sign in sign up
<<
Home , Genetic engineering, Gene therapy

HUMAN G E N E T H E R A P Y 2:115-122 (1991) Mary A n n Liebert, Inc., Publishers

Human : and Public Policy*

LEROY W A L T E R S

ABSTRACT

The firstt h r e e h u m a n gene t r a n s f e r / t h e r a p y clinical p r o t o c o l s a r e n o w u n d e r w a y after h a v i n g b e e n s u b j e c t e d t o a n extensive review process b y t h e Recombinant D N A A d v i s o r y Committee (RAC) a n d i t s H u m a n S u b c o m m i t t e e . T h e "Points t o C o n s i d e r " d o c u m e n t d e v e l o p e d b y t h e R A C established t h e f r a m e w o r k for e v a l u a t i n g genetic i n t e r v e n t i o n protocols. T h i s r e v i e w process is t a k i n g place in a b r o a d e r social c o n t e x t . Public attitude surveys in t h i s country have indicated a general lack of k n o w l e d g e in t h e area of genetic b u t a n a c c e p t a n c e o f s o m a t i c - c e l l g e n e t h e r a p y a s t r e a t m e n t f o r d i s e a s e . I n t e r n a t i o n a l l y , n u m e r o u s policy s t a t e m e n t s o n h u m a n genetic i n t e r v e n t i o n h a v e b e e n p u b l i s h e d , a l l o f w h i c h s u p p o r t t h e m o r a l legitimacy of s o m a t i c - c e l l g e n e t h e r a p y f o r t h e c u r e o f d i s e a s e . T h e d e b a t e o v e r t h e e t h i c a l i s s u e s r e l a t e d t o s o m a t i c - c e l l g e n e therapy has e v o l v e d over a t e n - y e a r - p e r i o d . T h e time h a s n o w come to b e g i n a f o r m a l public process f o r the ethical a s s e s s m e n t o f g e r m - l i n e g e n e t i c i n t e r v e n t i o n .

OVERVIEW SUMMARY human patients s i n c e 1 9 8 0 , a n d the f i r s t p u b l i c l y r e v i e w e d a n d approved h u m a n trials e v e r . An extensive discussion of the ethical issues relating to M y essay will f o c u s first o n the s o c i a l a n d ethical q u e s t i o n s - g e n e t h e r a p y h a s b e e n t a k i n g p l a c e f o r a n u m - raised b y these t h r e e p r o p o s a l s a n d b y the r e v i e w process t h a t ber o f y e a r s . A c o n s e n s u s n o w a p p e a r s t o e x i s t t h a t s o m a t i c - was employed to evaluate them. , I w i l l consider the cell g e n e therapy for the treatment of serious disease is broader s o c i a l c o n t e x t o f r e s e a r c h o n g e n e t h e r a p y , both in the morally correct. W a l t e r s , f r o m his position as a leading United S t a t e s a n d a b r o a d . F i n a l l y , I will d i s c u s s p o s s i b l e future ethicist w h o has f o l l o w e d t h e fieldo f g e n e t h e r a p y t h r o u g h - developments, e s p e c i a l l y g e n e t i c i n t e r v e n t i o n s t h a t w o u l d a f f e c t out i t s h i s t o r y , n o w proposes t h a t a f o r m a l p u b l i c d i s c u s s i o n future g e n e r a t i o n s . I n t h i s c o n n e c t i o n , I w i l l r e c o m m e n d that a should b e g i n o n g e r m - l i n e g e n e t h e r a p y . formal public process for t h e ethical a s s e s s m e n t of g e r m - l i n e genetic i n t e r v e n t i o n b e g i n n o w .

THE E T H I C A L E V A L U A T I O N O F GENE THERAPY IN T H E U N I T E D S T A T E S , 1 9 6 9 - 1 9 9 0 INTRODUCTION Public discussion of the ethics of human gene therapy goes THREE IMPORTANT MILESTONES in the history of back in t h i s c o u n t r y at l e a s t t o t h e 1 9 6 9 A m e r i c a n Association were p a s s e d b e t w e e n M a y 1989 a n d J a n u a r y 1 9 9 1 . In t h o s e for t h e A d v a n c e m e n t o f S c i e n c e ( A A A S ) m e e t i n g h e l d i n B o s t o n 20 months, t e a m s of researchers at t h e National Institutes o f in l a t e D e c e m b e r . I n a s y m p o s i u m at t h a t m e e t i n g B e r n a r d D a v i s Health ( N I H ) i n i t i a t e d o n e h u m a n gene transfer s t u d y a n d two presented a p a p e r entitled "Threat and Promise in G e n e t i c human g e n e t h e r a p y p r o t o c o l s . T h e s e a r e t h e first s u c h s t u d i e s i n Engineering." T h i s p a p e r w a s l a t e r p u b l i s h e d i n S c i e n c e w i t h t h e

Director, Center f o r B i o e t h i c s , K e n n e d y Institute o f E t h i c s , and A s s o c i a t e P r o f e s s o r o f P h i l o s o p h y , G e o r g e t o w n U n i v e r s i t y . *This e s s a y w a s o r i g i n a l l y p r e p a r e d f o r p r e s e n t a t i o n at t h e F e b r u a r y 1 9 9 1 A n n u a l M e e t i n g o f t h e A m e r i c a n A s s o c i a t i o n f o r t h e A d v a n c e m e n t o f in W a s h i n g t o n , D . C . T h e r e it w a s p a r t o f a s y m p o s i u m o r g a n i z e d b y W . F r e n c h A n d e r s o n a n d e n t i t l e d " G e n e T h e r a p y : Scientific P r o s p e c t s and S o c i e t a l I m p l i c a t i o n s . " S u b s t a n t i a l s e c t i o n s o f t h e e s s a y w e r e a l s o p r e s e n t e d at t h e N i n e t e e n t h C o n f e r e n c e o f E t h i c s , H u m a n i s m a n d M e d i c i n e , held o n M a r c h 2 3 , 1 9 9 1 , at the University o f M i c h i g a n M e d i c a l S c h o o l i n A n n Arbor. These s e c t i o n s will b e i n c l u d e d in the proceedings o f t h e conference a n d a r e p u b l i s h e d h e r e w i t h t h e p e r m i s s i o n o f t h e C o m m i t t e e o n E t h i c s , H u m a n i s m a n d M e d i c i n e at t h e U n i v e r s i t y o f M i c h i g a n M e d i c a l School.

