Great expectations: will stem cells be the bee's knees?

Regenerative medicine comes with a lot of expectations (See Figure). I hinted in my previous post that events during stem cell differentiation are a black box, which is a formidable obstacle against all the expected therapeutics because if we don't understand what makes them tick, then we cannot hope to tinker or to use them. The knowledge gaps exist on several levels, but they all revolve around the fact that there are many different types of pluripotent cells. They can be grouped into three major types: embryonic stem cells, adult stem cells, and induced pluripotent stem cells. Each type displays unique properties and there are no standardize protocols for working with them. In short, each is marching to a different drummer and each is, at least the way I see it, a separate field of study. I'll only provide brief summaries for them here because I don't want to belabor the details in this post. There are excellent resources from Scitable, the National Institute of Health (NIH), and numerous other institutions that can provide the textbook details.

The classic stem cell is the embryonic stem cell (ESC), which is typically isolated from an embryo before it commits to any cellular lineage (pre-gastrulation stage blastula, if you want to get technical). ESCs are considered the "gold standard" for pluripotency and self-renewal, and are what most people would think of as stem cells. These cells are the standard to which the other two cell types are compared. They are the least restricted in terms of developmental potential and can become any cell type.

The second type of stem cells is somatic stem cells, also called adult stem cells. My favorite term for them is "lineage-restricted progenitor cells." These cells typically contribute to tissue repair and maintenance. It is not entire clear if every organ has its own stock of somatic stem cells, or if they only exist in tissues with a high turnover rate (e.g. liver, blood, skin). Another mystery is whether these reservoirs are maintained for a lifetime, or if they can age and degenerate over time like everything else in the body. These progenitor cells reside in the gray area between bona fide stem cells and fully matured differentiated cells, and they're thought to be a very diverse population during early development but gain specificity over time. The way a progenitor cell decides and commits to be a specific lineage is an active area of study.

Lastly, the really tricky cell type is the induced pluripotent stem cells, or iPSCs. They are basically fully matured adult cells that are genetically reprogrammed to regain stem cell features, and become immortal shapeshifters. Since the 2006 seminal paper by Takahashi and Yamanaka (1), iPSCs have exploded onto the scene as a kind of freak that possesses many ESC properties, yet behave quite differently. iPSCs are capable of self-renewal, and can differentiated into various cell types. However, they are not blank slates and retain some memory of their past, which makes their behavior unpredictable and are difficult to control. The biology is certainly unique and poses some interesting questions. For example, are they just franken-cells or do they resemble anything found in nature? Can they yield meaningful biological insights? Can iPSCs derived from one person be used in another? If each iPSC cell line is unique (because each is derived from a different person or tissue type), how can rigorous experiments be designed? This last question is an important one because if no iPSC line can be deemed "normal", then it would be almost impossible to have an experimental control. This wasn't a problem initially because people have so much trouble just making iPSC lines. Now, that problem is almost solved thanks to new molecular tools and technologies (2–5). The newer problem is how to test iPSCs functions in a controlled manner.

I want to focus your attention on how we may reconcile the difficulties with the high expectations for stem cell-based therapy. I don't want to discourage anyone, but we should have realistic expectations and understand what the challenges are. The first thing we have to make peace with is the fact that there will not be a one-size-fits-all solution. While all three cell types can theoretically meet every expectation, the truth is each type is suitable for just one or two of them and only to a limited degree.

If you remember the thought experiment I proposed in my last post—the one suggesting you keep the shapeshifting nature of stem cells in mind—then you already understand at least 60% of the problem. In order to make any pluripotent cell do our bidding, we need a steady target to aim at when building our strategies...and that steady target does not exist. Each group of cells is a dynamic and constantly shifting population. Only a small percentage within the population would respond to whatever manipulation we throw at them at any given time. So, it is a laborious trial-and-error process to find a magical witch's brew that would yield a desired result. It would also mean we need a customized brew for every cell line, for every patient, and for every application.

With such demands on time and energy, the next obvious question is if it's worth the trouble and costs. If we must customize treatment for each patient, is it right to spend so much resource to benefit so few? I don't think any reasonable person would spend serious effort doing that, even though it may look that way. When all is said and done, the research is geared towards benefitting the many. So, it's really a race to find the key components the govern pluripotent cell biology and to develop the necessary technologies for manipulating them cheaply and efficiently. Think of it as assembling a customized computer. Once the major components are developed, they can be mixed-and-matched to benefit many. It's not as great as tailor-made, but it's as personal as can be practical. All of today's headline-grabbing discoveries are illustrating major biological principles and technical achievements that may be applied towards mass production. I would like to say I'll follow some logical order as I discuss them...but I can't. There are just too many converging and diverging points for a linear discussion. In my next post, I will use an example from adult stem cell transplantation to point out key lessons we have learned from its challenges and what can be applied to meet expectations.

I think we can all be optimistic about the future of regenerative medicine. It may seem like a convoluted mess now, but I think the problems are approachable if broken down in the right way. The research done today was unfathomable a mere decade ago, and may be ho-hum a few decades from now. Let's just try to relax and enjoy the ride.

Image credits: ©2008 Terese Winslow (http://stemcells.nih.gov/info/media/defaultpage.asp)

References:

1. Takahashi, K and Yamanaka, S. Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors. Cell 126(4), 663–676 (2006).
2. Kim, D. et al. Generation of Human Induced Pluripotent Stem Cells by Direct Delivery of Reprogramming Proteins. Cell Stem Cell 4(6), 472–476 (2009).
3. Anokye-Danso, F. et al. Highly Efficient miRNA-Mediated Reprogramming of Mouse and Human Somatic Cells to Pluripotency. Cell Stem Cell 8(4), 376–388 (2011).
4. Jia, F. et al. A nonviral minicircle vector for deriving human iPS cells. Nature Methods 7, 197-199 (2010).
5. Huangfu, D. et al. Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds. Nature Biotechnology 26, 795–797 (2008).