December 3, 1996
Early blood cell pinpointed; may hold key to successful gene therapy
TORONTO - An international team of researchers, led by Hospital for Sick Children geneticist John Dick, has identified a human blood cell which regrows the entire blood system. While scientists have known for years that such a bone marrow cell (called a stem cell) exists, it is not until now that they have been able to pinpoint it by examining its blood-producing activity.
The discovery, which provides greater understanding of how the blood system functions and enables development of new treatments including gene therapy for blood diseases such as leukemia, thalassemia and sickle cell anemia, is reported in the December issue of the scientific journal Nature Medicine.
Gene therapy for blood diseases involves inserting a normal gene into the stem cells of patients with the genetic disease. The altered stem cell then permanently produces blood cells which contain the normal gene.
"While gene therapy has been touted as the next major advance in the treatment of human blood diseases, it's been severely hampered by our inability to assess if we're getting the functioning gene into the right type of blood cell," explains Dr. Dick, who is also a professor of Molecular and Medical Genetics at The University of Toronto. "Now that we know what cell we're dealing with, we can work on understanding how best we can deliver genes into the cell and determine how to make that mechanism work for gene therapy."
Stem cells are extremely rare - making up just one in a million bone marrow cells - and are difficult to distinguish from other cells in the bone marrow. Until now, the only conclusive way to determine if a human stem cell had incorporated the new gene was to transplant that stem cell into a human patient and see if the cells it produced contained the new gene. This is a very costly procedure and ethical limitations of human clinical trials prevent detailed examination of which cell is the true stem cell.
Dr. Dick's research team built upon a unique biological system they have developed over the last few years. They successfully reproduced the entire human blood system in mice by transplanting human bone marrow cells into severe combined immune-deficient (SCID) mice and then injecting the mice with a hormone to stimulate cell growth. The "SCID mouse model," as it's now known, gave scientists a living organism in which to study the development of the human blood system.
In their current research, they found that only a very rare cell was able to regrow the human blood system in the mice. They went on to isolate the stem cell from all the other cells and study its properties. One of the important things they discovered was that genes could not be effectively inserted into this stem cell using methods currently employed by many researchers. This same poor result has also been recently reported from the human clinical trials. Thus, this research demonstrates that the SCID mouse model is a good predictor of what will happen in humans. The model can now be used to learn why genes are poorly inserted into stem cells and how to overcome this block.
In addition to gene therapy, there are many human treatments for cancer being developed based on stem cells. The SCID mouse model will enable scientists to identify stem cells and provide a method to determine the effectiveness of new treatments prior to advancing to the costly clinical trial phase. In addition to finding out ways to deliver genes into stem cells, scientists can now also begin to determine the mechanisms that control stem cell functions as it produces all the blood cells. Sometimes this process can go wrong by becoming too active and leukemia can occur. Dr. Dick's team identified a leukemia stem cell in 1994. Now it will be possible to identify changes between leukemia and normal stem cells to understand how human leukemia starts.
Funding for this research was provided by the Medical Research Council of Canada, The National Cancer Institute of Canada with funds from the Canadian Cancer Society, and the Canadian Genetic Diseases Network.
For more information, please contact:
Public Affairs
The Hospital for Sick Children
555 University Avenue
Suite 1742, Public Affairs, First floor Atrium
Toronto,
ON
M5G 1X8
Canada
Phone: 416-813-5058
Fax: 416-813-5328