115 116 WALTERS title " P r o s p e c t s f o r G e n e t i c I n t e r v e n t i o n i n M a n " ( D a v i s , 1 9 7 0 ) . to c u r e a d i s e a s e w o u l d immediately b e s c r e e n e d o u t b y this At the s a m e symposium, theological ethicist J a m e s Gustafson first q u e s t i o n . discussed " G e n e t i c E n g i n e e r i n g a n d t h e N o r m a t i v e V i e w of t h e 2. What alternative t h e r a p i e s a r e a v a i l a b l e f o r t h e t r e a t m e n t o f Human" (Gustafson, 1973). T h e public discussion continued the disease? The presupposition of this question is that through t h e 1 9 7 0 s , w i t h p e r i o d i c s y m p o s i a a n d a r t i c l e s . diseases for w h i c h no satisfactory therapy currently exists In 1 9 8 0 , t w o e v e n t s s p a r k e d r e n e w e d interest i n t h e e t h i c s o f are, o t h e r f a c t o r s b e i n g e q u a l , b e t t e r c a n d i d a t e s f o r t h i s n e w human gene therapy. T h e first w a s a letter t o then-President type of t r e a t m e n t than are diseases that c a n be effectively Carter from leaders of the Jewish, Catholic, a n d Protestant managed b y other m e a n s . religious c o m m u n i t i e s , e x p r e s s i n g c o n c e r n a b o u t t h e p o t e n t i a l l y 3. Based on prior l a b o r a t o ry a n d clinical s t u d i e s , h o w safe i s deleterious consequences of (President's treatment w i t h g e n e therapy likely t o b e for t h e p a t i e n t , for Commission, 1 9 8 2 ) . A few m o n t h s later t h e L o s A n g e l e s T i m e s the p a t i e n t ' s o f f s p r i n g , a n d for o t h e r p e o p l e w h o c o m e into broke the story o f D r . Martin Cline's u n a p p r o v e d attempts t o contact w i t h t h e p a t i e n t ? I n t h i s q u e s t i o n o n e c a n clearly s e e perform gene therapy on two patients afflicted with P- the m e r g e r o f t h e h u m a n - s u b j e c t s a n d the b i o h a z a r d s t r a d i - , o n e p a t i e n t i n I s r a e l a n d t h e o t h e r i n I t a l y . T h e t w o tions o f r e s e a r c h r e v i e w . major results of these events were, first, a detailed study of 4. Based o n p r i o r l a b o r a t o r y a n d clinical s t u d i e s , h o w effective ethical i s s u e s i n h u m a n genetic intervention b y the P r e s i d e n t ' s is t r e a t m e n t w i t h g e n e therapy likely to b e for t h e p a t i e n t ? Commission on (President's Commission, 1982), This question m a y present a considerable challenge to r e - and, second, a congressional hearing on "Human Genetic searchers if n o other a n i m a l species are naturally afflicted Engineering" convened in November 1982 by then-House- with a p a r t i c u l a r h u m a n d i s e a s e . member A l b e rt G o r e , J r . ( U . S . Congress, 1 9 8 2 ) . 5. Assuming that q u e s t i o n s 1 - 4 h a v e b e e n a n s w e r e d s a t i s f a c t o - From the S p l i c i n g L i f e r e p o r t o f t h e President's C o m m i s s i o n rily, w h a t p r o c e d u r e s w i l l b e e m p l o y e d to e n s u r e f a i r n e s s in and the c o n g r e s s i o n a l h e a r i n g o f 1 9 8 2 o n e can d r a w a s t r a i g h t the selection of subjects? This question is of particular line t o t h e r e v i e w p r o c e s s f o r g e n e t h e r a p y p r o p o s a l s c u r r e n t l y i n importance if l a r g e n u m b e r s of m e d i c a l l y eligible p a t i e n t s place in the United States. T h e mediating institution w a s the wish to p a r t i c i p a t e i n a c l i n i c a l t r i a l o f g e n e t h e r a p y . Recombinant D N A Advisory C o m m i t t e e ( R A C ) o f t h e N a t i o n a l 6. Assuming that all p r i o r questions have been satisfactorily Institutes of Health. By early 1983 the R A C had already answered, h o w will patients or their parents be properly functioned f o r a l m o s t 8 y e a r s a s t h e n a t i o n a l s t a n d a r d - s e t t i n g a n d informed about the proposed study, and how will their review b o d y for l a b o r a t o r y r e s e a r c h w i t h r e c o m b i n a n t D N A and consent b e e l i c i t e d ? T h i s q u e s t i o n i s e s p e c i a l l y p e r t i n e n t w i t h for early efforts to use recombinant D N A methods for the new and relatively c o m p l e x a p p r o a c h e s t o t h e r a p y . manufacture o f p h a r m a c e u t i c a l s . 7. Again a s s u m i n g t h a t all p r i o r q u e s t i o n s h a v e b e e n s a t i s f a c t o - In A p r i l 1 9 8 3 , R A C Chairman R o b e r t M i t c h e l l , a C a l i f o r n i a rily a n s w e r e d , w h a t s t e p s w i l l b e t a k e n t o p r o t e c t t h e p r i v a c y attorney, a s k e d the c o m m i t t e e whether it w i s h e d to s t u d y and of gene-therapy patient a n d the of m e d i c a l respond to t h e S p l i c i n g L i f e r e p o r t o f t h e P r e s i d e n t ' s C o m m i s - information about the course of their t r e a t m e n t ? Here the sion. T h e committee's affirmative response led, first, t o an subcommittee w i s h e d to p r e v e n t a r e c u r r e n c e o f t h e c i r c u s - expression of its willingness to review human gene therapy like atmosphere that has surrounded several instances of protocols a n d , s e c o n d , t o t h e creation o f a m e c h a n i s m for t h e therapeutic i n n o v a t i o n in t h e r e c e n t p a s t . conduct o f s u c h reviews. I n t h e s u m m e r of 1 9 8 4 a n i n t e r d i s c i - plinary s u b c o m m i t t e e t o t h e R A C was establishe d f o r t h e initial The public review process designed in 1984 and 1985 was review of g e n e therapy protocols. T h e subcommittee included applied t o a n actual c l i n i c a l p r o t o c o l f o r t h e first t i m e in 1988. laboratory scientists, c l i n i c i a n s , l a w y e r s , a n d ethicists in a p - The first p r o t o c o l , a g e n e - t r a n s f e r s t u d y p r o p o s e d b y S t e v e n A . proximately equal n u m b e r s . I n late 1984 a n d early 1985, this Rosenberg and associates at N I H , w a s initially s u b m i t t e d to a subcommittee developed and published a document entitled local r e v i e w committee on June 10th ( N 2 - T I L , 1990). Public "Points t o C o n s i d e r in t h e D e s i g n a n d S u b m i s s i o n o f S o m a t i c - review b y t h e R A C and t h e H u m a n G e n e T h e r a p y S u b c o m m i t t e e Cell H u m a n Gene Therapy Protocols" ( N a t i o n a l Institutes o f began in July 1988 and was completed, after unanticipated Health, 1 9 8 5 ) . ( F o r a d e t a i l e d c h r o n o l o g y o f e v e n t s i n t h e w o r k complications, i n J a n u a r y o f 1 9 8 9 . T h e s e c o n d p r o t o c o l a n d t h e of the R A C and the subcommittee from 1983 to the p r e s e n t , first h u m a n gene therapy proposal, t h e please s e e A p p e n d i x A.) (ADA) d e f i c i e n c y s t u d y o f N I H researchers R . M i c h a e l B l a e s e , From the beginning, the "Points to Consider" document W . French A n d e r s o n , a n d associates, w a s initially s u b m i t t e d t o combined e l e m e n t s f r o m t w o t r a d i t i o n s o f r e s e a r c h r e v i e w — t h e a local r e v i e w c o m m i t t e e o n February 23, 1990 ( A D A , 1990); concern to p r o t e c t the h u m a n subjects w h o participate in b i o - the p u b l i c r e v i e w p r o c e s s l a s t e d f r o m M a r c h 3 0 to J u l y 3 1 . A n medical research and the concern to protect w o r k e r s and the even s h o r t e r p e r i o d o f r e v i e w w a s r e q u i r e d f o r t h e third p r o t o c o l environment f r o m the p o t e n t i a l b i o h a z a r d s o f r e c o m b i n a n t D N A and t h e s e c o n d h u m a n g e n e t h e r a p y p r o p o s a l , t h e t u m o r n e c r o s i s research (Areen and King, 1990; J u e n g s t , 1990). T h e central factor study put forward by Dr. R o s e n b e r g and his N I H col- core o f t h e "Points t o C o n s i d e r " c a n b e stated i n t e r m s o f s e v e n leagues. T h i s p r o t o c o l w a s submitted for l o c a l r e v i e w o n April rather s i m p l e q u e s t i o n s . 23, 1990 ( T N F / T I L , 1990), a n d the p u b l i c r e v i e w p r o c e s s w a s completed o n July 3 0 a n d 31. 1. What is the disease to be treated? In other words, researchersWha t are the advantages and disadvantages of the current are asked whether the disease to b e treated is s u f f i c i e n t l y framework for r e v i e w i n g h u m a n gene therapy protocols in t h e serious t o w a r r a n t t h e u s e o f a n o v e l a n d untried a p p r o a c h t o United S t a t e s ? O t h e r c o m m e n t a t o r s m a y b e i n a b e t t e r p o s i t i o n t o therapy. A n y proposal t o e n h a n c e a h u m a n ability r a t h e r t h a n provide an objective, e x t e r n a l evaluation. T h e following re- ETHICS A N D PUBLIC POLICY 117 marks are b a s e d on participation in the r e v i e w process since ment c o m m i s s i o n e d L o u i s H a r r i s & Associates t o s u r v e y p u b l i c 1983. T h e m a j o r a d v a n t a g e s o f t h e e x i s t i n g f r a m e w o r k a r e t h a t it attitudes t o w a r d in g e n e r a l a n d g e n e therapy i n is p u b l i c a n d that it i s b a s e d o n a set o f n a t i o n a l s t a n d a r d s that particular. The poll w a s c o n d u c t e d a m o n g a r a n d o m sample o f were initially developed in a year-long process, a n d t h e n 1,273 U . S . adults b e t w e e n O c t o b e r 3 0 a n d N o v e m b e r 17, 1 9 8 6 periodically revised. B o t h the g e n e r a l p r e s s a n d the s c i e n t i f i c (OTA, 1987). O n e important finding of the survey was that press h a v e in fact d e v o t e d detailed attention to t h e first three public k n o w l e d g e of g e n e t i c issues is l i m i t e d : 6 3 % of r e s p o n - clinical p r o t o c o l s ; a n d interested m e m b e r s of t h e p u b l i c h a v e dents a c k n o w l e d g e d that t h e y h a d heard o r r e a d " a l m o s t n o t h - ample information a b o u t t h e d i s e a s e s b e i n g studied o r treated, ing" or " r e l a t i v e l y little" a b o u t genetic engineering (OTA, the researchers involved, a n d the major.issues raised in t h e 1987). W h e n asked a g e n e r a l question about the morality of review p r o c e s s . All t h i n g s c o n s i d e r e d , the f o r m a l r e v i e w p r o c e - genetically altering human cells, o n l y 5 2 % of r e s p o n d e n t s dures in p l a c e t o d a y a r e a v a s t i m p r o v e m e n t — f o r b o t h r e s e a r c h - replied t h a t s u c h a l t e r a t i o n s w e r e " n o t m o r a l l y w r o n g " ; a n o t h e r ers a n d t h e p u b l i c — o v e r t h e a d h o c a r r a n g e m e n t s t h a t p r e v a i l e d 6 % of r e s p o n d e n t s w e r e n o t s u r e ( O T A , 1 9 8 7 ) . H o w e v e r , w h e n in 1980. the respondents were presented with specific gene therapy Yet t h e R A C and its S u b c o m m i t t e e o n H u m a n G e n e T h e r a p y scenarios involving fatal diseases or n o n f a t a l birth defects, are in s o m e w a y s f r a g i l e institutions, a n d t h e c u r r e n t f r a m e w o r k between 7 7 % a n d 8 4 % either s t r o n g l y a p p r o v e d or s o m e w h a t for review is i n c e r t a i n respects untidy. Neither the parent approved ( O T A , 1987). A s k e d s p e c i f i c a l l y a b o u t s o m a t i c v e r s u s committee n o r t h e s u b c o m m i t t e e w a s created b y the C o n g r e s s . germ-like correction of " a g e n e t i c defect that would cause In f a c t , each w a s created i n p a r t t o fill a v a c u u m and in p a r t to usually fatal diseases," a surprising 6 2 % approved of both forestall congressional action, after Asilomar and a f t e r the modes of c o r r e c t i o n a n d another 1 4 % approved of c o r r e c t i n g Splicing L i f e r e p o r t . In t h e e a r l y 1 9 8 0 s t h e R A C agreed t o take "only the g e n e that w o u l d carry the disease to f u t u r e g e n e r a - on t h e c o n t e n t i o u s i s s u e o f t h e d e l i b e r a t e r e l e a s e o f r e c o m b i n a n t tions" ( O T A , 1973). A similar s u r v e y conducted in 1987 b y DNA into t h e e n v i r o n m e n t ; t h e o r g a n i s m s to b e released w e r e Research & Forecasts, Incorporated, for t h e D a n i s h f i r m N o v o ice-minus . A s a r e w a r d for its e f f o r t s , t h e R A C , or Industri A / S found that 7 5 % of A m e r i c a n s w h o were k n o w l - rather t h e S e c r e t a r y o f H e a l t h a n d H u m a n Services, w a s h i t w i t h edgeable a b o u t genetic e n g i n e e r i n g a p p r o v e the p r e v e n t i o n o f a l a w s u i t a n d c h i d e d b y the U n i t e d States C o u r t o f A p p e a l s f o r genetic disease through altering or e g g c e l l s (Novo the D . C . C i r c u i t f o r failing t o f u l f i l l all t h e r e q u i r e m e n t s o f t h e Report, 1987). In the Harris survey for O T A , only 4 4 % o f National E n v i r o n m e n t a l P o l i c y A c t ( A r e e n a n d K i n g , 1 9 9 0 ) . In respondents approved of s c i e n t i s t s changing the makeup o f 1985, the R A C w a s a l m o s t supplanted by a n interagency human cells to i m p r o v e t h e i n t e l l i g e n c e l e v e l o r p h y s i c a l char- super-RAC a n d a l m o s t r e m o v e d f r o m i n v o l v e m e n t w i t h h u m a n acteristics that c h i l d r e n w o u l d inherit; a m a j o r i t y o f r e s p o n d e n t s gene t h e r a p y i n a j u r i s d i c t i o n a l d i s p u t e b e t w e e n N I H a n d a s i s t e r disapproved ( O T A , 1983). agency ( B e a r d s l e y , 1 9 8 5 ; C u l l i t o n , 1 9 8 5 ) . There is also a n i n t e r n a t i o n a l context for the ethical and The untidiness o f the current f r a m e w o r k for r e v i e w stems public-policy d e b a t e a b o u t h u m a n gene therapy. W h i l e w e d o largely f r o m the f a c t t h a t t h e R A C is a c o m m i t t e e o f N I H , the not h a v e s u r v e y d a t a f r o m m o s t c o u n t r i e s o r o r g a n i z a t i o n s like principal f e d e r a l f u n d i n g a g e n c y f o r b i o m e d i c a l r e s e a r c h in the the data just cited, n u m e r o u s policy statements o n h u m a n United S t a t e s . T h u s , the R A C is t e c h n i c a l l y a u t h o r i z e d t o r e v i e w genetic i n t e r v e n t i o n h a v e b e e n p u b l i s h e d , e s p e c i a l l y s i n c e 1 9 8 0 . only gene-therapy proposals originating in institutions that In s e v e r a l y e a r s o f r e s e a r c h , I h a v e b e e n a b l e to i d e n t i f y 2 0 s u c h receive N I H funding for r e c o m b i n a n t D N A r e s e a r c h . A s the statements t h a t h a v e b e e n f o r m u l a t e d b e t w e e n 1 9 8 0 a n d 1 9 9 0 b y early h i s t o r y o f t h e A t o m i c E n e r g y C o m m i s s i o n d e m o n s t r a t e d , legislative b o d i e s , government a g e n c i e s o r c o m m i t t e e s , profe- it i s i n h e r e n t l y difficult f o r a s i n g l e government b o d y both t o sisonal o r g a n i z a t i o n s , or r e l i g i o u s b o d i e s . T h e sources o f t h e s e promote a n d to r e g u l a t e a f i e l d o f e n d e a v o r . statements i n c l u d e specific c o m m i t t e e s in D e n m a r k , S w e d e n , The untidiness o f the R A C ' s dual role b e c a m e even more and the G e r m a n Federal Republic, a s t a n d i ng committee in apparent w h e n the first g e n e transfer p r o t o c o l a n d the f i r s t t w o Australia, t h e Parliamentary A s s e m b l y of t h e C o u n c i l of E u - gene t h e r a p y p r o t o c o l s p r e s e n t e d to t h e R A C were d e s i g n e d b y rope, t h e W o r l d M e d i c a l A s s o c i a t i o n , the C a t h o l i c C h u r c h , a n d intramural s c i e n t i s t s f r o m N I H itself. Despite t h e s e institutional the W o r l d Council o f C h u r c h e s . W i t h o u t e x c e p t i o n , a l l 2 0 o f ambiguities, m y experience as a participant in t h e review these p o l i c y s t a t e m e n t s a c c e p t t h e m o r a l l e g i t i m a c y o f s o m a t i c process i s , first, that t h e N I H Director h a s encourage d t h e R A C cell g e n e t h e r a p y f o r t h e c u r e o f d i s e a s e . E v a l u a t i o n s o f g e r m - to f u l f i l l its r o l e c r i t i c a l l y a n d independently a n d , s e c o n d , that line g e n e t i c i n t e r v e n t i o n for t h e c u r e o r p r e v e n t i o n o f d i s e a s e a r e the r e v i e w s o f t h e initial p r o t o c o l s h a v e been performed in a mixed, w i t h a m a j o r i t y o f t h e policy s t a t e m e n t s o p p o s i n g s u c h professional m a n n e r b y w e l l q u a l i f i e d e x p e r t s i n b i o l o g y , m e d - intervention. N o n e of t h e 2 0 statements support t h e e n h a n c e - icine, ethics, and l a w , as w e l l a s b y articulate l a y p e o p l e . ment o f h u m a n c a p a b i l i t i e s b y g e n e t i c m e a n s . ( F o r a list o f t h e 2 0 statements, please s e e A p p e n d i x B . ) I d o not w i s h to a r g u e that t h e m o r a l i t y o f a p r a c t i c e c a n b e THE B R O A D E R SOCIAL C O N T E X T FOR determined b y s u r v e y s of either policy statements or public HUMAN G E N E T H E R A P Y RESEARCH opinion. H o w e v e r , a u n a n i m o u s j u d g m e n t o n s o m a t i c c e l l g e n e therapy b y t h o u g h t f u l individuals and groups from multiple The research protocols and the review process that I haveculture s a n d traditions a t least s u p p o r t s t h e p h i l o s o p h i c a l a r g u - described h a v e b o t h d e v e l o p e d withi n a m u c h broader n a t i o n a l ments i n f a v o r o f t h e practice. American public o p i n i o n c a n b e and international context. A major element of t h e national mistaken, as it h a s been in the past o n q u e s t i o n s of g e n d e r context is t h e attitude o f t h e A m e r i c a n people t o w a rd human equality a n d racial d i s c r i m i n a t i o n . H o w e v e r , t h e m o r a l s e n t i - gene therapy. F o r t u n a t e l y , t h e Office of T e c h n o l o g y A s s e s s - ments of o u r fellow citizens c a n be one important source of 118 WALTERS moral k n o w l e d g e for p h i l o s o p h e r s a n d a r e c l e a r l y r e l e v a n t t o t h e difficult t h a n that o f s o m a t i c cells a n d is n o t at p r e s e n t in policymaking process in d e m o c r a c i e s . B o t h policy statements prospect. H o w e v e r , s u c h t h e r a p y m i g h t b e t h e o n l y means by o p i n i o n leaders a n d the v i e w s o f t h e general p u b l i c f o r m the of treating certain conditions, and therefore continued broader context for the review and conduct of h u m a n gene discussion of both its t e c h n i c a l and its e t h i c a l aspects is therapy. essential. Before g e r m - c e l l t h e r a p y is u n d e r t a k e n , its s a f e t y must be very well established, f o r c h a n g e s in g e r m cells would affect t h e d e s c e n d a n t s o f p a t i e n t s ( C I O M S , 1990).

