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Stem Cells: Great Potential, Great Challenges

Scientists and other researchers are exploring the therapeutic potential of stem cells, as well as challenges they face around ethics and regulation.

Published January 1, 2004

By Catherine Zandonella
Academy Contributor

Stem cells, day 3 after passage. Image courtesy of Karl Marquez.University of California, San Diego a via Wikimedia Commons. Licensed via Creative Commons Attribution-Share Alike 3.0 Unported. No changes made.

To patients suffering from devastating and untreatable conditions such as spinal cord injuries, the near-limitless potential of stem cells offers a beacon of hope. These cells, if coaxed properly, can grow and divide into almost any cell type in the body. When kept in an incubator and served a specialized cocktail of growth factors, stem cells can give rise to neural cells, heart muscle cells, liver cells, and other cell types.

Finding the right recipe to control stem cells and make them differentiate into the right type of cell when and where one chooses, however, is a major challenge, according to researchers addressing a symposium on October 28, 2003. Titled “Stem Cell Technology: Emerging Science, Therapeutic Potential and Challenges Ahead,” the session was sponsored by The New York Academy of Sciences’ (the Academy’s) Biochemical Pharmacology Discussion Group and the Biochemical Group of the American Chemical Society.

Embryonic and Adult Stem Cells

There are essentially two types of stem cells: embryonic and adult. Embryonic stem cells may have the most promise for treating diseases because they are pluripotent, that is, they can grow and divide, or differentiate, into any cell type found in the fetus and adult. Scientists collect these cells at a very early stage of development, when the embryo is a fluid-filled sack with just a few cells in it, called a blastocyst.

When removed from the blastocyst and placed in an incubator, some of the cells can be grown for at least two years without any noticeable loss of their pluripotency. Due to ethical concerns about the use of human embryos for research, a presidential decision mandates that federal research funds can be used only for a handful of cell lines, created before August 9, 2001. Many researchers conduct studies on mouse embryonic stem cells as a steppingstone to understanding the human variety.

Adult stem cells may provide many of the same advantages as embryonic cells, without the ethical concerns. Researchers have known for decades that bone marrow contains stem cells that can repopulate a damaged blood supply. Liver, skin, and gut also contain stem cells that can regenerate damaged sections of these organs.

More recently, to the surprise of many developmental biologists, some researchers have found that adult stem cells can differentiate into entirely different tissue types. For example, if given the right stimuli, bone marrow stem cells appear to be able to differentiate into epithelial cells of the liver, kidney, lung, skin and GI tract as well as heart and skeletal muscle cells. In the past year, however, studies have presented alternative explanations to this differentiation and it remains to be proven that pluripotent stem cells exist in the adult.

Cells with “Free Will”

Austin Smith of the Institute for Stem Cell Research at the University of Edinburgh said that embryonic stem cells are attractive to researchers because they can be considered to have “free will.” The cells can remain as stem cells in a seemingly endless cycle of self renewal, or at a time of their choosing can exit self-renewal and differentiate into entirely new types of cells. But finding the signals that can keep the cells in self-renewal or shunt them towards the development of a specific cell type is a challenge.

If left to their own devices in culture, the cells tend to differentiate into what researchers call an “embroid body,” a tangled mass of overlapping cells where bone, liver, and even beating heart cells coexist. Smith found that by changing the ingredients of the cell culture medium in which the cells grow, he could make a sort of on/off switch for differentiation into neural cells. The results were published in Cell the same week as the presentation (Cell, 115, 281-292, October 31, 2003).

By trial and error, researchers are finding the key factors that control stem cell growth and differentiation. But might there be a more systematic way to discover why and how embryonic stem cells act as they do? Yes, said Ihor Lemischka, professor of molecular biology at Princeton University. He urged biologists to start thinking of stem cell biology as a system of circuits rather than as individual parts like genes, receptors, and signaling molecules.

