For the last 4 years, I have studied stem cells at the UT Health Science Center at San Antonio. I've learned a lot in that time, and just recently wrote my dissertation. It was nearly 160 pages describing a strategy I developed for improving the "quality" of stem cells from elderly individuals. Still, I hesitate to call myself an expert, because I am not sure what quality means. I put quality in quotation marks, because in the stem cell field, we have no clue what quality actually means. What I mean by this is that we don't know what characteristics you want or need from stem cells in order to treat various diseases, and our methods for measuring these characteristics are often imprecise.
Imagine being asked to draft an athlete for a team, but you aren't given all the information you would want. You aren't certain what sport you are drafting them for. You aren't sure what skills their teammates possess, and you aren't sure what the other teams might be able to do to stop them. So you start to think about criteria that might be important to being a good athlete, and you come up with a list:
Next, you start to think about how important each quality is and how to measure those qualities. Given the information you have this is a very difficult question. The importance of height (for instance), will be very different if we are talking about basketball vs. curling. The importance of height, for a basketball player, may also be impacted by the heights of the athlete's teammates. If the team already has several players that are close to 7ft tall, they may place less of a premium on having additional very tall players. Additionally, how particular criteria are measured may be different depending on the sport. Speed in basketball for instance may be how fast a player is able to sprint 10ft, turn around, and sprint 20 yards. Whereas, speed for a marathon runner may be how fast the athlete is capable of running 400m. For the sake of this example, let's consider the sport of basketball.
It is relatively easy to accurately measure height and reach, and all things equal, it would typically be an advantage to have greater height and reach when playing basketball.
Strength sounds straightforward to measure, but when you start to think about it, it gets much more difficult. What type of strength do we care about? Lower body? Upper body? Core? All of the above? Do we care about max weight an athlete can lift? Or do they have to be able to do multiple repetitions at a particular weight? Is it just strength? Or do we care about the ratio of strength to size? Are all types of strength equally important?
When we start to look at speed, it is equally mirky. Do we care about the athletes speed over 10 ft? Or 10 yards? Or 100 yards? If we time the athlete from the word "go", then the measurement of speed also takes into account reaction time. Are those equally important?
A similar story can be told for most of these criteria, but for some it is even more obvious. Just try coming up with a test for leadership or coachability!
This scenario, of trying to define tests that will predict success are analogous, to what must be done for stem cells, but we know much more about basketball than we know about stem cell therapies. In September the FDA is holding a meeting where they will hear testimony from experts from all corners of the stem cell field. The overarching theme is that we need new rules for the regulation of stem cells so that we can advance stem cell therapies. However, the obvious first question is how do we define "quality" stem cells? When I try to think about how we might do this, I think about the roles of stem cells in repair and maintenance in the body. They replenish our cellular reservoirs. They rebuild damaged tissues. And they act as our bodies' personal pharmacists through their secretions of various cytokines. So I come up with a few basic criteria that might be useful for measuring their potential to perform those functions:
- Self-renewal (the ability of cells to make more of themselves)
- rate (how fast can the cells divide)
- potential (how many total copies can each cell make)
- Differentiation (the ability of stem cells to specialize)
- efficiency (percentage of cells capable of differentiating)
- potency (number of different types of tissues a cell can form)
- Protein translation rate (how fast can the cells make protein - this is important for rebuilding tissue)
- Cytokine profile
Like the previous example, it is difficult to know how to interpret these criteria for therapies generally, so in order to simplify the scenario, we pick a single potential therapy. For the sake of argument, we will say we want to use the cells to treat osteoarthritis (OA).
Now we start with the first question.... Is self-renewal important for the treatment of osteoarthritis? I have written a review of academic articles on the treatment of OA with stem cells, and I am confident that no one actually knows the answer to this. For the sake of argument, however, lets say that we know for sure that self-renewal rate is important. Now we get into how do we test self-renewal rate. Is the first division important, or is it the average of the first 20 divisions? Is it good to divide quickly if the cells are only capable of 5 divisions? Do we only care about the logarithmic growth phase?
Similar questions can be asked about differentiation. When we are talking about the treatment of OA what type(s) of differentiation do we care about? What conditions are we going to measure this in? How are we going to measure it?
I won't go into all the questions we can ask about all of these criteria, but I wanted to illustrate the point, that what makes a good stem cell is an important question when we talk about wanting new criteria for FDA regulation of stem cell therapies, and before we can start to answer this, we need to know how to ask the question. The stem cell field isn't ready to ask these questions, and it definitely isn't ready to answer them.
I'll be following up this blog with another about potential ways to think about defining quality of stem cells using a technique developed by a friend and colleague at UT Arlington, George Kondraske). I may also edit this entry in the coming days to expand on the difficulties in asking and answering these questions in the stem cell field. In the meantime, I would love to hear any thoughts or ideas about how we might think about asking (or answering) these questions.