Proposal to Map and Sequence the Human Genome

Order Code IB88012 PROPOSAL T O MAP AND SEQUENCE THE HUMAN GENOME U p d a t e d F e b r u a r y 2, 1988 by Irene Stith-Coleman Science Policy Research Division Congressional Research Service CONTENTS SUMMARY ISSUE DEFlNITlON BACKGROUND A N D ANALYSIS S c i e n t i f i c Background M o t i v a t i o n f o r M a p p i n g a n d S e q u e n c i n g t h e Genome M a p p i n g a n d S e q u e n c i n g T h e E n t i r e Genome C o n t r o v e r s y O v e r a M a j o r Genome I n i t i a t i v e C u r r e n t A c t i v i t i e s on Genome R e s e a r c h Federal Agencies Private Sector lncernarional Activities D a t a Management a n d A n a l y s i s Other Policy Issues OTA a n d NAS S t u d i e s f o r C o n g r e s s Policy Options f o r Congressional Consideration LEG1 SLATLON CONGRESSIONAL HEARINGS, REPORTS, AND DOCUMENTS THE PROPOSAL TO MAP AND SEQUENCE THE HUMAN GENOME R e c e n t a d v a n c e s i n m o l e c u l a r b i o l o g y have made i t p o s s i b l e f o r s c i e n t i s t s t o d i s c o v e r t h e g e n e t i c makeup o f humans. This c a p a b i l i t y has l e d t o t h e s u g g e s t i o n of some e x p e r t s t h a t t h e e n t i r e human genome be s e q u e n c e d and mapped. T h i s would i n v o l v e d e t e r m i n i n g t h e l i n e a r o r d e r of t h e 3 b i l l i o n u n i t s t h a t make up t h e human genome, c a l l e d n u c l e o t i d e s , and l o c a t i n g t h e f u n c t i o n a l p a r t s of t h e genome known a s g e n e s . I n 1986, t h e Department o f Energy (DOE) p r o p o s e d t h a t t h i s be done i n a l a r g e - s c a l e c e n t r a l l y coordinated project. I f a p p r o v e d , t h i s would be t h e l a r g e s t b i o l o g i c a l s c i e n c e p r o j e c t e v e r u n d e r t a k e n , and would c o s t a n e s t i m a t e d few h u n d r e d m i l l i o n t o a s e v e r a l b i l l i o n d o l l a r s . The i n f o r m a t i o n o b t a i n e d from mapping and s e q u e n c i n g t h e human genome c o u l d be of s u b s t a n t i a l b e n e f i t f o r t r e a t i n g t h e 4 , 0 0 0 g e n e t i c d i s e a s e s known t o a f f l i c t humans. I n a d d i t i o n , i t c o u l d h a v e enormous p o t e n t i a l f o r comnercial a p p l i c a t i o n s i n f i e l d s such a s pharmaceuticals and a g r i c u l t u r e . I n d e e d , some s u p p o r t e r s view t h e p r o p o s e d i n i t i a t i v e a s being of s i g n i f i c a n t v a l u e i n h e l p i n g t h e United S t a t e s m a i n t a i n I t s c o m p e t i t i v e edge i n t h e a r e a of biotechnology. However, t h e p r o p o s e d p r o j e c t h a s l e d t o a g r e a t d e a l of d e b a t e among s c i e n t i s t s . Central t o t h i s d i s c u s s i o n i s t h e b e l i e f t h a t s i g n i f i c a n t improvements a r e n e e d e d i n t h e t e c h n o l o g i e s r e q u i r e d t o map and s e q u e n c e t h e e n t i r e genome. A n o t h e r i s s u e r a i s e d i s how t h e genome s h o u l d b e mapped and sequenced. Some e x p e r t s f e a r t h a t i n i t i a t i o n o f a m a j o r c e n t r a l i z e d p r o j e c t t o s e q u e n c e t h e e n t i r e human genome c o u l d r e s u l t i n f u n d s b e i n g d i v e r t e d from o t h e r c r u c i a l r e s e a r c h p r o j e c t s . Such s c i e n t i s t b e l i e v e t h a t a f i r s t p r i o r i t y s h o u l d be g i v e n t o mapping and s e q u e n c i n g o n l y t h e p o r t i o n s o f t h e genome t h a t h a v e known b i o l o g i c a l s i g n i f i c a n c e ( e n c o d e d by o n l y a b o u t 5% o f t h e genome's DNA). Contemplated i n t h i s o p t i o n i s an i n c r e m e n t a l s e l e c t i v e s e r i e s of p r o j e c t s w i t h r e d u c e d c o s t s s p r e a d o v e r a longer period. A d v o c a t e s of a m a j o r genome i n i t i a t i v e a r g u e t h a t t h e so-called "nonfunctional" D N A i n t h e genome may have i m p o r t a n t u n i d e n t i f i e d f u n c t i o n s , which c o u l d be d i s c o v e r e d by s e q u e n c i n g t h e e n t i r e genome. A number o f p u b l i c p o l i c y i s s u e s w i l l be p r e s e n t e d by f u t u r e r e s e a r c h on t h e human genome, w h e t h e r done i n a l a r g e - s c a l e p r o j e c t o r a s e r i e s of s m a l l e r p r o j e c t s . These i n c l u d e : o w n e r s h i p o f i n f o r m a t i o n q u e s t i o n s , s u c h a s c o p y r i g h t and p a t e n t r i g h t s t o g e n e t i c i n f o r m a t i o n ; e t h i c a l and l e g a l c o n c e r n s r e l a t e d t o how t h e i n f o r m a t i o n w i l l b e u s e d ; and i m p l i c a t i o n s t o i n t e r n a t i o n a l c o m p e t i t i v e i s s u e s , i n c l u d i n g t h e r o l e of f o r e i g n c o u n t r i e s i n t h e p r o d u c t i o n and u s e of human genome informat ion. ISSUE DEFINITION S c i e n t i s t s a r e now a b l e t o d i s c o v e r t h e e n t i r e g e n e t i c makeup o f humans. T h i s c a n be d o n e by d e t e r m i n i n g t h e l i n e a r o r d e r o f t h e 3 b i l l i o n u n i t s t h a t make up t h e human genome, c a l l e d s e q u e n c i n g , a n d i d e n t i f y i n g t h e l o c a t i o n o f t h e g e n o m e ' s f u n c t i o n a l p a r t s , o r g e n e s , known a s m a p p i n g . The D e p a r t m e n t o f E n e r g y (DOE) h a s p r o p o s e d t h a t t h e e n t i r e genome be mapped a n d s e q u e n c e d i n a l a r g e - s c a l e c e n t r a l l y c o o r d i n a t e d p r o j e c t . If a p p r o v e d , t h i s would b e t h e l a r g e s t b i o l o g i c a l s c i e n c e p r o j e c t e v e r undertaken. I t would c o s t a n e s t i m a t e d f e w h u n d r e d m i l l i o n t o s e v e r a l b i l l i o n d o l l a r s , and h a s p o t e n t i a l f o r producing major s c i e n t i f i c , m e d i c a l , and commercial b e n e f i t s . I n i t i a l i s s u e s f o r Congress a r e : S h o u l d F e d e r a l s p o n s o r s h i p of s u c h a " b i g s c i e n c e " p r o j e c t b e a u t h o r i z e d and funded? I f s o , u n d e r what terms, c o n t r o l s , a n d a g e n c y l e a d e r s h i p ? Or, should g e n e t i c r e s e a r c h proceed i n t h e "small science," less c o m p r e h e n s i v e mode t h a t h a s p r o d u c e d t h e p r o g r e s s o f r e c e n t d e c a d e s ? A p p l i c a t i o n s of human genome i n f o r m a t i o n o b t a i n e d b e e i t h e r a p p r o a c h w i l l p r e s e n t a number o f b i o e t h i c a l , c o r m e r c i a l , p r o p e r t y , a n d l e g a l p o l i c y issues. BACKGROUND AND ANALYSIS Scientific Background R e s e a r c h i n g e n e t i c s , t h e s c i e n c e of h e r e d i t y , h i s t o r i c a l l y h a s been d r i v e n by e f f o r t s t o t r e a t g e n e t i c d i s e a s e s i n humans. G e n e t i c d i s e a s e s a r e b e l i e v e d t o be t h e most w i d e s p r e a d o f a l l d i s o r d e r s , a c c o u n t i n g f o r some 4 , 0 0 0 known human d i s o r d e r s , many o f w h i c h a r e l e t h a l . The q u e s t f o r remedies has l e d t o s i g n i f i c a n t advances i n g e n e t i c s , p a r t i c u l a r l y during t h e p a s t d e c a d e , and h a s g i v e n s c i e n t i s t s t h e c a p a b i l i t y of d i s c o v e r i n g t h e e n t i r e g e n e t i c makeup o f humans. Such i n f o r m a t i o n c o u l d b e v e r y b e n e f i c i a l i n t h e s e a r c h f o r t h e c a u s e s of g e n e t i c d i s e a s e s . This p r o s p e c t i s e s p e c i a l l y s i g n i f i c a n t b e c a u s e i n most c a s e s , n o c u r e i s y e t a v a i l a b l e f o r g e n e t i c d i s e a s e s and d o c t o r s c a n o f f e r o n l y p a l l i a t i v e t r e a t m e n t s , i f any. The k e y t o u n r a v e l i n g t h e m y s t e r i e s b e h i n d g e n e t i c d i s e a s e s a p p e a r s t o r e s i d e i n t h e g e n e s o f t h e human genome. The genome, w h i c h i s f o u n d i n e a c h c e l l , c o n t a i n s t h e g e n e t i c c o d e t h a t d i r e c t s t h e e n t i r e makeup o f humans. T h e human genome c o n s i s t s of 23 p a i r s o f c h r o m o s o m e s , e a c h o f DNA (deoxyribonucleic a c i d ) w h i c h i s made u p o f a d o u b l e - s t r a n d e d m o l e c u l e c o n t a i n i n g l o n g s t r i n g s of four chemical groups