Basic Biomedical Research: Its Impact on Drug Discovery

11 Basic Biomedical Research: Its Impact on Drug Discovery

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B R I A N F. H O F F M A N , M . D . Department of Pharmacology, College of Physicians and Surgeons, C o l u m b i a University, 630 West 168th St., N e w York, Ν. Y .

The interdependence advance

argue, however, research

of discovery

in drug development

for the predictable

except in special

cal research

in biological

is clear;

success of

and drug development

are to continue,

have made

since university

meet this need. major financial

Although

support

and research

resources

government

for these activities,

for the pharmaceutical

to innovative

programs

in developing

ways to evaluate

developments

biomedi

If similar

in the

con

commit biomedical

are no longer sufficient

opportunities

possible

not

contributions

there must be a national

ment to support both training sciences

and

"goal-oriented"

cases. In the past, basic

of great value to the well being of mankind. tributions

research

this fact does

the ultimate

provide

there are

industry

and to collaborate in biomedical

must

to

with

to the

major

contribute universities

consequences

science

and

of

therapy.

A T a n y of the advances i n o u r u n d e r s t a n d i n g of b i o l o g y a n d disease h a v e l e d to t h e d i s c o v e r y of n e w drugs, a n d f u r t h e r t h e a v a i l a b i l i t y of n e w , b i o l o g i c a l l y active substances most o f t e n has r e s u l t e d i n t h e a c q u i s i t i o n of n e w u n d e r s t a n d i n g of n o r m a l a n d a b n o r m a l b i o l o g y . T h e best examples are f a m i l i a r to a l l ; I prefer to a v o i d a s s u m i n g a necessary a n d u n i q u e cause-effect r e l a t i o n s h i p b e t w e e n s e q u e n t i a l events.

Indeed, I a m

m u c h m o r e i m p r e s s e d b y t h e u n c e r t a i n t y of a t t r i b u t i n g cause t o effect a n d b y t h e a p p a r e n t r o l e of c h a n c e i n m a n y i m p o r t a n t discoveries. T h i s does n o t m e a n that I h a v e d o u b t s c o n c e r n i n g t h e m u t u a l i n d e p e n d e n c e of basic b i o l o g i c a l research a n d d r u g d e v e l o p m e n t .

It does

m e a n , h o w e v e r , that I w o u l d q u e s t i o n seriously a n y p l a n or system u n d e r w h i c h a major p a r t of o u r research a n d t r a i n i n g effort w a s d i r e c t e d cate g o r i c a l l y t o w a r d s c e r t a i n stated objectives s u c h as t h e s o l u t i o n of a p r o b 220

In Drug Discovery; Bloom, B., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1971.

11.

HOFFMAN

Basic Biomedical

221

Research

lem i n clinical medicine. I w o u l d be equally concerned b y any trend i n d r u g d e v e l o p m e n t w h i c h m i g h t seriously l i m i t the d i s c o v e r y of n e w c o m p o u n d s because t h e y d i d n o t h a v e a n i m m e d i a t e p r a c t i c a l a p p l i c a t i o n . D i s c o v e r y , b o t h i n b i o l o g i c a l science a n d d r u g d e v e l o p m e n t , o f t e n results f r o m a c o m p l e x r e a c t i o n .

most

T h i s r e a c t i o n requires m o r e t h a n

the i d e n t i f i c a t i o n of a p r o b l e m a n d t h e a c q u i s i t i o n of b i o l o g i c a l d a t a w h i c h d e s c r i b e i t . T h e r e a c t i o n also requires a r e a s o n — w h i c h m a y b e a m b i t i o n , c u r i o s i t y , o r a s o c i a l or e c o n o m i c p r e s s u r e — a reason to d o s o m e t h i n g a b o u t t h e p r o b l e m . It also requires the t e c h n i c a l a b i l i t y to d o w h a t seems Downloaded by SUNY STONY BROOK on November 3, 2014 | http://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch011

to b e i n d i c a t e d o r at least t h e means b y w h i c h the necessary t e c h n i q u e s c a n b e d e v e l o p e d . W h e t h e r or n o t necessary n e w t e c h n i q u e s m a t e r i a l i z e d e p e n d s not just o n the d r i v i n g force f o r t h e r e a c t i o n b u t o n other c o m p l e x interactions w h i c h i n c l u d e the state of k n o w l e d g e i n a v a r i e t y o f fields a n d t h e a d e q u a c y of i n f o r m a t i o n exchange b e t w e e n

them.

W h i l e these ingredients m a y constitute t h e major reactants a n d the energy source f o r d i s c o v e r y , t h e r e a c t i o n almost c e r t a i n l y w i l l s l o w l y i f at a l l i n the absence of a n essential catalyst.

proceed

T h i s catalyst is t h e

a d e q u a t e l y p r e p a r e d m i n d or, m o r e ofen, the conjoint a c t i o n of m o r e than one such m i n d . I w i l l describe o n l y o n e e x a m p l e of the c o m p l e x c h a i n of events that results i n d i s c o v e r y — d i s c o v e r y i n d r u g d e v e l o p m e n t , i n b i o l o g i c a l science, and

applied therapeutics—to

demonstrate

b o t h the i n t e r d e p e n d e n c e

of

discoveries i n b i o l o g y a n d d r u g d e v e l o p m e n t a n d the p r a c t i c a l benefit to society w h i c h results f r o m t h e t r a d i t i o n a l m o d e of o p e r a t i o n of o u r scientific c o m m u n i t y . I s o n i a z i d , one of t h e most active of the t u b e r c u l o s t a t i c d r u g s , w a s d i s c o v e r e d because i t h a d b e e n s h o w n that n i c o t i n a m i d e exerted tuberculostatic action ( I ) .

some

A d e l i b e r a t e search f o r m o r e effective b u t

r e l a t e d c h e m i c a l s r e v e a l e d that m a n y p y r i d i n e d e r i v a t i v e s , i n c l u d i n g c o n geners of i s o n i c o t i n i c a c i d , also w e r e active.

