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Model citizens (continued)
August 2013
by Randall Willis  |  Email the author

Clinical trial in a dish
One of the main research goals for stem cells is the development of incredibly precise models for human disease.
"The iPSC explosion opens up a whole new door for those companies to now have access to a 'disease-in-a-dish'," which would allow researchers to test new therapeutics against more realistic cellular targets rather than cells derived from cancer lines, says LTI's Pettersson.  
Parker gives the example of CDI's MyCell platform, which offers customers the ability to analyze the genetic variation and genetic diversity they wants from samples of interest they provide.
"It's not just a reprogramming service," he explains. "We typically push those customers to Life Technologies to buy our reprogramming kit if they just want to generate an iPSC. With MyCell, a customer can simply send us a blood sample from individuals in their clinical trials or development program. We will make that patient's iPSCs, we then scale that up, create a minibank, provide the line back to the customer to play around with and then we will produce a certain number of units of one of our differentiated cell products."
Parker describes this as an in-vitro clinical trial, which replicates the genetic diversity seen in Phase II or III trials into the preclinical research space and can help winnow new drugs more quickly, reducing massive clinical expenditures. As proof, he offers analysis done by Roche researchers when they examined MyCell.  
"Roche had a drug that when they were testing for arrhythmias, which had made it all the way into primates," he recounts.
None of the in-vitro and in-vivo models, until primates, had been able to pick up the arrhythmia issues. When evaluating CDI's portfolio, the Roche researchers decided to test that drug to see if they could detect the toxicity, and the effects were immediate.
"They said, had they had our cells [in the original screening], they would have saved $10-$20 million," Parker says.  
According to Parker, CDI is also in the process of developing an ethnic diversity panel of their various cell types, representing six or seven different ethnicities and with both male and female components, which should facilitate the discovery of toxicities and efficacies that might not be caught in simpler cell-based screens.  
More accurate human disease models don't necessarily mean the end of animal models, however, according to Piper.  
"I'd say some of the things you might see in a few organizations is people beginning to look at animal models instead of just humans," he says. "They're still going to test [a new therapeutic] in the animal first, so they'd like to be able to do the same sorts of things in perhaps a pig or a dog. If you can get very predictive in-vitro models for humans and animals, you'll likely need less numbers in your trials. That would be the hope." But beyond therapeutic testing in an R&D and clinical trial setting, how far might we be able to push stem cells?  
Personalizing screening  
As suggested earlier, steady improvements in stem cell methodology point to the future possibility of performing theranostic screening directly on a patient's own cells, providing an opportunity for personalized medicine in its truest sense.  
"It's not that outlandish to believe that in 10 years, this technology will develop to a point at which these things might get done faster," says Piper. "There are certainly technologies where you see people do direct reprogramming from a fibroblast to say, a neuron for instance, and that doesn't necessarily take 60 days, or we may find as time goes on that it's not necessary to derive clonal populations of an iPSC, and that we might be able to get a pool of cells that are sufficient enough to give you a predictable response."
A case in point for direct differentiation or transdifferentiation is the work being done at the Scripps Research Institute (TSRI) to turn bone marrow cells directly into brain cells. The discovery, which was presented in the Proceedings of the National Academy of Sciences, was a serendipitous offshoot of an effort to find antibodies that would stimulate a growth (GCSF) receptor on the bone marrow cells, but instead facilitated development into a neural progenitor cell.
"These results highlight the potential of antibodies as versatile manipulators or cellular functions," said lead investigator Richard A. Lerner in announcing the findings. "This is a far cry from the way antibodies used to be thought of, as molecules that were selected simply for binding and not function."  
The TSRI researchers see great potential in their antibody—and more globally in their findings—as a neurological therapeutic. As Lerner described it, the antibody could be injected directly into the blood stream of a patient and find its way to the bone marrow, where it could trigger the development of neural progenitor cells.
"Those neural progenitors would infiltrate the brain, find areas of damage and help repair them," he suggested.  
Such experiments are a long way off, however.
"If genomics and genetics was able to bring the bench to the bedside, what iPSC technology does is it allows you to bring the bedside back to the bench," opines Parker. "It really creates the full circle of personalized medicine."  

Energized by metabolism  
As the potential applications of stem cell biology continue to widen, several researchers are predicting something of a renaissance of cellular metabolism and a slow move away from purely 'omics approaches to drug discovery and disease modeling.
"Stem cells are very much taking on a field of their own," says David Ferrick, chief scientific officer of Seahorse Biosciences. "What's very clear about it is that it's much more functionally oriented. It's more morphologically based, so much more imaging, so much more about the media you put it in, the factors you have and less about the genetics."
"The orchestrated commissioning and decommissioning of metabolic pathways enables stem cell differentiation, and also supports reacquisition of pluripotency," echoed Andre Terzic and colleagues at the Mayo Clinic in a Cell Stem Cell perspective article last year. "Complementing genetic determinants of programming and reprogramming, the plasticity in energy metabolism is now recognized as a prerequisite in fulfilling the energetic needs of cell fate decisions."  
According to Ferrick and several other researchers, long before you see changes in gene expression or cellular morphology during reprogramming and differentiation, cells are undergoing subtle but distinct changes in energy metabolism.
"Glycolytic and OXPHOS [oxidative phosphorylation] pathway gene expression and DNA methylation patterns also change during reprogramming and pluripotency," explained UCLA's Michael Teitell and colleagues in another Cell Stem Cell review last year. "Several studies show that metabolism regulates reprogramming efficiency and that metabolic resetting is an active process during reprogramming."  
Ferrick offers apoptosis as an example.  
"Before caspase activation, when you first start getting the early events and the signaling cascade, programming has already started," he says. "You can already see changes in respiration, changes in glycolysis. So energetics is a necessary and required prerequisite for making your major functional changes in a cell, so it is an amazingly sensitive read out."  
And it's a readout that companies can measure using instruments like Seahorse's XF Analyzer, which monitors oxygen consumption as an aerobic indicator for mitochondrial action, and acidification as an indicator of glycolytic flux.
"You can actually see the cells go from a normal aerobic positioning straight down to a glycolytic positioning and back again," he says. "We can make that measurement in real time, and we can see it while it's switching before it's been irreversibly committed," offering researchers an opportunity to measure perturbations at any stage from growth process development to differentiation to molecular screening.
According to Teitell, this flux offers research insights on improving efficiencies in stem cell development as "manipulations that inhibit glycolysis … reduce reprogramming efficiency, whereas augmenting glycolysis … enhances iPSC reprogramming efficiency."  
For Ferrick, though, it's about putting function before genetics.  
"Stem cells allow you to create that characteristic biology by differentiating down different lineages, obtaining different lineages, doing the marker analysis, doing the functional analysis, knowing it 's a cardiomyocyte from a diabetic genotype that has whatever anomalous characteristic to it and then do the genetics on it to understand why it was that way," Ferrick explains. "So now you build a better biological hypothesis based on functional criteria."  
"Translation of insights gained from developmental metabolomics paves the way for a novel paradigm in tailored rejuvenation/regeneration strategies aimed at restoring compromised stem cell metabolism in aging and disease," concludes Terzic.



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