c a l l e d n u c l e o t i d e s , o r bases. These n u c l e o t i d e s , t o t a l l i n g a n e s t i m a t e d 3 b i 11i o n p a i r s , a r e a r r a n g e d i n v a r i o u s l a r g e 1 y unknown c o m b i n a t i o n s . D i s p e r s e d among t h e m a r e s e g m e n t s o f n u c l e o t i d e s t h a t f o r m t h e g e n o m e ' s e s t i m a t e d 1 0 0 , 0 0 0 f u n c t i o n a l u n i t s , known a s g e n e s . However, t h e s e e s t i m a t e d 1 0 0 , 0 0 0 g e n e s a r e e n c o d e d by o n l y 52 o f t h e 3 b i l l i o n n u c l e o t i d e p a i r s t h a t make up t h e genome; t h e r e m a i n i n g p a i r s h a v e no known f u n c t i o n . in a Genes a r e h e r e d i t a r y u n i t s t h a t a r e t r a n s f e r r e d from p a r e n t s t o c h i l d generally predictable fashion. A c t i v i t i e s o r i g i n a t i n g from t h e s e h e r e d i t a r y u n i t s g o v e r n numerous p r o c e s s e s i n c l u d i n g t h e g r o w t h , s t r u c t u r e , f u n c t i o n , embryonic development, and p o s s i b l y e v e n t h e a g i n g p r o c e s s o f an o r g a n i s m . F o r e x a m p l e , p r o t e i n s , whose p r o d u c t i o n i s o r c h e s t r a t e d by g e n e s c o n t a i n e d i n t h e genome, make up t h e s t r u c t u r a l c o m p o n e n t s o f b o n e , m u s c l e , b r a i n , b l o o d , a n d o t h e r human t i s s u e s , a n d r e g u l a t e most a c t i v i t i e s o f a l l l i v i n g o r g a n i s m s . Genes a r e b e l i e v e d t o r a n g e i n s i z e from l e s s chan 1 , 0 0 0 n u c l e o t i d e s t o a s many a s 1 , 0 0 0 , 0 0 0 . Many s L r u c t u r a 1 a n d f u n c t i o n a l a b n o r m a l i t i e s i n z n i m a l s a n d p l a n t s a r e known t o b e t h e r e s u l t of svxbtle c h a n g e s i n t h e When some e x t e r n a l a r r a n g e m e n t o t t h e n u c l e o t i d e s inaking up a g e n e . f a c t o r ( s u c h a s r a d i a t i o n ) o r some i n t e r n a l f a c t o r ( s u c h a s a n a c c i d e n t a l d e l e t i o n o r a s h i f t i n t h e p o s i t i o n of a n u c l e o t i d e ) o c c u r s , t h e r e s u l t may be m o d i f i c a t i o n o f t h e g e n e t i c c o d e a n d a c h a n g e i n t h e f u n c t i o n i n g o f t h e organism. S e v e r e e f f e c t s i n humans c a n r e s u l t f r o m a b n o r m a l i t i e s i n genes, a s seen i n i n d i v i d u a l s with conditions l i k e s i c k l e c e l l anemia, hemophilia, and H u n t i n g t o n ' s c h o r e a . Moreover, recent discoveries i n d i c a t e t h a t d e f e c t i v e g e n e s may p l a y a n i m p o r t a n t r o l e i n more p r e v a l e n t d i s e a s e s such a s h e a r t d i s e a s e , a r t h r i t i s , c a n c e r , and A l z h e i m e r ' s d i s e a s e , which p r e v i o u s l y were n o t t h o u g h t o f a s b e i n g h e r e d i t a r y . M o t i v a t i o n f o r H a p p i n g a n d S e q u e n c i n g t h e Genome I n t h e p a s t , t h e a p p r o a c h t a k e n t o mapping a n d s e q u e n c i n g t h e human genome was t h a t of i d e n t i f y i n g and d e t e r m i n i n g t h e o r d e r of the n u c l e o t i d e s i n g e n e s of b i o l o g i c a l i n t e r e s t , t y p i c a l l y t h o s e r e l a t e d t o s p e c i f i c g e n e t i c d i s e a s e s o r s p e c i f i c human f u n c t i o n s . For example, r e s e a r c h h a s been aimed a t l o c a t i n g t h e g e n e s r e s p o n s i b l e f o r d i s e a s e s l i k e s i c k l e c e l l a n e m i a and H u n t i n g t o n ' s , a n d t h e g e n e s i n v o l v e d i n p r o t e c t i n g humans f r o m i n f e c t i o n s . I n t h i s approach, s c i e n t i s t s have u s e d r e c e n t l y d e v e l o p e d t e c h n i q u e s l i k e r e c o m b i n a n t DNA t o i d e n t i f y , o r map, m o r e t h a n 1 , 3 0 0 o f t h e e s t i m a t e d 1 0 0 , 0 0 0 g e n e s c o n t a i n e d i n t h e human genome. To d a t e , a b o u t 500 o f t h e s e g e n e s h a v e b e e n p a r t i a l l y s e q u e n c e d , The a p p r o x i m a t e b u t o n l y 1 2 human g e n e s h a v e b e e n c o m p l e t e l y s e q u e n c e d . l o c a t i o n of a t l e a s t 2,000 o t h e r g e n e s a l s o h a s been i d e n t i f i e d w i t h modern b i o l o g i c a l t o o l s . Doctors a l r e a d y a r e using t h e s e f i n d i n g s t o h e l p d i a g n o s e a b o u t 30 human g e n e t i c d i s e a s e s d u r i n g t h e f i r s t 3 m o n t h s of pregnancy. However, a d d i t i o n a l r e s e a r c h i s n e c e s s a r y b e f o r e t h e y w i l l be a b l e t o t r e a t any of t h e s e g e n e t i c d i s e a s e s . I n a d d i t i o n t o t h e human h e a l t h a s p e c t , c o n g r e s s i o n a l i n t e r e s t i n a m a j o r i n i t i a t i v e t o s e q u e n c e a n d map t h e human genome h a s b e e n h e i g h t e n e d by t h e p o t e n t i a l c o m m e r c i a l a p p l i c a t i o n s of t h e i n f o r m a t i o n o b t a i n e d through biotechnologies. The f i e l d o f b i o t e c h n o l o g y i s now i n a n i n f a n t s t a t e ; h o w e v e r , t h e i n d u s t r y i s e x p e c t e d t o grow d r a m a t i c a l l y o v e r t h e n e x t s s v e r a l y e a r s when g e n e t i c d e v e l o p m e n t s w i l l s i g n i f i c a n t l y i n c r e a s e t h e number of p r o d u c t s , p a r t i c u l a r l y p h a r m a c e u t i c a l a n d a g r i c u l t u r a l . G e n e t i c r e s e a r c h a l r e a d y h a s p r o v i d e d numerous b i o l o g i c a l t o o l s , i n c l u d i n g Comercia1 r e c o m b i n a n t D N A , t h a t h a v e enormous c o r m e r c i a l p o t e n t i a l . a p p l i c a t i o n of such t e c h n i q u e s a r e e v i d e n t w i t h t h e p r o d u c t i o n of p h a r m a c e u t i c a l a n d a n i m a l d r u g s 1 i k e i n s u l i n , human g r o w t h h o r m o n e , a n d b o v i n e g r o w t h hormone. C u r r e n t l y , t h e U n i t e d S t a t e s i s i n a good p o s i t i o n t o c a p i t a l i z e on t h e biotechnology i n d u s t r y because i t i s t h e g e n e r a l l y accepted l e a d e r i n most of i t s applications. It i s u n c l e a r , however, whether t h e s p e c i a l i z e d i n f o r m a t i o n a n d " s p i n - o f f " t e c h n o l o g i e s l i k e l y t o be o b t a i n e d f r o m m a p p i n g a n d s e q u e n c i n g t h e human genome w i l l be o f s u f f i c i e n t economic v a l u e t o j u s t i f y i n i t i a t i n g a "big science'' p r o j e c t , a c e n t r a l i s s u e r e l a t e d t o t h e p r o p o s e d l a r g e s c a l e genome i n i t i a t i v e . An i m p o r t a n t c o n s i d e r a t i o n i s t h a t t h e commercial p a y o f f s from mapping and s e q u e n c i n g t h e human genome a r e n o t e x p e c t e d t o o c c u r u n t i l many y e a r s a f t e r a m a j o r genome p r o j e c t h a s b e e n i n i t i a t e d . A n o t h e r i s s u e t h a t h a s been r a i s e d c o n c e r n i n g p o s s i b l e F e d e r a l s u p p o r t f o r a m a j o r genome mapping and s e q u e n c i n g p r o j e c t i s t h e r o l e of t i n a n c i a l s u p p o r t f r o m p r i v a t e i n d u s t r y , w h i c h p r o b a b l y w i l l r e a p many o f t h e commercial b e n e f i t s . The p r i v a t e s e c t o r , t o d a t e , h a s e x p r e s s e d L i t t l e i n t e r e s t i n f u n d i n g a m a j o r human genome m a p p i n g a n d s e q u e n c i n g initiative. Many o f t h e r e s e a r c h e f f o r t s p r e s e n t l y b e i n g s u p p o r t e d by p r i v a t e i n d u s t r y a r e t a r g e t e d a t s p e c i f i c p o r t i o n s o f t h e genome t h a t a r e r e l a t e d t o known human d i s e a s e s o r f u n c t i o n s . T h i s approach i s viewed a s having the greatest near-term commercial p o t e n t i a l . Many U.S. b i o t e c h n o l o g y companies a r e r e l a t i v e l y s m a l l and c a n n o t a f f o r d t o c a r r y t h e e c o n o m i c b u r d e n r e q u i r e d t o map and s e q u e n c e t h e e n t i r e human genome. T h i s f a c t o r i s p a r t i c u l a r l y s i g n i f i c a n t b e c a u s e m a j o r human genome m a p p i n g and s e q u e n c i n g e f f o r t s a r e c u r r e n t l y being funded abroad i n c o u n t r i e s l i k e Japan. Much o f t h i s s u p p o r t comes f r o m l a r g