. He speaks clearly and succinctly, like a man on a mission to help you understand both what he’s talking about and why it’s important. He doesn’t shy away from words like “unify” and “revolutionary”, which gives assurance that they’re not outlying ideas but accurate descriptions of the future of stem cell research.

“No one team of researchers can do it all,” Gibson notes. “We have to be able to cross-communicate. We have to be able to not only publish to share the results but to be able to amass an arsenal of research techniques to strategize and best use the funds that are available.” As he details how shared funding and equipment can help further the field collectively, his passion belies a deeper motivation than a childhood interest in bugs. That’s when Gibson reveals the very personal motivation that complicates his straightforward story.

“I was actually afflicted with a chronic disorder when I was a teenager,” he says. “I’m a type 1 diabetic, and when I learned that when I was 16, it made me really question what it was I wanted to pursue in life.” He began looking into why we have disease in the first place and what was being done about it, and he hasn’t stopped.

Nearly two decades later, Gibson understands more about human disease than he could have ever imagined at 16. Yet he is quick to point out how much he and the rest of the stem cell field don’t know.

“Every time we learn something, we take three steps back,” he says with a laugh. “A lot of what we learn are things that we have been ascribing wrongly. So when we’re rewriting our knowledge on an everyday basis, it’s very difficult to even forecast how we can get to a level that we’ll be putting these types of cell-based therapeutics into play.”

More now than ever, Gibson remains focused on that forecast. His wife also lives with a chronic illness, and they’re raising three young children with a hard question always in the back of their minds. “There’s no direct test we can do to determine whether or not something will develop in our children,” he says. “If any of my children have to live through a chronic disorder, I wish that they’ll have something more in front of them.”

Gibson sees his work as an endeavor not to eradicate disease but to alleviate the challenges of living with it, an outcome that he intimately knows the value of. Just over a decade into human stem cell research directed toward cell-based therapeutics, more funding is being made available every year. Researchers are pursuing parallel paths to greater understanding of developmental biology and cell determination. And technology like Callisto is enabling scientists to ask and answer ever-more relevant and pioneering questions about the future of stem cell applications.

Reflecting on how far the science has come in such a short time, Gibson shares his realistic hope that life-changing stem cell therapies won’t be science fiction much longer. “I think that the knowledge we need could definitely be attained in the next decade,” he says. “And we could see cell-based therapeutics in our lifetime.”