F u r t h e r , i t w a s k n o w n that

the thiosemicarbazones c o u l d i n h i b i t the g r o w t h of M . tuberculosis. A n a t t e m p t to synthesize the t h i o s e m i c a r b a z o n e vided,

as the

first

intermediate

of i s o n i c o t i n a l d e h y d e p r o -

compound, isonicotinylhydrazine, or

isoniazid. T h i s is a n e x a m p l e of t h e d i r e c t i n t e r d e p e n d e n c e of d r u g d e v e l o p m e n t o n basic b i o m e d i c a l research.

K n o w l e d g e g a i n e d f r o m studies o n

m i c r o b i a l m e t a b o l i s m a n d k n o w l e d g e of o r g a n i c c h e m i s t r y w e r e u s e d to d e v e l o p a n effective t h e r a p e u t i c agent. Nevertheless, c h a n c e also p l a y e d a role i n the sense that the a c t i v i t y of i s o n i a z i d w a s d i s c o v e r e d a n d n o t o v e r l o o k e d . H o w e v e r , the sequence of discoveries d i d n o t stop here. W h e n i s o n i a z i d a n d its i s o p r o p y l d e r i v a t i v e , i p r o n i a z i d , w e r e a d m i n istered to patients w i t h tubeculosis, b o t h agents caused a m a r k e d i m p r o v e m e n t i n m o o d or sense of w e l l - b e i n g . B e c a u s e there w e r e p r o p e r l y


222

DRUG DISCOVERY

t r a i n e d c l i n i c a l investigators c o l l a b o r a t i n g w i t h basic scientists, i t soon w a s d e t e r m i n e d that this effect o n m o o d d i d not result solely f r o m amel i o r a t i o n of the basic disease b u t rather reflected a d i r e c t effect of the drugs employed ( 2 ) .

T h i s finding l e d to the use of these agents i n t r e a t i n g

depressed p s y c h i a t r i c patients a n d a c o n c o m i t a n t search for the m e c h a nism b y w h i c h they modified b r a i n function.

S o o n i t w a s f o u n d that

i p r o n i a z i d , b u t not i s o n i a z i d , i n h i b i t e d m o n o a m i n e oxidases

(3).

This

d i s c o v e r y l e d to the synthesis of other i n h i b i t o r s of M A O a n d , as a n i n c i d e n t a l result, to the i n t r o d u c t i o n i n t o the t h e r a p e u t i c a r m a m e n t a r i u m


of several a n t i h y p e r t e n s i v e agents. B e c a u s e of a v a r i e t y of u n d e s i r a b l e effects, the- M A O i n h i b i t o r s act u a l l y are of o n l y l i m i t e d v a l u e i n treatment of either p s y c h i a t r i c patients or hypertensives.

A l s o , as w e k n o w n o w , it is l i k e l y that m a n y effects of

these d r u g s result f r o m actions q u i t e i n d e p e n d e n t of their a b i l i t y to i n h i b i t M A O . T h e m e c h a n i s m b y w h i c h t h e y m o d i f y m e n t a l f u n c t i o n still is u n c l e a r .

N e v e r t h e l e s s , the

finding

that a d r u g w h i c h c o u l d i n h i b i t

M A O also m o d i f i e d b r a i n f u n c t i o n w a s q u i t e i m p o r t a n t since it p r o v i d e d one of the m a n y bits of i n f o r m a t i o n necessary to foster c o n t i n u e d interest i n the role of m o n o a m i n e s i n the transfer of i n f o r m a t i o n i n the c e n t r a l nervous system, a n d p r o v i d e d one of m a n y tools necessary f o r studies o n this p r o b l e m ( 4 ) .

T h e d o g m a of e l e c t r i c a l transmission across c e n t r a l

synapses w a s almost u n q u e s t i o n e d u n t i l n e u r o p h y s i o l o g i s t s s u c c e e d e d i n r e c o r d i n g p o s t s y n a p t i c potentials f r o m single neurones cellular microelectrodes

through intra-

( 5 ) — a n e x p e r i m e n t that c o u l d h a r d l y b e

de-

s c r i b e d as g o a l o r i e n t e d i n the sense w e n o w use this t e r m . T h i s interest i n the n a t u r e of c h e m i c a l t r a n s m i s s i o n i n the

central

nervous system continues to b e a r f r u i t . F o r e x a m p l e , studies o n nerve t e r m i n a l s of p o s t g a n g l i o n i c a d r e n e r g i c

fibers

(6)

a n d o n the

adrenal

m e d u l l a h a d , over a p e r i o d of m a n y years, p r o v i d e d a f a i r l y clear p i c t u r e of the biosynthesis, release, r e u p t a k e , a n d d e s t r u c t i o n of the transmitter n o r e p i n e p h r i n e .

adrenergic

O t h e r studies h a d s h o w n that i n patients

w i t h classical P a r k i n s o n ' s disease parts of the b r a i n — t h e substantia n i g r a a n d c o r p u s s t r i a t u m — c o n t a i n e d less d o p a m i n e t h a n d i d n o r m a l b r a i n s (7).

D o p a m i n e is one of the i n t e r m e d i a t e s i n the biosynthesis of n o r e p i -

nephrine from phenylalanine. E v e n t h o u g h the precise role of m o n o a m i n e s i n b r a i n f u n c t i o n s t i l l is u n c l e a r because of m a n y suggestions that they are responsible f o r cert a i n types of i n f o r m a t i o n transfer b e t w e e n

cells, the

finding

of a l o w

d o p a m i n e content was d e e m e d significant. Since d o p a m i n e does not enter the b r a i n f r o m the b l o o d stream, treatment attempted

of P a r k i n s o n ' s disease

was

with L-dopa-L-dihidroxyphenylanine—the normal biological

p r e c u r s o r of d o p a m i n e . T h e result of this e x p e r i m e n t w a s g r a t i f y i n g i n that L - d o p a p r o v e d to b e a n extremely v a l u a b l e t h e r a p e u t i c agent, far


11.

HOFFMAN

Basic Biomedical

Research

s u r p a s s i n g others f o r m e r l y a v a i l a b l e .