e c o r p o r a t i o n s who c a n b e t t e r a f f o r d t h e r e q u i r e d long-term investments. Factors such a s t h e s e , a s well a s t h e p r o s p e c t o f t h e b i o t e c h n o l o g y i n d u s t r y becoming a m u l t i b i l l i o n d o l l a r market i n t h e n e a r f u t u r e , has l e d t o concern t h a t t h e United S t a t e s could lose i t s lead in areas l i k e the pharmaceutical and a g r i c u l t u r a l i n d u s t r i e s t o i n t e r n a t i o n a l competitors l i k e Japan i f a major A m e r i c a n - s p o n s o r e d genome p r o j e c t i s n o t i n i t i a t e d . H a p p i n g and S e q u e n c i n g The E n t i r e Genome One a p p r o a c h t o mapping and s e q u e n c i n g t h e e n t i r e human genome i n v o l v e s c r e a t i n g w h a t ' s known a s a p h y s i c a l map o f t h e genome. To p r o d u c e t h i s map, t h e e n t i r e genome w i l l n e e d t o be b r o k e n i n t o o v e r l a p p i n g f r a g m e n t s , w h i c h would h a v e t o be c l o n e d ( m u l t i p l e c o p i e s made) and a r r a n g e d i n t h e l i n e a r o r d e r i n which t h e y a p p e a r i n t h e i n t a c t genome. A c o m p l e t e p h y s i c a l map w i l l show t h e e x a c t d i s t a n c e i n n u c l e o t i d e p a i r s b e t w e e n p o i n t s , o r Landmarks, a s t h e y a p p e a r o n t h e genome. Once t h e f r a g m e n t s h a v e b e e n c o r r e c t l y l i n e d u p , t h e o r d e r o f t h e n u c l e o t i d e s w i t h i n e a c h f r a g m e n t c a n be d e t e r m i n e d , o r s e q u e n c e d . This i n f o r m a t i o n w i l l h a v e l i m i t e d i m p o r t a n c e , h o w e v e r , w i t h o u t a n o t h e r map, known a s a g e n e t i c o r g e n e t i c l i n k a g e map. To c r e a t e t h i s map, s a m p l e s o f g e n e t i c m a t e r i a l ( e x t r a c t e d f r o m b l o o d s a m p l e s ) m u s t be t a k e n f r o m i n d i v i d u a l s of l a r g e f a m i l i e s r e p r e s e n t i n g s e v e r a l g e n e r a t i o n s . A c o m p l e t e g e n e t i c map w i l l show t h e c o r r e c t o r d e r and i d e n t i f i c a t i o n of t h e e s t i m a t e d 1 0 0 , 0 0 0 g e n e s a s t h e y a p p e a r on t h e 23 p a i r s o f chromosomes o f t h e human genome. As m e n t i o n e d p r e v i o u s l y , t h e s e 1 0 0 , 0 0 0 g e n e s a r e e n c o d e d by o n l y 5% o f t h e n u c l e o t i d e s c o n t a i n e d i n t h e e n t i r e human genome. Numerous r e s o u r c e s would be n e e d e d t o map a n d s e q u e n c e t h e e n t i r e human genome. T h e s e i n c l u d e t e c h n i q u e s t o map a n d s e q u e n c e g e n e t i c m a t e r i a l , a s w e l l a s computer hardware and s o f t w a r e t o s t o r e and a n a l y z e t h e m a s s i v e q u a n t i t y of g e n e t i c m a t e r i a l . W h i l e some o f t h e s e r e s o u r c e s a r e a v a i l a b l e , improvements a r e needed and a d d i t i o n a l t e c h n o l o g i e s w i l l have t o be developed. S i n c e t h e F e d e r a l Government, a m a j o r s u p p o r t e r of g e n e t i c s r e s e a r c h i n t h e p a s t , i s t h e p r i n c i p a l owner o f many o f t h e e x i s t i n g r e s o u r c e s , F e d e r a l s u p p o r t may be t h e most e f f e c t i v e way f o r t h e U n i t e d S t a t e s t o d e v o t e t h e n e c e s s a r y r e s o u r c e s t o a c o n c e r t e d genome project. However, i n a n e r a o f s e r i o u s F e d e r a l r e s o u r c e c o n s t r a i n t s , many a r e concerned about t h e possible d e p r i v a t i o n of resources i n o t h e r a r e a s of r e s e a r c h ( a g r i c u l t u r a l b i o t e c h n o l o g y , o t h e r b i o l o g i c a l r e s e a r c h ) i f a It b i g s c i e n c e " genome p r o j e c t i s f e d e r a l l y f u n d e d . C o n t r o v e r s y O v e r A Major Genome I n i t i a t i v e T h e r e h a s b e e n no f u n d a m e n t a l d i s a g r e e m e n t a b o u t t h e i m p o r t a n c e o f knowing t h e l o c a t i o n and t h e p r e c i s e chemical s t r u c t u r e of g e n e s , which c o u l d be o b t a i n e d f r o m a m a j o r genome i n i t i a t i v e . Much o f t h e d e b a t e among b i o l o g i s t s , h o w e v e r , h a s b e e n f o c u s e d o n t h e merits o f i n i t i a t i n g a m a j o r c e n t r a l i z e d e f f o r t t o s e q u e n c e t h e e n t i r e genome. To d a t e , t h e m a j o r i t y of t h e i n f o r m a t i o n o b t a i n e d on human g e n e s was g a t h e r e d by s c i e n t i s t s studying s p e c i f i c diseases, o f t e n i n a r e l a t i v e l y small s c a l e peer-reviewed r e s e a r c h environment. The N a t i o n a l I n s t i t u t e s of H e a l t h (NIH), t h e major s u p p o r t e r o f b i o l o g i c a l r e s e a r c h i n t h e w o r l d , h a s funded A l a r g e - s c a l e c e n t r a l i z e d genome p r o j e c t w o u l d n o t most o f t h i s r e s e a r c h . only change t h i s research approach s i g n i f i c a n t l y , but could a l s o a l t e r NIH's s t a t u s i n t h i s a r e a . Many r e s e a r c h e r s f e a r t h a t t h e m a s s i v e r e s o u r c e r e q u i r e m e n t s of a m a j o r genome p r o j e c t would c a u s e a d v e r s e e f f e c t s on o t h e r i m p o r t a n t b i o l o g i c a l r e s e a r c h , a n d t h a t r e s e a r c h f u n d s would be d i v e r t e d f r o m o t h e r c r u c i a l r e s e a r c h p r o g r a m s . A l t h o u g h t e c h n o l o g y c u r r e n t l y e x i s t s t o map a n d s e q u e n c e t h e human g e n o m e , much o f i t i s i n a n i n f a n t s t a t e o f d e v e l o p m e n t . Many s c i e n t i s t s , t h e r e f o r e , b e l i e v e t h a t a d d i t i o n a l technology development is needed b e f o r e a m a j o r c e n t r a l i z e d p r o j e c t s h o u l d be i n i t i a t e d . I f a m a j o r genome m a p p i n g a n d s e q u e n c i n g p r o j e c t was i n i t i a t e d w i t h e x i s t i n g t e c h n i q u e s , s c i e n t i f i c e x p e r t s e s t i m a t e t h a t i t n o t o n l y would c o s t s e v e r a l h u n d r e d million t o several billion dollars, b u t a l s o would r e q u i r e t h e p a r t i c i p a t i o n of hundreds of s c i e n t i s t s . I n a d d i t i o n , many o f t h e s e r e s e a r c h e r s c l a i m t h a t t h e r e s u l t i n g d a t a would h a v e a h i g h e r r o r r a t e . These e x p e r t s b e l i e v e t h a t the resource requirements c o u l d be s i g n i f i c a n t l y reduced i f t h e f i r s t research p r i o r i t y is given t o t h e a u t o m a t i o n of m a p p i n g a n d s e q u e n c i n g t e c h n o l o g i e s , i m p r o v i n g d a t a s t o r a g e and a n a l y s i s methods, and i n c r e a s i n g t h e s u p p o r t l e v e l s f o r c u r r e n t gene mapping r e s e a r c h p r o j e c t s . I f t h i s a p p r o a c h was t a k e n , t h e y a r g u e t h a t t h e t o t a l c o s t c o u l d be r e d u c e d by a t h o u s a n d - f o l d a n d t h e e r r o r r a t e c o u l d b e d e c r e a s e d by a t l e a s t t e n - f o l d a s s u m i n g t h a t a m a j o r e f f o r t was d i r e c t e d a t these areas over the next several years. ( L e r o y Hood a n d L l o y d S m i t h , Genome S e q u e n c i n g : How t o P r o c e e d , I s s u e s i n S c i e n c e a n d T h e Human T e c h n o l o g y , S p r i n g 1 9 8 7 : 36-46; a n d R o g e r S. J o h n s o n , Ph.D., Genome P r o j e c t : What I m p a c t on B a s i c R e s e a r c h ? , FASEB O f f i c e of P u b l i c A f f a i r s , December 1 9 8 7 : 5 0 2 - 5 0 5 ) . Some o p p o s i t i o n t o a m a j o r genome s e q u e n c i n g p r o j e c t i s b a s e d o n t h e f a c t t h a t 95% o f t h e 3 - b i l l i o n - u n i t g e n e t i c c o d e h a s n o known b i o l o g i c a l function. T h e s e c r i t i c s a r g u e t h a t e f f o r t s s h o u l d be f o c u s e d i n s t e a d on l o c a t i n g (mapping) and s t u d y i n g o n l y t h e f u n c t i o n a l g e n e s and t h e i r p r o d u c t s ( p r o t e i n s ) , and t h a t t h i s s h o u l d be done i n t h e d i v e r s e manner t h a t h a s been used i n t h e p a s t , r a t h e r t h a n a s a major c e n t r a l i z e d project. T h i s r e s e a r c h a p p r o a c h would b e d i r e c t e d a t s t u d y i n g