2001 ADLM Lectureship Award
W. French Anderson, MD, has had a distinguished career in which he has made significant advances in mammalian gene expression and gene transfer as a prelude to his pioneering work in initiating human gene therapy. His first major contribution was the discovery, isolation, and purification of the initiation factors required for the synthesis of proteins in mammalian cells (Nature 1970;226:511–4). His second important advance was the isolation and characterization of hemoglobin messenger RNA from patients with thalassemia and with sickle cell anemia. Dr. Anderson also demonstrated that the molecular defect in these diseases could be reproduced in the test tube, using human mRNA in a rabbit cell-free protein synthesizing system. The initial report of this work (J Clin Invest 1971;50:2458–60) describes the first successful application of molecular biology in isolating the genetic molecule (the mRNA) responsible for a human disease. Anderson and his colleagues then sought to identify the regulatory mechanisms that control the synthesis of hemoglobin mRNA and were the first to demonstrate that gene-specific regulatory factors exist for hemoglobin gene expression (Nature 1979;277:534–8).
Dr. Anderson and the late Dr. Elaine Diacumakos developed the technique of physical microinjection for inserting cloned genes into the nuclei of living mammalian cells (Proc Natl Acad Sci U S A 1980;77:5399–403). The microinjection procedure was subsequently used by Gordon and Ruddle to develop transgenic mice. Because the microinjection procedure could not be used to efficiently insert genes into bone marrow cells, Anderson and Dr. Eli Gilboa developed retroviral vectors that provided efficient gene transfer. In 1984, Dr. Anderson concluded in a highly quoted review (Science 1984;226:401–9) that retroviral vectors were the way to carry out human gene therapy and that adenosine deaminase (ADA) deficiency was the best initial prospect for gene therapy. He and Dr. Gilboa engineered a series of vectors that could be used for gene transfer in vivo (Science 1985;230:1395–8). One of these vectors, containing the human ADA gene, was successfully used to correct the ADA deficiency of defective T and B cells from ADA (-) patients in vitro (Proc Natl Acad Sci U S A 1986;83:6563–7). An autologous bone marrow transplantation/gene transfer protocol was then established in monkeys. Expression of the human ADA gene in the bloodstream of several primates was demonstrated (J Exp Med 1987;166:219–34).
Dr. Anderson then collaborated with Drs. Steven Rosenberg and Michael Blaese, NCI, NIH, to carry out the first approved human gene transfer/therapy clinical protocols. In the first protocol, a marker gene was used to help study a form of cancer therapy called adoptive immunotherapy. This study showed that gene transfer was safe and could be used to answer important scientific/clinical questions in patients (N Engl J Med 1990;323:570–8).
The first human gene therapy protocol was begun September 14, 1990. A 4-year-old girl with a genetic disease called severe combined immunodeficiency (SCID) caused by the absence of ADA was treated. T lymphocytes were removed from the patient at intervals of one to several months, a normal ADA gene was inserted into these lymphocytes via gene transfer, and the gene-corrected cells were returned to her body (Science 1995;270:475–80). Her immune system gradually returned to normal, and she has led an essentially normal life for the past 9 years. The success of this experiment has led to the emergence of the field of human gene therapy.
In collaboration with Dr. Esmail Zanjani, Dr. Anderson has explored the possibility of in utero gene therapy to correct genetic defects that cause irreversible damage before birth. Early studies used ex vivo gene transfer into hematopoietic stem cells (Blood 1989;73:1066–73), but more recent studies have demonstrated the success of direct vector injection into the fetus (Hum Gene Ther 1998;99:1571–85). Recently, Drs. Zanjani and Anderson reviewed this exciting but controversial new field (Science 1999;285:2084–8).
Dr. Anderson’s other major scientific interest at present is the development of retroviral vectors that can target specific cell types. His laboratory has carried out a systemic evaluation of the receptor-binding region of the envelope protein of the murine retrovirus used in human gene therapy clinical protocols (J Virol 1996:70:1768–74). They have demonstrated the molecular block in direct receptor-binding-domain substitution (Proc Natl Acad Sci U S A 1999;96:4005–10), but the success of using a modified approach (Hum Gene Ther 1997;8:2183–92).
Finally, Dr. Anderson has provided definitive reviews of the field of human gene therapy over a period of 20 years [major reviews in addition to the ones already listed: Science 1992;256:808–13 and Nature 1998;392(Suppl): 25–30].