Jennifer Puck, Pioneer Researcher in Immunodeficiency and X-SCID

Jennifer Puck

The second edition of the only comprehensive textbook on inherited disorders of the immune system, co-edited by UCSF Professor of Pediatrics and Human Genetics Jennifer Puck, MD, will soon be published in the United States. The new version has mushroomed in size from 35 to 48 chapters, reflecting the increase in the number of primary immune deficiency diseases that have been identified, as well as new information on their causes and treatments. Primary Immunodeficiency Diseases: A Molecular and Genetic Approach, to be published by Oxford University Press, USA, in 2007, is the world's only volume that addresses the full spectrum of these conditions, from babies born without the disease-fighting cells called lymphocytes to children and adults with rare and not-so-rare difficulties with excessive infections or unbalanced immune reactions that can attack a person's own tissues. The book, edited by Hans Ochs and Edvard Smith, as well as Puck, is a reference guide for immunologists, allergists, experts in infectious disease and pediatricians, as well as for individuals who perform research in immunology and genetics. Puck herself has authored six of the book's chapters. Today, there are between 120 and 140 distinct inherited disorders of the immune system that have been associated with specific gene mutations. Although none of them are common, and some occur in fewer than one in 20,000 or 50,000 births, recognizing these conditions early from clinical clues is critical to successful treatment. Puck herself is credited with leading a team that discovered the gene responsible for X-linked severe combined immunodeficiency syndrome, or X-SCID, which afflicted the well-known Boy in the Bubble of the 1980s. As a young researcher in training, Puck met the child and later analyzed his DNA and that of his relatives. But science has since moved past putting babies with X-SCID in germ-free isolation. "Now such patients, who would die without intervention, can have immune systems provided," said Puck from her laboratory in the Health Sciences East building. "This can be accomplished either through bone marrow transplantation or through gene therapy. "The problem that these children have from the start," Puck explained, "is that they don't have functioning T lymphocytes - cells that conduct the orchestra of the immune system. Lymphocytes are produced with a huge variety of antigen receptors that are premade, so that there is one in your body that can recognize every new germ - even the new kind of flu virus this season. "But some children with severe immune problems don't have the right cells to recognize invaders," Puck said, "and they also don't have the capability of making antibodies, which is what B lymphocyte cells do. So these infants get in big trouble after they're born because of infections that they pick up from the environment. Even germs that wouldn't make you or me sick can be devastating to these babies." For the last 20 years, the standard treatment for babies born with no immune system has been a bone marrow transplant from a person with a healthy immune system. But transplantation can be difficult because most patients lack a donor who is a perfect tissue match. Researchers currently are perfecting techniques that one day will allow them to correct the "spelling mistake" in the patient's genetic code, Puck said. "If you know the exact mistake, or mutation, in the particular gene that causes their problem, you can make a corrected copy of that gene, which you build into a transporter system called a vector that carries it into their cells." The corrected version of the cell is then cultured and reinserted into the patient's bone marrow, allowing production of lymphocytes that develop into a fully functioning immune system. Puck said that this gene therapy approach has been successful in pilot trials in Europe, which were first reported in 2000. But problems arose when three of the treated children developed leukemia related to the retrovirus vector that had been used for their treatment. Puck and her collaborators have carried out a similar trial in the United States, but only with very high-risk patients who have failed the standard bone marrow transplant approach, she said. So the risk of leukemia is balanced by the possible benefit of getting a better immune system. "The whole field of gene therapy is new, and clearly it has risks. But on the other hand, it has a lot of promise," she said. "Furthermore, the field of primary immunodeficiency diseases is leading the way in development of new treatments that may someday be used not only for rare immune diseases, but also for more common problems."