July 15, 2001
By DAVID J. ANDERSON
PASADENA, Calif. — As a biologist involved in stem cell research for over a decade, I find the current debate over human embryonic stem cells increasingly detached from scientific reality. Embryonic stem cells are primitive cells with a broad potential to differentiate into any specialized cell type in the body — liver cells, for example, or insulin-producing cells, or specific types of neural cells. They are infant cells that have not yet chosen a profession.
One argument being made against federal financing of embryonic stem cell research is that stem cells from adult tissues can be used instead. These less versatile adult stem cells normally generate only the specialized cell types of the organs that harbor them; the focus has been on blood-forming stem cells from bone marrow because they are relatively easy to access. Some experiments suggest these stem cells have the potential to make mid-career switches, given the right environment, but in most cases this is far from conclusive.
In any case, it is one thing to say that stem cells have the potential to do something; it is quite another to figure out how to reveal that potential and control it. What seems lost in the current debates is a sense of how difficult it really is, in practice, to get stem cells to do what you want them to.
Let me relate a story from my own experience to illustrate this. My laboratory at the California Institute of Technology studies neural stem cells, the stem cells that build the nervous system in the developing embryo. (We work on stem cells taken from rat embryos.) These are "tissue-specific" stem cells, gathered at a later stage of embryo development than embryonic stem cells, which are taken much sooner after an egg is fertilized.
If embryonic stem cells have an unlimited choice of occupational alternatives, these tissue-specific stem cells, even though not yet adult, are like young professionals already embarked on a career: they still have options, but fewer of them. For example, the neural stem cells can make several different types of neurons, as well as glia (the cells that provide the electrical insulation for nerve fibers), but they don't make blood or liver cells. Nevertheless, if we can find out how these stem cells choose among their various professional options, maybe it will help us understand how the more multifaceted embryonic stem cells make their choices.
I remember clearly the day when one of my graduate students rushed into my office to tell me that he had finally figured out how to reveal these neural stem cells' hidden potential. For years, these cells had been sitting in our petri dishes, stubborn and recalcitrant, refusing to reveal even an inclination to make neurons. So resistant were these cells to being prodded into becoming neurons by any molecular compounds we exposed them to that for a long time we thought they were relegated to producing only glial cells.
So you can imagine our surprise when the magic fertilizer that allowed some of them to blossom into neurons, sprouting axons and dendrites like branches on a bougainvillea, turned out not to be some complicated mixture of fancy hormones or proteins. Rather, it was a boring compound that we used to coat the plastic bottom of the petri dish in order to afford the cells a stickier platform to which to attach. Never would we have predicted that such a prosaic change could exert such a powerful effect. Yet it turned out to be the key that unlocked the hidden neuronal potential of these stem cells.
Now we knew that these stem cells could become neurons or glia — that there were at least two career paths available to them. But we still had no idea how they decided which path to choose. Day after day, week after week, month after month, we poked and prodded the cells with different molecular signals to try to force them into one career at the expense of the other. But like stubborn children heedless of their parents' sage advice, these stem cells seemed to have minds of their own. We'd plant a stem cell on its petri dish and come back the next week to find it had generated a whole village of cells, teeming with thousands of both neurons and glia — both career paths seemingly chosen at random.
One morning, another student showed up in my office and asked me coyly if I wanted to see something cool. When I stared down his microscope, I was amazed to see colonies of cells that had all become neurons — not a glial cell in sight! By trial and error and some educated guessing, he had finally found a molecular signal that the stem cells would heed, one that coerced them all into a neuronal career. In time, he found other signals that could lead the cells in other directions as well. While if left to their own devices these stem cells listened to their own drummer, you could coax them in a particular direction once you finally found the right beat.
All of this shows how difficult it can be to learn to speak the stem cells' language. If it is this hard to figure out how to make even a relatively educated neural stem cell make neurons rather than glia, imagine the challenge of discovering how to prod the more naïve embryonic stem cells into making one or the other of the 200 different specialized cell types in the body.
Yet this is still a more promising path of research than trying to coax adult stem cells, which may be present only in certain organs, to abandon their long-accustomed functions and generate wholly different types of cells for use in treating human disease. Research on adult stem cell plasticity should surely go on, but not at the expense of embryonic stem cell research.
My colleagues who work on embryonic stem cells are making steady and encouraging progress in revealing the potential hidden in their petri dishes. Yet much of stem cell research is still basically alchemy. We keep throwing things into the bubbling cauldron of our petri dishes until something emerges.
But the exciting thing is that something eventually does emerge — if you have the patience, dedication and financing to support the work. With such trial-and-error research, the more people there are working on the problem, the faster we will discover all the signals necessary to get embryonic stem cells to make all the different cell types in the body. Without federal funding, there will be only a limited number of people able to work on human embryonic stem cells and the research will proceed slowly. And as the solutions are delayed, people will die who might otherwise have been saved.
David J. Anderson is a biology professor at the California Institute of Technology.
Copyright 2001 The New York Times Company