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DeBakey awards showcase breadth of BCM research

By Ruth SoRelle, MPH

Margaret A. Goodell, PhD	Jeffrey M. Rosen, PhD

The 2004 Michael E. DeBakey, MD, Excellence in Research Awards went to researchers involved in stem cells, mouse models of disease and aging livers - once again demonstrating the depth of research being undertaken in the laboratories at Baylor College of Medicine.

During ceremonies announcing the awards, DeBakey said, "It is gratifying for me to come to these sessions and see the excellence in science and research taking place here."

Science, he said, is one of the most gratifying activities in which you can intellectually participate.

This year's award winners include:

• Margaret A. Goodell, PhD, associate professor of pediatrics in the section of hematology/oncology, member of the Center for Cell and Gene Therapy and faculty member of both interdepartmental graduate programs in cellular and molecular biology and developmental biology at BCM
• Monica J. Justice, PhD, associate professor of molecular and human genetics and faculty member of both interdepartmental graduate programs in cellular and molecular biology and developmental biology at BCM
• Jeffrey M. Rosen, PhD, C.C. Bell Professor of Molecular and Cellular Biology, professor of medicine, and faculty member for the interdepartmental graduate program in developmental biology at BCM
• Nikolai A. Timchenko, PhD, associate professor at the Huffington Center on Aging and of pathology at BCM

Each year, the awards go to four researchers nominated from within the College.

"These are not awarded for lifetime achievement," said James Patrick, PhD, senior vice president and dean for research at BCM. "These are given for the science. To get one, you have to have done a good experiment."

Each awardee receives a medal and $5,000 for his or her lab and enough money to pay for a celebratory dinner for the laboratory, said Patrick. The awards, he said, "recognize the heart and soul of the college."

The following summaries describe experiments from Drs. Goodell and Rosen.

Margaret Goodell, PhD - Understanding adult stem cells

Goodell works with adult stem cells, which are very different from the pluripotent embryonic stem cells that have sparked so much scientific and even political controversy. Pluripotent embryonic stem cells have the potential of becoming almost any kind of cell in the body, and occur only in developing embryos. Adult stem cells, on the other hand, by definition occur in adult tissues. They are usually the forerunners from which very specialized cells evolve.

Stem cells, she said, have two jobs - self-renewal and differentiation that results in formation of other kinds of cells that go on to make up the body's tissues.  The stem cells in the hematopoietic system, with which she is most concerned, make all the blood cells. 

What can stem cells do?

 "We wanted to know if one cell could generate blood, muscle, hepatocytes (liver cells) and other tissues," she said. To identify the stem cells, she used a method that she identified as a postdoctoral fellow, i.e., stem cells efficiently pump out a fluorescent dye.

Using this method and sorting the cells, she and other members of her laboratory transplanted one stem cell into a different mouse. Each stem cell was marked so that it could be differentiated from other blood cells. They found that the B-cells, T-cells and myeloid or bone-marrow forming cells were all generated from a single hematopoietic stem cell.

"This is a mouse whose blood is reconstituted with one hematopoietic stem cell," she said. "Our next question was could any cell contribute to the regeneration of liver and muscle?"

When she tested that premise, she found evidence that the hematopoietic stem cells did contribute to generation of both skeletal muscle and liver cells.

"Regeneration causes a whole colony of cells in the liver to derive from these blood-forming cells," she said. "In experimental animals, you can see the colonies of liver cells derived from that single blood-forming cell."

This occurs when a macrophage - an immune system cell that literally engulfs invading cells or materials - fuses with a cell that is to be regenerated. Eventually, a cell with two nuclei, but expressing the genes of the tissue that is regenerated, such as liver, is born.

Only a few of these kinds of cells are generated, she said. For that reason, she doubts that bone marrow transplants (which would mean transplanting stem cells) are a likely treatment for all kinds of disease, "but it does mean we might be able to use hematopoietic cells as gene delivery vehicles." The macrophages could provide new genes to the cells with which they fuse, but doing this successfully means boosting the rate at which such fusions occur.

Self-renewal

"On the other hand, the self-renewal function of stem cells is also important", she said. Knowing what genes regulate this process can make the process of bone marrow transplantation and gene therapy easier.

To understand it better, she and her team induced the hematopoietic stem cells of adult mice to renew themselves using a drug usually used in cancer treatment called 5-fluorouracil or 5-FU, which kills the mature blood cells and stimulates the stem cells to repopulate the bone marrow. Using a special technique called gene expression microarrays, Goodell and her team were able to watch the cells respond over time following treatment with 5-Fu, and were able to identify the kinds of genes that were characteristic of the various phases during the renewal process.

"Initially, most of the stem cells are not dividing and adhere closely to the surface of bone," she said. "After an insult such as the introduction of the drug, the cells pause and prepare for cell division. The cells become ultraquiescent for about a day. Then there is an early proliferation phase characterized by the expression of different kinds of proteins. In the late phase, there are more proteins expressed and an increase in energy metabolism. Then the cells become quiescent again." Goodell and her team have identified the genes involved in each of these stages.

"Our intention is to use what we have learned about self-renewal to expand (or grow) stem cell in vitro (in the laboratory)," she said. Understanding how stem cells renew themselves could produce new information about how cells become malignant.

"Some cancers may be started by a cancer stem cell," she said.

Jeffrey Rosen, PhD - Stem Cells in Breast Cancer

That notion is exactly what Rosen has been studying and for which he received his award. The idea is an old one, he said, but only recently have the tools to study it existed.

"We know that tumor cells might arise from stem cells," he said. "Tumors might contain self-renewable cancer stem cells that drive the growth of tumors and are resistant to conventional treatment."

He thinks the tumor stems cells may result either from the de-differentiation (or loss of tissue specificity) of a mature cell or from a mutated normal stem cell. In his laboratory, he and his team have identified mammary stem cells and found some of the molecules involved in the self-renewal roles of genes involved when tumors arise.

"Our hypothesis is that curing breast cancer will require the eradication of a small population of self-renewing cells that escape treatment and lead to recurrence and metastasis (or spread)," said Rosen. Breast cancer is a disease that can come back even 10 or more years after the initial successful treatment.

He and others in his laboratory have for the first time isolated a functional mammary stem cell population.

As he and others in his laboratory studied this population, he found that the different kinds of cells that typically make up breast cancers (called genetic heterogeneity) reflect the different cellular pathways involved. In studying the cells that give rise to the lobular and alveolar cells found in the mammary gland, Rosen and his colleagues found that the response to treatment reflected the stem cells from which the tumor arose. Specifically, the stem cells appear to be more resistant to killing by radiation.

For example, when the tumor cells in vitro are treated with radiation, the bulk of the cells are killed, leaving the stem cells behind. Therefore, it may take a combination of therapies that target both the bulk of the tumor and the stem cells to complete eradicate the disease, he said.

"We will have to treat not only the proliferating tumor cells but also those that self-renew and contribute to tumor recurrence," he said.

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