223

H a d means n o t b e e n a v a i l a b l e to

p r o v i d e L - d o p a i n suitable a m o u n t s a n d h a d 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 b e e n u n w i l l i n g to invest i n t h e synthesis a n d e x p e r i m e n t a l use of this c o m p o u n d , the c l i n i c a l hypothesis

resulting f r o m the biological data

p r o b a b l y s t i l l w o u l d a w a i t a d e q u a t e test. Studies o n t h e m e t a b o l i s m of a m i c r o o r g a n i s m — M . t u b e r c u l o s i s — not o n l y c o n t r i b u t e d to t h e treatment of p s y c h i a t r i c d i s o r d e r s a n d h y p e r t e n s i o n b u t also p l a y e d a r o l e i n p r o v i d i n g a t r u l y d r a m a t i c i m p r o v e m e n t i n t h e treatment of a n e x t r e m e l y i m p o r t a n t disease of t h e c e n t r a l n e r v o u s


system, a disease w h i c h afflicts m a n y p e o p l e a n d severely l i m i t s t h e i r a b i l i t y to f u n c t i o n .

T h e r e are m a n y l i n k s i n this c h a i n of events, a n d

some c a n b e i d e n t i f i e d as chemists, b i o l o g i c a l scientists, or c l i n i c i a n s . U n seen l i n k s are t h e u n i v e r s i t i e s , t h e donors w h o s u p p o r t e d research, t h e a d m i n i s t r a t o r s 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 , a n d t h e patients w h o v o l u n t e e r e d to take n e w , u n t r i e d d r u g s .

Role of Government H o w w e r e these l i n k s f o r g e d , a n d h o w d i d t h e y c o m e to f o r m s u c h a chain?

W h a t changes m i g h t decrease t h e l i k e l i h o o d that n e w d i s c o v -

eries w i l l result f r o m s i m i l a r sequences?

O f paramount importance i n

this r e g a r d is t h e r o l e of g o v e r n m e n t a n d g o v e r n m e n t s u p p o r t of research a n d t r a i n i n g . O v e r t h e past 25 years g o v e r n m e n t a l s u p p o r t has g r o w n i n m a g n i t u d e a n d therefore i n i m p o r t a n c e . For

this reason m a n y are distressed b y recent changes w h i c h h a v e

i n f l u e n c e d a n d w i l l c o n t i n u e to i n f l u e n c e b o t h basic b i o l o g i c a l research and

drug development.

Some

of these changes m a y b e d e s c r i b e d as

changes i n n a t i o n a l p o l i c y . M a n y , q u i t e o b v i o u s l y , a r e t h e i n e v i t a b l e a n d u s u a l l y r a n d o m b y - p r o d u c t s of t h e l i f e processes of b u r e a u c r a t i c a n d p o l i t i c a l entities a n d t h e interactions b e t w e e n t h e m . T h e most i m p o r t a n t , h o w e v e r , are changes i n the attitudes of g o v e r n m e n t a n d of society. O n e often reads that t h e t i m e has c o m e f o r g o v e r n m e n t to c u r t a i l its s u p p o r t of " p u r e " research i n t h e b i o l o g i c a l sciences a n d e m p h a s i z e t h e s u p p o r t of " g o a l - o r i e n t e d " projects.

A r g u m e n t s affirm that e n o u g h b a s i c

b i o l o g i c i n f o r m a t i o n is a v a i l a b l e to solve m a n y c u r r e n t l y p r e s s i n g m e d i c a l p r o b l e m s i f o n l y i t w e r e or c o u l d b e a p p l i e d . T h i s a r g u m e n t o f t e n i n c l u d e s t h e statement that n o t o n l y s h o u l d s u p p o r t of b a s i c research b e c u r t a i l e d b u t there s h o u l d b e a change i n t h e p a t t e r n of t r a i n i n g i n t h e b i o l o g i c a l sciences a n d m e d i c i n e . T h i s change w o u l d result i n t h e t r a i n i n g of m o r e technologists, w h o w o u l d find t h e means to a p p l y e x i s t i n g k n o w l e d g e to h u m a n p r o b l e m s , a n d t h e t r a i n i n g of m o r e p h y s i c i a n s , w h o w o u l d i m m e d i a t e l y m a k e n e w remedies a v a i l a b l e to those i n n e e d of them.

T h e r e are as m a n y i m p l i c a t i o n s to these statements as there are

untested assumptions u n d e r l y i n g t h e m .


224

DRUG

DISCOVERY

It is true that g o v e r n m e n t s u p p o r t of b a s i c research a n d t r a i n i n g has b e e n almost u n b e l i e v a b l y generous a n d effective since the e n d of W o r l d W a r II.

It also is true that d u r i n g this p e r i o d , a n d l a r g e l y as a result of

this same s u p p o r t , our k n o w l e d g e of b i o l o g y a n d disease has i n c r e a s e d at a p h e n o m e n a l rate. W h a t is n o t true is that society has f a i l e d to benefit f r o m these activities a n d f r o m the e x p e n d i t u r e of tax dollars m a d e i n their support. concomitant

Table I. Downloaded by SUNY STONY BROOK on November 3, 2014 | http://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch011

Parenthetically,

contributions

w h a t is q u i t e u n f a i r is to n e g l e c t

made

b y the

pharmaceutical

industry

Additions to the Therapeutic A r m a m e n t a r i u m Therapeutic

Use

Drug or Class

Antiarrhythmics

Procaine amide, Lidocaine Diphenylhydantoin Propranolol

Arteriosclerosis, Hyperlipidemia

Nicotinic acid Clofibrate Cholestyramine

Diuretics

Carbonic Anhydrase inhibitors Benzothiadiazines Ethacrinic acid Furosamide A l d o s t e r o n e antagonists

Antineoplastic Agents

A l k y l a t i n g agents Antimetabolites A n t i p r o l i f e r a t i v e agents

Antibiotics

Penicillin Streptomycin Chloramphenicol Erythromycin Nystatin Amphotericin Griseofulvin Bacitracin Polymycin Tetracyclines Neomycin Kanamycin Tyrothricin Cephalosporin Gentamycin Novobiocin


0

the and

11.

HOFFMAN

Basic Biomedical Table I.