g e n e s a s s o c i a t e d w i t h known d i s e a s e s o r human f u n c t i o n s . P r o p o n e n t s o f a m a j o r c e n t r a l i z e d genome p r o j e c t c o u n t e r t h a t t h e s o - c a l l e d n o n f u n c t i o n a l DNA c o n t a i n e d i n t h e human genome p e r h a p s h a v e important f u n c t i o n s not yet i d e n t i f i e d w h i c h may b e r e s o l v e d by s e q u e n c i n g t h e e n t i r e genome. Moreover, a d v o c a t e s f o r t h i s p r o j e c t a r g u e t h a t b e t t e r management a n d o r g a n i z a t i o n o f a v a i l a b l e t e c h n o l o g y may b e a g r e a t e r p r i o r i t y f o r s e q u e n c i n g a n d m a p p i n g t h e human genome t h a n developing a d d i t i o n a l technology. T h i s a p p r o a c h would s i g n i f i c a n t l y i m p r o v e t h e t i m e a n d money r e q u i r e m e n t s , a c c o r d i n g t o D r . W a l t e r G i l b e r t o f H a r v a r d U n i v e r s i t y , a l e a d i n g p r o p o n e n t o f a n a j o r genome i n i t i a t i v e . C u r r e n t A c t i v i t i e s o n Genome R e s e a r c h Federal Agencies The F e d e r a l Government c u r r e n t l y i s t h e m a j o r s u p p o r t e r o f genome r e l a t e d r e s e a r c h i n t h e United S t a t e s . Much o f t h i s work i s a d m i n i s t e r e d by t h e N a t i o n a l I n s t i t u t e s o f H e a l t h (NIH) a n d t h e D e p a r t m e n t o f E n e r g y (DOE). NIH, t h e p r i n c i p a l s u p p o r t e r o f b i o l o g i c a l r e s e a r c h , i s s p e n d i n g a b o u t $300 m i l l i o n e a c h y e a r on g e n e s e q u e n c i n g a n d m a p p i n g r e l a t e d research. A p p r o x i m a t e l y $90 m i l l i o n o f t h e s e f u n d s a r e f o c u s e d o n human genome r e s e a r c h a n d s u p p o r t more t h a n 3 , 0 0 0 p e e r - r e v i e w e d research projects. C o n g r e s s h a s a p p r o p r i a t e d a n a d d i t i o n a l $17.2 m i l l i o n t o N I H f o r FY88 t o e x p a n d r e s e a r c h e f f o r t s i n g e n e m a p p i n g . NIH a l s o a d m i n i s t e r s a n d p a r t i a l l y f u n d s ( w i t h DOE a n d NSF) GenBank, GenBank i s a o n e o f t h e m a j o r DNA s e q u e n c e d a t a b a s e s t h a t a r e a v a i l a b l e . i n t e r n a t i o n a l computerized d a t a b a s e t h a t r e c o r d s , s t o r e s , and d i s s e m i n a t e s DNA s e q u e n c e d a t a . I t i s l o c a t e d a t Los Alamos N a t i o n a l L a b o r a t o r y a n d i s c l o s e l y l i n k e d t o t h e o t h e r m a j o r DNA s e q u e n c e d a t a b a s e , t h e E u r o p e a n M o l e c u l a r B i o l o g y L a b o r a t o r y i n H e i d e l b e r g , West Germany. The N a t i o n a l L i b r a r y o f M e d i c i n e h a s b e e n i n v o l v e d i n d e v e l o p i n g d a t a b a s e s t h a t c o n t a i n DNA d a t a i m p o r t a n t f o r m a p p l n g a n d s e q u e n c i n g t h e genome. One of t h e s e d a t a b a s e s , O n - l i n e M e n d e l i a n I n h e r i t a n c e i n Man (OMIM), i s a c o m p u t e r i z e d v e r s i o n of t h e book w h i c h h a s t h e same name t h a t V i c t o r McKusick o f J o h n H o p k i n s U n i v e r s i t y i n was c r e a t e d by D r . OMIM i s a g e n e m a p p i n g B a l t i m o r e , M D , a p i o n e e r i n t h e a r e a of g e n e t i c s . This database i s d a t a b a s e t h a t c o n t a i n s d i s e a s e r e l a t e d DNA i n f o r m a c i o n . a l s o l i n k e d t o t h e Human Gene Mapping L i b r a r y owned by t h e Howard Hughes Medical I n s t i t u t e . NLM a l s o a d m i n i s t e r s t h e r e c e n t l y e s t a b l i s h e d N a t i o n a l Biotechnology Information Center. This center w i l l serve as a repository f o r s t o r i n g and d i s s e m i n a t i n g g e n e t i c i n f o r m a t i o n , and a l s o a s a p l a c e f o r IB88012 CRS- 7 02-02-88 c o o r d i n a t i n g and s u p p o r t i n g e x i s t i n g g e n e t i c d a t a b a s e s . The N a t i o n a l B i o t e c h n o l o g y I n f o r m a t i o n c e n t e r was a p p r o p r i a t e d $ 3 . 8 3 m i l l i o n f o r FY88. DOE, who f i r s t f o r m a l l y p r o p o s e d a m a j o r c e n t r a l i z e d human genome p r o j e c t , p l a n s t o s p e n d $12 m i l l i o n d u r i n g FY88 on human g e n o m e - r e l a t e d research. Most o f t h i s work w i l l b e t a r g e t e d a t a p p l i e d b i o l o g y a n d e n g i n e e r i n g n e c e s s a r y t o do s e q u e n c i n g a n d mapping. I n t h e p a s t , much o f t h e g e n e t i c s r e s e a r c h s u p p o r t e d by DOE was a i m e d a t e x a m i n i n g t h e m u t a g e n i c e f f e c t o f e n v i r o n m e n t a l c o n t a m i n a n t s l i k e r a d i a t i o n o n human As a r e s u l t , DOE e m p l o y s s c i e n t i s t s who h a v e e x p e r t i s e genetic material. i n d i s c i p l i n e s l i k e m o l e c u l a r b i o l o g y , e n g i n e e r i n g and m a t h e m a t i c s . DOE'S e x p e r t i s e and r e s o u r c e s a r e r e f l e c t e d i n t h e a g e n c y ' s p r o p o s a l f o r a p r i m a r y genome p r o g r a m f o r FY88, w h i c h w i l l be a i m e d a t d e v e l o p i n g i n s t r u m e n t a t i o n , m a t h e m a t i c a l , and o t h e r a i d s f o r s e q u e n c i n g and mapping. A s m e n t i o n e d e a r l i e r , DOE a l s o p a r t i a l l y f u n d s t h e GenBank d a t a b a s e . Other Federal agencies a l s o a r e involved i n supporting r e s e a r c h i n g e n e t i c s , o r a r e f u n d i n g p r o g r a m s i n a r e a s t h a t would s u p p o r t a genome mapping and sequencing e f f o r t . The N a t i o n a l S c i e n c e F o u n d a t i o n (NSF) It f u n d s r e s e a r c h t o d e v e l o p new i n s t r u m e n t a t i o n f o r m o l e c u l a r b i o l o g y . a l s o p a r t i a l l y s u p p o r t s t h e GenBank d a t a b a s e . The U.S. D e p a r t m e n t o f A g r i c u l t u r e (USDA) h a s a n i n c r e a s i n g commitment t o g e n e t i c s r e s e a r c h , b u t t h e i r r e s e a r c h e f f o r t s a r e f o c u s e d p r i m a r i l y on o r g a n i s m s o f i n t e r e s t i n However, much o f t h i s a g r i c u l t u r e , i .e., a f f e c t i n g a n i m a l s a n d p l a n t s . w o r k , p a r t i c u l a r l y t h a t on a n i m a l d i s e a s e s , h a s a v e r y h i g h r e l e v a n c e t o s i m i l a r work o n human d i s e a s e . In addition, other agencies l i k e the N a t i o n a l Bureau of S t a n d a r d s and t h e C e n t e r s For D i s e a s e C o n t r o l a r e a l r e a d y involved in functions l i k e q u a l i t y control t h a t w i l l be important t o t h e genome p r o j e c t . C o o r d i n a t i o n a n d c o l l a b o r a t i o n among a g e n c i e s a r e i m p o r t a n t , and t h i s h a s been i n i t i a t e d between s e v e r a l a g e n c i e s , i n c l u d i n g NIH, DOE, a n d NSF. Private Sector Two c o m p a n i e s a r e l a r g e l y r e s p o n s i b l e f o r a m a j o r p o r t i o n o f t h e human genome r e l a t e d r e s e a r c h c u r r e n t l y b e i n g s u p p o r t e d by t h e p r i v a t e sector. They a r e C o l l a b o r a t i v e R e s e a r c h I n c . , a b i o t e c h n o l o g y company l o c a t e d i n B e d f o r d , MA, a n d t h e Howard Hughes M e d i c a l I n s t i t u t e (HHMI), a n o n - p r o f i t o r g a n i z a t i o n ( e x e c u t i v e o f f i c e s l o c a t e d i n B e t h e s d a , MD), t h e w o r l d ' s l a r g e s t s o u r c e of p r i v a t e funds f o r h e a l t h and biomedical research. Many o f t h e e f f o r t s s u p p o r t e d by b o t h t h e s e o r g a n i z a t i o n s a r e t a r g e t e d a t mapping g e n e s r e l a t e d t o s p e c i f i c d i s e a s e s . Collaborative Research r e c e n t l y announced t h e completion o f i t s genetic linkage map" a n d H H M I s c i e n t i s t s a r e e x p e c t e d t o c o m p l e t e a s i m i l a r map s o o n . T h e s e g e n e t i c maps make u s e o f s e g m e n t s o f DNA c a l l e d r e s t r i c t i o n f r a g m e n t l e n g t h p o l y m o r p h i s m s (RFLPs) t h a t a r e u s e d a s m a r k e r s i n t h e human genome. The genome o f e a c h i n d i v i d u a l , e x c e p t f o r i d e n t i c a l t w i n s , d i f f e r s f r o m a n o t h e r p e r s o n ' s genome by