A F U T U R E ISSUE: G E R M - L I N E G E N E T I C Robert Cook-Deegan has suggested in a recent article that the INTERVENTION issue of germ-line genetic intervention is likely to arise in a specific c l i n i c a l c o n t e x t . H e outlines t w o possible s c e n a r i o s . I n My remaining comments are put forward in a spirit of the f i r s t , a c o u p l e r e q u e s t s p r e i m p l a n t a t i o n d i a g n o s i s f o l l o w i n g exploration. T h e y d o n o t r e p r e s e n t t h e v i e w p o i n t o f a n y o r g a n i - in vitro fertilization but e x p r e s s e s a m o r a l preference for g e n e zation. In p a r t i c u l a r , I a m not s p e a k i n g o n b e h a l f o f t h e Human therapy rather than discard if t h e diagnosis shows the early Gene T h e r a p y Subcommittee to t h e N I H RAC. to b e affected with a g e n e t i c disease. In the second The time is ripef o r a d e t a i l e d p u b l i c d i s c u s s i o n o f t h e ethical scenario, b o t h members of a c o u p l e are h o m o z y g o u s for the issues surrounding germ-line genetic intervention in h u m a n s . same genetic d i s e a s e , yet b o t h w i s h to b e t h e g e n e t i c p a r e n t s o f There a r e s e v e r a l r e c e n t d e v e l o p m e n t s that m a k e this d i s c u s s i o n their c h i l d r e n . P r e s u m a b l y all o f t h e i r p r o g e n y w o u l d b e a f f e c t e d especially a p p r o p r i a t e in t h e d e c a d e o f t h e 1 9 9 0 s . T h e first is t h e unless gene therapy were undertaken at s o m e stage of their gradually increasing use of p r e i m p l a n t a t i o n diagnosis as a offspring's d e v e l o p m e n t ( C o o k - D e e g a n , 1 9 9 0 ) . I n b o t h o f t h e s e clinical procedure in i n v i t r o fertilization programs in this scenarios germ-like transmission could be a foreseeable but country a n d a b r o a d . T h e list o f c o n d i t i o n s t h a t c a n b e tested f o r unintended side effect of a therapeutic procedure intended currently includes the t r i s o m i e s , D u c h e n n e ' s muscular d y s t r o - primarily to c u r e d i s e a s e in a n ( e m b r y o n i c ) i n d i v i d u a l . phy, a - a n d p-thalassemia, a n d sickle cell a n e m i a (Buster a n d A more distant and less probable scenario would be t h e Carson, 1 9 8 9 ; Abstracts, 1 9 9 0 ; H a n d y s i d e etal., 1 9 9 0 ; Monk, development o f t e c h n i q u e s for t h e g e n e t i c repair o f s p e r m and 1990; Verlinsky et a l . , 1 9 9 0 ) ; n e w conditions, i n c l u d i n g c y s t i c egg cells before fertilization occurs. W h a t I a s a layperson fibrosis, will s u r e l y b e a d d e d to t h i s list i n t h e f u t u r e , expecially envision i s a m e t h o d b y w h i c h t h e l o c u s o f a g e n e t i c d e f e c t c o u l d as the h u m a n project completes the first y e a r s of a be precisely targeted in a reproductive cell, the defective projected 15 y e a r s o f i n t e n s i v e i n t e r n a t i o n a l e f f o r t . sequence r e m o v e d , a n d a p r o p e r l y f u n c t i o n i n g s e q u e n c e s u b s t i - A second factor is that laboratory models for the genetic tuted f o r t h e d e f e c t i v e s e q u e n c e . ( T h e a n a l o g y f r o m the r e a l m o f modification of nonhuman mammalian preimplantation em- word processing would be the use of the search-and-replace bryos have been developed by numerous laboratories, u s i n g function.) T h i s kind of genetic repair, if it is e v e r technically multiple m e t h o d s f o r g e n e t i c a l t e r a t i o n o f t h e e m b r y o s ( H a m m e r feasible, c o u l d again be undertaken in r e s p o n s e to reasonable etal., 1 9 8 4 ; S t o u t e t a l , 1 9 8 5 ; C o s t a n t i n i e r a / . , 1 9 8 6 ; M a s o n e f requests b y patients, either h o m o z y g o t e s o r h e t e r o z y g o t e s , w h o al, 1 9 8 6 ; S o r i a n o e t a l , 1 9 8 6 ; H o o p e r s a l , 1987;Readhead^r want to r e d u c e t h e p r o b a b i l i t y o f t r a n s m i t t i n g a g e n e t i c d e f e c t t o al, 1987; C o n n e l l y et a l , 1989; G o r d o n , 1989). Phenotypic their c h i l d r e n a n d grandchildren. alterations in the animals resulting from these can There is p r e c e d e n t within the R A C and the H u m a n Gene readily be produced, and the transmission of specific genetic Therapy Subcommittee for such anticipatory discussion o f characteristics t o t h e o f f s p r i n g o f t h e s e t r a n s g e n i c a n i m a l s i s a l s o future technological possibilities. I n D e c e m b e r 1985 the sub- possible, t h o u g h less predictable. committee heard presentations by two scientists o n retroviral Third, the taboo mentality that at t i m e s surrounded the vectors and o n l a b o r a t o r y research with transgenic mice. In discussion o f g e r m - l i n e g e n e t i c i n t e r v e n t i o n i n t h e e a r l y 1 9 8 0 s i s January 1986 the R A C held a similar forum on r e t r o v i r a l gradually being replaced b y a w i l l i n g n e s s to consider other vectors, b o n e marrow transplantation, a n d candidate diseases possibilities, beyond g e n e therapy, f o r a l l e v i a t i n g for t r e a t m e n t b y g e n e t h e r a p y . P e r h a p s t h e t i m e i s ripef o r s i m i l a r or preventing human disease. Since 1983 several respected forums, o r e v e n a s u s t a i n e d s t u d y p r o c e s s , r e g a r d i n g germ-line ethicists, i n c l u d i n g John Fletcher (Fletcher, 1983, 1985) a n d genetic i n t e r v e n t i o n . Eric J u e n g s t ( F o w l e r ^ a l , 1989), a n d clinicians, including W . The broader precedent for the germ-line discussion I a m French Anderson (Anderson, 1989) and Robert M . C o o k - recommending is, h o w e v e r , t h e i n t e r n a t i o n a l p u b l i c discussion Deegan ( C o o k - D e e g a n , 1990), h a v e v e n t u r e d to e x a m i n e g e r m - of somatic cell g e n e therapy that occurred in the years 1969 line intervention in a relatively neutral a n d objective manner. through 1988. W h e n the first c l i n i c a l g e n e transfer a n d gene Even more surprising than this academic discussion is the therapy proposals were put forward in 1988 and 1990, t h e r e Declaration of I n u y a m a , a d o p t e d by 102 participants f r o m 2 4 were s u r p r i s e s , to b e s u r e . T h e target c e l l s in t h e e a r l y p r o t o c o l s countries at a J u l y 1 9 9 0 m e e t i n g o f t h e C o u n c i l o f I n t e r n a t i o n a l were lymphocytes, not cells, and malignant Organizations o f M e d i c a l Sciences ( C I O M S , 1990) [ s e e p a g e s - was not on everyone's short list o f candidate dis- 123-129, this i s s u e ] . T h e pertinent section o f t h e declaration, eases. But the central ethical questions in somatic cell gene which h a s n o t b e e n w i d e l y c o v e r e d b y the W e s t e r n press, reads transfer a n d therapy were well understood by researchers, b y as f o l l o w s : politicians, b y the p r e s s , a n d b y the g e n e r a l p u b l i c . I n a d d i t i o n , a national public review process w a s in place to receive and VI. The modification of human germ cells for therapeutic review t h e f i r s t p r o p o s a l s i n l i g h t o f t h o s e q u e s t i o n s . I t i s , in m y or preventive purposes would be technically m u c h more view, n o t t o o early to intensify a n d broaden the d i s c u s s i o n of ETHICS A N D PUBLIC POLICY 119