Therapeutic

Use

225

Research Continued Drug or Class

Tuberculostatics

Aminosalicylic acid Isoniazid Cycloserine Viomycin Streptomycin

Antimalarials

Chloraquine Primaquin Chloraguanide Pyrimethamine Trimethoprim

H e a v y metals antagonists Dimercaprol Ethylenediamine tetraacetic a c i d Penacillamine Deferoxamine Psychiatric disorders

Convulsive disorders

a

Phenothiazines Buterophenones Rauwolfia alkaloids Benzodiazepines M A O inhibitors Imipramine Amitriptyline L i t h i u m salts Acetylureas Oxazolidinediones Succinimides

A p a r t i a l listing

m a n y other components of the p r i v a t e sector of o u r e c o n o m y .

A simple

means of e v a l u a t i n g one aspect of the p r a c t i c a l benefits to society of t h e research a n d research t r a i n i n g d u r i n g this p e r i o d is to c o m p a r e the drugs l i s t e d u n d e r selected headings i n a l e a d i n g textbook

of p h a r m a c o l o g y

p u b l i s h e d i n 1940 ( 8 ) to the same listings i n a c u r r e n t text ( 9 ) . S u c h a list is p r o v i d e d i n T a b l e I. T h e p e r i o d i n q u e s t i o n w a s one d u r i n g w h i c h b i o l o g i c a l scientists a n d the p h a r m a c e u t i c a l i n d u s t r y p r o v i d e d m o r e n e w a n d effective

remedies

f o r i m p o r t a n t illnesses

t h a n d u r i n g a n y other


226

DRUG DISCOVERY

p e r i o d i n history. A l s o , d u r i n g this t i m e there was a n almost p a r a l l e l i m p r o v e m e n t i n the means a v a i l a b l e for r e c o g n i z i n g a n d d i a g n o s i n g diseases a n d i n techniques for treatment

w h i c h d i d not d e p e n d o n d r u g

a d m i n i s t r a t i o n . T o say or i m p l y that there has b e e n a f a i l u r e to translate the n e w discoveries of b i o l o g i c a l science into s o c i a l l y u s e f u l means f o r the p r e v e n t i o n a n d treatment of disease is s i m p l y to i g n o r e fact.

Un-

d o u b t e d l y , there is a n e e d for the d e l i v e r y of i m p r o v e d h e a l t h c a r e to a greater n u m b e r of p e o p l e .

H o w e v e r , i n m a n y w a y s , this p r o b l e m is

almost e n t i r e l y u n r e l a t e d to the nature a n d effectiveness of past g o v e r n Downloaded by SUNY STONY BROOK on November 3, 2014 | http://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch011

m e n t a l s u p p o r t of basic b i o m e d i c a l research. E q u a l l y fallacious is the a s s u m p t i o n that the system of government s u p p o r t of b i o l o g i c a l research w o u l d b e c o m e m o r e effective i f the s u p p o r t b e c a m e m o r e " g o a l o r i e n t e d . " U n d e r this system, I assume,

problems

w o u l d be i d e n t i f i e d a n d r a t e d i n terms of r e l a t i v e i m p o r t a n c e .

Also,

s u p p o r t w o u l d be a l l o c a t e d to solve those p r o b l e m s w h i c h a p p e a r e d to be most i m p o r t a n t a n d w i t h i n the c u r r e n t scope of scientific a n d t e c h n i c a l competence.

A l l i e d w i t h this change i n the s u p p o r t of research w o u l d be

the i n e v i t a b l e shift i n a l l o c a t i o n of f u n d s for research t r a i n i n g . E x p e r i e n c e has s h o w n that w h i l e this i d e a is not necessarily incorrect, most often it is not a p p l i c a b l e to the r e a l w o r l d of b i o l o g i c a l i n v e s t i g a t i o n . T h i s is so because i n most instances w e s i m p l y d o not have e n o u g h basic i n f o r m a t i o n to i d e n t i f y the p r o b l e m s to be s o l v e d . If w e are u n a b l e to i d e n t i f y the p r o b l e m c l e a r l y , even the most p r o f i c i e n t m a n a g e r cannot m a k e the other necessary decisions. T h e past p r o v i d e s so m a n y examples w h i c h s u p p o r t this

statement

that it is d i f f i c u l t to k n o w w h i c h ones to select. H o w e v e r , I w i l l m e n t i o n a f e w . O n e m i g h t q u i t e reasonably d e c i d e that d e a t h d u e to m y o c a r d i a l i n f a r c t i o n c o n s t i t u t e d a s o c i a l l y i m p o r t a n t p r o b l e m . F u r t h e r , one m i g h t assume, as m a n y d i d several years ago, that i n h i b i t i o n o n some aspect of the b l o o d c l o t t i n g m e c h a n i s m w o u l d p r e v e n t or m o d i f y the i n c i d e n c e of c o r o n a r y artery o c c l u s i o n a n d thus decrease m o r t a l i t y f r o m m y o c a r d i a l i n f a r c t i o n . W e a l l are f a m i l i a r w i t h the t r e m e n d o u s a m o u n t of t i m e a n d effort d e v o t e d to the use of anticoagulants i n attempts to m o d i f y the course of c o r o n a r y artery disease a n d w i t h the n e g l i g i b l e results w h i c h c a m e f r o m this " g o a l - o r i e n t e d " p r o g r a m . A l l are f a m i l i a r w i t h the i n i t i a l e n t h u s i a s m for s u c h things as cancer c h e m o t h e r a p y , a r t i f i c i a l hearts a n d , most recently, heart transplants.

E a c h program provides good evidence

to s u p p o r t the c o n t e n t i o n that i d e n t i f i c a t i o n of a p r o b l e m u s u a l l y has b e e n m a d e i n terms of superficialities. F o r e x a m p l e , the " p r o b l e m " i n terms of c a r d i a c t r a n s p l a n t a t i o n , w a s not a q u e s t i o n of the s u r g i c a l feasib i l i t y of the t r a n s p l a n t a t i o n p r o c e d u r e , the a v a i l a b i l i t y of agents w h i c h w o u l d suppress the i m m u n e response of the p a t i e n t or even the a v a i l a b i l i t y for techniques for tissue t y p i n g .