p e r h a p s o n e - t e n t h o f a p e r c e n t o f t h e i r nucleotides. I E chromosomes from two p e o p l e a r e c u t u s i n g s p e c i a l e n z y m e s t h a t w i l l s n i p t h e DNA a t known p o i n t s , some o f t h e p i e c e s o f DNA f r a g m e n t s p r o d u c e d w i l l d i f f e r i n l e n g t h s ; t h e s e v a r i a t i o n s a r e known as RFLPs. C e r t a i n RFLPs show up o n l y i n t h e DNA o f p e o p l e w i t h a n i n h e r i t e d d i s e a s e l i k e H u n t i n g t o n ' s and c y s t i c f i b r o s i s , a n d a r e l o c a t e d n e a r t h e d e f e c t i v e gene. T h e s e c h a r a c t e r i s t i c s make RFLPs v e r y u s e f u l m a r k e r s t o h e l p diagnose associated genetic diseases, a s well a s t o h e l p pinpoint t h e l o c a t i o n of a s s o c i a t e d genes. The C o l l a b o r a t i v e R e s e a r c h g e n e t i c l i n k a g e map c o n s i s t s o f 4 0 4 m a r k e r s l o c a t e d a l o n g t h e human genome. The company h a s a l r e a d y announced i t s i n t e n t t o s e e k p a t e n t s f o r any o f t h e i r i d e n t i f i e d m a r k e r s t h a t a r e u s e d t o d i a g n o s e a d i s e a s e , a s w e l l a s f o r t h e s i t e p n t h e genome of a n y g e n e t h a t t h e company's s c i e n t i s t s i d e n t i f y u s i n g i t s p r i m a r y g e n e t i c map. T h i s a p p r o a c h i s v i e w e d by t h e company a s b e i n g n e c e s s a r y i n o r d e r t o p r o t e c t i t s p r o p r i s t a r y r i g h t s w h i l e a l s o making i n f o r m a t i o n available t o other scientists. However, r e s e a r c h e r s h a v e r a i s e d t h e c o n c e r n t h a t t h e company h a s n o t made i t s d a t a a v a i l a b l e e x c e p t i n a f e w provisional cases. S c i e n t i s t s believe t h a t they should have quicker a c c e s s t o C o l l a b o r a t i v e ' s R e s e a r c h d a t a , which c o u l d a c c e l e r a t e t h e p r o c e s s of s e a r c h i n g f o r t r e a t m e n t s f o r g e n e t i c d i s e a s e s . Howard Hughes M e d i c a l I n s t i t u t e - s u p p o r t e d s c i e n t i s t s h a v e a s t r o n g c o l l a b o r a t i v e r e l a t i o n s h i p w i t h b i o l o g i s t s working i n t h e a r e a of genetics. T h i s I n s t i t u t e (HHMI) a l s o owns i m p o r t a n t human genome r e l a t e d r e s o u r c e s ; f o r e x a m p l e , H H M I owns t h e Human Gene Mapping L i b r a r y (HGML), t h e l a r g e s t e x i s t i n g c o m p u t e r i z e d d a t a b a s e f o r t h e human g e n e map. This d a t a b a s e i s l i n k e d t o t h e OMIM d a t a b a s e , a s m e n t i o n e d a b o v e , a n d i s a c c e s s i b l e t o r e s e a r c h e r s a c r o s s t h e world a t no charge. S c i e n t i s t s can u s e t h i s c o m p u t e r i z e d s y s t e m t o o b t a i n a v a i l a b l e i n f o r m a t i o n on DNA a s s o c i a t e d w i t h h e r e d i t a r y d i s e a s e s , i n c l u d i n g l o c a t i o n i n t h e genome o f a n y g e n e o r m a r k e r t h a t h a s b e e n i d e n t i f i e d , who d i d t h e w o r k , a n d a n y related references. HHMI s c i e n t i s t s a r e a l s o d e v e l o p i n g a g e n e t i c l i n k a g e map. This map, w h i c h i s a n t i c i p a t e d t o be c o m p l e t e d s o o n , r e p o r t e d l y c o n t a i n s 4 7 5 markers. G e n e t i c l i n k a g e maps w i l l s i g n i f i c a n t l y s p e e d up t h e p r o c e s s o f i d e n t i f y i n g t h e 1 0 0 , 0 0 0 human g e n e s . However, t h e m a r k e r s l o c a t e d s o f a r a r e s e p a r a t e d by 10-20 m i l l i o n b a s e s , o r more. Thus, t h e j o b o f z e r o i n g i n on human g e n e s r e m a i n s d i f f i c u l t e v e n w i t h t h e i n f o r m a t i o n c o n t a i n e d i n e x i s t i n g g e n e t i c 1i n k a g e maps. As research i n t h i s area continues t o p r o g r e s s , g e n e t i c l i n k a g e maps a r e e x p e c t e d t o become m o r e d e t a i l e d , c o n t a i n i n g s e v e r a l thousand markers, o n l y about 1 m i l l i o n b a s e s a p a r t , o v e r t h e e n t i r e human genome. Once t h e r e s o l u t i o n o f t h e s e maps i m p r o v e s , s c i e n t i s t s s h o u l d be a b l e t o l o c a t e t h e g e n e s t h e m s e l v e s m o r e q u i c k l y , w h i c h i s r e q u i r e d i n o r d e r t o make a c o m p l e t e g e n e t i c map. Researchers s u p p o r t e d by b o t h H H M I a n d C o l l a b o r a t i v e R e s e a r c h , a s w e l l a s t h o s e b e i n g f u n d e d by t h e F e d e r a l Government a r e a c t i v e l y a t t e m p t i n g t o c r e a t e more d e t a i l e d g e n e t i c l i n k a g e maps. P r e s e n t l y , s e q u e n c i n g o f t h e human genome i s l e s s d e v e l o p e d t h a n m a p p i n g , w i t h l e s s t h a n 1% of t h e human genome h a v i n g b e e n s e q u e n c e d t o date. W h i l e many s c i e n t i s t s b e l i e v e t h a t t h e genome s h o u l d n o t b e s e q u e n c e d u n t i l t e c h n o l o g i e s a r e i m p r o v e d , a t l e a s t o n e s c i e n t i s t , Nobel P r i z e l a u r e a t e W a l t e r G i l b e r t , a d v o c a t e s i n i t i a t i n g genome s e q u e n c i n g now with t h e technologies already available. D r . G i l b e r t r e c e n t l y announced h i s i n t e n t i o n t o s e q u e n c e t h e human genome a s a p r i v a t e v e n t u r e by f o r m i n g a b i o t e c h n o l o g y company c a l l e d Genome C o r p o r a t i o n . Although G i l b e r t has n o t y e t r a i s e d a l l t h e r e q u i r e d funds needed t o s t a r t h i s company, h e h a s a l r e a d y s t a t e d h i s p l a n s t o c o p y r i g h t t h e genome s e q u e n c e s t h a t h e d e t e r m i n e s , a n d s e l l t h i s i n f o r m a t i o n t o r e s e a r c h e r s who w i s h t o T h e s e p l a n s h a v e e v o k e d d e b a t e among many s c i e n t i s t s who b e l i e v e use it. t h a t genome i n f o r m a t i o n s h o u l d b e p u b l i s h e d a n d r e m a i n i n t h e p u b l i c domain. International Activities Current congressional concern with t r a d e imbalances has focused a t t e n t i o n on J a p a n e s e a c t i v i t i e s a n d p o l i c i e s i n b i o t e c h n o l o g y . Several of the t e c h n o l o g i e s n e e d e d f o r mapping a n d s e q u e n c i n g a r e u n d e r development i n Japan. For example, r e s e a r c h t a r g e t e d a t d e v e l o p i n g a u t o m a t e d s e q u e n c i n g d e v i c e s was u n d e r w a y i n 1 9 8 6 , a c c o r d i n g t o D r . A k i y o s h i Wada, a p i o n e e r p r o p o n e n t o f t h e J a p a n e s e human genome m a p p i n g ( A sequencer developed i n t h e United S t a t e s i s and s e q u e n c i n g e f f o r t s . u s e d i n DOE l a b o r a t o r y w o r k . ) I n J a p a n , t h e S c i e n c e and Technology C o u n c i l i s s u p p o r t i n g s t u d i e s on a super-DNA s e q u e n c e r p r o j e c t , s t a r t e d a b o u t 1981. T h i s p r o j e c t i n v o l v e s t h e development o f r o b o t i c t e c h n i q u e s . The p r o j e c t h a s i n c o r p o r a t e d e x i s t i n g t e c h n o l o g i e s a s w e l l as d e v e l o p i n g new t e c h n i q u e s . F o r e x a m p l e , t h e F u j i F i l m Company h a d d e v e l o p e d a s p e c i a l f i l m t o meet t h e r e q u i r e m e n t s f o r e l e c t r o p h o r e t i c s e p a r a t i o n processes. T h e s e f i l m s a r e now b e i n g s o l d c o m n e r c i a l l y i n t h e U n i t e d Also, S t a t e s a n d w i l l b e i n c o r p o r a t e d i n t h e p r o c e s s d e s c r i b e d by Wada. m e t h o d s d e v e l o p e d i n t h e U n i t e d S t a t e s and E n g l a n d f o r p r e p a r i n g DNA f o r s e q u e n c i n g a r e b e i n g u s e d i n t h e J a p a n e s e d e v i c e s a s s e m b l e d by H i t a c h i S o f t w a r e Company a n d by S e i k o . Wada i n d i c a t e s t h a t DNA s e q u e n c i n g s h o u l d be a c c o m p l i s h e d i n a s e q u e n c i n g f a c t o r y e q u i p p e d w i t h a u t o m a t e d s y s t e m s a n d t h a t t h e s e q u e n c i n g s h o u l d be c o o r d i n a t e d a t a n i n t e r n a t i o n a l c e n t e r open t o a l l r e s e a r c h e r s . He i s s a i d t o f a v o r h a v i n g t h e c e n t e