Stem Cells

Written and produced by Bill Stonebarger

Here is an experiment. You are watching human stem cells dividing. And dividing. And dividing. So far as we know today these are the only cells in the world that can keep dividing and dividing and dividing ... Indefinitely. The only cells in the world, in other words, that are immortal!

The dividing stem cells you are watching here are from the laboratory of James Thomson, a professor at the University of Wisconsin. It was here in this laboratory in Madison, Wisconsin that Thomson and his colleagues first discovered a way to culture stem cells and to get pictures like these. And it is here at what is called the WiCell Institute that five of the most fruitful stem cell lines in the world are now being cultured and distributed for world-wide research.

What exactly is a stem cell? Dr Timothy Mulcahy, one of James Thomson’s colleagues, explains.

“Well, I think the simplest way to explain that is to think of stem cells as a pretty much a blank cell. It is a cell that has the potential to do anything that any cell in the body does, but it hasn’t received specific instructions yet as to which particular program to follow. So the beauty of stem cells is in the potential they offer for medicine, for example, is if we can understand the signals that will tell the cells which programs to follow we could then develop cells to replace cells that are injured in heart attacks, or we could make neural cells that could replace deficits that people suffer in Parkinson’s disease and others. So unlike any other cell in the body which is already following a preordained program, these cells are sitting there waiting to be told what to do and if we can understand the science of how to do that we have a very powerful tool to treat disease.”

Where do stem cells come from?

There are two kinds of stem cells. One type is embryonic stem cells. The second type is adult stem cells. Let’s look first at embryonic stem cells. Embryonic stem cells, as the name implies, come from a very early stage of the human embryo. All human embryos begin with a male sperm uniting with a female egg. This fertilization usually happens inside the mother’s body.

In modern in-vitro fertilization clinics, however, couples who for one reason or another cannot conceive normally, allow their sperm and egg cells to unite in a laboratory petri dish. The fertilized eggs in the laboratory are given the right nutrients and allowed to grow to a very early stage and then implanted in the uterus of a potential mother where they grow to term and are born as healthy babies. In in-vitro fertilization there are usually more embryos formed than the couple can or want to use, and the unused ones are frozen or destroyed.

Today some of these unused embryos are being made available, with the consent of the donors, to scientists like James Thomson who want to study stem cells.

A fertilized egg in the right environment begins to divide. One cell divides to become two cells. Two divide to become four. Four become eight; eight-sixteen; sixteen-thirty-two; thirty-two sixty-four; sixty-four, one hundred and twenty-eight.

At this point, 5 to 7 days after fertilization, the embryo is still a clump of cells, embryonic stem cells we call them. Each of these hundred or so stem cells has the potential to further divide and then differentiate to form blood cells, muscle cells, bone cells, nerve cells, skin cells. Eventually the trillions of cells that make up a human baby. At this very early stage, however, it is only a potential. As yet the embryo has no differentiated cells, no tissues, no organs, no feelings, no consciousness, no experience.

What Thomson and other researchers around the world have done is to take some of these very early stem cells before they have begun to differentiate, separate them out and culture them in the laboratory.

“Unlike a lot of cell lines that we grow routinely in the lab, we know how to grow very well, these cells are very finicky and we really don’t completely understand all the nutrient requirements, for example, that they have, so we can’t easily grow them. So one of James’s major accomplishments was discovering a system, which would allow us to grow them in the laboratory....It is very, very labor intensive in the sense that you have to watch the cells very carefully, you have to be very scrupulous in what you provide in terms of media and nutrients for the cells, and you have to make sure that they don’t begin to differentiate and that is one of the tricks here.

“These cells because they are a kind of blank slate to start with, if they receive a signal to tell them to start going down a certain path they will go down that pathway so a lot of what we want in the laboratory and what James is interested in to study the cells in their very earliest stages before they have the pathways to follow.”