germ-line genetic intervention—even if t h e fruits of current [March 15: subgroup m e t to c o n s i d e r i s s u e s r a i s e d in 1 5 letters research e f f o r t s b e c o m e a p p a r e n t o n l y in t h e 2 1 s t c e n t u r y . commenting o n F e d e r a l R e g i s t e r v e r s i o n o f " P o i n t s t o C o n - sider"] April 1 ( t h i r d meeting): further refinement of the "Points to APPENDIX A: C H R O N O L O G Y O F M A J O R Consider" i n t h e l i g h t o f p u b l i c c o m m e n t s EVENTS, 1 9 8 3 - 1 9 9 1 [May 3: R A C meeting, report f r o m W o r k i n g G r o u p ] [August 19: revised v e r s i o n o f " P o i n t s t o C o n s i d e r " p u b l i s h e d Meetings Leading to the Formation of the Working in F e d e r a l R e g i s t e r ] Group on H u m a n Gene Therapy [September 6 : p l a n n e d fourth m e e t i n g c a n c e l e d ] [September 2 0 : subgroup m e t to c o n s i d e r i s s u e s r a i s e d in f o u r 1983 letters c o m m e n t i n g on s e c o n d Federal Register version of "Points t o C o n s i d e r " ] April 11: RAC meeting; endorsed proposal to form a working[Septembe r 2 3 : R A C meeting; "Points t o C o n s i d e r " a c c e p t e d ] group to r e s p o n d to P r e s i d e n t ' s C o m m i s s i o n report entitled December 16 ( f o u r t h meeting): presentations b y W . F r e n c h Splicing L i f e Anderson (on r e t r o v i r a l v e c t o r s ) , G e o r g e S c a n g o s ( o n trans- June 2 4 : First m e e t i n g o f w o r k i n g g r o u p ; r e c o m m e n d a t i o n t h a t genic a n i m a l s ) , a n d S a m u e l A c k e r m a n (on t h e F D A process RAC be prepared to deal with ethical a n d social issues in for regulating investigational n e w d r u g s ) ; working group specific proposals to apply genetic to h u m a n s ; expressed its willingness t o r e v i e w p r e c l i n i c a l data also, r e c o m m e n d a t i o n that m e m b e r s h i p o f R A C be m o d i f i e d to e n a b l e it to c o n s i d e r s u c h i s s u e s Meetings of the Human Gene Therapy Subcommittee September 19: R A C accepted working group's proposals, asked f o r f u r t h e r d i s c u s s i o n o f g u i d e l i n e s a n d r e v i e w p r o c e - 1986 dures December 13: Second (and final) meeting of w o r k i n g group; [January 27: RAC meeting; presentations by David Martin (on draft l a n g u a g e for r e v i s i o n o f N I H Guidelines for R e s e a r c h candidate d i s e a s e s f o r t r e a t m e n t b y g e n e t h e r a p y ) , R o b e r t s o n Involving R e c o m b i n a n t D N A Molecules p r o p o s e d ; interdis- Parkman ( o n a l l o g e n e i c b o n e m a r r o w t r a n s p l a n t a t i o n ) , a n d A . ciplinary w o r k i n g g r o u p o r s u b c o m m i t t e e o f R A C suggested Dusty M i l l e r ( o n t h e u s e o f r e t r o v i r a l vectors)] as i n i t i a l r e v i e w g r o u p f o r h u m a n g e n e t h e r a p y p r o p o s a l s [February 2 5 : memorandum from E x e c u t i v e S e c r e t a r y o f R A C 1984 and S u b c o m m i t t e e to " i n t e r e s t e d p a r t i e s " requesting s u b m i s - sion o f p r e c l i n i c a l d a t a ] [No s p r i n g m e e t i n g o f S u b c o m m i t t e e ] January 5: Working group proposal published in Federal Reg- [May 12: W . F r e n c h Anderson resigned from Subcommittee ister because o f h i s plans t o s u b m i t a g e n e t h e r a p y p r o t o c o l i n t h e February 6 : R A C accepted w o r k i n g g r o u p p r o p o s a l foreseeable future] April 2 6 : N I H Director a c c e p t e d R A C recommendations Summer: Working G r o u p o n H u m a n G e n e T h e r a p y a p p o i n t e d ; August 8 (fifth meeting): review and revision of "Points to membership included four l a b o r a t o r y scientists, three clini- Consider"; consideration of March 26, 1986, letter from cians, t h r e e ethicists, t h r e e l a w y e r s , a n d t w o public p o l i c y Committee for R e s p o n s i b l e ( C R G ) p r o p o s i n g that experts NIH Guidelines o n r e c o m b i n a n t D N A research b e r e v i s e d t o exclude h u m a n gene t h e r a p y if it could alter g e r m line cells and unless t h e t h e r a p y is aimed solely at t h e r e l i e f o f a " l i f e Meetings of the Working Group on Human threatening or severely disabling condition"; s u b c o m m i t t e e Gene Therapy drafting a n d approval o f a letter r e j e c t i n g t h e C R G request; acceptance o f c o n c e p t o f p r o d u c i n g a l a y - l a n g u a g e s u m m a r y 1984 of t h e " P o i n t s t o C o n s i d e r " [September 2 9 : R A C meeting a n d a c c e p t a n c e o f S u b c o m m i t t e e [September 26: subgroup meeting; drafting of an outline forpositio a n o n C R G letter] guidance d o c u m e n t ] October 12 (initial p l e n a r y meeting): discussion o f a t h i r t e e n - 1987 page draft entitled "Points to Consider in the Design and Submission o f H u m a n G e n e T h e r a p y P r o t o c o l s " [January 9: Lay Summary Subgroup meeting] [October 2 9 : R A C meeting, report f r o m W o r k i n g G r o u p ] April 2 4 (sixth m e e t i n g ) : " H u m a n Gene Therapy: P r e c l i n i c a l November 1 6 ( s e c o n d m e e t i n g ) : discussion o f 1 1 - p a g e c o m p o s - Data D o c u m e n t " b y W . French A n d e r s o n et a l received a n d ite draft entitled "Points to C o n s i d e r in t h e Design a n d initially d i s c u s s e d ; c o m m e n t s o n the l a y - l a n g u a g e s u m m a r y Submission o f S o m a t i c C e l l G e n e T h e r a p y P r o t o c o l s " draft, n o w called " G e n e r a l I n f o r m a t i o n o n G e n e T h e r a p y f o r Human P a t i e n t s " 1985 [No m e e t i n g i n J u l y 1987] December 7 ( s e v e n t h m e e t i n g ) : detailed r e v i e w o f " P r e c l i n i c a l [January 22: "Points to Consider" published in Federal RegisterData D o c u m e n t " b y Anderson et a l ; further r e f i n e m e n t o f for c o m m e n t ] "Gene T h e r a p y for H u m a n P a t i e n t s " 120 WALTERS

