A few months after the American Chemical Society won its lawsuit against the pirate site, the game of virtual whack-a-mole continues.
A flurry of induced pluripotent stem cell banks are coming online, but they face significant business challenges.
September 1, 2014|
NISSIM BENVENISTY, RUSSO E (2005) FOLLOW THE MONEY—THE POLITICS OF EMBRYONIC STEM CELL RESEARCH. PLOS BIOL 3(7): e234. doi:10.1371/journal.pbio.0030234About four years ago, Jay Tischfield, the director of RUCDR Infinite Biologics, a long-standing biorepository at Rutgers University, found himself sitting on a gold mine. RUCDR had recently gotten into the business of banking and distributing induced pluripotent stem cell (iPSC) lines. This was still early days in iPSC derivation, only a few years after scientists had figured out how to turn skin cells into cells capable of differentiating into a wide variety of different cell types.
But not long into this new endeavor, “something important happened in the field,” Tischfield recalls. Researchers reported that they could induce pluripotency from blood cells. It just so happened that RUCDR was in possession of a massive collection of blood cell lines, each with a heap of information on the donor. “There we were, standing on what is perhaps one of the world’s, if not the world’s, largest collection of genetically defined . . . lymphocytes from literally almost a half a million subjects,” he says. “And it turned out these were fantastic for making iPSCs.” Suddenly, the opportunities for iPSC derivation and banking seemed endless.
The question, of course, was how to pick which lines to derive iPSCs from. To bank them all would be unfeasible, let alone uneconomical. “What you don’t want to have happen is liquid nitrogen tanks filled with cells nobody wants,” explains Michael Sheldon, the director of stem cell laboratories at RUCDR. “You might as well take dollar bills and flush them down the toilet.”
As a growing number of iPSC banks begin to come online, they’re facing many of the same questions. Chief among them: Which cells will be best for business?
Nearly a decade ago, the world was introduced to iPSCs. Although a seemingly simple protocol, deriving iPSCs and then maintaining and storing them can be a burden. The idea behind an iPSC bank is that the repository does all the organizational and maintenance labor and quality assurance assays—and in some cases, the derivation itself—and distributes cells to researchers for a fee.
In 2011, the National Institutes of Health’s Center for Regenerative Medicine, then led by Mahendra Rao, launched an iPSC banking initiative. Rao’s vision was to have biorepositories participate in the storage and distribution of lines that would be deposited by NIH-funded researchers, a model he referred to as “crowdsourcing.”
“It’s actually worked quite well,” says Rao, who is now the vice president for regenerative medicine at the New York Stem Cell Foundation (NYSCF). In just the past year or so, the number of iPSC lines has exploded. “I would say in the existing repositories there are already 200, 250 lines,” he says. “Within the next year or so, that number should quadruple. And in the next five years, there should be 10,000 or 20,000 lines.”
RUCDR and the NYSCF are just two of a number of institutions banking these cell lines. Others include the Coriell Institute in Camden, New Jersey; WiCell in Madison, Wisconsin; the Harvard Stem Cell Institute; the European Bank for Induced Pluripotent Stem Cells; and StemBANCC. (See Ruth McKernan and Fiona Watt’s more complete list of iPSC banking initiatives, published in Nature Biotechnology, November 2013.)
Although there may be some overlap, each iPSC banking program tends to serve a particular niche of researchers. The California Institute for Regenerative Medicine (CIRM), for instance, is building an iPSC bank to include cell lines from people with cardiomyopathy, blinding eye diseases, and Alzheimer’s, among other things. Michael Yaffe, the associate director for research activities at CIRM, says it is important not to duplicate the efforts of other iPSC banking initiatives. In planning the program, Yaffe explains, “we wanted to make as many [cell lines] as possible. Then it became an economic argument: How many could we afford and how much could we push a deriver to handle?”
CIRM settled on a goal of 9,000 lines derived from 3,000 individuals—what will amount to the largest iPSC bank in the world. Yaffe says he anticipates that the first of these will be available for distribution by the end of this year or early 2015. What’s still unsettled, however, is pricing. It’s a tricky calculation, given that the utilization of the lines is unknown.
“If a few large pharmaceutical companies buy a complete set of all the lines, that would keep the bank established and running for many years,” Yaffe says. “If academic researchers are going to buy a few lines at a time or a few lines each, it will create some challenges for the sustainability of the bank.”
The price tags at iPSC banks range from as low as $200 per line up to about $1,500. “The economic models are really hard to deal with,” says Sheldon at RUCDR. Banks have to project which cell lines will be worth expanding and how many assays should be done up front.
It remains to be seen which lines—and banks—will be the most popular and economically successful. For now, banks are primarily focused on iPSCs to be used in basic research, disease modeling, and drug screening, rather than for therapeutic development. But clinical-grade banks are likely to come next.
The first clinical trial using iPSCs was approved last year in Japan, using iPSCs derived from participants’ own cells to treat age-related macular degeneration. Such iPSC-based therapies could get more traction if ready-made cell lines were more widely available, according to Ian Wilmut, a professor emeritus at the MRC Centre for Regenerative Medicine at the University of Edinburgh. “If you go to patient-specific cells, people think it would be so expensive and so slow,” he says. As with other tissues in repositories, banked iPSC lines for human treatments would gain clinical value from including a wide variety of human leukocyte antigen (HLA) genotypes to get as close to an immune match as possible.
“The advantage of an HLA bank is you can pre-manufacture it, so it’s an off-the-shelf [therapy],” says Emile Nuwaysir, the chief operating officer of the Madison, Wisconsin-based company Cellular Dynamics International (CDI). “[If] it’s not a complete match, you may still require immune suppression. You can think of it, conceptually, as a step toward a fully personalized therapy.”
CDI, which is also the deriver of the iPSC lines for the CIRM initiative, is leading the way toward a therapeutic-grade iPSC bank. The first stage, currently in progress, is to bank cell lines from donors who have the five most common HLA genotypes in North America. Nuwaysir explains that to have a match available for 95 percent of the population at two predominant HLA loci, a bank would need 200 lines. A three-allele match would require 900 cell lines. Both are feasible, he says. “Neither of those numbers scare us.”
“The wild card is the regulators,” says Rao. He pointed out that the minute these cells undergo any sort of processing, they’re subject to US Food and Drug Administration (FDA) regulation. “Now, if you’re going to differentiate them into neurons, the FDA is going to say, ‘Where are the clinical trials?’” says Rao. “Who’s going to take charge of getting those data?”
Wilmut is part of an international group of stem-cell leaders working on getting regulatory uniformity across countries, so that banked therapeutic iPSC lines could be distributed worldwide. He says it’s important to get a consensus on regulations and quality criteria now, before companies move ahead with developing therapies. And it’s clear from the progress over the last eight years—which saw both the initial demonstration of iPSC derivation and the first clinical trials in humans—that the field is moving at the speed of light.
“The return for it potentially, for anybody, is huge,” says Wilmut. “And this is why we would think it’s well worth making the effort, and now is the time.”
A version of this article appeared on www.the-scientist.com on June 30, 2014.