SciFri 6.17.05: Stem cell research: from crosshairs to crossroads

The blastocyst, a ball of cells that can fit on the tip of a needle, is the source of embryonic stem cells.

What are stem cells, and why does the U of M want to expand its study of them?

By Deane Morrison

Published on June 17, 2005

In September 2000, University of Minnesota doctors gave six-year-old Molly Nash, who suffered from the rare and often fatal disease Fanconi's anemia, an infusion of umbilical cord blood from her newborn brother. Included in the transplant were stem cells destined to become new blood cells. The stem cells migrated to her bone marrow and took up residence, replacing Molly's diseased blood-forming cells, which doctors had destroyed to make room for the newcomers. Four months later, Molly had a healthy supply of blood cells bearing the genetic signature of her brother's stem cells--and a new life.

The Nash case helped put stem cells in the spotlight, and the light has only grown brighter--and hotter. (Stem cells are so called because all cells in the body stem from them.) Few object to using stem cells from adults or from umbilical cord blood for research into the treatment of disease, but opposition to the use of stem cells derived from human embryos has been vocal. As the issue continues to generate headlines, the science of stem cells occupies an ever more prominent place on the national stage.

"This is a make or break time for stem cell research at the University," says Kaufman. "...If we want to make this one of the top three public [research] universities, this is an area that has to be maximally supported. We have exactly the right infrastructure to do this. We can do it on a small scale, or do it right."

The story of stem cells begins when an egg is fertilized and begins to divide. The egg, and the cells formed by the first couple of divisions, are totipotent. That is, their potential is total in that each of these cells can form a whole new organism. After a few divisions, however, isolated cells have lost this ability.

As cell division continues, the embryo becomes a hollow ball of cells called a blastocyst. Inside the ball is a clump of cells known as the inner cell mass, or ICM. After the blastocyst implants in the uterine wall, the ICM cells develop into the new organism. During in vitro fertilization, many blastocysts are formed, each of which could fit on the tip of a needle. One or more are implanted into the mother, and the rest are frozen or discarded. Embryonic stem cell lines are created when scientists remove the ICM cells from a blastocyst and culture them in the laboratory to make more cells. These cells appear to be identical, and they are pluripotent--they can form every cell type found in the body, but not the placenta and other supporting tissues necessary to produce a new organism.

As the embryo develops in the mother, its cells differentiate, meaning they turn into the mature cells that perform the various functions of the body. But some persist as stem cells, especially in tissues like the intestinal lining, bone marrow, and skin, where they give rise to a steady stream of mature cells to replace those that have worn out. These are adult stem cells, and they are found in many body tissues. They are multipotent--each can give rise to cells belonging to a certain related group, such as blood cells, skin cells, or muscle cells, but not to cells of other groups.

Adult stem cells have been used therapeutically. For example, Doris Taylor, holder of the Medtronic Bakken Chair in Cardiovascular Repair, made news several years ago when she repaired rabbits' hearts using adult stem cells called myoblasts, which are found in muscle and normally mature into skeletal muscle cells. The stem cells in umbilical cord blood are also adult stem cells. Such cells have been used to treat leukemia and other diseases occurring mostly in children.

The controversy "stems" from the fact that in order to produce embryonic stem cell lines, an embryo must be destroyed so that its ICM cells can be cultured. In August 2001, President Bush announced new rules that forbade the use of federal funds to support research on any embryonic stem cells except those in about 60 already existing lines. But only 20 or so of those lines have turned out to be useful. Many were contaminated with mouse cells, which had been used as "feeder" cells to keep the human embryonic cells alive and dividing, but not differentiating (once differentiated, a cell is no longer a stem cell). Another problem is that the cells didn't represent a diverse population of human ethnic groups or diseases, so any research carried out on them would not shed light on conditions associated with certain ethnicities or on the ways certain diseases affect human development.

"When Bush made this decision, the idea was in part that these were enough lines to get research going and show what these cell lines could do," says Dan Kaufman, an assistant professor in the University of Minnesota's Stem Cell Institute. "Congress may now want to broaden the rules."

Kaufman came to the University from the University of Wisconsin, where he worked with James Thomson, who, along with collaborators, derived the first five human embryonic stem cell lines. Kaufman uses some of the federally approved lines of human embryonic stem cells to study all the factors necessary to create hematopoietic (blood) stem cells suitable for bone marrow transplant or mature red cells or platelets for transfusion. He is one of two researchers at the institute who work on human embryonic cells; the other is Meri Firpo, a new hire whose main interest is producing pancreatic cells that can aid diabetics. The cell lines she derived while at the University of California at San Francisco are also on the approved list.

In November, California voters approved $3 billion for [embryonic stem cell] research over the next 10 years. Also in November, Wisconsin Gov. Jim Doyle announced plans to invest nearly $750 million in [this] research and other medical experiments.

While the Nash case and the work of Doris Taylor point up the therapeutic potential of adult stem cells, researchers at the Stem Cell Institute see advantages for using embryonic cells for other types of work. For example, embryonic cells can be used to investigate basic questions about human development, unravelling the complex journey of a fertilized egg as it becomes a complete human being.

More than 20 years of work with mouse embryonic stem cells has shown their value for studying development. "Hundreds of people at the University use mouse embryonic stem cells," says Kaufman. "It's a mature field--it's how we understand mammalian genetics." A standard in the field is the "knockout mouse," a mouse in which a gene or genes have been inactivated early in development. The effects of the genes can be deduced by noticing what trait(s) in the mouse are changed. With human embryonic stem cells, one could also knock out genes and note the effects on the development of human cell types.

The Nash case points up another potential for the cells. Molly's brother was the result of in vitro fertilization, which produced numerous tiny embryos. Doctors tested embryos to ensure that Molly's future sibling would be free of Fanconi's anemia, as well as immunologically compatible with Molly. But "leftover" embryos that carry a genetic disease could be used to derive cell lines in which scientists could determine how the disease affects the development of different tissues, which may point the way to future treatments. Now, disease-carrying embryos are almost certain to be destroyed because few surrogate mothers would want to be implanted with them.

The potential for scientific breakthroughs with embryonic stem cells has driven several states to try to support such research with nonfederal funds. For example, in November, California voters approved $3 billion for such research over the next 10 years. Also in November, Wisconsin Gov. Jim Doyle announced plans to invest nearly $750 million in embryonic stem cell research and other medical experiments. In Minnesota, fund-raising for embryonic stem cell research has begun. Last year, a family foundation contributed $25,000 apiece for adult and embryonic stem cell research, says Jennifer Soderholm, director of development for the Department of Medicine and the Stem Cell Institute. But private contributions big enough to offset the lack of federal funds don't come easily.

"I think people want to learn more about stem cells' potential before they donate," says Soderholm.

"Stem cell research has the most promise for preventing and curing disease of anything I have seen come along in my lifetime," says Frank Cerra, senior vice president for health sciences. "To achieve this potential, both embryonic and adult stem cells need to be used in research. University policy does allow the use of embryonal stem cells from blastocysts formed for fertility reasons but no longer needed for that purpose. The policy also requires that private dollars support the research on these cell lines. We need to be successful in attracting private dollars for this important research to move ahead. Stem cell research is one of the key priorities of our fund-raising efforts."

"This is a make or break time for stem cell research at the University," says Kaufman. "We have the opportunity to get great new direction and still have [Stem Cell Institute director Catherine] Verfaillie affiliated. University, state, and philanthropic sources have to kick in and support this. If we want to make this one of the top three public universities, this is an area that has to be maximally supported. We have exactly the right infrastructure to do this. We can do it on a small scale or do it right."