1988 March 30 ( e l e v e n t h meeting): initial presentation of human gene t h e r a p y p r o t o c o l f o r A D A deficiency b y D r s . B l a e s e a n d [No meeting on April 11] Anderson; r e c o m m e n d a t i o n that l i m i t o n n u m b e r o f p a t i e n t s [June 1 0: human g e n e t r a n s f e r p r o t o c o l o f S t e v e n A . R o s e n b e r g in h u m a n gene transfer p r o t o c o l b e l i f t e d et a l formally s u b m i t t e d for l o c a l r e v i e w ] [March 3 0 : R A C meeting; further r e v i e w o f B l a e s e a n d A n d e r - July 2 9 (eighth m e e t i n g ) : decision to e x t e n d s c o p e o f s u b c o m - son protocol; c r i t i c i s m of S u b c o m m i t t e e procedures for r e - mittee oversight to include h u m a n gene transfer p r o t o c o l s ; viewing clinical p r o t o c o l s ; acceptance o f S u b c o m m i t t e e r e c - initial r e v i e w of h u m a n gene transfer p r o t o c o l s u b m i t t e d by ommendations re lifting limit on n u m b e r of p a t i e n t s i n Steven A. R o s e n b e r g et a l ; decision to d e f e r approval approved p r o t o c o l ] pending s u b m i s s i o n o f a d d i t i o n a l r e q u e s t e d d a t a [April 2 3 : human gene therapy protocol o f D r . R o s e n b e r g and [September 29: conference call b y s u b c o m m i t t e e members, associates f o r u s e o f t u m o r n e c r o s i s f a c t o r g e n e i n t r e a t m e n t o f decision to r e c o m m e n d further d e f e r r a l o f R o s e n b e r g et al. malignant m e l a n o m a formally s u b m i t t e d for l o c a l r e v i e w ] human gene transfer protocol pending submission of the June 1 (twelfth m e e t i n g ) : approval o f B l a e s e - A n d e r s o n h u m a n additional d a t a r e q u e s t e d ] gene t h e r a p y p r o t o c o l , c o n t i n g e n t o n s u b m i s s i o n o f a d d i t i o n a l [October 3 : R A C meeting; a p p r o v a l o f R o s e n b e r g et a l . h u m a n data o n several p o i n t s gene t r a n s f e r p r o t o c o l b y majority v o t e ] July 30 (thirteenth meeting): approval of B l a e s e - A n d e r s o n [October 18: Letter b y N I H Director Wyngaarden to R A C human gene therapy protocol for the treatment of A D A Chairman McGarrity stating t h a t h u m a n gene transfer p r o t o - deficiency a n d o f R o s e n b e r g et a l . g e n e t h e r a p y p r o t o c o l f o r col o f R o s e n b e r g et a l . should b e r e s u b m i t t e d , w i t h a d d i t i o n a l treatment of malignant melanoma using marked TIL cells data, to t h e S u b c o m m i t t e e ] carrying t h e g e n e f o r t u m o r n e c r o s i s f a c t o r ; d e f e r r a l o f h u m a n December 9 (ninth m e e t i n g ) : approval o f h u m a n gene t r a n s f e r gene t r a n s f e r p r o t o c o l f r o m St. J u d e ' s H o s p i t a l protocol s u b m i t t e d b y R o s e n b e r g et a l ; d i s c u s s i o n o f o p t i m a l [July 3 1 : R A C meeting; a p p r o v a l of t w o h u m a n gene therapy mode of interaction between Subcommittee and R A C ; ap- protocols] proval o f " G e n e r a l Information D o c u m e n t " ; d i s c u s s i o n and [October 16: R A C meeting; discussion of regional meetings rejection of p r o p o s a l from the Foundation on E c o n o m i c and o f f u t u r e p r o t o c o l s ] Trends to e s t a b l i s h a H u m a n A d v i s o r y Committee November 30 (fourteenth meeting): approval of h u m a n gene parallel t o t h e R A C and its S u b c o m m i t t e e transfer p r o t o c o l f r o m the U n i v e r s i t y o f P i t t s b u r g h u s i n g T I L cells and interleukin-4; a p p r o v a l of h u m a n gene transfer 1989 protocol f r o m St. J u d e ' s Hospital studying relapse in a c u t e myelogenous ; deferral of additional h u m a n gene [January 30: RAC meeting; NIH Director reported on his transfer p r o t o c o l s f r o m S t . J u d e ' s H o s p i t a l a n d t h e U n i v e r s i t y approval o f t h e h u m a n g e n e t r a n s f e r p r o t o c o l ; F o u n d a t i o n o n of W i s c o n s i n ; l e t t e r f r o m Alexander C a p r o n about t h e s c o p e Economic Trends announced filing of lawsuit to prevent ofthe S u b c o m m i t t e e ' s m a n d a t e enrollment o f patients in p r o t o c o l , f u r t h e r a d v o c a t e d e s t a b - lishment of H u m a n Eugenics Advisory Committee; R A C 1991 approval o f " G e n e r a l I n f o r m a t i o n D o c u m e n t " ] [No M a r c h meeting o f S u b c o m m i t t e e ] [February 4: RAC meeting; approval of human gene transfer [March 3 1 : meeting o f P o i n t s t o C o n s i d e r S u b c o m m i t t e e ] protocol f r o m St. J u d e ' s Hospital studying relapse in a c u t e July 31 (tenth meeting): revision of " P o i n t s to Consider," myelogenous leukemia; deferral of h u m a n gene transfer especially i n o r d e r t o i n c l u d e f o r m a l l y h u m a n g e n e t r a n s f e r a s protocol f r o m t h e U n i v e r s i t y o f P i t t s b u r g h ; f u r t h e r d i s c u s s i o n well a s h u m a n g e n e t h e r a p y of t h e f u t u r e r o l e o f R A C ] [September 1: revised "Points to Consider" document pub- lished i n t h e F e d e r a l R e g i s t e r ] [October 6: R A C meeting; revised "Points to Consider" a p - proved, w i t h m i n o r r e v i s i o n in title] APPENDIX B: P O L I C Y S T A T E M E N T S ON HUMAN G E N E T H E R A P Y — A N 1990 INTERNATIONAL CHRONOLOGY