T h e p r o b l e m w a s m u c h larger,


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227

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m u c h m o r e subtle a n d , to m e , s t i l l o n l y i l l d e f i n e d . H a d i t n o t b e e n f o r the a p p a r e n t effectiveness

of the first successful c a r d i a c t r a n s p l a n t a t i o n

( a g a i n the role of chance i n d i s c o v e r y ) I f e e l q u i t e c e r t a i n that t h e same p e o p l e w h o p l a n n e d f o r a massive p r o g r a m of c a r d i a c t r a n s p l a n t a t i o n i n this c o u n t r y w o u l d h a v e c o m e to q u i t e a different d e c i s i o n . O b v i o u s l y , sometimes, " g o a l - o r i e n t e d " research c a n b e a n d has b e e n effective.

T h i s h a p p e n s w h e n b o t h the i n f o r m a t i o n necessary to i d e n t i f y

the p r o b l e m a n d the t e c h n i q u e s necessary f o r its s o l u t i o n n o t o n l y a r e a v a i l a b l e b u t are k n o w n to the p r o p e r p e o p l e . W h e n this h a p p e n s , t h e Downloaded by SUNY STONY BROOK on November 3, 2014 | http://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch011

g o a l often is a c h i e v e d reasonably e x p e d i t i o u s l y as w a s the case i n the synthesis o f B A L as a n antidote to l e w i s i t e (10)

or the d e v e l o p m e n t o f

Ρ A M as a n antidote f o r the o r g a n o p h o s p h o r o u s c o m p o u n d s (11).

How

ever, the success of attempts to solve l i m i t e d a n d c l e a r l y d e f i n e d p r o b l e m s does n o t argue that s i m i l a r success c a n b e a n t i c i p a t e d w h e n large, p o o r l y u n d e r s t o o d , a n d often i l l d e f i n e d p r o b l e m s are set as goals. H e r e I w i l l mention only one example. r h y t h m are a n i m p o r t a n t m e d i c a l p r o b l e m .

Disturbances

of c a r d i a c

Q u i n i d i n e , the d-isomer of

q u i n i n e , is one of the most effective agents a v a i l a b l e f o r the treatment o f c a r d i a c a r r h y t h m i a s . T h e d i s c o v e r y that q u i n i n e , a n d s u b s e q u e n t l y q u i n i d i n e , c o u l d b e u s e d to treat c e r t a i n a r r h y t h m i a s must b e a t t r i b u t e d t o l u c k . A patient of W e n c k e b a c h , a f a m o u s V i e n n e s e p h y s i c i a n , n o t e d i n 1912 that w h e n h e took q u i n i n e f o r his m a l a r i a i t also c a u s e d h i s r a p i d , i r r e g u l a r pulse to b e c o m e s l o w e r a n d m o r e r e g u l a r . I n 1918 F r e y c o m p a r e d several c i n c h a n a a l k a l o i d s a n d f o u n d that q u i n i d i n e w a s m o r e effective i n t r e a t i n g a t r i a l

fibrillation

than quinine. Subsequently, quini

d i n e w a s f o u n d to b e effective against m a n y other c a r d i a c a r r h y t h m i a s . S i n c e q u i n i d i n e has m a n y effects o n l i v i n g systems, its use as a t h e r a p e u t i c agent is associated w i t h m a n y toxic or u n d e s i r a b l e actions. F o r years the search f o r a better agent has c o n t i n u e d . B a s i c scientists i d e n t i fied the actions of q u i n i d i n e o n the heart, a n d m a n y representatives o f the p h a r m a c e u t i c a l i n d u s t r y s y n t h e s i z e d a n d e v a l u a t e d a host of c h e m i cals w i t h s i m i l a r actions. H o w e v e r , to m y k n o w l e d g e , n o c l i n i c a l l y supe r i o r d r u g ever r e s u l t e d . O n l y r e c e n t l y h a v e w e b e g u n to u n d e r s t a n d w h y . It w a s i n a p p r o p r i a t e to a t t e m p t to i m p r o v e o n q u i n i d i n e as a n a n t i a r r h y t h m i c d r u g u n t i l there w a s some r e l i a b l e i n f o r m a t i o n o n its m e c h a n i s m of a c t i o n . T h i s c o u l d n o t b e o b t a i n e d u n t i l there w a s a n u n d e r s t a n d i n g of the m e c h a n i s m s responsible f o r the p r o d u c t i o n of a r r h y t h m i a s i n diseased hearts, a n d the t e c h n i q u e s a n d i n f o r m a t i o n necessary f o r this u n d e r s t a n d i n g s t i l l are insufficient. T o b e m o r e specific, i t w a s i n c o r r e c t to i d e n t i f y the n e e d to treat c a r d i a c a r r h y t h m i a s or e v e n a specific dis t u r b a n c e of r h y t h m as a " p r o b l e m " a n d e q u a l l y i n c o r r e c t to set t h e search for a c o m p o u n d e x e r t i n g some b u t n o t a l l of the actions o f q u i n i d i n e as a "goal."


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A l t h o u g h I h a v e strong reservations c o n c e r n i n g the a b i l i t y of g o v e r n m e n t to i d e n t i f y p r o b l e m s a n d set goals f o r b i o m e d i c a l research, I d o r e c o g n i z e the fact that g o v e r n m e n t m u s t r e m a i n i n v o l v e d i n s u p p o r t of these activities. I n d e e d the n e e d f o r c o n t i n u i n g g o v e r n m e n t a l s u p p o r t is greater n o w t h a n at a n y t i m e i n the past. reasonable

W h i l e at one t i m e i t w a s

f o r universities to s u p p o r t some f r a c t i o n of research

research t r a i n i n g , changes b o t h i n the cost of research a n d t h e resources of the universities are s u c h that w e h a v e b e c o m e

and

financial

completely

dependent on continuing and increasing government participation.

