Stem Cell Research, a primer

[Science!]
ADULT STEM CELL RESEARCH
and the Future of Medicine

by Natalie Kardos

Stem cells. We’ve all heard the hype and at least one side of the story. But have we heard all the details? What are these mythical, magical cells that seem to hold the possibility of cures for many diseases, at the possible expense of embryonic lives?

First of all, what defines a stem cell? There are several requirements. The first is that they are cells that have the potential to divide and create cells that are of different types. For instance, one cell may give rise to both red blood cells and white blood cells – two types of cells with very different functions. Given that most cells are supposed to divide and create exact replicas of themselves, this is a very strange phenomenon. Scientists are still in the process of figuring out how this occurs and how we can use it to our medical benefit. Right now, this is the main problem that lies in the way of utilizing so-called “adult” stem cells.

Another issue with utilizing adult stem cells is that they are simply very hard to find. Not only are they exceedingly rare, but for most types of stem cells, a definitive set of markers has not been determined. Markers are a way of distinguishing different populations of cells, and they can also sometimes be used to isolate these cells from a large population of different types of cells. Physically, they are usually proteins that are found sticking out of a cell’s surface. On a cellular level, they provide contact with the cell’s outside environment and can receive signals from other cells that tell them how to act. Different types of cells respond to different signals, and sometimes the response to the same signal can vary. This is all dependent on which marker proteins a cell contains. Therefore, they are usually a reliable way to tell different cell types apart.

However, a specific marker protein is rarely found on one type of cell, and thus it is usual for a combination of marker proteins to be used to identify specific cell types. In the case of most types of adult stem cells, the jury is still out on what combination of markers defines that cell population. Therefore, they are extremely hard to reliably isolate.

A second characteristic of a stem cell is that it can divide an infinite number of times, while retaining its capability of forming different cell types. Most cells in our bodies have a finite number of cell divisions. After this point, they die off due to a combination of factors. One of the factors is simple mutation. On average, a cell accumulates one mutation per cell division, and after enough time, these mutations start interfering with the cell’s normal processes. In most cases, this actually prompts the cell to basically commit suicide for the good of the rest of the body. However, in some cases, these mutations interfere with the suicide program, which can lead to cancer.

Another factor that causes cells to normally die after a certain amount of divisions is that every time a cell divides, it has to make a copy of all of its DNA. However, the machinery that does this is imperfect in most cells and therefore, each time a copy of a chromosome is made, a little bit of DNA is left off the end of each chromosome. At first this isn’t a problem, because the DNA at the very end of each chromosome is sort of “spacer” DNA. It doesn’t code for protein, and therefore it’s not a problem if a little bit of it is lost. However, the more a cell divides, the more DNA it loses, and eventually it does start eating away at the gene sequences that code for important proteins. Again, this usually causes the cell to kill itself for the greater good.

Interestingly, stem cells have devised a way to keep this DNA at the end of their chromosomes when they divide. They basically have activated a protein that usually does not do anything in a normal cell. Cancer cells have also found a way to turn on this machinery, but scientists don’t quite have it figured out just yet.

So those are the general characteristics that scientists use to define what is, and what is not, a stem cell. So what’s the deal with adult stem cells versus embryonic stem cells? Obviously, adult stem cells come from adults, and embryonic stem cells come from embryos. But there’s more to it then that.

As of now, scientists have not been able to find adult stem cells that can form every type of cell in the body. There have been reports of adult stem cells that were previously only thought to make certain cell types actually being forced to make new cell types, but these reports are few and far between. It is also sometimes hard to reproduce these results in different labs, even when the scientists are following the exact same procedure. There is still a lot to learn about how these adult stem cells work, and how we may be able to manipulate them to create all sorts of cells.

Embryonic stem cells, as stated, come from embryos that are usually about 5 days old. At this point, the embryo looks like a little ball of cells. And these cells are known to have the potential to make every single cell type found in the body. If you think about it, it has to be that way. We all start off as a single cell, and end up as a complex assortment of very specialized cells. So this single cell we started off with must have been able to “differentiate” into many different cell types. Five days after fertilization, all the cells in that cluster of cells have the potential to make any cell type in the body.

But this is where we run into ethical problems. To get these stem cells, an embryo must be created, and an embryo, no matter what stage, is considered by some people to be a human life. Once the stem cells are collected, this life does not exist anymore. Currently, there is no way to derive embryonic stem cells without undergoing this process.