r l o c a t e d i n Japan. Wada v i e w s t h i s work on a n a u t o m a t e d s e q u e n c e r a s a n o p p o r t u n i t y f o r J a p a n e s e companies t o use t h e i r s t r e n g t h s i n e l e c t r o n i c s , computers, and m a t e r i a l s s c i e n c e s i n t h e f i e l d of b i o l o g y . S e i k o , f o r example, i s s a i d t o h a v e b u i l t a new l i f e s c i e n c e s i n s t r u m e n t d i v i s i o n w i t h i n t h e corporation. Wada h o p e s t o h a v e h i s s e q u e n c i n g p r o j e c t f i n i s h e d i n 1 9 8 8 and o p e r a t i n g i n 1990. W h i l e t h e w o r k i n E n g l a n d i s n o t on t h e same f i n a n c i a l s c a l e a s t h e U n i t e d S t a t e s r e s e a r c h p r o g r a m , t h e work i s o f h i g h q u a l i t y . As a n e x a m p l e , a m a j o r c o n t r i b u t i o n i s b e i n g made by a n E n g l i s h g r o u p t h a t h a s a l m o s t c o m p l e t e d t h e p h y s i c a l m a p p i n g o f t h e e n t i r e genome o f a roundworm. A s a n o t h e r e x a m p l e , t h e I m p e r i a l R e s e a r c h C a n c e r Fund i n London r e c e n t l y i d e n t i f i e d r e s e a r c h t h a t has l o c a t e d t h e s i t e of a gene d e l e t i o n r e l a t e d t o colon cancer. B i o m e d i c a l r e s e a r c h i n a number o f F r e n c h L a b o r a t o r i e s a l s o i n v o l v e s a c t i v i t i e s o n g e n e m a p p i n g and s e q u e n c i n g . I n terms of i n t e r n a t i o n a l p a r t i c i p a t i o n , p r o b a b l y o n e o f t h e b e s t known e f f o r t s i s t h a t o f t h e Human Polymorphism Study C e n t e r i n P a r i s . T h i s French-based international o r g a n i z a t i o n s e r v e s a s a r e f e r e n c e d e p o s i t o r y of important g e n e t i c A unique material t h a t is accessible t o researchers across the globe. a r r a n g e m e n t o f t h i s o r g a n i z a t i o n , w h i c h r e q u i r e s l o n g - t e r m commitment a n d c o o p e r a t i o n , h a s been r e s o l u t i o n o f t h e p r o b l e m o f d a t a s h a r i n g . The C e n t e r r e q u i r e s p a r t i c i p a n t s t o s h a r e t h e d a t a t h e y s e c u r e from t h e c e l l l i n e s provided but t h e p a r t i c i p a t i n g l a b o r a t o r i e s a r e r e v e a l d a t a on t h e s p e c i f i c p r o c e s s e s w h i c h a r e u s e d . not required to a primary f a c i l i t y of importance i n t h e I n West G e r m a n y , international e x c h a n g e program i s t h e European Molecular Biology L a b o r a t o r y (EMBL) a t H e i d e l b e r g . EMBL p a r t i c i p a t e s ( v i a i t s N u c l e i c S e q u e n c e D a t a L i b r a r y ) i n t h e GenBank p r o j e c t . About 50% o f t h e d a t a i n t h i s p r o j e c t i s s a i d t o b e corning f r o m E u r o p e . Automated s e q u e n c i n g d e v i c e s a r e a l s o under development. Data Management and A n a l y s i s D e s p i t e p r o f e s s i o n a l d i s a g r e e m e n t s a b o u t t h e DOE t o t a l m a p p i n g a n d sequencing p r o p o s a l , t h e r e i s g e n e r a l consensus t h a t improvements a r e r e q u i r e d i n managing t h e i n f o r m a t i o n systems a l r e a d y a c c u m u l a t i n g d a t a from s c a t t e r e d mapping and s e q u e n c i n g a c t i v i t i e s . Such d a t a i n c l u d e collections of: DNA i n " l i b r a r i e s " a n d c e l l " b a n k s " ; b i o l o g i c a l " p r o b e s " used a l s o f o r d i a g n o s t i c and g e n e t i c s t u d i e s ; m u l t i p l e f a m i l y c e l l l i n e s used i n c o l l a b o r a t i v e g e n e t i c s t u d i e s ; b i o l o g i c a l "vectors" used f o r r e c o m b i n a n t DNA; a n d s i m i l a r m a t e r i a l s r e s o u r c e s . The sequencing d a t a a r e expected t o increase a t a rapidly accelerating rate in the near future. While t h e q u a n t i t y of s e q u e n c i n g data i s large, i t is not unusually so i n the information processing f i e l d . The t a s k , however, o f p r o c e s s i n g s e q u e n c i n g d a t a t o f a c i l i t a t e a n a l y s i s i s m o r e c o m p l i c a t e d t h a n most o t h e r a r e a s , demands s p e c i a l s o f t w a r e p r o g r a m s l a r g e c a p a c i t y computers with f o r a n a l y s i s a s well a s h i g h - s p e e d networking c a p a b i l i t i e s . Some r e s e a r c h e r s s u g g e s t e s t a b l i s h i n g a new t e r m , " b i o t e c h n i c s , " f o r t h e u s e of computer technologies f o r a l l biological d i s c i p l i n e s . P r o c e s s i n g o f t h e DNA c o d e h a s b e e n d e s c r i b e d a s b e i n g v e r y s i m i l a r t o t h e p r o c e s s i n g and a n a l y s i s o f words from c o r n o n l y used l a n g u a g e s . Thus t h e d e v i c e s which sequence n u c l e i c a c i d s o r p r o t e i n s a r e "reading" a language i n t h e c a s e of t h e genome -- e v o l v e s f r o m o n l y except t h a t t h e language f o u r l e t t e r s symbolizing t h e f o u r bases present i n t h e sequence. Since programs a r e a v a i l a b l e f o r r e a d i n g and s t o r i n g l a n g u a g e s , and i n t h e c a s e o f c r y p t o a n a l y s i s , l o g i c f o r c o d i n g a n d d e c o d i n g , i t is c o n c e p t u a l l y p o s s i b l e f o r computer programmers t o d e s i g n t h e programs n e c e s s a r y f o r s t o r i n g b i o l o g i c a l d a t a i n a form p e r m i t t i n g r e t r i e v a l o f s p e c i f i c s e q u e n c e s and v a r i o u s m a n i p u l a t i o n s and c o m p a r i s o n s . This w i l l not be an e a s y t a s k , h o w e v e r , b e c a u s e of t h e n e e d t o r e t a i n a c c e s s t o d a t a f i l e d A t the current stage w i t h d i f f e r e n t p r o g r a m s i n a number o f d a t a b a s e s . of c o m p u t e r u t i l i z a t i o n , g e n e t i c i s t s a r e s t i l l w o r k i n g a t t h e e a r l y b i n a r y l e v e l of computer languages. G e n e t i c i s t s w i l l soon need a more e f f e c t i v e computer assembly language and w i l l e v e n t u a l l y r e q u i r e a g e n e t i c programming computer l a n g u a g e . -- E x i s t i n g i n f o r m a t i o n s y s t e m s r a p i d l y a r e becoming outmoded f o r c u r r e n t needs i n genetics. The N a t i o n a l L i b r a r y o f M e d i c i n e ' s l a r g e c o m p u t e r i z e d d a t a b a s e i s of i m m e d i a t e r e l e v a n c e t o a l l m a p p i n g a n d sequencing p r o j e c t s . The d a t a management s y s t e m w h i c h h a s e v o l v e d a t NLM t o h a n d l e r e f e r e n c e and o t h e r p u b l i s h e d documents i s a c c e s s i b l e a l l o v e r t h e world. Dr. D o n a l d L i n b e r g of NLM s u g g e s t s t h a t t h e r e i s a n e e d f o r new s y s t e m s o f d a t a e n t r y , s t a n d a r d i z a t i o n o f n o m e n c l a t u r e , a n d a n u r g e n t r e q u i r e m e n t f o r more e f f e c t i v e s y s t e m s o f d a t a r e t r i e v a l a n d a n a l y s i s . The Howard Hughes M e d i c a l I n s t i t u t e (HHMI) h a s i n i t i a t e d e f f o r t s t o improve t h e i n t e r f a c e between a v a r i e t y of d a t a and m a t e r i a l s b a s e s providing information t o investigators i n genetics. I n f a c t , it is p o s s i b l e t h a t H H M I may become a m a j o r p r i v a t e f i i c i l i t a t o r o f t h e HHMI's interest i n t h i s task c o o r d i n a t i o n o f many p r i v a t e DNA d a t a b a s e s . h a s p r e c e d e n c e i n The Gene Mapping L i b r a r y s u p p o r t e d b y HHMI a t Yale. I t may n o t b e l o g i c a l t o e m b a r k on a m a j o r s e q u e n c i n g p r o j e c t t o produce Large q u a n t i t i e s of e s s e n t i a l d a t a u n t i l t h e i n f o r m a t i o n system GenBank, i n t o w h i c h s u c h d a t a would b e e n t e r e d i s a d e q u a t e f o r t h e t a s k . t h e d a t a b a s e t h a t s h a r e s i n f o r m a t i o n w i t h t h e European M o l e c u l a r B i o l o g y L a b o r a t o r y , a p p e a r s t o be u n a b l e t o k e e p up w i t h d a t a e n t r y t a s k s a s t h e amount of i n f o r m a t i o n e x c e e d s a v a i l a b l e manpower. If researchers are to have a s u c c e s s f u l i n t e r f a c e between t h e d e s c r i p t i v e d a t a b a s e s a s s o c i a t e d w i t h c