One of the scientific co-founders of San Diego-based Fate Therapeutics, along with his team at The Scripps Research Institute, is reporting a major advance that will make it faster, cheaper, and potentially practical on an industrial scale to turn adult cells into stem cells that can morph into any type of cell in the human body.
Sheng Ding and his colleagues at Scripps have found a combination of three conventional small-molecule chemical compounds that can coax adult human cells into an embryonic-like state. The new technique is about twice as fast as existing methods, and produces 200 times more cells per batch. The research in how to efficiently make these so-called “induced pluripotent stem cells” was sponsored by Fate, and is being published online today in the journal Nature Methods.
The technology, which is exclusively licensed to Fate through its sponsored research agreement with Scripps, is a big feather in the cap for the startup company as it seeks to strike deals with pharmaceutical and biotech companies that are looking get into the stem cell game. Fate has been a leader in the field since its founding two years ago by a group of top stem cell scientists from Harvard University, the University of Washington, Stanford University, and Scripps. One of those co-founders was Ding, a young scientist who got his first faculty post in 2003 at Scripps.
“This is the first example in human cells of how reprogramming speed can be accelerated. I believe that the field will quickly adopt this method, accelerating [induced pluripotent stem cell] research significantly,” Ding said in a statement from Scripps.
The latest advance builds on the discoveries of Shinya Yamanaka of Kyoto University and James Thomson of the University of Wisconsin, who showed for the first time two years ago that scientists could transform adult human cells into a pluripotent state, like that of cells in an early embryo. That was important because it was a way to circumvent the political and ethical controversy over destroying embryos in order to harvest their stem cells for research.
Pioneering as that work was, it was nowhere near ready for prime-time use in the biotech and pharmaceutical industries. Yamanaka and Thomson used viruses to insert multiple copies of four genes into adult cells. Two of the genes are known to cause cancer. Given that risk, it’s almost impossible to imagine regulators ever allowing cells with that kind of genetic modification to be injected into people who want to, say, regenerate new pancreas cells to treat their diabetes. The other big problem with the original method was that it took four weeks from start to finish, and only worked in about one out of every 10,000 cells.
Today’s announcement is the second big stem cell paper this year from the Ding lab. In May, the Ding lab reported that it had essentially gotten around the first technical challenge with genetic modifications. Ding and his colleagues discovered a way to use genetically engineered protein drugs that could coax adult cells into a pluripotent state without the danger of using cancer-causing genes delivered by viruses. That work was published in the journal Cell Stem Cell.
Five months later, Ding has taken another big step ahead that could make stem cell research much more practical for pharmaceutical companies, says Fate Therapeutics CEO Paul Grayson. As anybody who follows the biotech industry knows, genetically engineered protein drugs—like Amgen’s etanercept (Enbrel) or Eli Lilly’s cetuximab (Erbitux)—are expensive to manufacture. Essentially, using proteins like that to induce a pluripotent state would be cost-prohibitive for what Fate wants to do. That’s why Ding’s team went on a search for small molecules that would do the job.
Fate envisions using induced pluripotent stem cells—at least in the early days of the field—primarily to support basic research into the discovery of new drugs. The rationale is that if you can create new neurons in a lab dish that are like neurons harvested from the human brain, then that could be a very useful platform for testing new drugs designed to deter or reverse the changes associated with Alzheimer’s, multiple sclerosis, or Parkinson’s. Further in the future, induced pluripotent stem cells that have been made to differentiate into neurons might be injected into people as regenerative treatments.
So if Fate is going to create a method for churning out these valuable induced pluripotent cells, it will have to be fast, cheap, and reproducible, like all good industrial processes. That’s why Ding’s paper today is so important, Grayson says. Small molecule compounds are really cheap and readily available compared with genetically engineered proteins.
“This is Sheng’s next big leap forward,” Grayson says. “It makes the whole process much more efficient.” With small molecules, Grayson adds: “We’re talking about dollars per gram instead of tens of thousands of dollars,” as with genetically engineered proteins.
But the researchers aren’t getting carried away with excitement; lots of big challenges remain. One of the critical ones is with what scientists call “heterogeneity,” which essentially means they need to make sure they’re getting consistent results. For example, the FDA would want to be absolutely certain that induced pluripotent stem cells can be differentiated into, say, neurons with uniform consistency, so that it knows exactly what is being injected into a person.
Fate isn’t trying to pretend that it has the process of making induced pluripotent stem cells completely nailed for pharmaceutical industry grade experiments. “As Rudy Jaenisch has said, you can wait for it all to be figured out and miss the boat, or you can work on it now and help shape it,” Fate spokeswoman Jessica Yingling told me last month, citing remarks by MIT and Whitehead Institute biologist Rudolf Jaenisch, an advisor to Fate.
It will be very interesting to see if this latest paper by Ding, and the speed and efficiency gains it may represent, will be enough to get Big Biotech and Big Pharma to jump on the bandwagon with Fate, and start to help shape it, to use Jaenisch’s phrase. After all, Fate has raised $25 million in capital since its founding, and it is growing fast. With ambitions like this, it will definitely need more capital. Grayson was a bit cagey about what the new results mean for his ability to do deals with pharma companies, but he did say, “It’s great for the field, and for Fate Therapeutics in our relationship with Big Pharma.”