Madison, Wis. – Cut a flat worm in half, the tail will grow a new head and the head a new tail. Cut it right down the middle, it will grow a mirror image. How does it know what to grow?
Flies re-grow damaged tissues. Small fish regenerate heart muscle. Why can’t humans?
How do stem cells know to become heart, muscle, liver, neurological and other cell types?
These questions are at the center of the brave-new-world of stem cell biology and were the topic of the recent 3rd annual Stem Cell Symposium. The overriding lesson from the conference is that stem cells regulate their development into different tissues using mechanisms that are conserved across species as divergent as worms, flies, fish and mammals. All very interesting for a developmental biologist, but does any of this have practical application for using stem cells to treat human disease? The answer is yes, and let me explain.
A primer on stem cell science
Consider what needs to be accomplished for an immature stem cell to differentiate into, say a beating heart cell. First, there needs to be a stimulus that tells the stem cell to move specifically into the cardiac developmental pathway. The stem cell must then begin expressing heart cell genes while repressing all other genes that would cause it to become liver, blood, kidney and all other cell types.
Once the stem cell develops into a cardiac muscle cell, it remains that type of cell. We never see a heart cell become a skin cell and vice versa. Cellular development is unidirectional and this has been one of the central tenants of developmental biology.
Then along comes Scottish scientist, Ian Wilmut, who did an experiment in the mid 1990s that no self-respecting developmental biologist would attempt since we all “knew” that a fully mature cell does not go backward in development.
Wilmut removed the nucleus from an egg cell and replaced it with the nucleus from a fully mature cell taken from a different animal. Keep in mind that this donor nucleus had already been directed to express only those genes of the tissue it was taken from and to repress the expression of genes from all other tissues.
Wilmut then transferred this engineered egg into the womb of a pseudo-pregnant sheep, where the egg should have died. Instead, a sheep was born that was a genetic twin of the nucleus donor and the world was introduced to the first cloned animal, Dolly.
For the first time, we realized that the genetic program of an adult cell can be reprogrammed to relinquish its adult cell properties and return to a stem cell state, capable of developing into a fully grown sheep.
About the same time that Dolly was born, UW-Madison scientist Jamie Thomson published his seminal work demonstrating the ability to grow monkey and human embryonic stem cells (or ESCs). These are the immature cells obtained from five-day-old embryos that are able to develop into all tissues of the adult body.
Fast forward 10 years to the conference, where Thomson gave an update on his recent report that he is able to reprogram adult cells to become stem cells without having to transplant cell nuclei. When he looked at recent research from different labs, he noted that only a few regulatory genes are needed to maintain cells in their nascent developmental stage. As the research presented at the conference illustrated, these regulatory genes work across different species, so this mechanism is highly conserved in biology.
Thomson used routine gene transfer technology to induce expression of three different regulatory genes in the cells of mature fibroblasts and, amazingly, these mature cells were re-programmed to become stem cells! What Wilmut was able to do by transferring a cell nucleus to an enucleated egg can now be done in a petri dish.
At the conference, Thomson explained that these “induced pluripotent cells” or iPCs behave exactly like ESCs. This means that mature cells from an adult can be re-programmed back to the stem cell state where they are able to generate anew, all tissues of the human body.
What is the future for stem cells?
UW-Madison stem cell researcher Clive Svendsen, who moderated the conference, believes that in about a year, we can use all of this new information to develop ways to derive iPCs by simply changing the tissue culture environment in which adult cells are grown. Thus, it soon may be very easy to derive stem cells that contain your precise genetic makeup and without having to destroy an embryo or create a clone of you.
Svendsen opined that this could lead to a big boost in the tissue storage business as people bank tissues when they are young for making stem cells if they should need them later. This would be necessary because, as Thomson explained, chronologically young cells are more efficient at being reprogrammed than cells from older animals.
As exciting as the science was at the conference, there remain problems to resolve before stem cells are used in the clinic. First, as with ESCs, when injected into animals, iPCs will form tumors. Therefore, we need to develop a fail-safe way to completely separate or incapacitate contaminating stem cells from the functional tissues grown from them before we put them into patients. The FDA recently held a meeting to grapple with this problem in anticipation of clinical trials.
Next, even if we can use stem cells to regenerate damaged tissues, we still need to learn the causes of degenerative diseases because simply replacing the dying cells without dealing with what causes them to die will only be a short-term fix.
Still ethical issues?
Finally, and potentially an explosive issue, there remains an ethical question regarding iPCs that no one seems to have addressed. When a mature cell is reprogrammed, how far back does it go? Are iPCs, like ESCs, only able to develop into different body tissues, or can an iPC, if given the chance, form an embryo? Of course, if the iPC cells are more like fertilized eggs than stem cells, then all bets are off.
The ethical issues arise again. Both Svendsen and Thomson admitted that this idea had not been tested. Svendsen even owned up that no one in the field wants to test it because they are worried what the answer might be.
Recent columns by Steve Clark
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