The use of stem cells is in a weird adolescence right now where misinformation is at epic levels. We have physicians, sales reps, and others involved in using, selling, and studying stem cells who aren’t quite clear what it is they’re using, selling, and studying. Case in point this morning is a new study being performed at the Andrews Institute. Let me explain.
The New Andrews Study
First, I’m not really focused on Andrews here as there are countless clinics making claims that can’t be supported, and this one just happens to be on the radar because of a recent press release and news story about a new research study. This could have literally been any other clinic or press release where the statements being made are nonsensical.
The new research is using a technique developed in Malaysia called the “Saw Technique.” This involves giving the patient a dose of Neupogen and then performing peripheral blood apheresis and collecting the nucleated cell fraction. The harvested cells are then saved in cold storage and eventually reinjected into the knee after surgery some 14 times over 18 months. The idea is that new cartilage will grow.
What Are Neupogen and Apheresis?
Neupogen is a drug that can force nucleated cells (a tiny fraction of which are stem cells) out of the bone marrow and into the peripheral blood. Apheresis is a technology that takes the blood out of the patient, filters it through a centrifuge system to remove some of the cells, and then puts it back in. Hence, the protocol mobilizes cells from the marrow where the apheresis machine can pick some of them up in the bloodstream.
Both of these technologies are more invasive than merely taking the bone marrow out using a bone marrow aspirate procedure. Hence, it’s always been a mystery to me why one would use heavy-handed drugs and a machine that strips the blood instead of just performing a bone marrow aspiration. However, the invasiveness of the procedure isn’t the focus of this blog, but, instead, some of the stem cell numbers claimed by the clinic.
A Statement About the New Study That Makes Little Sense
In a recent news story on the Andrew’s study, the following information was shared, “One of the techniques that has evolved is that physicians at KLMSC administer Neupogen, which is a drug that makes stem cells in your bone marrow go to your blood stream,” Dr. Anz said. “The stem cells are collected with an Apheresis machine, which is a machine that uses centrifuge as well as optics to sort cells. Right now a bone marrow aspirate can produce between 7,000 to 14,000 stem cells; with Apheresis and Neupogen mobilization you can produce up to 120 million stem cells.”
Hmm…As a stem cell expert with more experience in using stem cell injections to treat orthopedic conditions than almost anyone else on earth, the last part of this statement about stem cell numbers makes little sense. Let me explain.
Manufacturing Stem Cells?
So let’s begin with the above numbers. The 7,000 to 14,000 is the number of mesenchymal stem cells (MSCs) in the average bone marrow aspirate in a middle-aged patient. So what would it take to get that number to 120,000,000 MSCs? It would take what we do at our licensed Grand Cayman site. You would have to culture expand the stem cells taken from a bone marrow aspirate for several weeks, feeding them every few days with growth factors.
Can Neupogen accomplish this kind of culture expansion? Nope, that’s not what this medication does in the body. Neupogen mobilizes the nucleated cells that already exist in the marrow out to the bloodstream. Also, it’s much less than 100% efficient, so you would always get more stem cells per milliliter by just drawing directly the marrow (a bone marrow aspirate).
How do I know this? Many years ago we were working with a company that used Neupogen and apheresis to collect cells. They wanted us to be able to isolate MSCs from their collections and to use those in orthopedic treatments. We were excited at the possibility but disappointed that we were unable to culture any MSCs from their collection. Are we the only group who has been unable to culture and isolate MSCs from these apheresis collections? No, this study on equine apheresis collections also had the same issue.
So if Neupogen doesn’t grow new MSCs and if the cells collected in the peripheral blood don’t include the same 7,000 to 14,000 MSCs quoted above, where on earth did the Andrews Institute get these numbers? I’m pretty sure I know what happened, but for the average reader to understand it better, just a little more background is needed.
First, what does Neupogen do if it doesn’t grow MSCs? It can mobilize nucleated cells (1–3% of which are hematopoietic stem cells [HSCs]) out of the marrow. HSCs are stem cells that make new blood. These are different from MSCs in that MSCs have been shown to be involved in cartilage repair and HSCs have not.