One big difference between stem cells and all other cells of the body is that all other cells have an internal clock. They only divide a set number of times, and then die off. Some years ago a researcher named Leonard Hayflick discovered what that set number was. About 50. That is, human body cells seem to reproduce about 50 times and then that’s it, they die of old age. And this is one of the reasons that you too, barring accidents or disease, eventually die of old age.

“Stem cells are such that their biology allows them to continue to grow as far as we can tell, indefinitely and so that gives us two opportunities: One, we can have a long period of time to study the cells. Two, we can get large numbers of cells which are going to be necessary for any therapeutic applications. So the real trick and we don’t quite understand why these cells don’t start their biological clock, their clock is set at zero and hasn’t started timing, and again that is one of the most incredible features.”

The hope is that researchers around the world will discover the right signals that will make stem cells turn into healthy muscle cells, or blood cells, or nerve cells. There have been some successes already.

Dan Kaufman and his colleagues at the WiCell Institute discovered ways to signal stem cells to develop into the blood cells you see in this photo through the microscope.

In November of 2001 Dr. Su-Chun Zhang and his colleagues at WiCell Institute produced stem-cell derived neurons. The stem cells were successfully transplanted into the brains of newborn mice.

“The neuron that we’re seeing after transplant is almost identical to what the neuron should be in the healthy brain,” reported Dr. Zhang. “These transplanted cells had no experience in the brain, and we wanted to see if they would mirror the development of the mouse brain,. And they do. These are the cells that will be used, ultimately, to treat Parkinson’s and other central nervous system disorders.”

In 2005 Hans Keirsteed of the University of California demonstrated that injecting embryonic stem cells into the damaged spinal cords of rats did help them regain mobility! “I am extremely enthusiastic,” Said Keirsteed. “I am past the point of hope. In my mind the question is when. What we are seeing in these animal models is tremendous.”

A private biotechnology company, Geron in Menlo Park, California, is planning the first actual clinical trials of this technique with selected human subjects in the summer of 2006.

Keirsteed was also one of the leaders in California’s Proposition 71, which passed overwhelmingly in 2004 and is now providing $3 billion in new funding for embryonic stem cell research.

Other promising examples are treatments for diabetes and heart disease being worked on every day in California, Wisconsin and many other states and countries around the world. Dr. Mulcahy explains some of this work.

“In the laboratory and in laboratory animals now it has been possible to get embryonic stem cells to differentiate into the cells that make insulin and to respond to sugar the way cells in the body normally would... Another area that offers a lot of promise is in the treatment of heart disease. When someone has a heart attack the blood supply to part of the heart is cut off and those cells basically starve themselves of oxygen and die. Like many adult tissues cells in the heart don’t repopulate, they don’t re-divide ever in an adult so once you’ve lost those cells, you have lost them forever. “

“There is a lot of evidence now with stem cells that you can inject stem cells into an animal for which there has been an experimental heart attack induced and the stem cells actually home into the site of injury in the heart and actually differentiate in the heart cells which actually begin to contribute to the functioning of the heart so there is a lot of hope that it can be used to treat heart disease which is one of the major causes of death in this country.”

Probably long before such stem cells are actually injected into live beating human hearts, they will almost certainly be useful in another related application. Once you learn to form cultures of specialized cells derived from stem cells, new drugs can be tested on these cell cultures instead of on live animals or people. This will not only save large amounts of time and money, it will also save large amounts of animal and human pain and suffering.

James Thomson, lead developer of the first stem cell lines at the University of Wisconsin, Madison, announced in 2005 that he and two of his colleagues were starting a private company to generate just such cells. In his case they want to produce embryonic cell-derived heart cells. These cells would be made available to researchers around the world specifically for drug testing, rather than direct transplantion into humans.

Besides embryonic stem cells there are adult stem cells. These are cells that come from adult tissues. Adult stem cells, however, are much more difficult to isolate, do not seem to have the same indefinite life span, and while they can change somewhat into other kinds of cells, they do not seem to be able like embryonic stem cells to develop into any of the more that 200 cell types in the human body.