[February 5: R A C meeting; p r e s e n t a t i o n s b y Drs. R o s e n b e r g , 1980 Blaese, a n d Anderson o n t h e progress of the h u m a n gene transfer protocol; presentation by former N I H D i r e c t o r World Council of Churches, Conference on Faith, Science, and Fredrickson o n the f u t u r e r o l e o f t h e R A C ; a c c o r d i n g to D r . the F u t u r e , Faith a n d S c i e n c e i n a n Unjust W o r l d Fredrickson, h u m a n g e n e t h e r a p y s h o u l d b e c e n t r a l t o R A C ' s . role] 1982 [February 2 3 : human g e n e t h e r a p y p r o t o c o l o f D r s . R . M i c h a e l Blaese and W . F r e n c h Anderson and associates for ADA Parliamentary Assembly, Council of Europe: Recommendation deficiency f o r m a l l y s u b m i t t e d for l o c a l r e v i e w ] 934 ( 1 9 8 2 ) o n g e n e t i c e n g i n e e r i n g [March 1: revised " P o i n t s t o C o n s i d e r " a n d " G e n e T h e r a p y f o r World Council of C h u r c h e s , W o r k i n g Committee on Church Human Patients: I n f o r m a t i o n for the General Public" p u b - and Society, M a n i p u l a t i n g L i f e lished i n t h e F e d e r a l R e g i s t e r ] United States, President's C o m m i s s i o n for t h e S t u d y o f E t h i c a l ETHICS A N D PUBLIC POLICY 121

