I’m doing a series of posts on my recent conversation with BioTime CEO and pioneer of the stem cell field, Dr. Mike West.
You can read Part 1 and Part 2 on Geron, ACT, and the history of the pluripotent stem cell field, particularly embryonic stem cells (ESCs).
Today in Part 3, I am focusing on a key, broad flaw that West described as pervasive in the stem cell field.
In Part 4, I’ll discuss his proposed solution.
To introduce what he views as the fundamental flaw so common amongst stem cell research as is his way, West used a powerful analogy.
He described how he and his son were at an amusement park. His son was playing, as West described it, “that game where you throw the ball up onto this wall of pegs” and the goal is to get the ball to end up at the bottom in a specific spot. If it does, as West put it, “you win the giant stuffed dragon that is sitting up high at the top” of the stand.
The only problem is that with these kinds of games, which reminded me of pachinko, the ball almost never ends up where you need it to be at the end to win the prize.
West says that the same kind of thing is true with pluripotent and other kinds of stem cells. When scientists play stem cell pachinko (differentiation and purification), the ball (meaning the stem cell) doesn’t necessarily end up where we want it in the sense of specific differentiation.
West says that with only rare exceptions such as with ESC-produced retinal pigmented epithelial cells (RPEs), stem cell companies cannot really get their pluripotent stem cells to differentiate into anywhere close to 100% pure populations even with various purification regimens at the end.
The cellular product at the end is a heterogeneous mixture, says West.
What this means is that for most commercial as well as academic stem cell products, purity is just a myth. This not only impacts potential therapies, but also stem cell research as differentiated pluripotent stem cells are heterogeneous mixtures. This is the key flaw in the stem cell field today, says West.
“No one wins the big stuffed animal at the top,” said West, “because there is maybe 80% purity and identity of the remaining 20% of cells is largely unknown.”
For example, if we differentiate ESCs to try to make specific brain cells such as oligodendrocyte precursor cells (OPCs), we may get mostly OPCs, but the remainder is a heterogeneous mixture of many other cell types including presumably some undifferentiated ESCs, but also many other progenitor cell types.
“The vast majority of differentiated stem cell preps have contamination,” said West, “and the reality is that in most cases researchers do not know the identities of the contaminating cells. Unlike with hematopoiesis, in most cases with ESC differentiation there is no equivalent of the CD antigens to help scientists figure out what they’ve produced from ESCs.”
West told me that he believes that in a general sense the cells that contaminate preps of differentiated products from pluripotent stem cells are “highly proliferative progenitors that are characterized by relatively high expression of cancer-associated genes.”
To illustrate the potential negatives of these contaminates over the long run, West told another story about his son. His son had a puzzling bump on his neck that West noticed at the dinner table one night. Over time, the big red bump stuck around and the family was concerned. They wondered what it was as the years passed and eventually determined when his son was five years old that it was an embryonic hold over: a cyst of foregut endoderm. His son had it surgically removed and he is fine.
The point of his story is that embryonic progenitor cells can manifest different fates over a period of years both in actual people but also in stem cell culture and potentially in patients who receive transplants of heterogeneous cell preps. This also illustrates the critical importance of long-term safety studies. West summed it up as follows:
“The same kind of thing that happened with my son can also potentially happen after transplantation of differentiated cells made from ES cells. You can get ectopic, undesired tissues forming from progenitor cell contaminants that may take years to appear.”
West believes that the widespread problem of heterogeneous differentiated stem cell cultures intended for transplantation into patients is serious. Such progenitors may have even caused the cysts in rodents transplanted with Geron’s OPC product.
It seems that the same kind of problem applies to many kinds of adult stem cells as well. For example, “adipose MSCs” intended for transplant are not pure, but rather contain a host of different cell types, not just MSCs. Blood cells, endothelial cells, pericytes, diverse stromal cells, fibroblasts, and more.
What can we do about this big challenge? West’s proposed solution will be the topic of Part 4 of this series. Stay tuned.
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Thanks for posting it. Too often I see researchers detached form the reality when it comes to stem cells in this aspect – they boast on the high purity of the differentiated populations in their hands, when there are sometimes not even means to quantify it. Perhaps it is due to such a high competitiveness of the stem cell field?
Even if we find a new approach to differentiation, such as mimicking the proper niche, better chemical cocktails etc, we still need the markers allowing us to check the outcome.
On the other hand, waiting until we find the 100% pure population so we can use them clinically, is unrealistic. Perhaps we will never get there? And perhaps, and at least that is the outcome with MSCs so far, the cells will be inevitably tamed after getting into body’s micro-environment. And perhaps only then?
Personally I am an advocate of letting people access the therapies as fast as possible, however those who try them should be fully aware of the infancy of science here and potential undesired outcomes.
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Lack of purity might be a “concern” if you think according to the cells==drugs model. But let us remember that the story behind your recent post
https://www.ipscell.com/2013/07/perspectives-on-human-micro-liver-like-structures-made-from-ips-cells/
was that it took a mixture of several types of cells to approximate a desired result. And the linear thinking that one might just seed a scaffold turned out to be totally unproductive!
This is not surprising when one takes an evolutionary point of view, bodies are formed from the local interactions of cells and their environment — maybe, even, some of the necessary cells might be “dangerous” but they are mopped up along the way.
Unfortunately, cells are not created by GMP, they are created by 4 billion years of evolution… Evolution is messy, it does NOT conform to FDA regulations.
I’m not a cell biologist but it seems to me that to get the local interactions to work for a desired outcome, it’s more about setting up the right “ecosystem” of cells and chemicals (perhaps drugs, also).
Brian, you make a good point and raise some additional interesting questions.
Perhaps part of the issue here is more fundamental and that is that the whole notion of purity when it comes to a cellular therapy is a myth to begin with?
But an attractive myth.
Evolution and biology are just too messy to allow for any true purity.
I suppose there may be operational purity in a sense. For example, if cells are more than say 95% pure that’s pretty darn good, although I have seen reports that claim that differentiated iPS cell and ES cell end products have only 1 remaining undifferentiated pluripotent stem cell out of 50,000 total cells. That seems astonishing. Then again perhaps there are far more potentially undesirable cells in the gmish that are not pluripotent stem cells any longer but that also are not the target desired differentiated cell type either. They fall somewhere inbetween and drop off the radar screen.
This raises another separate, but related issue that even if we accept for the moment the argument that purity is a myth, it is nonetheless of huge importance to know what you are in fact dealing with in terms of “impurities”.
Let’s say a differentiated stem cell product is 80% pure to use West’s example. What the heck are the other 20% of the cells? Too often in the field stem cell scientists just do not know and some are almost certain to be cells that we do not want to be putting into patients.
My gut feeling is that the danger of the 20% unknown may scale according to how far removed the cells are from a “natural state for the body at hand”. Different classes of cells+manipulations == different levels of risk?
OK, I’m using wishy washy language but I see that people who actually do know a thing or two have thought about this in a much more rigorous way than I can. One of the reasons I read your blog.
I can’t wait for Part 4 of your interview with Dr West.
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