Adult stem cells, however, like embryonic stem cells, do offer great promise in specific disease applications. Here the biology of stem cells research merges with the biology of modern cloning technology.

Dr. Neal First, one of the world’s foremost experts in animal cloning, explains one such application and connection.

“The best example of this is research on HIV now. One of the more highly promising therapies on HIV is to engineer blood cells. We call them stem cells. But these are stem cells for the blood lineage are different from stem cells of the embryonic lineage. So we have embryonic stem cells that will make any and all cells of the embryo. But these are blood cell lineage that will make any and all blood cells. And by starting at that stage and engineering the cells properly one has the ability to create cells that will resist the HIV organism and so it is possible to repopulate the blood in place of the cells that are susceptible and two, in some case to destroy the HIV organism.

“Now what cloning does is provide the opportunity to multiply these cells, engineer the cells in transplantation ... These prospects are very exciting and that’s what people are really referring to when they talk about transplantation. And that more than the organ transplant.”

Research on this cellular level also merges with research on the molecular level. The 13-year long Human Genome Project was successfully completed in 2003. We now have a map of the complete DNA sequences that govern human cell life, including cell reproduction. These are the codes that govern the production of all of the proteins made by all of the cells in the human body.

“Many of those proteins are going to be the critical triggers for deciding which way this blank cell is going to go when the time comes and we are already working with investigators on campus to try to look at what genes are uniquely expressed in these cells at their earliest stages, what genes are turned on or turned off when we decide to try to make heart cells from the embryonic stem cells. Having a blue print available is going to be an invaluable tool to help us sort that out.”

Along with the potential for basic research in biology and breakthroughs in the treatment of human health problems like heart attacks, diabetes, Parkinson’s disease, Alzheimer’s disease, birth defects and cancer, there are ethical, legal and moral issues in stem cell research, as in cloning and other biotechnology research and applications.

Dr. Alta Charo is an international expert on legal and ethical issues of stem cell and other research involved in reproductive studies. She has recently worked on a national committee appointed by the President to look into these questions.

In addition to the usual way of obtaining stem cells from embryos created in in-vitro fertilization clinics (as was the case with all five of James Thomson’s cell lines), Dr. Charo pointed out other more controversial ways now being explored.

“Now there are other ways to obtain embryos for the purpose of deriving stem cells. One is in-vitro fertilization lab to simply make an embryo specifically to retrieve its stem cells. “The second is to use cloning technology to make embryos from which stem cells can be derived.

“Now that last experiment has been touted as essential to something called therapeutic cloning which most people understand as the prospect of cloning one of your own cells in order to derive stem cells from it which would in turn be developed into tissue that now is genetically identical to you ... matched for use in transplants.”

Most of the ethical objections to stem cell research come from people who feel strongly that the human embryo, even at its earliest stages, is a human person and entitled to the same protections that all human beings have whatever their age, abilities or disabilities.

“I think that what constitutes a morally significant form of life is one that has gone on for centuries and is not likely to be resolved anytime in our lifetime. At face it touches on things that cannot be proved, on things that cannot be explored through experimentation. For example, whether you think that the essence of moral significance lies in potentiality, or you think the essence of moral significance lies in a kind of experiential view of life, that is, if you believe that the real potential to develop under the right circumstances into a baby means that this form of life must be protected, in other words the acorn should be protected as if it were already an oak, then you are making this value judgment based upon a vision of the world that could transcend time in which we see life as part of a continuum across time.

“On the other hand, there are people for whom that is not a relevant factor and they ask only do we have an entity that can experience itself and can feel disappointment and pain, in other words, can be harmed. And they look at an embryo and say no, it doesn’t even have the biological substrate to be self aware and to have formed a desire to continue to exist, and so it is in no way wrong to harm it. These are very different views about moral significance and they can’t be brought together..”

How can we as a society then decide such irreconcilable differences? Should we simply put them up to a vote, and let the majority rule?

