This past week I blogged on the strange new trend of culture expanded stem cells being sold under the guise of what sounds like IRB or FDA approval but really isn’t when you peek under the covers. These ventures are selling cells by their quantity, a perverse incentive that reminds me of a real-estate debacle we had this week. This is bad for doctor and patients, so let me explain why.
Culture expanded stem cells are those that are grown in culture to higher numbers. They are a drug here in the U.S., even if they’re your cells. So any use of culture-expanded stem cells here in the states requires an FDA approval even for a study. This is the same type of treatment we offer in Grand Cayman through a licensed site.
This past week my colleagues and I were looking at purchasing a small office building that used to be a bank. It was a very cool property with much potential, but turning a bank into a doctor’s office would take some serious vision and work. We were told that the cost of the property was $1.4 million, a very good deal despite the work it would require. However, once we expressed an interest, the price jumped to $2.6 million! This was especially bizarre when we found out that the property had just been purchased 18 months ago for $1.4 million. I had never before seen that happen and was not happy that our real-estate agent seemed more interested in trying to justify the new price than anything else. Why? While he represents our interests, he gets paid much more if we bite at the higher price. This is called a perverse or nonaligned incentive.
The same perverse incentives exist in the business of growing stem cells. For example, during the webinar I reviewed this week on the culture expanded stem cell scheme, the presenter says, “…the cells are being expanded at the bank, and this can take four to eight weeks…” What’s wrong with that statement, and why does it represent a perverse incentive that’s good for the folks selling the cells but not for the patient or physician ordering the cells? To understand that, I first need to teach you some basic cell biology as it pertains to culture expanded stem cells.
It’s human nature to believe more is better, and medicine has the same issue. After all, if 1 million stem cells are good, aren’t 100 million much, much better? That depends on many issues, but in the context of culture expansion, it may be the opposite in that less is more. Why?
I’ve covered this phenomenon in previous blogs on the cell drug industry gearing up to culture billions of cells from young donors. However, let’s review some of that research again. In particular, studies performed on how the length of time adult stem cells are grown adversely impacts their potency.
A study performed in Sweden looked at the viability of stem cells grown for short periods versus longer periods and frozen, for cell potency. The short-term cultured cells had a 100% patient response rate, while the long-term cultured cells only worked half of the time. What other research shows that short-term cultured cells just work better than those cultured for longer periods (see study 2, study 3, and study 4)? The last study referenced shows very stark differences in survival between the short-term and long-term cultured cells. For example, in patients who were rejecting organs and stem cells were used to fight the rejection, 75% of the kids who got cells passaged 1–2 weeks survived at one year compared to only 21% of the kids who received cells that were grown 2–3 weeks! So “long-term” culture in these studies is only a few weeks. Let’s compare that to what’s being sold by these cell banks.
Now let’s compare the extent of time in culture to what the presenter said about how long the cells would be grown in this new culture-expanded-cells-on-order scheme. In the studies above, long-term culture is generally defined as more than 2–3 weeks. The presenter said that it took 4–8 weeks to grow the cells! That’s not uncommon as many US and ex-US cell banks selling cells do the same. Why? Because while more is likely not better for patients, it is better for the bottom line of these ventures.
Think about the business plan of a for-profit culture-expansion company. You start with X number of stem cells and your big equipment costs are fixed. Additionally, there are fixed costs in harvesting and establishing an initial cell culture. After that, there are smaller marginal costs in growing the cells to more numbers. Hence, selling cells by 50 or 100 million aliquots means that the more you grow, the higher the profit margin. Hence, if you can keep the cells growing for 4–8 weeks to get a billion, this is the way to maximize the bottom line. However, as the studies above show, it also minimizes the potency of the cells and maximizes the likelihood that the cells will be ineffective.
We have been licensing culture-expansion sites for the last six years, after culturing our first stem cells in 2005–6. We have had sites in China and Grand Cayman, and now we’re expanding to the Middle East, and we will hopefully be back in China soon. We’ve never charged patients based on the number of frozen cells they withdraw from the “bank.” In fact, the more cells you grow, the lower the cost per treatment as there is one fee to take, culture, and reimplant cells. Why? Because we want to align incentives with the patient. We have never advocated for growing cells more than a few weeks as we need to produce the best cells possible that will produce the best treatment possible. Hence, we have zero incentive to grow the cells out for longer periods and make them less potent.
We learned many years ago that a critical step in evaluating cell quality was checking cell genetics. This means that the cells are tested via karyotyping to determine if they have the correct chromosome configuration. It’s a pain in the neck for our licensed sites that grow cells as it adds cost and resources. However, about 2–3% of the time, we detect a sample where even the short-term culture we use will produce abnormal cells. The FDA has also recently brought this up as an issue, largely based on research studies like this one that shows that genetic abnormalities can develop in stem cells in culture.
Genetic testing is always missing from every commercial cell bank that I have observed selling culture-expanded cells whether it be here or ex-U.S. This safeguard is certainly lacking in the American CryoStem project I blogged about this week, and it’s missing from European and Latin American outfits as well. This is scary, as given how long these cells are being grown, it’s likely that a significant number of samples are being sold back to patients with severe genetic abnormalities.
The upshot? Becoming an educated consumer of culture expanded stem cell products would seem to be a good thing in this new antiregulatory cycle. Whether any of the new US culture-expansion stem cell schemes will survive the year is doubtful, but if they do, making sure that doctors and patients understand that growing cells to get the most possible is often a net negative for the purchaser while a huge boon to the grower!
About the Author
Christopher J. Centeno, M.D. is an international expert and specialist in regenerative medicine and the clinical use of mesenchymal stem cells in orthopedics. He is board certified in physical medicine as well as rehabilitation and in pain management through The American Board of Physical Medicine and Rehabilitation.…