o l l e c t i o n s o f DNA, p r o b e s , a n d o t h e r m a t e r i a l s a n d t h e d a t a b a s e s f i l i n g r e s e a r c h i n f o r m a t ion, t h e i n f o r m a t i o n m u s t be s t o r e d a n d r e t r i e v a b l e q u i c k l y and a c c u r a t e l y . Many of t h e i n t e r f a c i n g p r o g r a m l a n g u a g e s now u s e d a r e q u i t e cumbersome. J o u r n a l e d i t o r s c a n no l o n g e r cope w i t h t h e mass o f s e q u e n c i n g d a t a a n d , s i n c e t h e s e d a t a a r e n o t b e i n g p r i n t e d , t h e r e must b e a c c e s s t o o t h e r r e s o u r c e s f o r i n v e s t i g a t o r s t o u s e f o r f i l i n g t h e r e s u l t s o f t h e i r work. S u c h s y s t e m s m u s t n o t o n l y be r e a d i l y a c c e s s i b l e but open t o a l l c o l l a b o r a t o r s . This implies an expanded l e v e l of i n t e r n a t i o n a l c o o r d i n a t i o n . A l t h o u g h t h e r e a r e some d a t a b a s e s f u n d e d p r i m a r i l y by f o r e i g n o r p r i v a t e f u n d s , most o f t h e s y s t e m s of m a j o r s i g n i f i c a n c e a r e s u p p o r t e d by Federal funds. F o r t h i s r e a s o n , i t may be p o s s i b l e t o s e c u r e t h e d e s i r e d l e v e l s o f c o o r d i n a t i o n a n d s t a n d a r d i z a t i o n by a n i n c r e a s e d e f f o r t i n A l l of t h e agencies associated with databases relevant F e d e r a l programs. t o p r o g r a m s i n m o l e c u l a r g e n e t i c s would be i n v o l v e d . The B u r e a u o f S t a n d a r d s a l s o c o u l d be i n c l u d e d , s i n c e t h i s a g e n c y i s a l r e a d y w o r k i n g i n computer language s t a n d a r d i z a t i o n a c t i v i t i e s . Other Policy Issues Work i n t h e f i e l d o f b i o t e c h n o l o g y h a s r a i s e d a number of e t h i c a l and Legal i s s u e s . One m a j o r c o n c e r n a b o u t m a p p i n g a n d s e q u e n c i n g t h e human genome i n v o l v e s t h e p o t e n t i a l u s e s of t h e i n f o r m a t i o n o b t a i n e d f r o m such a s e f f o r t . W h i l e t h e a c t u a l p r o c e s s would n o t c r e a t e s i g n i f i c a n t e t h i c a l o r l e g a l i s s u e s , t h e a v a i l a b i l i t y of a p h y s i c a l map o r g e n e s e q u e n c e s c o u l d b r i n g p r o c e s s e s t h a t would r a i s e t h e s e i s s u e s much c l o s e r . Few would a r g u e t h a t a n i m p o r t a n t b e n e f i t o f s u c h i n f o r m a t i o n w o u l d b e t h e a b i l i t y t o b e t t e r u n d e r s t a n d and someday t r e a t g e n e t i c d i s e a s e s . Knowledge g a i n e d t h r o u g h mapping a n d s e q u e n c i n g e f f o r t s , h o w e v e r , w i l l make i t p o s s i b l e t o p r e d i c t i n d i v i d u a l s ' s u s c e p t i b i l i t y t o d i s e a s e s , many of which would n o t o c c u r u n t i l l a t e r i n l i f e . The p o t e n t i a l u s e o f t h i s information, so-called "predictive-genetics," raises significant ethical, s o c i a l , and l e g a l c o n c e r n s . W h i l e a n i n d i v i d u a l may want t o know h i s l h e r s u s c e p t i b i l i t y t o a n i l l n e s s s u c h a s h e a r t d i s e a s e , h e may n o t w i s h t o know t h a t h e c a r r i e s a d e f e c t i v e g e n e c h a t w i l l c a u s e a n o n t r e a t a b l e f a t a l disorder l i k e ~ u n t i n g t o n ' sdisease. I n t h e f i r s t c a s e , t h e r i s k of h e a r t d i s e a s e may b e r e d u c e d by e n v i r o n m e n t a l f a c t o r s such a s d i e t a r y However, i n t h e m o d i f i c a t i o n , which i s w i t h i n t h e i n d i v i d u a l ' s c o n t r o l . c a s e of a d i s e a s e l i k e Huntington's, t h e i n d i v i d u a l who c a r r i e s t h e d e f e c t i v e gene c u r r e n t l y can do n o t h i n g t o prevent t h e d i s e a s e and i t c a n n o t b e e f f e c t i v e l y t r e a t e d by d o c t o r s . Of s t i l l g r e a t e r c o n c e r n i s t h e p o t e n t i a l u s e o f p r e d i c t i v e g e n e t i c s by h e a l t h a n d l i f e i n s u r a n c e c o m p a n i e s , and e m p l o y e r s , t o w i t h h o l d i n s u r a n c e G r , c h a r g e e x o r b i t a n t i n s u r a n c e r a t e s b a s e d on i n d i v i d u a l d i s e a s e s u s c e p t i b i l i t y . A n o t h e r m a j o r e t h i c a l c o n c e r n r a i s e d by t h e a v a i l a b i l i t y o f m a p p i n g and s e q u e n c i n g d a t a i s t h e p o s s i b l e u s e o f such i n f o r m a t i o n t o s c r e e n t h e g e n e t i c makeup o f u n b o r n c h i l d r e n . Some p r e d i c t t h a t t h e d i s c o v e r y o f g e n e t i c d e f e c t s w i l l l e a d t o a n i n c r e a s e i n t h e number o f a b o r t i o n s performed. D a t a on c u r r e n t l y a v a i l a b l e g e n e t i c t e s t s f o r f e t u s e s i n d i c a t e t h a t d i s c o v e r y o f d e f e c t s l e a d s t o a n a b o r t i o n i n many c a s e s . Although many g e n e t i c d e f e c t s c a n b e i d e n t i f i e d i n f e t u s e s , n o t h e r a p e u t i c t r e a t m e n t i s now a v a i l a b l e t o c o r r e c t most o f t h e s e d e f e c t s . This s i t u a t i o n i s n o t e x p e c t e d t o improve i n t h e n e a r f u t u r e . A major l e g a l i s s u e s u r r o u n d i n g t h e human genome m a p p i n g a n d s e q u e n c i n g p r o p o s a l i s w h e t h e r t h e i n f o r m a t i o n o b t a i n e d s h o u l d b e owned by p r i v a t e e n t i t i e s through p a t e n t s , copyright, or other intellectual A s i g n i f i c a n t amount o f t h e m a p p i n g a n d s e q u e n c i n g d a t a i s p r o p e r t y law. e x p e c t e d t o be commercially v a l u a b l e because it w i l l a i d i n t h e d e v e l o p m e n t of p r o d u c t s s u c h a s t h e r a p e u t i c d r u g s . Some p r i v a t e c o m p a n i e s a r e p r e s e n t l y i n v o l v e d i n m a p p i n g a n d s e q u e n c i n g t h e human genome w i t h a m a j o r o b j e c t i v e b e i n g c o m n e r c i a l a p p l i c a t i o n of t h e i n f o r m a t i o n o b t a i n e d t o d e t e c t and treat s p e c i f i c d i s e a s e s . What r o l e s h o u l d p r i v a t e c o m p a n i e s p l a y i n m a p p i n g a n d s e q u e n c i n g t h e human genome, a n d w h a t r e w a r d s , i f a n y , s h o u l d t h e s e companies r e c e i v e a s i n c e n t i v e s t o p a r t i c i p a t e i n t h e s e e f f o r t s a r e unresolved issues. Representatives of t h e p r i v a t e s e c t o r a l r e a d y have voiced t h e i r i n t e n t i o n s t o c o p y r i g h t , p a t e n t , and s e l l g e n e t i c d a t a g e n e r a t e d f r o m mapping a n d s e q u e n c i n g t h e human genome. O p p o n e n t s o f p r i v a t e o w n e r s h i p of g e n e t i c i n f o r m a t i o n b e l i e v e t h a t i t w i l l impede a c c e s s t o a n d d i s t r i b u t i o n o f s c i e n t i f i c i n f o r m a t i o n t h a t i n t h e p a s t h a s been p u b l i s h e d f o r g e n e r a l use. M o r e o v e r , some b e l i e v e p r i v a t e o w n e r s h i p w i l l make s c i e n t i s t s i n v o l v e d i n genome m a p p i n g reluctant t o share data. For example, c o n c e r n h a s been r a i s e d t h a t i m p o r t a n t s t e p s i n mapping a n d s e q u e n c i n g g e n e t i c m a t e r i a l f o r a d i s e a s e s u c h a s c y s t i c f i b r o s i s c o u l d be h e l d c o n f i d e n t i a l u n t i l a l l t h e s t e p s a r e resolved. I t i s p o s s i b l e , however, t h a t i f such p r e l i m i n a r y i n f o r m a t i o n was made a v a i l a b l e t o o t h e r s c i e n t i s t s , t h e e n t i r e p r o j e c t c o u l d be completed f a s t e r . A major consequence of t h i s p r a c t i c e c o u l d be a d e l a y i n t h e d e t e c t i o n a n d t r e a t m e n t o f human d i s e a s e s . OTA and NAS S t u d i e s for C o n g r e s s The O f f i c e o f T e c h n o l o g y A s s e s s m e n t i s c u r r e n t l y c o n d u c t i n g a s t u d y f o r t h e C o n g r e s s on mapping a n d s e q u e n c i n g t h e human genome. Several i s s u e s w i l l be h i g h l i g h t e d : the controversy about t h e proposal f o r a major c e n t r a l i z e d approach; r e s e a r c h f u n d i n g r e q u i r e m e n t s ; t