Genes, Stem Cells and Bone Marrow Transplants
First published May 2003
Pediatric immunologist Morton Cowan has been refining ways to use stem cells to treat sick children for more than 20 years.
While politics ties up research that uses embryonic stem cells, the immature cells manufactured in human bone marrow are the workhorses of bone marrow transplant. Marrow is drawn from a donor and infused into a recipient. If all goes well, millions of stem cells mature as needed into red blood cells, platelets, and the various white blood cells needed for an immune response to pathogens.
The seven-room Pediatric Bone Marrow Transplant Unit at UCSF Children's Hospital uses versions of this technique to treat children with severe combined immune deficiency (SCID) and other immune system disorders, inherited marrow stem cell defects such as thalassemia and sickle cell disease, inborn errors of metabolism such as Hurler's mucopolysaccharidosis and adrenoleuko-dystrophy, severe aplastic anemia, and cancers such as leukemia, neuroblastoma and brain tumors.
Cowan was among the first in the U.S. to introduce a technique that isolates the stem cells in the donor's blood while depleting mature donor T cells. In 1982, he successfully treated a child with SCID, while preventing a dangerous reaction called graft versus host disease, or GvHD.
His lab continues to develop methods to enhance stem cells and encourage them to mature and act as the child's own, while preventing GvHD. Before these techniques, no child could be treated unless a donor could be found who matched at least six immune system markers called histocompatibility antigens. Children with inborn immune disorders often do not have perfectly matched siblings, and often must be treated sooner than a bone marrow matching search would allow. So stem cell enrichment has saved many lives.
More recently, Cowan and the scientists in his laboratory, led by research geneticist Lanying Li, have cloned the gene that causes a high incidence of SCID among the Navajo and Apache. (See "Two Different Worlds," page 3.) In the June 2002 issue of the Journal of Immunology , the UCSF team defined the structure of the gene, dubbed SCIDA after the Athabascan origins of the Navajo and Apache languages.
They showed that a mistake in coding stops the gene from making a complete version of a protein called Artemis, which is necessary for a normal immune system to develop. Moreover, they demonstrated that, in the test tube, inserting a normal gene results in its taking over the function of the defective one.
This work began before genomics speeded up many steps in gene characterization. Cowan and Li say that the work's reward has been the opportunity to use new knowledge to improve treatment for SCIDA patients and others with severe immune disorders.
Part of the excitement of the discovery is that it gives new clues to a critical step in the body's response to disease. When the Artemis protein does not form properly, it blocks a process called V(D)J recombination. Normally, the immune system generates a diverse repertoire of receptors capable of recognizing a huge number of potential pathogens, thanks to a random rearrangement of DNA segments called variable (V), diversity (D) and joining (J). Without V(D)J recombination to form receptors, B cell and T cell development is blocked at an immature stage. Pathogens invade, but immune cells do not recognize them and mount a response.
SCIDA is one of the most severe types of SCID. Between 25 and 30 percent of SCID cases show this level of severity -- called B-minus – T-minus – NK plus SCID because B and T cells do not mature though natural killer (NK) cells are normal. B- T- NK+ SCID can be caused by defects in Artemis, but also by defects in other autosomal recessive genes, all involved in V(D)J recombination and DNA repair.