THE USE OF DNA FOR GENE THERAPY—THE NEED, EXPERIMENTAL APPROACH, AND IMPLICATIONS* H. VASKEN APOSHIAN\ A number ofbasic and practical concepts are now avaüable to guide us in the development ofDNA as a drug for the treatment ofinherited diseases ofman. Some ofthese concepts are: first, the one gene-one enzyme hypothesis first put forth by Beadle and Tatum [i] in 1941; this was later modified to the one cistron-onepolypeptide concept; second, the WatsonCrick base-pair double-helical structure ofDNA [2]; third, the synthesis of DNA in ceU-free systems [3]; fourth, the deciphering of the genetic code [4]; and finally, the many concepts contributed by molecular virology , for example, transformation, transduction, etc. These basic scientific findings are the foundation for many other technical developments that are needed for the eventual treatment or cure of certain kinds of human diseases which we can group as inborn errors ofmetabolism. The purpose ofthis paper is to consider three questions concerning DNA therapy of human disease. i. How great is the need for DNA as a therapeutic agent? 2.Are there model systems now available that can be used experimentally to answer specific questions related to the development ofDNA as a therapeutic agent? 3.Should the health science community begin to prepare the political and lay community for the moral and other implications ofgene therapy? The Needfor DNA as a Therapeutic Agent First ofaU, how great is the need for DNA as a therapeutic agent? Is this ofpractical importance for human health, or is it ofonly inteUectual interest ? One method of determining the need for a drug is to estimate the number o£future life years that have been lost by deaths due to the diseases * Presented in part at the American Society for Pharmacology and Experimental Therapeutics meetings, autumn 1969. Supported in part by U.S. Public Health Service research grant 5 Roí CA 10497 from the National Cancer Institute and GB 15673 from the National Science Foundation. t Department ofCell Biology and Pharmacology, University ofMaryland School ofMedicine, Baltimore, Maryland 21201. 98 H. Vasken Aposhian · DNAfor Gene Therapy Perspectives in Biology and Medicine · Autumn 1970 againstwhichthedrug mightbeuseful. Stickle [5, andpersonalcommunication ] has estimated the number offuture life years that have been lost because ofheart disease, cancer, stroke, and birth defects during 1967. For his studies, a birth defect was defined as a structural or metabolic disorder present at birth, geneticaUy determined or the result of environmental influence during embryonic or fetal life. As shown in figure 1, birth defects1 claim approximately 4.5 times as many future life years as heart disease, eight times as many as cancer, and ten times as many future life years as stroke. Yet, the President's Commission on HeartDisease, Cancer, 35 30---------—------------------------------25 --------------------------------------------to o 20 co LU U-IO 0 HEARTCANCER STROKEBIRTH DISEASEDEFECTS Fig. i.—Comparison ofthe future life years lost because ofdeaths caused by heart disease, cancer, stroke, and birth defects (from Stickle [5, and personal communication]). and Stroke, using only deaths and disabilities as the criteria, stated that compared with heart disease, cancer, and stroke "all the other enemies of man . . . fade into relative insignificance" [6]. However, heart disease, cancer, and stroke, in general, strike late in life and the deaths they cause result in the loss offewer future years oflife than do birth defects. The clinical manifestations ofa birth defect can occur at any age from birth through maturity (fig. 2). Cystic fibrosis usuaUy occurs early in life; Wilson's disease, in young adulthood; and diabetes meUitus ofthe mature onset type, in the elderly. While some genetic diseases are rare, others are 1 Not all birth defects can be called inborn errors ofmetabolism. However, precise statistics on the occurrence ofthe diseases that can be called inborn errors of metabolism are not available. 99 not. For example, cystic fibrosis has a frequency ofaboutone out of1,0002 ,ooo births [7, 8]. A conservative estimate in 1967 has stated that 15 mülionpeople in the United States alonehave congenital diseases which affect their daily lives [9]. In addition, approximately 36 miUion life years in the United States are lost due to birth defects [5, 9, and G. Stickle, personal communication]. It might be pertinent...