Last week, I reported on this new breakthrough in stem cell research, in which scientists have discovered how to trigger the stem cell state in adult somatic cells, like skin cells, producing an induced stem cell, a pluripotent cell that can then be lead down the path to any of a multitude of useful tissue types. I tried to get across the message that this is not the end of embryonic stem cell (ESC) research: the work required ESCs to be developed, the technique being used is unsuitable for therapeutic stem cell work, and there’s a long, long road to follow before we actually have stem cell “cures” in hand. A review on LiveScience emphasized similar reservations. Seizing on this one result as an excuse to end research on ESCs would be a great mistake.
So let’s consider what it takes to turn a stem cell into a medically useful tool. One “simple” (we’ll quickly see that it is anything but) example is finding a cure for type 1 diabetes. We understand that problem very well: people with this disease have lost one specific cell type, the β cells of the pancreas, which manufacture insulin. That’s all we have to do: grow up a dish full of just one cell type, the β cells, and plant them back in the patient’s gut, and presto, no more diabetes (setting aside the chronic difficulty of removing whatever destroyed the patient’s original set of β cells, that is). Sounds easy. It’s not.
Turning one cell type into another cell type is a routine procedure in normal development: a good part of development is simply that, the process of induction, or using external signals to activate a particular pattern of gene regulation in a target cell. What we want to do is induce a generic stem cell to express all the genes and proteins found in a β cell — we want to know what the switch used by the embryo might be. If we know how the embryo normally switches on the β cell genes, we’ll just flip that same switch in our culture of stem cells.
Here’s our first problem: in normal development, we don’t go straight from pluripotent stem cell direct to pancreatic β cell. There is a simple molecular switch, all right, but it’s a switch to turn a restricted cell type, a pancreatic endocrine progenitor cell, into a β cell. Only the pancreatic endocrine progenitor cell has a receptor for the molecular signal (it’s in a state developmental biologists call competent). You could throw buckets of the signal, whatever it is, at the stem cell, but if the stem cell is not competent, it is blind and will not respond. So, clearly, what we need to find is the molecular signal to switch the stem cell into a pancreatic endocrine receptor cell, hit it with that, then expose it to the β cell inducing signal.
But wait! The embryo’s cells do not normally switch from stem cell direct to pancreatic endocrine receptor cell — it isn’t competent to receive the pancreatic endocrine receptor cell signal. We need to convert our stem cells into pancreatic endoderm cells first, so that they’ll be able to read that signal.
And so it goes, back and back. Development is hierarchical and sequential, and you have to carefully shepherd your cells through a whole series of steps in order to get to that final desired state; there don’t seem to be any shortcuts, or at least not any shortcuts that don’t create additional dangers. In order to understand how to turn on the β cell fate, we need to understand the whole developmental pathway that leads to that cell, and we have to recreate it in the dish. Here’s the normal developmental hierarchy:
To make a β cell, you have to first convert ES cells into mesendoderm, then into endoderm, then into Anterior Definitive Endoderm (ADE), then into midgut endoderm, then into general pancreatic tissue, then into pancreatic endocrine cells, and finally, you can apply a signal to switch them into the β cell state. This is a non-trivial problem in a dish. In the embryo, the series of switches are applied to the cells as different tissues come into contact with them and as the internal environment of the embryo changes over the course of normal development — but all those signals are absent in a dish that only contains stem cells, so the researcher has to apply them sequentially and in the proper dosage manually. As the diagram illustrates, many of the signals are known—molecules like nodal and FGF and Notch.
Here’s the good news: researchers can do this! The yields aren’t great, and it takes a meticulously applied protocol, but human embryonic stem cells have been grown in culture and carefully steered down the developmental pathway to produce β cells that secrete insulin. An example of the steps and various molecular markers assayed is shown below.
Notice that in order to do all of this work we need detailed knowledge of the normal course of pancreas development, and many labs and many experiments are required to work out all of the steps. β cells derived from human ESCs have been made in culture, though, and have even been transplanted into mice with type 1 diabetes, where they have rescued the mice from hyperglycemia. So the cure is around the corner, right?
Not quite. Efficiency and expense are a huge issue; none of these protocols are ready to deliver volumes of transplant-ready β cells. Another issue is that the transplanted cells aren’t quite right—sure, they express insulin, but they have other properties that are odd for β cells, and they might not be a stable, self-regenerating population. Another very serious concern brought up in my previous description is that scientists are working with pluripotent stem cells, and one common assay is to inject these cells into a host mice and observe the development of teratomas, cancerous tumors that contain many different tissue types. Some of the experiments that transplanted pancreatic cells induced in culture from stem cells had the side effect of riddling the host pancreas with teratomas … an ugly fate for a mouse, and one you definitely don’t want to risk in a human patient.
Being able to generate induced stem cells from human skin cells is an important step, but it’s only one step, and it’s also a step at the very beginning of the process; the political triumphalism that is being used to declare the ethical dilemmas resolved and the biggest problem in stem cell research completely solved are premature and wrong. We have a long way to go yet before medicine can deliver useful therapies from what is currently very basic research, and we also need ever more detailed understanding of the intricacies of development in the human embryo.
And note that what I described above is the path to solve a relatively simple problem, the induction of a single cell type. The reconstruction of whole organs and the repair of complex tissues is orders of magnitude more complex. It’s good to get excited about the science being done at every step, but we also have to be realistic about the immensity of the problem being addressed. Let’s not get so satisfied with the small but crucial answers being found that we lose sight of the grander goals, and shut down research in the mistaken idea that the big problems have been solved.
Spence JR, Wells JM (2007) Translational embryology: using embryonic principles to generate pancreatic endocrine cells from embryonic stem cells. Dev Dyn 236:3218-3227.