In 2001, President Bush came up with what he considered a compromise between studying the exciting medical potential of these cells and the moral dilemma posed by creating embryos for the sole purpose of generating these cells. His compromise was to allow funding of stem cell “lines” that had already been created (more about those lines in a second), but not fund any research that involves the creation of new lines. This may sound like a good compromise to most people, but it actually falls quite short of what is necessary to be able to use these cells for any medical benefit.

So what are these stem cell “lines,” and why are they just not good enough? In science terms, a cell line is a bunch of cells that have been successfully grown “in culture.” Basically, this means that they grow on a dish in the lab, under conditions that are meant to roughly duplicate those found inside the body. This means feeding them complex mixtures of nutrients and other proteins that are necessary for them to continue growing without undergoing cell suicide. However, this isn’t an exact replica of what’s gong on in the human body. And by growing them in a confined space, you are automatically selecting for the cells that don’t commit suicide when they come in too close of contact with other cells. This is a characteristic that is shared with cancer cells, which aren’t exactly an accurate model of normal human cells.

Also, cells growing in culture continue to divide. With normal cells, you run into the problem of them dying off after a certain number of divisions, due to the loss of the ends of their chromosomes. Fortunately, with stem cells we don’t run into these problems because they have turned on the machinery that retains the ends of their chromosomes. However, you still run into the problem of one mutation occurring during each cell division. Therefore, the longer these cells live in culture, the more mutations they pile up. And with each mutation the stem cell accumulates, the less it actually functionally resembles a normal stem cell. The implications of this are vast. It may mean that any research done on these cell lines is useless. Even if we determine a way to coax stem cells into becoming specific cell types, normal cells may not behave the same way. Also, due to these mutations, it is unlikely that any of the cells from these cell lines can be introduced back into humans, say as a cure for Parkinson’s disease. The chance of these cells causing cancer upon reintroduction into humans is just too high. It’s like saying, “Hey, we can cure your Parkinson’s, but only by giving you cancer.” What kind of a treatment is that?

A slightly lesser problem with these cell lines is that they were all formed before we knew how to grow them properly. It was not fully understood what nutrients these cells needed to survive. So we cheated a little bit and started out by growing them on a layer of mouse cells that secreted all kinds of nutrients, and that managed to keep these cells alive. However, while growing on these mouse cells, it is entirely possible that the stem cells came into contact with mouse pathogens or other factors that could be detrimental to humans, or at least cause the cells to act differently from normal stem cells. These are just more reasons why these cell lines will never be used to treat humans, and may not be the most useful research tools. Since 2004, scientists have discovered ways to grow embryonic stem cells without the help of mouse cells. Unfortunately, all of the stem cell lines that are in compliance with the federal regulations have been in contact with mouse cells at one point or another, and any new lines that are created using the new techniques are not eligible for federal funding. It’s quite strange to continue funding something that doesn’t really have a medical use, while simultaneously banning funding of something that could very well save a lot of human lives.

So how close are we to actually having viable stem cell treatments for diseases? Well, it all depends on the disease. For instance, a treatment for spinal cord injuries is probably pretty far into the future, because it involves the repair of many different cell types. In contrast, a treatment for Parkinson’s could be just around the corner. That corner, in this case, is FDA approval. Parkinson’s is caused by the death of one specific cell type, and this cell type is fairly easy to replace with stem cells. A number of studies in both rats and mice with Parkinson’s-like symptoms have shown remarkable promise. However, in order to treat human patients, it is likely that new embryonic stem cells will have to be derived, for reasons already mentioned in this article. And since our government is the biggest source of funding for most labs, the lack of funding for creating new stem cells is putting this research on hold, or at least slowing it down substantially.

It’s easy to understand the ethical dilemmas surrounding embryonic stem cells these days. But what most people don’t understand is that they are merely a starting point for scientists. It’s hoped that in the future we will be able to use adult stem cells to do everything that embryonic stem cells can do. Allowing embryonic stem cell research won’t hinder adult stem cell research. It’s merely that, if we want to coax adult stem cells into behaving like embryonic stem cells, we need to have a firm understanding of how embryonic stem cells work. And the way to do that is not to study mutated embryonic stem cells that have been out of their natural environment for a long time. The key to understanding these cells is to study them in an environment as close to normal as possible, which means using newly isolated cells, at least for the time being. Unfortunately it means destroying a few embryos (mostly embryos from fertility clinics that were already created and would eventually be thrown out anyway), but in the long run, it may save millions of lives. NK