The


cost of b i o m e d i c a l research increases as a f u n c t i o n of its c o m p l e x i t y , a n d this c o m p l e x i t y u s u a l l y increases i n p r o p o r t i o n to the a m o u n t of i n f o r m a t i o n a v a i l a b l e o n the p r o b l e m u n d e r s t u d y . A l a r g e r a n d l o n g e r f r a c t i o n of t h e d w i n d l i n g

financial

resources of the universities w i l l h a v e to be

a l l o c a t e d to meet the ever-pressing n e e d to increase the size of classes a n d increase the a m o u n t of t i m e f a c u l t y m e m b e r s devote to t e a c h i n g . A t the same t i m e the i n c o m e a v a i l a b l e to the universities is d e c r e a s i n g i n r e l a t i o n to necessary expenses.

A s a result, the a b i l i t y of the universities

to s u p p o r t p r e d o c t o r a l candidates, p o s t d o c t o r a l trainees, a n d e s t a b l i s h e d investigators w i l l decrease u n t i l , i n the absence of a d e q u a t e

government

f u n d i n g , i n m a n y areas these activities sooner or later w i l l cease to exist. T h e r e are other reasons w h y g o v e r n m e n t s u p p o r t of b a s i c b i o m e d i c a l research a n d t r a i n i n g not o n l y s h o u l d c o n t i n u e b u t s h o u l d be a n a t i o n a l c o m m i t m e n t . T h e best p e o p l e w i l l not enter the l o n g a n d d i f f i c u l t t r a i n i n g p r o g r a m s i n b i o m e d i c a l science unless they are r e a s o n a b l y c e r t a i n that u p o n c o m p l e t i o n of t h e i r t r a i n i n g t h e y w i l l h a v e a n o p p o r t u n i t y to use t h e i r skills a n d k n o w l e d g e effectively a n d p r o d u c t i v e l y . E v e n i f i t w e r e p o s s i b l e for the universities to c o n t i n u e t r a i n i n g p r o g r a m s , i n the absence of d i r e c t s u p p o r t of research h i g h l y competent investigators w o u l d

be

f o r c e d to t u r n to other activities. S o m e m i g h t t u r n to t e a c h i n g , b u t i t is not a l w a y s correct to assume that t h e best l a b o r a t o r y scientist w i l l b e the best teacher.

W h a t is essential to attract the best p e o p l e a n d to ensure

c o n t i n u i n g s c h o l a r l y a c t i v i t y i n b i o m e d i c a l science is a reasonable guarantee that the t r u l y c o m p e t e n t investigator w i l l b e able to devote his l i f e to the studies w h i c h seem to h i m most i m p o r t a n t , m o s t interesting, a n d most e x c i t i n g . It is not sufficient to guarantee d i r e c t g o v e r n m e n t a l s u p p o r t of research i n b a s i c b i o m e d i c a l science. T h e r e also m u s t b e c o n t i n u i n g s u p p o r t of t r a i n i n g a n d c o n t i n u i n g salary s u p p o r t of q u a l i f i e d investigators. If one c o n c l u d e s that there w i l l b e a c o n t i n u i n g n e e d f o r l o n g t e r m s u p p o r t of b a s i c b i o m e d i c a l research, t h e n one also m u s t ask w h a t s h o u l d be the n a t u r e of this s u p p o r t a n d h o w s h o u l d i t b e a l l o c a t e d ?

Although

it m a y be i n e v i t a b l e that g o v e r n m e n t agencies w i l l i d e n t i f y b r o a d areas i n b i o m e d i c a l research w h e r e , because of r e a l or i m a g i n e d s o c i a l pressure,


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s u p p o r t w i l l b e m o r e generous, f u n d s also s h o u l d b e m a d e a v a i l a b l e i n other areas to s u p p o r t research o n g o o d ideas. T h e h i s t o r y of t h e N a t i o n a l Institutes o f H e a l t h a n d 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 has b o r n e o u t the lesson l e a r n e d t h r o u g h o u t t h e centuries b y the universities. A reasonable r e t u r n o n a n i n v e s t m e n t is most l i k e l y i f s u p p o r t is g r a n t e d t o i n d i v i d u a l s w h o h a v e d e m o n s t r a t e d t h e i r a b i l i t y to i d e n t i f y i m p o r t a n t p r o b lems a n d w o r k effectively t o w a r d s t h e i r s o l u t i o n . Nevertheless, s u p p o r t also m u s t b e m a d e a v a i l a b l e to the n e w a n d u n t r i e d investigator w h o has h a d g o o d t r a i n i n g a n d w h o has a g o o d i d e a . O b v i o u s l y , e v a l u a t i o n of this Downloaded by SUNY STONY BROOK on November 3, 2014 | http://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch011

sort of i d e a c a n b e m a d e o n l y b y the best scientists, w h o s h o u l d serve n o t o n l y o n the i n i t i a l r e v i e w o f a p p l i c a t i o n s f o r research s u p p o r t b u t also s h o u l d p a r t i c i p a t e i n a l l subsequent decisions. T h e i d e n t i f i c a t i o n of research goals m u s t n o t p r e c l u d e the s u p p o r t of g o o d ideas, w h i c h are t r u l y rare, o r the s u p p o r t of g o o d scientists.

This

a r g u m e n t is b a s e d s t r o n g l y o n the c o n t e n t i o n that i t u s u a l l y is i m p o s s i b l e to i d e n t i f y the p a r t i c u l a r g r o u p of discoveries w h i c h w i l l p r o v i d e t h e keystone to the s o l u t i o n of a p r o b l e m .

F u r t h e r , w h e n a s o l u t i o n mate-

rializes, the benefits to society often are i m m e a s u r a b l e .

O n e only need

t h i n k o f the effect o f a d e q u a t e c h e m o t h e r a p e u t i c agents o n t u b e r c u l o s i s ; the t r e m e n d o u s change i n t h e treatment a n d w e l l - b e i n g of the e m o t i o n a l l y i l l w h i c h r e s u l t e d f r o m the d i s c o v e r y of c h l o r p r o m a z i n e a n d a host o f other d r u g s w h i c h m o d i f y m o o d a n d affect or the i m m e n s e benefit w h i c h r e s u l t e d f r o m t h e d e v e l o p m e n t of effective means to i m m u n i z e against poliomyelitis. W h i l e I h a v e m o r e or less d e s c r i b e d a p r o g r a m of g o v e r n m e n t supp o r t s i m i l a r to the v e r y best parts of past a n d present N a t i o n a l Institutes of H e a l t h ( N I H ) p r o g r a m s , I b e l i e v e that some changes i n the p a t t e r n of s u p p o r t s h o u l d b e c o n s i d e r e d . research

O b v i o u s l y the a l l o c a t i o n of f u n d s f o r

training should be completely

free o f p o l i t i c a l i n f l u e n c e o r

r e g i o n a l , e c o n o m i c , or other considerations.