h e need f o r more c o o r d i n a t i o n ; l e g a l i s s u e s c o n c e r n i n g p a t e n t s and c o p y r i g h t s ; technology transfer; international cooperation; and economic It is anticipated t h a t t h e report w i l l be released about competitiveness. March 1 9 8 8 . T h e B o a r d on B a s i c B i o l o g y , Commission on L i f e S c i e n c e s , N a t i o n a l R e s e a r c h C o u n c i l , N a t i o n a l Academy o f S c i e n c e s , h a s r e c e n t l y p u b l i s h e d a The N a t i o n a l r e p o r t e n t i t l e d "Mapping a n d S e q u e n c i n g t h e Human Genome." Academy o f s c i e n c e s ( N A S ) c o m m i t t e e recommended, among o t h e r t h i n g s , t h a t a m a j o r human genome m a p p i n g a n d s e q u e n c i n g p r o j e c t be i n i t i a t e d , a n d t h a t t h e g r e a t e s t p r i o r i t y b e g i v e n t o d e v e l o p i n g new m a p p i n g t e c h n i q u e s . The c o m i t t e e a l s o r e c o m n e n d e d t h a t $ 3 b i l l i o n b e e a r m a r k e d f o r t h i s genome i n i t i a t i v e o v e r a p e r i o d o f 1 5 y e a r s a t a r a t e o f $200 m i l l i o n a n n u a l l y , a n d t h a t t h e r e s e a r c h s h o u l d b e d o n e by i n d i v i d u a l s c i e n t i s t s a n d "mediums i z e d " r e s e a r c h teams, a s opposed t o a l a r g e c e n t r a l i z e d p r o j e c t . The committee based i t s recomnendations on t h e p o t e n t i a l m e d i c a l a p p l i c a t i o n s o f t h e d a t a a n d n o t on t h e i s s u e of i t s p o t e n t i a l i m p a c t on t h e c o m p e t i t i v e n e s s o f t h e U.S. b i o t e c h n o l o g y i n d u s t r y . P o l i c y Options For Congressional Consideration C o n g r e s s h a s a l r e a d y t a k e n s t e p s t o expand s u p p o r t f o r g e n e mapping and s e q u e n c i n g e f f o r t s . Examples of t h i s i n c l u d e t h e c r e a t i o n of t h e N a t i o n a l Biotechnology I n f o r m a t i o n C e n t e r a t N I H , and i n c r e a s e d f u n d s f o r NIH-supported g e n e mapping r e s e a r c h . I n a d d i t i o n , DOE h a s u n d e r t a k e n a n i n i t i a t i v e a i m e d a t m a p p i n g a n d s e q u e n c i n g t h e human genome. Some o b s e r v e r s b e l i e v e t h a t t h e c u r r e n t l e v e l o f genome s u p p o r t i s a d e q u a t e . However, s h o u l d C o n g r e s s d e t e r m i n e : t o s u p p o r t f u r t h e r e x p a n s i o n o f genome related programs, t o promote t h e c o m p e t i t i v e n e s s of t h e U.S. b i o t e c h n o l o g y i n d u s t r i e s , a n d / o r t o a d d r e s s g e n e t i c d i s e a s e s , i t may c o n s i d e r t h e f 01 l o w i n g o p t i o n s : (1) K e e p t h e c u r r e n t human genome r e s e a r c h p r o g r a m , but i n c r e a s e t h e funding a v a i l a b l e f o r peer-reviewed g r a n t s . The e x i s t i n g r e s e a r c h p r o g r a m , f o r t h e most p a r t , i s b a s e d on r e s e a r c h p r o p o s a l s a p p r o v e d a c c o r d i n g t o merit. The m a j o r o b j e c t i v e of t h i s program, a s i n p r i v a t e s e c t o r programs (e.g., Collaborative Research), i s d i r e c t e d a t m a p p i n g a n d s e q u e n c i n g p i e c e s o f t h e human genome t h a t h a v e known b i o l o g i c a l s i g n i f i c a n c e . An e x a m p l e o f t h i s a p p r o a c h would b e f u n d i n g a p r o j e c t a i m e d a t m a p p i n g a n d sequencing t h e gene f o r Huntington' s disease. The p r i m a r y c o m n e r c i a l a p p l i c a t i o n of t h i s k i n d o f i n f o r m a t i o n would l i k e l y be i n t h e p h a r m a c e u t i c a l i n d u s t r y . I n c r e a s e r e s o u r c e s t o e x i s t i n g F e d e r a l r e s e a r c h programs r e l e v a n t t o genome m a p p i n g a n d s e q u e n c i n g i n a l l o r g a n i s m s of economic i m p o r t a n c e t o t h e United S t a t e s , i n c l u d i n g a g r i c u l t u r a l p l a n t s and animals (livestock, plant commodities, agricultural pests). The commercial a p p l i c a t i o n s of t h i s kind of i n f o r m a t i o n would b e b r o a d - b a s e d , a n d would p r o b a b l y i n c l u d e human h e a l t h a n d a g r i c u l t u r a l products. (3) Expand e x i s t i n g r e s e a r c h p r i o r i t i e s t o i n c l u d e i n i t i a t i v e s d i r e c t e d toward technologies that w i l l improve t h e e f f i c i e n c y of genome mapping a n d s e q u e n c i n g . These i n i t i a t i v e s would a l s o i n c l u d e i m p r o v i r 4ata integration a n d c o o r d i n a t i o n s o t h a t genome i n f o r m a t i b . . c o u l d be b e t t e r u t i l i z e d once c o l l e c t e d . T h i s o p t i o n might 3 c o u p l e d w i t h o p t i o n s ( 1 ) and ( 2 ) above. (Note: The r e s e a r c h p r i e s l i s t e d i n (1)-(3) above a b l i s h m e n t of a c o o r d i n a t i n g m i g h t be a c c o m p a n i e d by t t body t o f a c i l i t a t e communi . L a n between r e p r e s e n t a t i v e s o f different r e s e a r c h programs and t o harmonize d a t a c o l l e c t i o n , a s well as monitor o v e r a l l progress.) (4) An a l t e r n a t i v e t o t h e a p p r o a c h e s d i s c u s s e d i n t h e a b o v e o p t i o n s would be t o i n i t i a t e a new c e n t r a l i z e d e f f o r t a i m e d a t s e q u e n c i n g a n d mapping t h e e n t i r e human genome. Program admini s t r a t i o n , i n c l u d i n g e s t a b 1 i s h m e n t of research p r i o r i t i e s , would o c c u r t h r o u g h a p r i n c i p a l c e n t r a l b o d y . WE, which a d v o c a t e s t h i s t y p e of program, p r o p o s e s t h e d e v e l o p m e n t o f h a r d w a r e and s o f t w a r e t o i m p r o v e t h e e f f i c i e n c y o f genome mapping a n d c o m p r e h e n s i v e s e q u e n c i n g o f a l l t h e 3 b i l l i o n n u c l e o t i d e p a i r s i n t h e human genome r a t h e r t h a n a f o c u s on o n l y t h o s e s e g m e n t s o f known biological significance. LEG1 SLATION 393 (Pepper) E s t a b l i s h e s t h e National Center f o r Biotechnology Information w i t h i n t h e D e p a r t m e n t o f H e a l t h a n d Human S e r v i c e s a s a component o f t h e N a t i o n a l L i b r a r y of M e d i c i n e . I n t r o d u c e d J a n . 6 , 1987; r e f e r r e d t o C o m m i t t e e on E n e r g y a n d C o m e r c e . B.R. H.R. 3006 ( L u j a n ) E s t a b l i s h e s t h e C o u n c i l f o r R e s e a r c h on E n a b l i n g T e c h n o l o g i e s , t h e N a t i o n a l P o l i c y Board on t h e Human Genome and t h e Human Genome C o n s o r t i u m , and a r e g i o n a l I n s t i t u t e s f o r E n t r e p r e n e u r i a l S t u d i e s . Introduced July 2 3 , 1 9 8 7 ; r e f e r r e d t o C o m m i t t e e s on Armed S e r v i c e s , on E n e r g y a n d Commerce, and on S c i e n c e , S p a c e , and Technology. Ref e r r e d to S u b c o m m i t t e e on E n e r g y a n d Power Aug 3 , 1 9 8 7 . S. 1480 ( D o m e n i c i ) E s t a b l i s h e s t h e C o u n c i l f o r R e s e a r c h on E n a b l i n g T e c h n o l o g i e s a n d t h e N a t i o n a l P o l i c y Board on t h e Human Genome and t h e Human Genome C o n s o r t i u m . I n t r o d u c e d J u l y 10, 1987; r e f e r r e d t o Committee on Energy and N a t u r a l Resources. R e f e r r e d t o S u b c o m m i t t e e on R e s e a r c h a n d D e v e l o p m e n t S e p t . 1 7 , 1987. S . 1966 ( C h i l e s ) Amends t h e P u b l i c H e a l t h S e r v i c e Act t o i m p r o v e i n f o r m a t i o n a n d r e s e a r c h on b i o t e c h n o l o g y a n d t h e human genome, a n d o t h e r p u r p o s e s . I n t r o d u c e d Dec. 1 8 , 1 9 8 7 ; r e f e r r e d t o C o m m i t t e e on L a b o r a n d Human Resources. E x e c u t i v e comment r e q u e s t e d f r o m D e p a r t m e n t s o f H e a l t h a n d Human S e r v i c e s , A g r i c u l t u r e , D e f e n s e , Commerce, a n d E n e r g y , a n d OMB J a n . 1 5 , 1988. CONGRESSIONAL HEAKINGS, REPORTS, AND DOCUMENTS U.S. Congress. House. Committee on A p p r o p r i a t i o n s . Energy and w a t e r development a p p r o p r i a t i o n s b i l l , 1988. J u n e 1 7 , 1987. Washington, 1987. p. 76-69. (100th Congress, 1st U.S. G o v t . P r i n t . Off s e s s i o n . H o u s e . R e p o r t n o . 100-162) .,