Problems in Medicine and Biomedical Research, Splicing search o n G e n e T h e r a p y in H u m a n s : B a c k g r o u n d a n d G u i d e - Life report lines European C o m m i s s i o n , W o r k i n g Party, Ethics o f N e w Repro- 1983 ductive T e c h n o l o g i e s ( T h e G l o v e r R e p o r t )

Pope John Paul II, Address on "The Ethics of Genetic Manipu-1990 lation" to t h e 3 5 t h G e n e r a l A s s e m b l y of t h e W o r l d Medical Association in V e n i c e Council for International Organizations of Medical Sciences (CIOMS), "Genetics, Ethics and Human Values: Human 1984 Genome Mapping, Genetic Screening and Gene Therapy (The D e c l a r a t i o n o f I n u y a m a ) " Denmark, Indenrigsministeriet (Ministry ofthe Interior) Frems- kridtets P r i s ( T h e P r i c e o f P r o g r e s s ) Sweden, Gen-Ethikkommitten (Genetic Ethics Committee), REFERENCES Genetisk I n t e g r i t e t ( G e n e t i c I n t e g r i t y ) United States, C o n g r e s s , O f f i c e of T e c h n o l o g y Assessment, Abstracts of the First International Symposium on Preimplantation Human G e n e T h e r a p y : B a c k g r o u n d P a p e r Genetics. (1990) In V i t r o Fertiliz. E m b r y o T r a n s f e r 7 , 183-213. ADA Human Gene Therapy Clinical Protocol. ( 1 9 9 0 ) . H u m . Gene 1985 Ther. 1 , 3 2 7 - 3 2 9 , 3 3 1 - 3 6 2 . ANDERSON, W . F . (1989). H u m a n g e n e t h e r a p y : W h y draw a l i n e ? J. United States, National Institutes of Health, Human Gene Med. P h i l o s . 14,681-693. Therapy S u b c o m m i t t e e ( f o r m e r l y , W o r k i n g G r o u p o n H u m a n AREEN, J. a n d K I N G , P . ( 1 9 9 0 ) . L e g a l regulation a n d h u m a n g e n e therapy. H u m . G e n e T h e r . 1, 151-161. Gene Therapy), "Points to Consider in the Design and BEARDSLEY, T . ( 1 9 8 5 ) . G e n e therapy: NIH/FDA dispute likely to Submission of H u m a n Somatic-Cell Gene Therapy Proto- delay r e s e a r c h . Nature 3 1 6 , 5 6 7 . cols'7 BUSTER, J . E . , a n d C A R S O N , S . A . ( 1 9 8 9 ) . Genetic d i a g n o s i s ofthe Federal R e p u b l i c o f G e r m a n y , M i n i s t e r a n d M i n i s t e r f o r preimplantation e m b r y o . A m . J. M e d . G e n e t . 3 4 , 2 1 1 - 2 1 6 . Research a n d T e c h n o l o g y , W o r k i n g G r o u p (the B e n d a C o m - CIOMS (Council for I n t e r n a t i o n a l Organizations o f M e d i c a l Sciences). mission), I n - V i t r o F e r t i l i s a t i o n , G e n o m a n a l y s e u n d G e n t h e r - (1990). "Genetics, Ethics and Human Values: H u m a n Genome apie (In Vitro Fertilization, Genome-Analysis, and Gene Mapping, G e n e t ic Screening and Gene Therapy." T o k y o and In- Therapy) uyama C i t y , July 2 2 - 2 7 . COOK-DEEGAN, R . M . (1990). H u m a n gene therapy and c o n g r e s s . 1986 Hum. G e n e T h e r . 1, 163-170. National C o u n c i l o f C h u r c h e s , G o v e r n i n g B o a r d , p o l i c y state- CONNELLY, C . S . , F A H L , W . E . , a n d I A N N A C C O N E , P . M . ( 1 9 8 9 ) . ment o n " G e n e t i c S c i e n c e f o r H u m a n Benefit" The role o f t r a n s g e n i c a n i m a l s in the a n a l y s i s o f v a r i o u s biological aspects o f n o r m a l a n d pathologic status. Exp. C e l l R e s . 183, 257- 276. 1987 COSTANTINI, F . , C H A D A , K . , a n d M A G R A M , J. ( 1 9 8 6 ) . Correc- tion of m u r i n e b e t a - t h a l a s s e m i a b y g e n e t r a n s f e r into the g e r m l i n e . German Federal Republic, Tenth Bundestag, Enquete-Kommis- Science 2 3 3 , 1192-1194. sion ( C o m m i t t e e o f I n q u i r y ) , C h a n c e n undRisiken d e r G e n - CULLITON, B . J . ( 1 9 8 5 ) . N e w biotech r e v i e w b o a r d p l a n n e d . Science technologie ( O p p o r t u n i t i e s a n d R i s k s o f G e n e t i c T e c h n o l o g y ) 229, 7 3 6 - 7 3 7 . World M e d i c a l A s s o c i a t i o n , "Statement o n G e n e t i c C o u n s e l i n g DAVIS, B.D. (1970). Prospects for genetic intervention in m a n . and Genetic Engineering" (39th W o r l d Medical Assembly, Science 1 7 0 , 1279-1283. Madrid) FLETCHER, J . C . ( 1 9 8 3 ) . M o r a l p r o b l e m s a n d e t h i c a l i s s u e s i n p r o s p e c - Canada, M e d i c a l Research Council, G u i d e l i n e s on Research tive h u m a n g e n e therapy. Virginia L a w R e v . 6 9 , 5 1 5 - 5 4 6 . Involving H u m a n Subjects FLETCHER, J.C. ( 1 9 8 5 ) . Ethical I s s u e s in a n d beyond prospective Australia, National Health and Medical Research Council, clinical trials o f h u m a n g e n e t h e r a p y . J. M e d . P h i l o s . 10, 2 9 3 - 3 0 9 . FOWLER, G., J U E N G S T , E . T . , and Z I M M E R M A N , B.K. ( 1 9 8 9 ) . Medical Research Ethics Committee, Ethical Aspects of Germ-line g e n e therapy a n d the c l i n i c a l e t h o s o f m e d i c a l genetics. Research o n H u m a n Gene Therapy Theoret. M e d . 1 0 , 151-165. GORDON, J.W. (1989). T r a n s g e n i c animals. I n t . R e v . C y t o l . 1 1 5 , 1988 171-229. GUSTAFSON, J.M. (1973). G e n e t i c engineering and the n o r m a t i v e European Medical Research Councils, "Gene Therapy in Man" view o f t h e h u m a n . I n E t h i c a l I s s u e s in B i o l o g y a n d M e d i c i n e . P . N . American M e d i c a l A s s o c i a t i o n , C o u n c i l o n E t h i c a l a n d J u d i c i a l Williams, ed. ( S c h e n k m a n Publishing C o m p a n y , C a m b r i d g e , M A ) Affairs, "Opinion o n G e n e T h e r a p y and Surrogate M o t h e r s " pp. 4 6 - 5 8 . [Report E : ( 1 - 8 8 ) ; title p r o v i d e d ] HAMMER, R.E., P A L M I T E R , R . D . , a n d B R I N S T E R , R . L . (1984). Partial correction o f m u r i n e h e r e d i t a r y g r o w t h d i s o r d e r b y g e r m - l i n e incorporation o f a n e w g e n e . Nature 3 1 1 , 6 5 - 6 7 . 1989 HANDYSIDE, A.H., K O N T O G I A N N L E.H., H A R D Y , K., and WINSTON, R . M . L . ( 1 9 9 0 ) . Pregnancies f r o m b i o p s i e d h u m a n p r e - Canada, Medical Research Council, Discussion Paper: Re- implantation e m b r y o s s e x e d b y Y-specific D N A amplification Na- ture 3 4 4 , 7 6 8 - 7 7 0 . 122 WALTERS