F u n d s for the support re-

search t r a i n i n g s h o u l d n o t b e d i v e r t e d to other types of t r a i n i n g s u c h as residency programs.

F u n d s a l l o c a t e d f o r research s h o u l d n o t b e u s e d to

d e l i v e r h e a l t h services or to d e v e l o p p r o g r a m s .

There probably should

be greater f l e x i b i l i t y i n the s u p p o r t p r o g r a m s at a l l levels. tant, s u p p o r t of research t r a i n i n g p r o b a b l y s h o u l d b e less

More imporcategorical.

I n m a n y instances i t w i l l p r o b a b l y b e necessary to p r o v i d e t h e b i o l o g i c a l scientist o f the f u t u r e w i t h a m o r e v a r i e d e d u c a t i o n a l experience t h a n c a n b e d e r i v e d f r o m o u r present system.

I t m i g h t b e reasonable to d e v e l o p

t r a i n i n g p r o g r a m s w h i c h w o u l d c o m b i n e offerings i n b i o c h e m i s t r y a n d p h a r m a c o l o g y o r chemistry, p h a r m a c o l o g y , a n d p h y s i o l o g y w i t h the a d m i x t u r e t a k i n g p l a c e either at the p r e d o c t o r a l o r p o s t d o c t o r a l l e v e l . P r o grams

such

as the M e d i c a l Scientist

Program, which provide M . D .

candidates w i t h research t r a i n i n g i n basic b i o l o g i c a l science, s h o u l d b e


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strengthened.

F i n a l l y , as o u r u n d e r s t a n d i n g of b i o l o g y a n d

medicine

increases, there w i l l be an i n c r e a s i n g n e e d for p e o p l e t r a i n e d not o n l y i n the c u r r e n t b i o m e d i c a l d i s c i p l i n e s b u t also i n areas w h i c h w e c a n n o t yet identify. I a m not i n s i s t i n g that o u r present system, or systems formerly* e m p l o y e d , are i d e a l . C l e a r l y , means s h o u l d b e d e v e l o p e d to p r o v i d e the b a s i c b i o l o g i c a l scientist w i t h a n u n d e r s t a n d i n g a n d a p p r e c i a t i o n of the i m p o r t a n c e of a p p l y i n g the results i n his research to s o c i a l l y i m p o r t a n t problems.

T h i s c a n be d o n e i n p a r t b y the universities a n d m e d i c a l


centers, b u t this r e q u i r e m e n t presents a n o p p o r t u n i t y a n d c h a l l e n g e

to

the p h a r m a c e u t i c a l i n d u s t r y . T h e effective transfer of i n f o r m a t i o n f r o m basic to a p p l i e d research d e p e n d s o n a n u n d e r s t a n d i n g o n the p a r t of s t a n d i n g o n the p a r t of the m e d i c a l p r a c t i t i o n e r or the

pharmaceutical

i n d u s t r y of the p o s s i b i l i t i e s w h i c h have b e e n m a d e a v a i l a b l e b y

basic

research. T h i s sort of u n d e r s t a n d i n g c a n result o n l y i f the b a s i c b i o l o g i c a l scientist is i n c o n t i n u i n g c o n t a c t w i t h the v a r i o u s i n d i v i d u a l s w h o m i g h t a p p l y the results of his research to the s o l u t i o n of p r a c t i c a l p r o b l e m s . O b v i o u s l y , therefore, means s h o u l d b e d e v e l o p e d to c h a n g e the attitudes of a l l c o n c e r n e d a n d to foster c o n t i n u i n g contact b e t w e e n i n d i v i d u a l s a n d groups w h o o r d i n a r i l y d o not take a d v a n t a g e of the c o n t r i b u t i o n s m a d e i n d i s c i p l i n e s r e l a t e d to their o w n . I h a v e no suggestions w h i c h are c e r t a i n to solve these p r o b l e m s . I d o h a v e some ideas w h i c h m i g h t deserve c o n s i d e r a t i o n . I a m not c o n c e r n e d so m u c h w i t h means to c h a n g e the attitudes of the basic b i o m e d i c a l scientist. T h e search for relevance a l r e a d y is a major c o n c e r n of the y o u n g , a n d this c o n c e r n o n l y w i l l increase i n the f u t u r e . I a m m o r e i n t e r e s t e d i n d e v e l o p i n g means to foster the exchange of ideas a n d i n f o r m a t i o n .

In-

d u s t r y s h o u l d p a r t i c i p a t e m u c h m o r e i n the s u p p o r t of t r a i n i n g i n a l l the b i o m e d i c a l sciences a n d not e m p h a s i z e so strongly areas of d i r e c t interest s u c h as c h e m i s t r y or c l i n i c a l p h a r m a c o l o g y .

It also s h o u l d c o n t r i b u t e to

t r a i n i n g at b o t h the p r e d o c t o r a l a n d p o s t d o c t o r a l levels.

This contribu-

t i o n n e e d not be o n l y d i r e c t financial s u p p o r t , it p r o b a b l y s h o u l d i n c l u d e the p a r t i c i p a t i o n of i n d u s t r y p e r s o n n e l a n d the use of s p e c i a l i z e d f a c i l i t i e s a v a i l a b l e i n i n d u s t r y . I n p h a r m a c o l o g y , f o r e x a m p l e , students c o u l d b e n e fit greatly f r o m contact w i t h experts i n d r u g d e v e l o p m e n t or i n c l i n i c a l evaluation.