The Stem Cell Research Database

To catalogue the complex array of genes involved in stem cell regulation, Lemischka and colleagues started the Stem Cell Research Database. By mining the database for common stem cell genes in mice and humans, Lemischka said, researchers can home-in on the most important genes to study (Science, 298, 601-4, Oct. 18, 2002). He is now examining the function of these genes by systematically deleting them and seeing how they affect stem cell behavior.

While basic research can be done in mice embryonic stem cells, some researchers will need to verify their findings in human cells. Melissa Carpenter, who until summer 2003 was director of stem cell biology at Geron Corp. and now is at the Robarts Research Institute in Canada, has worked closely in characterizing four of the human embryonic cell lines that are available to researchers who want to use federal funds in their work.

Taking note of the growth patterns, lifespan, and potential of these cell lines is essential if they are to be used for basic research, drug discovery and, eventually, therapies in patients. Curiously, although these cells are all “stem cells,” they do not behave identically in culture. If allowed to differentiate, they each form a different array of cell types. However, using a variety of tests, Carpenter’s team at Geron was unable to find major differences between the undifferentiated hES cell lines cells, and a microarray analysis of three of the lines found only a 5-10% difference in gene expression.

Stem Cells and the Heart

In related studies, the researchers were able to differentiate the stem cells into neurons (Exp Neurol 172(2), 383-97, 2001, and liver cells (hepatocytes) (Cell Transplant, 12(1), 1-11, 2003) and beating heart muscle cells. These heart cells beat faster when given common cardiac-stimulating drugs and stopped beating altogether when treated with calcium-channel blockers in a dose-dependent and reversible manner (Circ Res., 91, 501-508, Sept. 20, 2002). Researchers hope that these human cells could someday be injected into a heart attack victim to help repair damaged cardiac muscle.

Meanwhile, George Daley’s group at the Children’s Hospital, Harvard Medical School, is working on embryonic stem cells that can make blood. Just as a bone marrow transplant can restore a leukemia patient’s immune and blood systems, a single embryonic stem cell should in theory be able to do the same thing. But so far, attempts to practice the technique in mice have failed because these transplanted embryonic stem cells, similar to the mouse yolk sac, fail to produce blood cells in the adult mice.

Daley and his group have genetically altered the cells so they make extra quantities of a protein called HoxB4, which drives the cells to engraft mice and differentiate into both branches of the blood cell family – lymphoid and myeloid. The researchers found that they could ramp up blood cell production even more, turning up expression of another gene, Cdx4, which may work by boosting HoxB4 gene expression (Nature, 425, 300-6, Sept. 18, 2003). By enhancing the expression of both genes, Daley and colleagues achieved the result that 70-80% of the host mouse’s blood cells were from the donated stem cells.

Great Hope

Embryonic stem cells raise great hopes and great ethical concerns, but adult stem cells may provide therapeutic advantages without the ethical concerns. However, warned Diane Krause of Yale University, the jury is still very much out on how much potential these cells have – and even on the existence of highly plastic adult stem cells. Recent findings indicate that fusion between the host’s cells and the donated cells may be what is causing the results.

Nonetheless, Krause’s lab has done some pioneering work showing that bone marrow stem cells transplanted into mice have the potential to differentiate into lung cells and liver cells (Cell, 105, 369-77, May 4, 2001) and she showed recent unpublished work showing that this can occur without fusion. However, other researchers recently showed that such results can be due to fusion between the bone marrow cells and the recipient mouse’s lung or liver cells. “Even if it is fusion,” said Krause, “we need to ask, is this something that we can use for therapeutic benefit?”

While great strides have been made in finding individual factors that control the growth and differentiation of stem cells, much remains to be done to understand and control them. Lemischka summed up the challenge by quoting science philosopher and mathematician Jules Henri Poincaré, “Science is built up of facts as a house is of stones, but a collection of facts is no more science than a heap of stones is a house.”

Also read: The Complexities of Stem Cell Research


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