“Well, I personally think there is a lot of guidance within the philosophy of our Constitution. The United States is not governed by pure popular majority. Instead we have a mix. On topics of rather ordinary concern we allow the popular will to prevail so people will be allowed to drink or drive or both or drink or drive at 18 or 20 or at 21 and put them to a popular vote. On the other hand, there are areas of life that we have said are so central to a personal identity that even when popular sentiment would suggest that things should be restricted, we will permit them until the most compelling arguments have been made for restriction and until we have been shown that there is no other way to handle the concern other than restricting the activity.

“Those are things that are listed in the Bill of Rights, the freedom of association, of speech, of practicing your own religion, and it is also a set of things that have been identified by the Supreme Court as implicit within the Constitution and Bill of Rights such as the freedom to marry. Now one of the areas that we need to examine is the freedom of scientific inquiry. There have been suggestions over the years that this is something akin to free speech that just as free speech insures the long term stability of a civic society by providing an outlet for dissent, so we don’t have violent revolution, so scientific inquiry insures the continued development of new knowledge which helps to stabilize society.

"In my mind that is a very important question because if we see it as fundamental to the long term stability of a civic society than it is something that needs to be protected even if it is against the popular will.”

What about the future? What will happen 10 to 20 years from now with stem cell research, scientifically and ethically.

In April of 2005 the National Academy of Sciences proposed new ethical guidelines for research on embryonic stem cell lines that attempt to bridge some of the differences between religious and scientific points of view. The new guidelines oppose reproductive cloning but support therapeutic cloning; pave the way for research projects that inject human stem cells into some animals, but oppose injecting them into non-human primates like monkeys or apes; advise that human embryos should not be grown in culture for more than 14 days, the time when the first hints of a human nervous system begin to appear; and recommend that human egg donors not be paid.

At present the legal status of stem cell research in the United States is a mixed story. Some states have passed laws to ban both reproductive and therapeutic cloning for stem cell research. Other states are considering such bans. On the other hand some states, like California, have passed popularly supported referendums to give generous support to stem cell research in all its variations.

On the federal level there are no laws at present restricting stem cell research. The US government, however, has ordered the National Institutes of Health to refuse federal funding for any stem cell research using embryonic stem cell lines created after Aug. 9, 2001. This restriction is being contested by many scientists as well as many scientific, religious and political groups.

There are similar conflicts about the ethical and legal status of stem cell research in western European countries.

Countries in Asia like China, South Korea, Singapore and Taiwan, on the other hand, place no restrictions on embryonic stem cell research and scientists there are making rapid progress in therapeutic cloning, as well as many other frontiers of genetic engineering and cutting-edge biology.

How fast will progress take us in the 21st century? No one can be sure.

Dr Mulcahy gives voice to the majority view of scientists today.

“I would say 10 to 20 years from now I fully expect that we will have a number of effective treatments using embryonic stem cells, I also would predict that much like what happened in the case of in-vitro fertilization, which at its inception was a real hot button, it will evolve into a much more accepted and appreciated medical tool..”

Just as Dr. Mulcahy pointed to the change of public attitudes about in vitro fertilization over a few decades, Dr. Charo pointed to a similar change in other controversial areas in the past.

"When the first stem cell announcement came out from James Thomson's lab, we saw the very same people rethinking their opinions and saying `well, you know we have these large numbers of people with these terrible diseases like Parkinson's and diabetes, and heart disease, am I really willing to sacrifice, well maybe not for the very earliest embryos, maybe my concerns are really about more advanced forms of fetal life.'

"And we saw it shifting. `But of course, cloning is a terrible thing, and I don't like cloning in any fashion.' Then at the end of 2001 we begin to see a more specific discussion about real medical advances that might be made possible by using cloning -- just to copy a cell and make it divide a few times, but not make it into a baby. And the very people who were most adamantly opposed to cloning, are beginning to separate their opinions into an opposition to reproductive cloning and a tolerance of research cloning."

And indeed, that research continues today. On cloning. On genomes. And on stem cells.

The consequences for the 21st century, for the third millennium are still to be determined.