Understanding stem cell biology

 

Interest in stem cells is not new.  Biologists have been keen to understand how they work since the late 1800s.  Recently there has been renewed interest in discovering how stem cells might be used to cure diseases or treat injuries such as spinal cord traumas and burns.  In order to do this we need to know much more about the basic biology of stem cells.  What is a stem cell?  All organisms are made of cells.  Some organisms, like bacteria or yeast, consist of only one cell.  Complex organisms like people are made of nearly 15 trillion cells.  Special groups of cells in complex organisms are set aside to do different functions that the organism needs—these are called tissues and organs.  Liver cells make up the liver and they do liver things, like detoxify chemicals.  Blood cells carry oxygen and fight disease, while muscle cells create force on the skeleton (made by bone cells) in order that we can move.  But every person of 15 trillion cells was once a single cell, a fertilized egg.  How this one cell divides and divides and how each new cell decides where in the body to go and what kind of cell to be is one of the great remaining mysteries of biology.  We do know that as this happens, cells change from being able to have many potential fates, to deciding what they will be and being just that one kind of cell.

 

Controlling the decision of what to become

 

We already know how some kinds of stem cells make their decisions, but only in the crudest terms.  Stem cell cultures grown in a laboratory dish under the right conditions will divide and divide to produce a large population of stem cells, each retaining their ability to become many kinds of specialized cell.  But change the growth conditions, and amazing things can happen.  If the conditions are changed in one way, the stem cells will change into nerve cells.  Change the growth conditions in another way, and the stem cells will become heart muscle cells.  A third way, fat cells and a fourth way, bone cells.  For many of the experimental stem cell cultures used in labs around the world the exact features of the culture conditions that triggers these changes are unknown.  Also unknown is the means by which the stem cell responds to this signal, and how the signal changes the activities of the stem cell.  Specialized cells have special jobs and for any job, tools are required.  The tools of the cell are its proteins, for example the red blood cells carry oxygen using the protein hemoglobin, which is produced only in red blood cells, because the genes that code for it are turned on when a cell becomes a red blood cell, but not in other cells.  Likewise every specialized cell has a specialized set of genes turned on to produce the proteins it needs to do its special job.  So we know that as a stem cell becomes a specialized cell, it makes the proteins that are found in cells that do that job.

 

What could we do if we knew how to control stem cells?

 

The ability to control stem cell growth and decision-making would help us use stem cells for curing disease.  How?  If we could get stem cells growing without making their decisions, we could make a large enough population of cells and then trigger them to turn into whatever kinds of cells we need.  If heart tissue is damaged, we would trigger differentiation of heart cells, and then inject or place these cells in the damaged heart.  Perhaps cells would only make their final decisions once they come to a place where other cells help them finish deciding what to do.  In essence we would trigger the cells to make a large part of the decision and apply them to the place where we hope they will pitch in and repair the damaged or degenerating organ.  This is going to take a lot of work and experimentation, so brand new therapies may be many years away.  But success has already been obtained with many stem cell approaches, some of which have been used for many years already.  Bone marrow transplants are a common kind of stem cell therapy that works fairly well if the “match” is good between the donor and the recipient.  Bone marrow is where blood stem cells live.  Blood cells are constantly generated throughout life, so blood stem cells exist in everyone through adulthood.

 

Early changes in stem cells tell about their final decisions

 

In our lab we have a special expertise we have been developing for many years.  This method allows us to observe special changes in a step of gene expression called “RNA splicing” which can change the kinds of proteins the cells are producing.  We observe these changes using “microarrays”, tiny chips of glass that contain many thousands of tiny spots of DNA that can tell us about which genes are on and in what way they are being spliced.  As a stem cell comes to the decision about what kind of cell it will become, a change comes over the cell.  As in decisions that people make for themselves, this change is not immediately evident from the outside.  With our technology, we can see the inside evidence for this decision at a very early stage.  Changes in gene expression and in particular in RNA splicing are necessary early events we can see early on, before the cell begins to change its outside character.  Using this information, we will be trying to understand what it is about the cell’s environment or growth conditions that lead it to make these earliest decisions, and where in the cell and by what mechanisms these decisions are made.  Such information will help us with the rules for turning stem cells into the exact kinds of cells we want them to be.  This knowledge will be critical for developing safe and effective stem cell therapies for use in humans.  Because safety is important, we are only working with mouse stem cells at this time, however in fundamental ways, mice and humans are very much the same.  So most of what we can learn with mice can very quickly be tested with human cells.

 

This project is funded by a training grant from The California Institute for Regenerative Medicine.  Early technology development was supported by University of California Cancer Research Coordinating Committee, the National Institute of General Medical Sciences, The Packard Foundation, and The Howard Hughes Medical Institute.  Affymetrix, Inc. has been a helpful collaborator.

 

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