Hence, I believe that the second number quoted above (120,000,000) is not the number of MSCs at all as that makes no sense given what we know about Neupogen, what we experienced trying and failing to get MSCs to grow from apheresis collections, and the study I quoted. Instead, this is likely the total nucleated cell count of the cells collected via apheresis. This is called TNCC. What’s that?
What Is TNCC?
TNCC (total nucleated cell count) is simply the total number of nonblood cells and nonplatelets collected. These are cells with a “nucleus”; hence, they are called “nucleated.” While in the bone marrow, some small percentage of these cells are stem cell with many more HSCs than MSCs; this doesn’t happen as much in the peripheral blood where stem cells are even rarer.
There’s another possibility that the 120,000,000 number represents HSCs, which still makes this an apple-to-oranges comparison. Why? As already stated, the 7,000 to 14,000 number is clearly an MSC number. There are many more HSCs in the bone marrow than MSCs. For example, 1–3% of the bone marrow nucleated cells are HSCs, so if the average bone marrow aspirate has a 500M TNCC, then there are millions of HSCs at the low end.
How Did These Numbers Get Mixed Up So Badly?
So, to recap, we know that while the statement sounds like the smaller number of tens of thousands of stem cells in the bone marrow are the same stem cells that this process magically morphs to 120 million, that’s clearly not accurate. Basically, we have an apples-to-oranges comparison. The stem cells in the bone marrow are the MSCs capable of cartilage repair, and the “stem cells” in the second number are either not stem cells, but nucleated cells, or they could be HSCs, which have not been shown to repair cartilage.
How did this get mixed up so badly? We have no educational standards for stem cell use. Physicians are not taught this stuff in medical school or residency, so what they know comes from a weekend course or the odd lecture at a conference they attend. Hence, it’s not only the Andrew’s Institute physicians who mix these numbers up but also a plethora of physicians around the country. As I have said before, there is more physician misinformation right now about stem cells than useful information.
So if There Aren’t 120 Million Stem Cells, How Does This Protocol Work?
This is, in fact, the billion-dollar question. While we know that MSCs can repair cartilage, we don’t really have robust information that peripheral blood cells or HSCs can do the same. While there are some indications that you can find rare stem cells in the blood that may help cartilage healing, these would also be found in simpler-to-obtain mixes like platelet-rich plasma (PRP). If this protocol is shown to work in this study, the key may be the number of injections more than what is injected. Let me explain.
This protocol calls for 14 injections over 18 months. That’s an unprecedented number of biologic injections into a joint. In fact, I don’t think we have a single patient in 13 years whose knee joint has been injected that many times with orthobiologics, like PRP, bone marrow concentrate, or culture-expanded stem cells. Given that just injecting platelet-rich plasma into a joint 14 times over 18 months would be an unprecedented level of cartilage growth stimulus, my guess is that if you did that to a patient, you could show cartilage growth using specialized MRI techniques (like the dGEMRIC MRI used in this study). Hence, my educated guess is that the success of this protocol likely isn’t dependent on the Neupogen or the apheresis but, in fact, on the crazy number of times the knee is injected with a cocktail that can ramp up the repair response.
Also, this protocol being tested at Andrews is very expensive. Neupogen alone is $5,000–7,000 a dose. Add in apheresis and cGMP storage and handling of the cells, a surgery, and 14 injections, and this could easily run 100K or more. What if you didn’t need any of it other than the frequent injections of much cheaper PRP to get the same results at one-tenth the price?
To “put my money” where my mouth is, we’re going to begin a small pilot that will inject knee arthritis patients ten times with high-dose PRP over six months and measure cartilage volume on MRI. I suspect that for a fraction of the price and invasiveness, we’ll see similar results to the Saw protocol. Only time will tell for sure.
The upshot? We have a physician-education problem concerning the basic science behind stem cells. This issue extends right to famous sports-medicine clinics and universities because we have no core curriculum that everyone accepts and trains under. In this case, we have an obvious apples-to-oranges comparison problem. Also, my guess is that the protocol being tested doesn’t even likely work through “stem cells” but more likely through the collection of blood platelets and other cells picked up by apheresis and then reinjected an unprecedented 14 times!