Model citizens (continued)

Stem cells’ promise of disease-in-a-dish opens doors to truly personalized medicine

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Clinical trial in a dish
One of the main research goals for stem cells is thedevelopment of incredibly precise models for human disease.
"The iPSC explosion opens up a whole new door for thosecompanies to now have access to a 'disease-in-a-dish'," which would allowresearchers to test new therapeutics against more realistic cellular targetsrather than cells derived from cancer lines, says LTI's Pettersson.
Parker gives the example of CDI's MyCell platform, whichoffers customers the ability to analyze the genetic variation and geneticdiversity they wants from samples of interest they provide. 
"It's not just a reprogramming service," he explains. "Wetypically push those customers to Life Technologies to buy our reprogrammingkit if they just want to generate an iPSC. With MyCell, a customer can simplysend us a blood sample from individuals in their clinical trials or developmentprogram. We will make that patient's iPSCs, we then scale that up, create aminibank, provide the line back to the customer to play around with and then wewill produce a certain number of units of one of our differentiated cellproducts."
Parker describes this as an in-vitro clinical trial, which replicates the geneticdiversity seen in Phase II or III trials into the preclinical research spaceand can help winnow new drugs more quickly, reducing massive clinicalexpenditures. As proof, he offers analysis done by Roche researchers when theyexamined MyCell.
"Roche had a drug that when they were testing forarrhythmias, which had made it all the way into primates," he recounts.
None of the in-vitroand in-vivo models, untilprimates, had been able to pick up the arrhythmia issues. When evaluating CDI'sportfolio, the Roche researchers decided to test that drug to see if they coulddetect the toxicity, and the effects were immediate.
"They said, had they had our cells [in the originalscreening], they would have saved $10-$20 million," Parker says.
According to Parker, CDI is also in the process ofdeveloping an ethnic diversity panel of their various cell types, representingsix or seven different ethnicities and with both male and female components,which should facilitate the discovery of toxicities and efficacies that mightnot be caught in simpler cell-based screens.
More accurate human disease models don't necessarily meanthe end of animal models, however, according to Piper.
"I'd say some of the things you might see in a feworganizations is people beginning to look at animal models instead of justhumans," he says. "They're still going to test [a new therapeutic] in theanimal first, so they'd like to be able to do the same sorts of things inperhaps a pig or a dog. If you can get very predictive in-vitro models for humans and animals, you'll likely needless numbers in your trials. That would be the hope."
But beyond therapeutic testing in an R&D and clinicaltrial setting, how far might we be able to push stem cells?
Personalizing screening
As suggested earlier, steady improvements in stem cellmethodology point to the future possibility of performing theranostic screeningdirectly on a patient's own cells, providing an opportunity for personalizedmedicine in its truest sense.
"It's not that outlandish to believe that in 10 years, thistechnology will develop to a point at which these things might get donefaster," says Piper. "There are certainly technologies where you see people dodirect reprogramming from a fibroblast to say, a neuron for instance, and thatdoesn't necessarily take 60 days, or we may find as time goes on that it's notnecessary to derive clonal populations of an iPSC, and that we might be able toget a pool of cells that are sufficient enough to give you a predictableresponse."
A case in point for direct differentiation ortransdifferentiation 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 findantibodies that would stimulate a growth (GCSF) receptor on the bone marrowcells, but instead facilitated development into a neural progenitor cell.
"These results highlight the potential of antibodies asversatile manipulators or cellular functions," said lead investigator RichardA. Lerner in announcing the findings. "This is a far cry from the wayantibodies used to be thought of, as molecules that were selected simply forbinding and not function."
The TSRI researchers see great potential in theirantibody—and more globally in their findings—as a neurological therapeutic. AsLerner described it, the antibody could be injected directly into the bloodstream of a patient and find its way to the bone marrow, where it could triggerthe development of neural progenitor cells.
"Those neural progenitors would infiltrate the brain, findareas 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 thebedside, what iPSC technology does is it allows you to bring the bedside backto the bench," opines Parker. "It really creates the full circle ofpersonalized medicine."

Energized by metabolism
As the potential applications of stem cell biology continueto widen, several researchers are predicting something of a renaissance ofcellular metabolism and a slow move away from purely 'omics approaches to drugdiscovery 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'svery clear about it is that it's much more functionally oriented. It's moremorphologically based, so much more imaging, so much more about the media youput it in, the factors you have and less about the genetics."
"The orchestrated commissioning and decommissioning ofmetabolic pathways enables stem cell differentiation, and also supportsreacquisition of pluripotency," echoed Andre Terzic and colleagues at the MayoClinic in a Cell Stem Cell perspectivearticle last year. "Complementing genetic determinants of programming andreprogramming, the plasticity in energy metabolism is now recognized as aprerequisite in fulfilling the energetic needs of cell fate decisions."
According to Ferrick and several other researchers, longbefore you see changes in gene expression or cellular morphology duringreprogramming and differentiation, cells are undergoing subtle but distinctchanges in energy metabolism.
"Glycolytic and OXPHOS [oxidative phosphorylation] pathwaygene expression and DNA methylation patterns also change during reprogrammingand pluripotency," explained UCLA's Michael Teitell and colleagues in another CellStem Cell review last year. "Severalstudies show that metabolism regulates reprogramming efficiency and thatmetabolic resetting is an active process during reprogramming."
Ferrick offers apoptosis as an example.
"Before caspase activation, when you first start getting theearly events and the signaling cascade, programming has already started," hesays. "You can already see changes in respiration, changes in glycolysis. Soenergetics is a necessary and required prerequisite for making your majorfunctional changes in a cell, so it is an amazingly sensitive read out."
And it's a readout that companies can measure usinginstruments like Seahorse's XF Analyzer, which monitors oxygen consumption asan aerobic indicator for mitochondrial action, and acidification as anindicator of glycolytic flux.
"You can actually see the cells go from a normal aerobicpositioning 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'sswitching before it's been irreversibly committed," offering researchers anopportunity to measure perturbations at any stage from growth processdevelopment to differentiation to molecular screening.
According to Teitell, this flux offers research insights onimproving efficiencies in stem cell development as "manipulations that inhibitglycolysis … reduce reprogramming efficiency, whereas augmenting glycolysis …enhances iPSC reprogramming efficiency."
For Ferrick, though, it's about putting function beforegenetics.
"Stem cells allow you to create that characteristic biologyby differentiating down different lineages, obtaining different lineages, doingthe marker analysis, doing the functional analysis, knowing it's acardiomyocyte from a diabetic genotype that has whatever anomalouscharacteristic to it and then do the genetics on it to understand why it wasthat way," Ferrick explains. "So now you build a better biological hypothesisbased on functional criteria."
"Translation of insights gained from developmentalmetabolomics paves the way for a novel paradigm in tailoredrejuvenation/regeneration strategies aimed at restoring compromised stem cellmetabolism in aging and disease," concludes Terzic.

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