HOOPER, M., HARDY, K., HANDYSIDE, A., HUNTER, S., a n d READHEAD, C , POPKO, B., T A K A H A S H I , N., S H I N E , H.D., MONK, M . (1987). H P R T - d e f i c i e n t ( L e s c h - N y h a n ) m o u s e e m b r y o s SAAVEDRA, R.A., S I D M A N , R.L., a n d H O O D , L. ( 1 9 8 7 ) . E x - derived from colonization by cultured cells. N a t u r e 3 2 6 , pression o f a m y e l i n basic p r o t e i n g e n e in t r a n s g e n i c shiverer m i c e : 292-295. Correction o f t h e d y s m y e l i n a t i n g p h e n o t y p e . Cell 4 8 , 7 0 3 - 7 1 2 . JUENGST, E . T . ( 1 9 9 0 ) . T h e N I H 'Points to C o n s i d e r ' and t h e l i m i t s o f SORIANO, P . , C O N E , R . D . , M U L L I G A N , R . C , a n d J A E N I S C H , R . human g e n e t h e r a p y . H u m . G e n e T h e r . 1 , 4 2 5 - 4 3 3 . (1986). Tissue-specific and ectopic expression of g e n e s introduced MASON, A.J., PITTS, S.L., NIKOLICS, K., S Z O N Y I , E . , into transgenic m i c e b y r e t r o v i r u s e s . Science 2 3 4 , 1 4 0 9 - 1 4 1 3 . WILCOX, J.N., S E E B U R G , P.H., a n d S T E W A R T , T.A. (1986). STOUT, J.T., C H E N , H . Y . , B R E N N A N D , J., C A S K E Y , C.T., a n d The hypogonadal mouse: R e p r o d u c t i v e functions restored b y gene BRINSTER, R . L . ( 1 9 8 5 ) . E x p r e s s i o n o f h u m a n H P R T in t h e c e n t r a l therapy. Science 2 3 4 , 1 3 7 2 - 1 3 7 8 . nervous s y s t e m o f t r a n s g e n i c m i c e . N a t u r e 3 1 7 , 2 5 0 - 2 5 2 . MONK, M . (1990). E m b r y o research a n d g e n e t i c d i s e a s e . N e w Scien- TNF/TIL H u m a n G e n e T h e r a p y Clinical P r o t o c o l . (1990). H u m . Gene tist 1 2 5 , 5 6 - 5 9 , 6 J a n u a r y . Ther 1 , 4 4 3 - 4 6 2 , 4 6 3 - 4 7 1 , 4 7 3 - 4 8 0 . N2-TIL H u m a n Gene Transfer Clinical P r o t o c o l . ( 1 9 9 0 ) . H u m . Gene U.S., C o n g r e s s , H o u s e , Committee o n S c i e n c e a n d T e c h n o l o g y , S u b - Ther. 1 , 7 3 - 9 2 . committee o n Investigations a n d O v e r s i g h t . ( 1 9 8 2 ) . H u m a n Genetic National Institutes of Health. (1985). Recombinant D N A research; Engineering. 9 7 t h C o n g r e s s , 2 n d S e s s i o n , N o v e m b e r 16-18. request for p u b l i c c o m m e n t o n 'Points to C o n s i d e r in t h e D e s i g n a n d VERLINSKY, Y., P E R G A M E N T , E., and S T R O M , C. (1990). T h e Submission of H u m a n Somatic-Cell G e n e T h e r a p y Protocols.' Fed. preimplantation diagnosis of genetic diseases. J . I n Vitro F e r t i l i z . Reg. 5 0 , 2 9 4 0 - 2 9 4 5 . Embryo Transfer 7 , 1 - 5 . Novo R e p o r t : A m e r i c a n A t t i t u d e s a n d B e l i e fs a b o u t G e n e t i c E n g i n e e r - ing. ( 1 9 8 7 ) . ( N o v o Information C e n t e r , c/o R e s e a r c h a n d F o r e c a s t s , Address reprint requests to: Inc., N e w York). Dr. L e R o y Walters Office of Technology Assessment. (1987). New Developments i n Kennedy Institute o f E t h i c s Biotechnology—Background P a p e r : Public P e r c e p t i o n s o f B i o t e c h - Georgetown University nology. ( U . S . G o v e r n m e n t Printing O f f i c e , Washington, D C ) . Washington, D . C . 20057 President's C o m m i s s i o n for t h e S t u d y o f E t h i c a l P r o b l e m s in M e d i c i n e and B i o m e d i c a l a n d B e h a v i o r a l R e s e a r c h . (1982). Splicing L i f e : T h e Social a n d E t h i c a l I s s u e s o f G e n e t i c E n g i n e e r i n g w i t h H u m a n B e i n g s . Received for p u b l i c a t i o n A p r i l 1 1 , 1 9 9 1 ; a c c e p t e d A p r i l 2 3 , 1 9 9 1 . (U.S. G o v e r n m e n t Printing O f f i c e , Washington, D C ) , p p . 9 5 - 9 6 .