I n d u s t r y also s h o u l d be w i l l i n g to p a r t i c i p a t e m o r e f u l l y i n

the s u p p o r t of basic research, as o p p o s e d to research w h i c h c l e a r l y c o n tributes to the e v a l u a t i o n of p o t e n t i a l t h e r a p e u t i c agents. M e a n s s h o u l d be d e v e l o p e d to f u r t h e r the e x c h a n g e of p e r s o n n e l b e t w e e n i n d u s t r y a n d the a c a d e m i c institutions. T h i s c o u l d b e d o n e b y d e v e l o p i n g p r o g r a m s u n d e r w h i c h m e m b e r s of either g r o u p c o u l d s p e n d one or t w o years w o r k i n g as a m e m b e r of the other. T h e f a c u l t y m e m b e r m i g h t benefit greatly f r o m an o p p o r t u n i t y to w o r k f u l l - t i m e i n a l a b o r a -


11.

HOFFMAN

Basic Biomedical

231

Research

tory w h e r e h e w o u l d h a v e access to t h e p e r s o n n e l a n d facilities d e v e l o p e d b y a p h a r m a c e u t i c a l c o m p a n y a n d , t h r o u g h h i s presence,

m i g h t even

m a k e some c o n t r i b u t i o n . A m e m b e r o f a n i n d u s t r i a l research g r o u p s i m i l a r l y m i g h t benefit f r o m a year o r t w o i n a b a s i c science

department.

F i n a l l y , i n d u s t r y c o u l d t r y to m a k e greater use o f t h e m e m b e r s o f t h e basic b i o m e d i c a l science departments i n o u r universities. S e v e r a l m e m bers o f s u c h a d e p a r t m e n t , c a r e f u l l y selected because o f d e m o n s t r a t e d competence

a n d k n o w l e d g e , m i g h t p r o v i d e i n v a l u a b l e a d v i c e at m a n y

points d u r i n g the sequence of steps l e a d i n g to t h e i n t r o d u c t i o n o f a n e w Downloaded by SUNY STONY BROOK on November 3, 2014 | http://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch011

d r u g a n d l i k e l y w o u l d serve m o r e effectively i n this c a p a c i t y t h a n t h e t r a d i t i o n a l consultant.

M o r e i m p o r t a n t , h o w e v e r , w o u l d b e t h e f a c t that,

t h r o u g h s u c h a n arrangement, m a n y b a s i c b i o m e d i c a l scientists w o u l d b e b r o u g h t i n t o contact w i t h representatives o f i n d u s t r y a n d w o u l d l e a r n o f n e w attitudes, p r o b l e m s , a n d areas o f c o n c e r n . T h e system s h o u l d i n c l u d e a f o r m a l m e c h a n i s m to s t u d y t h e p r o b a b l e a n d possible l o n g range effects o f a n y possible d i s c o v e r y . F o r e x a m p l e , if means c a n b e d e v e l o p e d to i m p l a n t a r t i f i c i a l hearts i n m a n y e l d e r l y patients, someone s h o u l d ask i f i t is reasonable to d o so i n terms o f cost, a c t u a l c o n t r i b u t i o n to t h e w e l l - b e i n g o f t h e patients a n d p o s s i b l e conse quences. I f a large f r a c t i o n o f research s u p p o r t is t o b e a l l o c a t e d to studies o n genetic e n g i n e e r i n g , some p a r t o f that s u p p o r t s h o u l d b e m a d e a v a i l able t o evaluate t h e u l t i m a t e p s y c h o l o g i c a l , s o c i a l , a n d e c o n o m i c effects of success.

A s w e approach the time w h e n more a n d more

becomes

possible, t h e i d e n t i f i c a t i o n o f research goals b e c o m e s less i m p o r t a n t t h a n a serious c o n s i d e r a t i o n o f the consequences of d i s c o v e r y . I n this area a n effective joint a c t i o n b y i n d u s t r y a n d a c a d e m i a w o u l d b e most i m p o r t a n t and perhaps w o u l d contribute

to t h e s o l u t i o n of m a n y o f the other

problems.

Literature Cited (1) Fox, H. H., "The Chemical Attack on Tuberculosis," Trans. Ν.Y. Acad. Sci. (1953) 15, 234-242. (2) Delay, J., Deniker, P., Harl, J. M., "Utilisation en Therapeutique Psy chiatrique d'une Phenothiazine d'Action Centrale Elective," Ann. Medpsychol. (1952) 110, 112-117. (3) Zeller, A. E., Barsky, J., Fouts, J. R., Kirchheimer, W. F., Van Orden, L. S., "Influence of Isonicotinic Acid Hydrazide (INH) and 1-Isonicotinyl 2-Isopropyl Hydrazide (IIH) on Bacterial and Mammalian En zymes," Experientia (1952) 8, 349-350. (4) Brodie, Β. B., Shore, P. Α., "A Concept for a Role of Serotonin and Norepinephrine as Chemical Mediators in the Brain," Ann. Ν.Y. Acad. Sci. (1957) 66, 631-642. (5) Eccles, J.C.,"The Physiology of Synapses," Springer-Verlag, Berlin; Aca demic Press, New York, 1964. (6) Euler, U. S. von, "Twenty Years of Noradrenaline," Pharmacol. Rev. (1966) 18, 29-38.


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(7) Hornykiewicz, O., "Dopamine (3-Hydroxytryptamine) and Brain Func tion," Pharmacol. Rev. (1966) 18, 925-964. (8) Goodman, L., Gillman, Α., "The Pharmacological Basis of Therapeutics," MacMillan, New York, 1941. (9) Goodman, L., Gillman, Α., "The Pharmacological Basis of Therapeutics," 2nd ed., MacMillan, New York, 1970. (10) Stocken, L. A., Thompson, R. H. S., "Reactions of British Anti-Lewisite with Arsenic and Other Metals," Physiol. Rev. (1949) 29, 168-194. (11) Wilson, I. B., Ginsburg, S., "A Powerful Reactivator of Alkylphosphate -Inhibited Acetylcholinesterases," Biochem. Biophys. Acta (1955) 18, 168-170. Downloaded by SUNY STONY BROOK on November 3, 2014 | http://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch011

RECEIVED November 5, 1970.


Basic Biomedical Research: Its Impact on Drug Discovery

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